fighting pain

Transcript

fighting pain

fighting pain
combattere il dolore
fighting pain
Volume 1 – Numero 2 – Marzo 2014
Sommario
fp editoriale
(a cura di M. Allegri)
pagina
3
pagina
5
pagina
11
a cura della redazione
pagina
13
Intervista a Carlo Mango
pagina
15
Carlo Mango Interview
pagina
21
pagina
26
pagina
27
fp clinici
Il dolore nel bambino
F. Benini, C. Po
Fondazione Maruzza Lefebvre D'Ovidio Onlus
E. Castelli
fp istituzioni
Intervista a Marco Spizzichino
Fondazione Cariplo e sostegno dei giovani talenti
M. De Gregori
fp pazienti
Dolore cronico: un’entità nosologica complessa
W. Raffaeli, C.E. Minella
proceedings
6th Meeting SIMPAR (Study in Multidisciplinary Pain Research)
Rome, March 28-29, 2014
Oral Communications
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31
Posters
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71
fighting pain
Volume 1 – Numero 2 – Marzo 2014
Obiettivo della rivista
Redazione
Editor-in-Chief
fighting pain – combattere il dolore
HPS – Health Publishing
Massimo Allegri, Pavia
è la rivista italiana contro il dolore
& Services S.r.l.
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20124 Milano
alla gestione del dolore nelle sue
Tel +39 02 2772 991
implicazioni non solo clinico-
Fax + 39 02 2952 6823
terapeutiche, ma anche sociali
e-mail: info@fightingpain.it
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Uno sguardo a 360 gradi su
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Editorial Manager
Marianna Di Croce
Publication Manager
Laura Prosdocimi
In copertina
trattamento del dolore in Italia,
sulla realtà internazionale e sulle
Hay almas que tienen
diverse opportunità terapeutiche
Tecniche miste su tela
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della letteratura scientifica e della
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clinical practice.
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fighting pain – combattere il dolore è un quadrimestrale pubblicato da HPS – Health Publishing & Services S.r.l., Piazza Duca d’Aosta 12,
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fighting pain – combattere il dolore è una testata registrata presso il Tribunale di Milano, reg. n. 250 del 19 luglio 2013.
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Finito di stampare nel mese di Marzo 2014, Geca S.r.l. (San Giuliano Milanese – MI)
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Editoriale
Questo secondo numero di “Fighting pain” ha
l’onore di poter “ospitare” gli articoli dei relatori e
gli abstract dei partecipanti alla sesta edizione del
SIMPAR (Study in multisciplinary pain research). Dal
punto di vista culturale e scientifico ritengo che la
storia di SIMPAR e di “Fighting pain” sia molto simile
e che in entrambi vi sia la volontà di diffondere
e valorizzare in misura sempre maggiore una
maggior consapevolezza scientifica e culturale della
“malattia dolore”, così come descritta nell’articolo a
firma di William Raffaeli e Cristina Minella.
L’unione di questi due percorsi e l’elevato profilo
scientifico del Scientific ed Editorial Board della rivista
vogliono essere garanzia del profilo editoriale di questa
pubblicazione giunta al suo secondo numero.
Come descritto anche nel primo numero,
tuttavia, “Fighting pain” non vuole “solo” essere
il volano di una nuova modalità di comunicazione
scientifica che possa presto essere indicizzata nei
principali motori di ricerca internazionali, ma si
propone anche un secondo binario parallelo (di
analoga importanza) che guardi alle Istituzioni e al
“mondo sociale” che ruota intorno alla necessità di
migliorare continuamente l’approccio sociosanitario
al cittadino che è affetto da dolore cronico. Per
dare la giusta importanza a tale “secondo binario”,
in questo numero abbiamo avuto l’onore di poter
ospitare tre significativi contributi.
In primo luogo il contributo di Marco Spizzichino, che
fa seguito all'intervista al professor Fanelli pubblicata
nel primo numero, per valutare come l’esperienza della
legge 38/2010 e della sua applicazione sia stata vissuta
nel mondo delle Istituzioni e quali sforzi siano stati
effettuati per rendere tale legge realmente usufruibile
dal cittadino (che, come è bene ricordare, ha il diritto
© 2014 Health Publishing & Services S.r.l. – Tutti i diritti riservati
di accedere alla terapia del dolore e alle cure palliative).
Secondo, il contributo di Franca Benini e Chiara
Po e quello di Elena Castelli di Fondazione Lefebvre
per analizzare in dettaglio come il mondo clinicoscientifico e il mondo delle Onlus stiano veramente
facendo passi straordinariamente importanti nel
permettere un adeguato controllo del dolore anche
nel bambino. Infatti, se il dolore è ancora molto
spesso negletto o poco gestito, tale problematica è
ancora più drammatica nel bambino; esperienze come
quelle della Fondazione Lefebvre e del centro diretto
dalla dottoressa Benini sono davvero uno dei fiori
all’occhiello della “buona salute” presenti in Italia.
Infine l'intervista a Carlo Mango, responsabile
della ricerca e sviluppo della Fondazione Cariplo,
per capire come una delle Fondazioni più impegnate
nell’aiutare la ricerca, con bandi estremamente
competitivi e riconosciuti internazionalmente,
intenda aiutare la ricerca italiana a mantenere la
sua unicità e importanza a livello internazionale.
Quindi spero che, anche grazie a questo numero così
ricco, “Fighting pain” diventi sempre più un punto di
riferimento per diffondere la ricerca italiana aiutando
una sempre maggiore “contaminazione” tra mondi
apparentemente diversi ma che vogliono cercare, come
fine ultimo, di migliorare la qualità di vita delle persone.
Spero che vi siano sempre più contributi scientifici
e culturali da parte di tutti i lettori; nel contempo,
il Comitato Scientifico ed Editoriale si impegna a
valorizzare il più possibile le eccellenze italiane in tale
ambito, soprattutto dei numerosi giovani ricercatori
e clinici che sono presenti in Italia nonostante tutte
le difficoltà del momento.
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Editorial
The second issue of Fighting pain is honored to
how much the clinical and scientific world and Onlus
include the articles and abstracts of speakers and
are improving their ability to control and manage
researchers attending the VI Edition of SIMPAR
pain not only in adults, but also in children. In fact,
Meeting. I believe that SIMPAR and Fighting pain
while pain is often neglected and poorly managed in
backgrounds and intents are quite similar, as both
general, the problem is even more dramatic in kids.
aim to spread and support a wider scientific and
This makes realities like the Lefebvre Foundation
cultural awareness of the ‘pain disease’, as described
and the Center directed by Franca Benini among the
in William Raffaeli and Cristina Minella article.
flagships of ‘modern’ healthcare Centers in Italy.
The combination of these two efforts and the
Finally, Carlo Mango, the responsible for Cariplo
high profile of the Scientific and Editorial Board are
Foundation R&D (Research and Development),
guarantees of the Journal standards.
granted an interview explaining the Foundation
However, as already outlined in the first issue,
institutional goal of helping the Italian research to
Fighting pain has a dual scope. First, it aims to
maintain its uniqueness and international role. The
pioneer a new form of scientific communication
Cariplo Foundation is one of the Italian Foundations
and to be soon indexed on the most important
most active in supporting research and does that
international search engines. An equally important
through
goal for the Journal is to involve the Institutions and
competitive grants.
internationally
recognized,
extremely
civil society in the continuous improvement of the
I hope that this Journal, also thanks to these
social- and healthcare attitude toward the citizen
articles, will become a benchmark in spreading Italian
affected by chronic pain.
research, therefore increasing the ‘contamination’
To underline the importance of the second goal,
between worlds that are apparently different, but
this issue contains three contributions totally
that have the same goal to improve people quality
dedicated to this topic.
of life.
First, following the interview to Prof. Fanelli
I also hope that we will get more and more scientific
published in the first issue of Fighting pain, the
and cultural contributions from our readers; in the
interview to Marco Spizzichino helps to evaluate
meanwhile, the Scientific and Editorial Committee
how Institutions experienced and implemented the
commits to highlight as much as possible the
law 38/2010, and how much the citizen (who has the
Italian excellence, with particular regard to young
right to pain therapy and palliative care) has really
researchers and clinicians who live in this Country
been able to take advantage of this law.
even in this difficult time.
Second, Franca Benini and Chiara Po, and Elena
Castelli of Lefebvre Foundation extensively outline
fighting pain – combattere il dolore – Volume 1 – Numero 2 – Marzo 2014
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Franca Benini, Chiara Po
Centro Regionale Veneto di Terapia del Dolore e Cure Palliative Pediatriche,
Dipartimento della Salute della Donna e del Bambino, Università di
Padova, Padova
Abstract
Pain in sick children, as in adults, is a frequent symptom and is irrespective of pathology
and child age. Pain breaks up the physical and psychological integrity of the young patient
and causes distress to the family, with a negative impact on quality of life. Anatomophysiological and behavioural studies have shown that in newborns and children nociception
and pain perception are peculiar. In the clinical management of pain much progress has
been made both in pain assessment and therapeutic approach, either pharmacological and
nonpharmacological. Also from a regulatory point of view, Law Act 38, dated 9th March
2010, represents a great advancement because of its innovative approach: pain management
and palliative care are a fundamental right also for children. Pain must always be assessed,
measured and managed effectively both in hospitals and community health services; all steps
must be recorded in the patient medical record. Notwithstanding, relief of children pain is still
far from perfect; awareness of the structural and functional differences typical of newborns/
children is still limited in clinical practice. Several Authors have defined the best practice,
highlighting that the approach to pain relief in children, as in adults, must be individualized,
multidisciplinary and global. The WHO pain ladder is a framework for providing symptomatic
pain relief; first proposed for children in 1998, since then it has been revised and now it
comprises new drugs and new strategies (“step up – step down”). Even recently (2013) the
PIPER project for pediatric pain management in Italian hospital Emergency Rooms (ERs) has
shown that pain is measured only in 40% of children admitted to a pediatric ER and that only
rarely therapeutic interventions appropriately address the degree and/or quality of pain. Much
work must still be done to implement the Law Act 38/2010, and that requires a common effort
from all parties involved
fighting pain – combattere il dolore, 1(2)2014: 5-10
Come nell’adulto, anche in ambito pediatrico il dolore è un sintomo frequente in corso di malattia:
spesso segnale importante per la diagnosi iniziale, fattore sensibile nell’indicarne evoluzioni positive
o negative durante il decorso, innegabile presenza in corso di molteplici procedure diagnostiche e/o
terapeutiche e costante riflesso di paura e ansia per tutto quello che la malattia comporta. È un
sintomo trasversale che, indipendentemente dalla patologia e dall’età del bambino, mina in maniera
importante l’integrità fisica e psichica del paziente e angoscia e preoccupa i suoi familiari con un
notevole impatto sulla qualità della vita.
In questi ultimi anni la letteratura si è arricchita di molti lavori e ricerche sulla nocicezione e
percezione del dolore: studi anatomo-fisiologici e comportamentali hanno chiarito come entrambe
presentino specifiche peculiarità in ambito neonatale e pediatrico. A livello clinico progressi importanti
Indirizzo per la corrispondenza:
Dott.ssa Franca Benini, Centro
Regionale Veneto di Terapia del
Dolore e Cure Palliative Pediatriche,
Università degli Studi di Padova,
Via 8 Febbraio, 35122 Padova
Email: [email protected]
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sono stati fatti sia riguardo alla valutazione del
dolore nelle diverse età pediatriche sia nell’ambito
dell’approccio terapeutico, farmacologico e non
farmacologico (1-3). Le conoscenze raggiunte
sono oggi tante e tali da poter assicurare un
corretto ed efficace approccio antalgico nella
maggior parte delle situazioni.
Anche a livello legislativo/normativo in Italia
sono stati fatti notevoli progressi nell’ambito
del dolore pediatrico: la Legge 38, emanata
il 9 marzo 2010, pone delle indicazioni del
tutto innovative: la terapia del dolore (TD)
e le cure palliative (CP) sono definite come
diritto alla salute del bambino (4). Viene
riconosciuta la “peculiarità” della persona
bambino e viene sancita la necessità di una
risposta ai bisogni, specifica e dedicata, sia a
livello clinico-organizzativo che formativo e
informativo. La legge inoltre sancisce alcune
regole importanti per la gestione del dolore
quali il fatto che il dolore deve essere sempre
valutato, misurato e trattato efficacemente
in tutti i reparti di degenza e a livello dei
servizi territoriali e che tutto il processo deve
essere registrato in cartella clinica. Tuttavia,
nonostante la disponibilità di strumenti e la
possibilità concreta di dare adeguata risposta,
moltissime tuttora sono le conferme che la
gestione del dolore pediatrico è lontana dalle
reali possibilità e che perdura una situazione
di limitata attenzione al problema.
Peculiarità a livello anatomo-fisiologico
In questi ultimi anni studi anatomo-fisiologici
e comportamentali hanno chiarito come il
dolore in ambito neonatale/pediatrico presenti
peculiarità specifiche (5-7). È infatti ormai certo
che, a partire dalla fine del secondo trimestre di
gestazione, il sistema nervoso è anatomicamente
e funzionalmente competente per la nocicezione.
Ma alcune differenze strutturali e funzionali
dell’età neonatale-pediatrica condizionano in
maniera importante la quota e gli effetti del
dolore percepito (Figura 1).
Fra queste:
1. Nel feto, nel neonato e nel bambino fino
a 12-18 mesi di età, vi è una ridotta attività
delle vie inibitorie discendenti, che bloccano
l’ingresso dello stimolo doloroso. Questo
comporta che, quanto più giovane è il paziente,
a parità di stimolo doloroso tanto maggiore è la
quota di dolore percepito.
Figura 1 – Peculiarità del dolore in età neonatale/pediatrica
Nel feto, nel neonato e lattante fino
a 12-18 m: ritardata espressione delle
vie inibitorie discendenti
• maggiore eccitabilità del sistema nocicettivo
a parità di stimolo ➝ minore inibizione centrale e
periferica ➝ maggior dolore percepito
Conseguenze
Nel neonato e bambino
piccolo: maggiore risposta
endocrinometabolica al dolore
• reazione da stress maggiore e più prolungata
• maggiore rischio di complicanze legate al dolore
(peggioramento clinico, prolungamento ospedalizzazione...)
Nel neonato e bambino piccolo:
plasticità del sistema nervoso a
livello di terminazioni periferiche,
spinale e centrale
• stimoli dolorosi ripetuti possono aumentare proliferazione
delle terminazioni nervose, aumentare eccitabilità delle aree
del midollo spinale deputate, attivare circuiti neuronali
• l'esperienza del dolore può determinare l'architettura
definitiva del sistema nocicettivo nell'adulto
anatomiche e
fisiologiche nel
breve termine
...
e nel lungo
termine
Fin dall'età neonatale esiste
memoria del dolore
• la memoria si forma già in fasi molto precoci e condiziona il
percepito per tutta la vita
fp clinici
2. Nel neonato e nel bambino piccolo,
rispetto alle età successive, vi è una riposta
endocrino-metabolica che accompagna il
dolore (reazione da stress) maggiore e più
prolungata. Questo espone il piccolo paziente
a un maggiore rischio di complicanze dovute
al dolore. Confermate infatti da più lavori in
letteratura sono, in età neonatale-pediatrica,
le conseguenze del dolore non trattato a
breve (peggioramento clinico, complicanze e
prolungamento dell’ospedalizzazione) e lungo
termine (dolore cronico, alterazione della soglia
del dolore, problemi psico-relazionali).
3. La maturazione del sistema nocicettivo
non è completa al momento della nascita
ma prosegue durante il periodo neonatale
e nell’infanzia. L’estrema plasticità del
sistema nervoso in questo periodo della vita
è in causa nel far sì che stimolazioni dolorose
ripetute non coperte da adeguata analgesia
possano indurre modificazioni anatomiche
e funzionali persistenti del sistema nervoso
immaturo. Quindi il dolore che si verifica nelle
prime età della vita è in causa nel determinare
l’architettura definitiva del sistema nocicettivo
dell’adulto.
4. Sin dall’età neonatale esiste una “memoria
del dolore”: molti studi infatti evidenziano che la
memoria si forma e arricchisce in fasi molto precoci
e condiziona il percepito per tutta la vita.
Tali peculiarità strutturali e funzionali
della nocicezione in ambito neonatale–
pediatrico, nonché le peculiarità del paziente
bambino, persona in continua evoluzione sia a
livello fisiologico che cognitivo e relazionale,
condizionano in maniera importante l’approccio
globale al dolore, a livello sia di valutazione che
di terapia.
Valutazione del dolore pediatrico
La valutazione del dolore in ambito pediatrico presenta alcune problematiche specifiche: limiti sono posti infatti dall’età del bambino, dal livello di sviluppo cognitivo, dalla situazione clinica e socio-culturale nonché dalla
frequente presenza di fattori affettivi ed emozionali quali paura e ansia. Per tali motivi non
esiste un metodo/scala di valutazione del dolore valido per tutta l’età pediatrica, ma sono a
disposizione scale/metodi diversi, in grado di
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indagare in maniera efficace e validata l’entità
del dolore provato, nelle diverse età e situazioni (Scale di autovalutazione ed eterovalutazione, Metodi comportamentali e fisiologici)
[3,8]. Fra le molte a disposizione, sono tre le
scale algometriche che per efficacia, efficienza
e applicabilità risultano le più indicate per la
misurazione del dolore nel bambino competente, da 0 a 18 anni:
1. scala FLACC per bambini di età inferiore
ai 3 anni o per bambini che per deficit motori
o cognitivi non possono fornire una valutazione
soggettiva del dolore;
2. scala con le facce di Wong-Baker per
bambini di età superiore a 3 anni;
3. scala numerico-verbale per bambini di età
superiore/uguale a 8 anni.
Strumenti specifici sono stati studiati per la
valutazione del dolore in neonati/bambini che
per situazione clinica o per patologia presentino
problemi particolari, quali i bambini/neonati ricoverati in ambito critico o pazienti con deficit
neuromotorio.
La terapia
Vari Autori hanno dato un grosso impulso
nell’ambito dell’approccio terapeutico definendo la best practice di gestione e riconfermando l’assoluta necessità di un intervento
individualizzato, multispecialistico e globale,
che faccia ricorso sia farmaci che a metodiche
non farmacologiche (2,3). La proposta di una
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terapia farmacologica non può prescindere da
alcune raccomandazioni.
• Il dolore va sempre cercato, trattato e
profilassato: nessun dolore è così piccolo da non
meritare attenzione.
• La scelta terapeutica deve essere fatta in
base all’entità del dolore. L’Organizzazione
Mondiale della Sanità (OMS) nel 1998
ha proposto come guida al trattamento
farmacologico del dolore pediatrico la “scala
a 3 gradini” (ideata per il dolore oncologico)
[9] dove, alla diversa intensità di dolore
(dolore lieve, moderato o severo), corrisponde
una precisa indicazione terapeutica; una
revisione nel 2010 ha esteso la “scala” alla
gestione anche del dolore acuto e introdotto
un quarto gradino (metodiche analgesiche
invasive), nuovi farmaci e nuove strategie di
gestione (“step up – step down”). Nel 2012 le
linee guida OMS per la gestione del dolore
cronico in età pediatrica hanno introdotto
un’ulteriore versione della scala, a due gradini,
sottolineando la necessità di utilizzare farmaci
potenti in caso di dolore moderato/severo
(Figura 2).
• La scelta del farmaco deve essere fatta sulla
base della diagnosi del dolore, in relazione alle
condizioni cliniche, alla durata prevista e alle
capacità di adattamento di bambino e famiglia
alla proposta. La prescrizione va fatta alla dose
corretta per età e per chili di peso.
• La via di somministrazione deve essere la
più semplice e meno invasiva possibile e il timing
ideale è a “orario fisso”.
• L’efficacia del trattamento del dolore e
l’eventuale comparsa di effetti collaterali devono
essere sempre monitorate.
• Il bambino (quando possibile per età e
situazione) e la famiglia devono essere informati
sulle scelte e sulle strategie di monitoraggio
nell’ottica di una collaborazione positiva.
Attualmente i farmaci proposti per la
gestione del dolore in età pediatrica sono
diversi e possono essere suddivisi in quattro
categorie di riferimento: farmaci non oppioidi,
oppioidi, adiuvanti e anestetici locali. Studi di
farmacocinetica e farmacodinamica hanno
puntualizzato indicazioni e limiti di ciascuna
categoria. Hanno dato le indicazioni all’uso
dei non-oppioidi (soprattutto paracetamolo,
Figura 2 – L'evoluzione delle scale della terapia farmacologica del dolore pediatrico
WHO 1986: scala a tre gradini per il
trattamento del dolore
se il dolore
persiste
o aumenta
se il dolore
persiste
o aumenta
WHO 2012: scala a due gradini per il
trattamento del dolore persistente nel
bambino
Oppioidi forti con
o senza adiuvanti
Oppioide forte
STEP 1
Non oppioidi – FANS con
o senza adiuvanti
STEP 4
STEP 3
Dolore acuto
Dolore cronico non controllato
Crisi acute di dolore cronico
STEP 2
Oppioidi deboli
Dolore
moderato-severo
Dolore lieve
Procedure
neurochirurgiche
Oppioidi forti
Metadone
Somministrazione orale
Cerotti transdermici
STEP 1
Analgesici non
oppioidi
FANS
STEP 2
Paracetamolo
FANS
Oppioidi deboli con
o senza adiuvanti
Blocchi nervosi
Epidurale
Pompa PCA
Blocchi neurolitici
Stimolatori spinali
2010: la scala analgesica WHO è
ancora valida? Step up – step down
Dolore cronico
Dolore non oncologico
Dolore oncologico
FANS con o senza adiuvanti
a ogni step
FANS, farmaci antinfiammatori non steroidei; PCA, analgesia controllata dal paziente.
fp clinici
ibuprofene, ketorolac); è stata riconfermata
l’estrema efficacia dei farmaci oppioidi
(morfina, ossicodone, fentanile, tramadolo)
per i quali sono state ridimensionate le
paure legate agli effetti collaterali e messe in
luce le scelte e strategie d’utilizzo più sicure
e congrue; sono state confermate anche
in ambito pediatrico indicazioni, efficacia
ed efficienza dei farmaci adiuvanti e delle
tecniche anestesiologiche.
Inoltre, accanto all’uso dei farmaci, sempre
più frequenti anche in ambito pediatrico sono le
indicazioni terapeutiche e le conferme di efficacia di metodiche antalgiche non farmacologiche
psicologiche e fisiche (3-10). Fra le tecniche psicologiche, le più usate sono le tecniche di supporto
(ambientale e sociale), cognitive (adeguata informazione, tecniche di distrazione e immaginative)
e comportamentali (tecniche di rilassamento,
biofeedback). Molte le possibilità di intervento
anche nell’ambito della terapia fisica: le più usate
sul bambino sono il massaggio, la crioterapia e le
tecniche agopunturali.
Stato dell’arte, analisi delle criticità e
proposte
Nonostante la ricchezza di dati e conferme in
letteratura, a livello clinico siamo ancora lontani
da una situazione ottimale. La scarsa attenzione al
problema si evidenzia sia in ambito ospedaliero che
territoriale, con impatti diversi legati logicamente
alle diverse patologie e al diverso grado di gravità,
ma sempre con importante ricaduta negativa
sul vissuto di malattia, sulla qualità della vita
del bambino e della sua famiglia e sul rapporto
fiduciario fra utenza e istituzione sanitaria.
L’Associazione Ospedali Pediatrici Italiani
(AOPI) nel 2006 ha evidenziato, attraverso
un’indagine condotta negli ospedali pediatrici italiani, che la valutazione del dolore è
un parametro scarsamente considerato nella
routine clinica. Solo nel 50% dei casi è previsto un protocollo di valutazione antalgica uniforme nei diversi reparti di degenza, e anche
quando questo strumento è predisposto, la
valutazione del dolore viene eseguita nel 50%
dei casi e solo in particolari Servizi. Il progetto
PIPER [progetto multicentrico per la gestione del dolore pediatrico nei Pronto Soccorso
(PS) italiani reso possibile dal supporto non
9
condizionato di Angelini] ha evidenziato anche recentemente (2013) che solo nel 40%
dei bambini che accedono al PS pediatrico il
dolore viene misurato con scale validate, che
la valutazione del dolore resta una procedura
di sola competenza infermieristica e non presenta frequentemente una risposta terapeutica
corrispondente all’entità-qualità del dolore descritto (11). Altre conferme di ipotrattamento
farmacologico si hanno in ambiti clinici diversi: nella gestione del dolore che accompagna
la terminalità (solo nel 25% dei casi di dolore
dichiarato viene attuata una terapia efficace),
nel dolore acuto che accompagna le patologie
infettive intercorrenti (trattamento in assenza
di febbre inferiore al 15%) e nella gestione del
dolore procedurale (percentuale di trattamento variabile dallo 0% al 50%) [3]. Per quanto
riguarda la terapia non farmacologica, il divario
fra proposta scientifica e applicazione clinica è
ancora più grande. L’utilizzo di tecniche validate e non improvvisate è limitato a pochi Centri
e in limitate situazioni cliniche. Molteplici e
reali le motivazioni di questa situazione; alcune
criticità, tuttavia, giocano un ruolo fondamentale nel rallentare il “cambiamento”. Fra queste:
• purtroppo il dolore in ambito pediatrico
è visto ancora come strumento di crescita e di
potenziamento del carattere: in quanto tale,
diventa strumento educativo e quindi giustificato;
• la complessità e specificità del problema: il
bambino è una realtà complessa dove continue
modificazioni fisiche, psichiche, relazionali ed
esperienziali, correlate alla crescita, rendono necessario un intervento dinamico, personalizzato,
globale e competente sia per quanto riguarda
l’utilizzo degli strumenti di valutazione/misurazione sia per la definizione di un programma
farmacologico/non farmacologico adeguato all’età
e alla situazione;
• la carenza di formazione efficace e di
motivazione professionale sia a livello medico
(dove il problema è certamente più evidente)
che infermieristico;
• carenza di competenze: nei curricula formativi universitari e di specializzazione, lo spazio
riservato al problema dolore è limitato. Questo
condiziona, e forse in parte anche giustifica, un
deficit di attenzione all’argomento, sia a livello clinico che di ricerca;
10
• paura riguardo l’uso dei farmaci in ambito
pediatrico neonatale: tale paura riguarda molte delle molecole usate in analgesia pediatrica
e neonatale ed è condizionata sia dagli eventuali problemi legali in caso di insorgenza di
effetti imprevisti (l’80% dei farmaci analgesici
in pediatria è off label) che dalla scarsa dimestichezza nell’uso di talune molecole (soprattutto gli oppioidi);
• limitata disponibilità di prodotti farmaceutici e presidi adeguati anche all’uso in età pediatrica e neonatale.
Sono passati quasi tre anni dall’emanazione
della Legge 38/10 e, anche se lentamente, le
cose stanno cambiando.
1. Da un punto di vista organizzativo, undici
Regioni hanno avviato e sono in varia fase di deliberazione/realizzazione della Rete e del Centro
di Riferimento del Dolore e delle Cure Palliative
Pediatriche; in quattro Regioni tale rete è stata
attivata ed è funzionante.
2. Si sta facendo uno sforzo importante
nell’ambito della formazione: in otto Regioni
sono stati avviati percorsi formativi ad hoc per
gli operatori della salute. A livello nazionale
in alcune Università sono stati attivati Master
di I° e II° livello specifici per l’età pediatrica;
continua il progetto “NienteMale Junior” del
Ministero, con il supporto non condizionato
di Angelini, che prevede una formazione sulla
gestione del dolore tutorata e monitorata nella
sua ricaduta clinica, a cascata, su tutti i medici pediatri che lavorano nel Sistema Sanitario
Nazionale (SSN), sia ospedalieri che pediatri
di famiglia.
3. Si continua a lavorare nell’ambito dell’informazione al pubblico. A livello nazionale,
sono in via di sviluppo alcune iniziative che nel
2014 avranno come obiettivo proprio l’informazione di bambino e famiglia su possibilità e
strategie per un corretto approccio al dolore.
Tutto ciò è segno certamente di una nuova
“attenzione” al problema.
Bibliografia
children with early pain experiences. Pain.
2006;125(3):278-85.
7. Walker SM, Franck LS, Fitzgerald M, et al. Longterm impact of neonatal intensive care and surgery on
somatosensory perception in children born extremely
preterm. Pain. 2009;141(1-2):79-87.
8. Schechter NL, Berde CB, Yaster M. Pain in Infants
Children and Adolescents. Baltimore, MD: Williams and
Wilkins, 1996.
9. World Health Organization. Cancer pain relief and
palliative care in children. Geneva: WHO, 1998.
10. Golianu B, Krane E, Seybold J, et al. Non-pharmacological techniques for pain management in neonates.
Semin Perinatol. 2007;31(5):318-22.
11. Ferrante P, Cuttini M, Zangardi T, et al.; PIPER
Study Group. Pain management policies and practices in
pediatric emergency care: a nationwide survey of Italian
hospitals. BMC Pediatr. 2013;13:139. doi: 10.1186/14712431-13-139.
1. World Health Organization. Persisting Pain in
Children. Important Information for Physicians and Nurses. Geneva: WHO, 2012.
2. World Health Organization. Persisting Pain in
Children. Important Information for Policy-Makers. Geneva: WHO, 2012.
3. Ministero della Salute – Benini F, Barbi E, Gangemi M, et al. Il dolore nel bambino. Strumenti pratici di
valutazione e terapia. Milano: Value Relations International srl, 2010.
4. Legge 15 marzo 2010 N. 38. “Disposizioni per garantire l'accesso alle cure palliative e alla terapia del dolore”. www.parlamento.it/parlam/leggi/10038l.htm
5. Slater R, Cantarella A, Gallella S, et al. Cortical pain responses in human infants. J Neurosci.
2006;26(14):3662-6.
6. Hermann C, Hohmeister J, Demirakça S, et al.
Long-term alteration of pain sensitivity in school-aged
Conclusioni
La strada da percorrere è ancora lunga e lo
sforzo per produrre il cambiamento sancito dalla
Legge 38/2010 deve essere uno sforzo condiviso. Formazione, informazione e monitoraggio
rappresentano certamente strumenti importanti,
ma devono integrarsi in decisioni organizzative e
programmatorie ad hoc e rappresentare uno stimolo continuo per gli operatori sanitari, di motivazione e professionalità.
fp clinici
11
Fondazione Maruzza Lefebvre D'Ovidio Onlus
Elena Castelli, Segretario Generale
è
dei bambini inguaribili. Tale documento sarà presentato
un’organizzazione non profit, creata da Antonio ed Eugenia
in collaborazione con l’Autorità Garante per l’Infanzia e
Lefebvre D’Ovidio il 7 ottobre 1999 in seguito alla scomparsa, a
l’Adolescenza entro il 2014 e la sua traduzione inglese è al
soli quarant’anni, della figlia Maruzza.
vaglio degli esperti della Human Rights Watch.
La
Fondazione
Maruzza
Lefebvre
D’Ovidio
Onlus
Da quindici anni la Fondazione opera nel campo delle
• La Fondazione ha aderito come partner al master
cure palliative per garantire alle due fasce più fragili della
interuniversitario (sei università coinvolte) di terapia del dolore
popolazione, bambini e anziani, la migliore qualità di vita
e cure palliative pediatriche che ha come capofila l’Università
possibile e il diritto a essere curati da personale adeguatamente
di Padova.
e specificatamente formato.
• La Fondazione rappresenterà l’Italia in un tavolo di lavoro
In riconoscimento del suo impegno in questo campo, nel
che vedrà riuniti i maggiori esperti internazionali di terapia
luglio 2013, è stata insignita dal Presidente della Repubblica
del dolore e cure palliative pediatriche; tale gruppo dovrà
Giorgio Napolitano della Medaglia d’oro al Merito della
condividere e definire un piano strategico globale al fine di
Sanità pubblica.
sviluppare, nei prossimi dieci anni, la conoscenza e i servizi di
Numerosi sono i progetti e le iniziative realizzati a livello
terapia del dolore e cure palliative pediatriche.
nazionale e internazionale in questi anni nell’ambito
• Considerato il successo e la risonanza ottenuti dal “1st
della formazione, della ricerca, dell’informazione e della
European Congress on Paediatric Palliative Care”, svoltosi
progettazione di nuovi modelli assistenziali.
nel novembre 2012, il prossimo 19-21 novembre 2014 la
Importanti collaborazioni sono state instaurate con gli
organismi di riferimento nel settore pediatrico: la Società
Italiana di Pediatria (SIP), l’Associazione Culturale Pediatri (ACP)
e la Società Italiana di Neonatologia (SIN).
Fondazione Maruzza organizzerà a Roma, presso l’Auditorium
Antonianum, il “2nd Congress on Paediatric Palliative Care – a
Global Gathering” con l’obiettivo di fornire ai maggiori esperti
in materia, provenienti da tutto il mondo, una piattaforma
internazionale dove confrontarsi, discutere e valutare le
In virtù della sottoscrizione di un Protocollo d’Intesa con il
diverse esperienze.
Ministero della Salute, la Fondazione sostiene e affianca le
Regioni nella realizzazione della rete di terapia del dolore e
cure palliative pediatriche secondo quanto previsto nella legge
38/2010.
Un’attenzione
particolare
è
sempre
stata
riservata
alla formazione. Con l’istituzione della Scuola “Il Sole a
Mezzanotte”, dal 2005 a oggi sono stati formati più di 3000
tra medici, infermieri, psicologi, fisioterapisti e volontari.
I nuovi impegni della Fondazione:
• È stato avviato, in collaborazione con “Vivere senza
dolore Onlus”, il progetto: “Spegni il dolore – La rete delle
lampade” al fine di stimolare gli ospedali pediatrici o i reparti
di pediatria a valutare l’attenzione posta nel trattamento del
dolore del bambino.
• Un gruppo di esperti coinvolti dalla Fondazione ha redatto
la “Carta dei Diritti del Bambino Morente”, primo documento
al mondo che pone l’attenzione alla difesa della dignità
È nostra convinzione che qualunque sfida
vada raccolta e affrontata perché un bambino
anche se malato è sempre, e prima di tutto,
un bambino.
12
12
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fp istituzioni
Intervista a
Marco Spizzichino
Dopo l’intervista (Fighting pain 2014;1:23-6) a Guido Fanelli, uno dei più strenui promotori della
Legge 38/10 e coordinatore del gruppo di lavoro che ne ha messo a punto i contenuti, per completare
il quadro della genesi di questo provvedimento legislativo che tanto ha già influito sulla presa in
carico del dolore cronico, abbiamo rivolto alcune domande a Marco Spizzichino della Direzione
Programmazione Sanitaria Ufficio XI Cure palliative e terapia del dolore del Ministero della Salute.
Il racconto di Marco Spizzichino conduce il lettore attraverso il percorso ministeriale che ha portato
alla definizione della legge e, oltre a documentare un iter che ha superato alcuni nodi di non facile
soluzione, contiene un breve bilancio e un’apertura alle prospettive future.
D. Ricorda un momento preciso in cui il tema dolore è diventato oggetto di discussione a livello ministeriale?
R. Sicuramente con l’accordo sancito in Conferenza Stato – Regioni per il progetto “Ospedale senza dolore”
quando era Ministro il Prof. Veronesi; io non mi occupavo ancora dell’argomento ma per la prima volta a
livello istituzionale fu messo in luce che il dolore era un aspetto che riguardava non solo “la patologia” in senso
stretto, ma aveva una forte ripercussione sulla sfera sociale delle persone.
D. Sempre all’interno del Ministero, come e da chi è nata l’idea di mettere a punto una legge dedicata al dolore?
R. La spinta è stata sicuramente parlamentare, in quanto erano stati presentati diversi progetti di legge a riguardo
sia dalla maggioranza che dall’opposizione. L’allora Ministro della Salute, Prof. Fazio, incaricò il Prof. Fanelli di
coordinare le attività ministeriali ed è in quel contesto che è stato partorito il modello assistenziale HUB e SPOKE.
D. Come si è passati dall’idea iniziale alla sua concretizzazione con la definizione della prima bozza di legge?
R. Tutti gli uffici del Ministero sono stati impegnati nel lavoro di revisione delle bozze iniziali; devo dire che
anche le Commissioni parlamentari, sia del Senato che della Camera, fecero un lavoro straordinario in tal
senso, in totale sinergia con la struttura ministeriale, apportando miglioramenti significativi.
D. Può riassumere brevemente il percorso ministeriale che ha portato dalla prima bozza di legge alla stesura finale
della Legge 38/10?
R. Il lavoro si è concentrato sulla creazione di una sintesi tra le due bozze presentate dalla maggioranza e
dall’opposizione, inserendo poi gli elementi che erano emersi dal tavolo di lavoro ministeriale. Così si è passati
dalla Proposta di legge 1771 alla Legge 38.
D. Durante le varie fasi di delineazione della legge quali sono stati i nodi più difficili da sciogliere?
R. Sicuramente quelli legati ai professionisti, sia per quanto ha riguardato l’identificazione delle figure
professionali deputate a operare nelle reti assistenziali sia per la definizione dei percorsi formativi.
D. Come mai a suo avviso è stata necessaria l’emanazione di una legge che regolamentasse la gestione del dolore
cronico, a differenza di quanto avviene per altre malattie?
13
14
Intervista a Marco Spizzichino
R. Io credo che il progetto “Ospedale senza dolore” abbia rappresentato una vera rivoluzione nel modo di
percepire il dolore nel mondo sanitario, ma forse poneva il baricentro dell’assistenza esclusivamente a livello
ospedaliero. Con la Legge 38/2010 si è cercato di dare un nuovo equilibrio alla rete assistenziale, definendo il
nuovo progetto “Ospedale – territorio senza dolore”.
D. Lei ha fatto parte della prima commissione per le cure palliative pediatriche che ha prodotto un primo
documento intitolato “Cure palliative rivolte al neonato, bambino e adolescente”. Il documento ha portato a una
maggiore sensibilizzazione sul tema del dolore pediatrico. In concreto cosa è cambiato da allora nella gestione del
dolore nel bambino?
R. I pediatri mi hanno raccontato che un tempo si negava l’idea che i bambini provassero dolore. Da allora a
oggi molti passi avanti sono stati compiuti e il livello di attenzione verso il dolore pediatrico è andato sempre
più crescendo. Questo risultato è dimostrato in modo particolare dalla richiesta di formazione su questo tema
da parte dei professionisti.
D. Come si concilia la necessità di dare piena operatività agli indirizzi della Legge 38/10 con la crisi economica che
sta vivendo il nostro Paese e i continui tagli alla spesa sanitaria?
R. Molto semplicemente: il dolore non trattato crea una spesa sanitaria molto maggiore di quanto possa
determinarsi se curato nel modo adeguato. Sono investimenti a medio termine, che comportano a volte vere
e proprie riorganizzazioni, ma i risultati in termini di contenimento della spesa sono certi.
D. A quasi 4 anni dall’emanazione della Legge 38/10 qual è il bilancio complessivo in merito all’attuazione della
legge?
R. Sicuramente positivo. Stiamo operando un cambiamento culturale oltre che assistenziale. Il Ministero, in
totale sinergia con i professionisti sanitari, i farmacisti e con la medicina di base sta cercando di vincere una
battaglia molto faticosa contro quello che comunemente è chiamato “dolore inutile”. Con le Regioni, come
dimostrano gli atti sottoscritti in sede di Conferenza Stato – Regioni, c’è una totale condivisione di finalità e
intenti su questo tema.
D. In un’ipotetica graduatoria dei Paesi nel mondo nei quali vi è un trattamento adeguato del dolore, che posto
occuperebbe l’Italia?
R. Per l’impegno istituzionale direi il primo. Abbiamo una legge unica nel panorama europeo e tale ruolo
ci è stato riconosciuto anche dalle associazioni europee di pazienti durante la stesura delle raccomandazioni
sul trattamento del dolore; constatare che in tale documento erano contenuti molti elementi presenti nella
Legge 38/2010 è stato un motivo di grande orgoglio per quanto è stato fatto nel nostro Paese. Il percorso
per la creazione delle reti assistenziali in tutte le Regioni è sicuramente più complesso, ma sono fiducioso
nell’impegno di tutti.
D. A livello simbolico cosa ha rappresentato per il Ministero della Salute la promozione di una legge su un tema che
ha importanti implicazioni etiche e che rappresenta un grande passo avanti in ambito socio-sanitario?
R. Una risposta concreta e di civiltà a chi soffre ma non sempre ha la possibilità di esprimersi, restituendo
dignità alla persona.
D. Quale momento di questa avventura ricorda con più piacere?
R. Il 15 marzo 2010 ero in vacanza con la mia famiglia quando ricevetti la telefonata del Prof. Fanelli il quale
mi annunciava che la Legge 38 era stata approvata in via definitiva alla Camera all’unanimità definendo il
consenso verso questo nostro sogno: fu un momento di grande emozione.
D. Quale obiettivo più ambizioso si proporrebbe per il futuro?
R. Per ora mi sentirei soddisfatto se si riuscisse a far attuare quanto previsto dalla Legge 38, con un punto di
particolare attenzione per gli aspetti legati all’ambito pediatrico.
fp istituzioni
La Fondazione Cariplo è una fondazione bancaria che svolge attività di sostegno dello
sviluppo sociale, culturale ed economico nei settori ambiente, arte e cultura, ricerca
scientifica e servizi alla persona. Attività che, dalla sua nascita, la Fondazione ha declinato
in numerosi e importanti progetti sia propri, sia realizzati in partnership con Fondazioni
italiane ed estere.
Il sostegno alla ricerca e il forte impegno sociale di Fondazione Cariplo incontrano appieno
il motivo ispiratore che ha portato alla nascita di Fighting Pain: trattare e approfondire il
tema dolore con elevate competenze scientifiche e allo stesso tempo contestualizzarlo nel
sociale in virtù delle sue implicazioni non esclusivamente clinico-terapeutiche. È con tale
spirito che abbiamo intervistato Carlo Mango, Direttore Area Scientifica e Tecnologica di
Fondazione Cariplo.
D. La Fondazione Cariplo ha una forte vocazione alla ricerca scientifica. Come nasce questo interesse?
R. La Fondazione Cariplo ha sempre avuto un interesse e un impegno attivo nell’ambito della
ricerca scientifica, anche in considerazione della grande propositività delle Università localizzate in
Lombardia e nel Piemonte orientale. La forte presenza di Università in tali aree si rispecchia nelle
elevate competenze degli organi della Fondazione: abbiamo persino avuto due premi Nobel nella
Commissione Centrale di beneficenza, Renato Dulbecco e Carlo Rubbia, che hanno lavorato per
la Fondazione nel corso degli anni. Quindi, una vocazione rilevante in questo ambito, che è uno
dei quattro settori ai quali la Fondazione Cariplo eroga i propri contributi, insieme ad ambiente,
arte e cultura e servizi alla persona. Possiamo quindi affermare che la ricerca scientifica sta
estremamente a cuore alla nostra organizzazione.
D. La Fondazione promuove iniziative a sostegno dei giovani ricercatori, un’attività di elevato valore etico
considerando che, a causa della mancanza di fondi, spesso progetti di grande importanza non vengono
portati a termine. Ci illustra l’impegno della Fondazione in tale ambito?
R. Il primo aspetto che occorre evidenziare è che Fondazione Cariplo è sempre stata attenta
ai giovani ricercatori. Lo è e lo sarà ancora di più in futuro: a maggio 2013 sono stati rinnovati
tutti gli organi della Fondazione, che si è posta tre grandi obiettivi da perseguire in tutte le sue
aree di intervento. In testa a questi obiettivi, insieme al welfare di comunità e al benessere della
persona, c’è proprio il sostegno ai giovani ricercatori. Per quanto attiene la peculiarità della ricerca
scientifica, certamente vi è un impegno etico e certamente vi è carenza di fondi. Sicuramente c’è
la necessità di off rire delle possibilità di crescita ai giovani ricercatori, tenendo conto anche delle
loro vocazioni e aspettative, in vista dell’inserimento nel mercato del lavoro. Quindi, per quanto
concerne il tema della ricerca, quello che off riamo deve essere non solo in linea con le aspettative,
ma costituire un’eccellenza di sviluppo personale e professionale perché la ricerca questo è, e
richiede da questo punto di vista la massima attenzione.
Cosa faremo? Sostanzialmente vareremo dei programmi. Oggi abbiamo varato un programma
in ambito oncologico, di cui parlerò successivamente, che si chiama TRIDEO (TRansforming
IDEas in Oncological research award). Abbiamo un programma in collaborazione con la Regione
15
16
Lombardia che fa parte dell’Accordo Quadro Capitale Umano, con cui sosteniamo percorsi di
crescita professionale di giovani nell’ambito della collaborazione Università-Imprese: in questo
caso abbiamo finanziato 17 progetti per un ammontare di oltre 12 milioni e mezzo di euro. Un altro
programma che rientrava in questo accordo con la Regione Lombardia prevedeva il reclutamento
di ricercatori stranieri di fama internazionale che venissero in Italia a “tirar su” i nostri migliori
giovani, creando quindi opportunità in Italia.
Altra iniziativa sulle vocazioni scientifiche è il Lindau Nobel Laureate Meeting, un meeting che si
tiene ogni anno sul lago di Costanza, in cui 600 giovani partecipano durante una settimana molto
“intensa” a incontri con una cinquantina di premi Nobel. Fino a qualche anno fa il meeting era
precluso ai giovani italiani, ma dal 2009 esiste questa possibilità: i nostri giovani fanno richiesta,
vengono valutati da un peer reviewer e hanno la possibilità di parteciparvi.
D. Come mai questo meeting era precluso ai giovani italiani?
R. Perché non c’erano partner italiani disposti a pagare le borse di studio per farli partecipare.
Fondazione Cariplo ha avuto in questo un ruolo determinante e ha addirittura allargato l’offerta di
finanziamento interpellando anche altri soggetti intenzionati a co-finanziare la partecipazione dei
giovani italiani al meeting. Per esempio abbiamo stretto un accordo con la Fondazione della Cassa di
Risparmio di Padova proprio in questo ambito, perché c’erano alcuni giovani molto meritevoli.
Poi, sempre riguardo ai giovani, molto importante è l’Accordo Quadro Cariplo-Microsoft. È un
progetto finanziato da Microsoft Corporate, quindi anche Cariplo ha dovuto fare domanda di
contributo tramite un bando, aggiudicandoselo per due anni di seguito. Sosteniamo un numero
elevatissimo di giovani; nel primo anno, il 2012, sono stati 17mila e per il prossimo bando ci
muoveremo su cifre analoghe accompagnandoli in attività che prevedono alla fine la creazione di
un’impresa innovativa. Un dato quindi estremamente interessante e importante.
Altro punto è che da quest’anno il nostro bando storico sulla ricerca medica, il Bando Ricerca
Biomedica condotta da Giovani Ricercatori, sarà in parte dedicato (si tratta di circa 3 milioni di
euro) ai giovani ricercatori con una logica non solo meritocratica, che viene garantita sempre e
comunque nei programmi dalla Fondazione, ma, come avviene nello European Research Council,
vi sarà un ulteriore elemento: i ricercatori dovranno essere realmente i responsabili scientifici dei
progetti che presentano e avranno la “portabilità” dei contenuti. Questo significa che se non ci
sono le condizioni ideali per realizzare il progetto, i ricercatori manterranno il contributo andando
a realizzare il progetto altrove.
D. Spesso il mondo accademico è troppo lontano da quello delle imprese. Ci parla dell’iniziativa
TTVenture, nata da una joint-venture tra università e imprese?
R. TTVenture (fondo per il trasferimento tecnologico) è un fondo chiuso di investimento di diritto
italiano, che investe in imprese-neoimprese ad alta intensità di ricerca e costituisce ormai una
realtà importante nell’ambito del venture capital in Italia. Ha una dotazione di 67 milioni di euro
ed è stato realizzato da un gruppo di Fondazioni di origine bancaria e dalla Camera di Commercio
di Milano. In questo ambito arriva un numero considerevole di richieste di contributo, circa un
migliaio da quando nel 2007 è stato varato; le richieste vengono selezionate e gli imprenditori
accompagnati nel loro percorso di credito nell’impresa. Si tratta ovviamente di numeri molto
piccoli ma che costituiscono realtà e si sostanziano nella creazione di impresa, la cui caratteristica è
quella di essere basata sull’attività intellettuale (dicevo prima ad alta intensità di ricerca) e quindi su
un asset di patrimonializzazione della conoscenza in seno a queste realtà; l’obiettivo non è quindi
solo quello di creare impresa.
Il tema è molto particolare perché unisce la logica degli investimenti alla logica erogativa che invece
sviluppiamo in altri programmi. Nel caso del TTVenture investiamo denaro cercando di dimostrare
che ci può essere anche un ritorno di investimenti in un settore specifico che è quello della creazione
di impresa a base scientifica, perché questa è in definitiva la caratteristica del programma.
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D. Non solo impegno nella ricerca scientifica in generale e nella valorizzazione dei risultati della ricerca
applicata, ma anche nella comunicazione e diffusione della scienza. In che modo la Fondazione favorisce lo
scambio e la circolazione del sapere scientifico?
R. La Fondazione certamente ha diverse forme di disseminazione, di valorizzazione della ricerca e
quindi di divulgazione scientifica. Un elemento che ci preme sottolineare è che la nostra Fondazione
ha delle policies specifiche in questo ambito, che sono state messe a punto nel corso degli ultimi anni
e che riguardano due aspetti fondamentali.
Il primo, la policy sulla proprietà intellettuale secondo la quale, a differenza delle policies oggi vigenti in
altri ambiti, la Fondazione Cariplo chiede una co-registrazione dei risultati della ricerca quando questi
si sostanziano in un brevetto, non per ottenere ritorni di investimento – quindi non vengono chieste
revenues economiche da questo percorso di valorizzazione – ma per avere la possibilità di tracciare
e di monitorare gli esiti delle nostre ricerche. Siamo quindi parte nel percorso di valorizzazione
ponendo un vincolo di co-registrazione, di informazione alla nostra Fondazione sui temi specifici
del percorso di valorizzazione, ma senza avere alcun tipo di ritorno economico. Questo ci consente
di monitorare i risultati finali del nostro contributo a una ricerca. Siamo di fronte a un punto chiave:
pensi a una ricerca che dura 2-3 anni a cui si aggiungono 2-3 anni di lavoro di valorizzazione;
molte volte questo percorso comporta il fatto che chi ha sostenuto la ricerca non è informato, dopo
la conclusione, dell’esito del progetto. Noi siamo interessati al risultato ultimo, a che cosa viene
generato, non solo perché misuriamo il risultato delle ricerche ma anche perché vogliamo verificare
che vengano preservati la natura e il tipo di impegno, anche etico, della nostra Fondazione.
Il secondo discorso molto importante in tema di policy riguarda la disseminazione e fruizione dei
risultati: la policy open access. La nostra Fondazione ha fatto la scelta di declinare una policy che lasci
libero il ricercatore – questo è importante – di scegliere dove valorizzare i risultati della propria
ricerca scientifica: lo può fare presso le riviste internazionali Nature, Science ecc. oppure in ambiente
open access, ma una cosa importante che noi chiediamo è che nel caso in cui scegliesse la prima
strada, finito il periodo di embargo delle riviste, deve mettere in pubblica fruizione, in open access
appunto, le sue pubblicazioni e anche i dati e i meta-dati. Non possiamo partire tutte le volte dal livello
zero di conoscenza: non faremmo un buon servizio alla nostra società.
L’impegno su questi temi è rilevante e si sostanzia, appunto, in policies precise che noi abbiamo
adottato tempo fa.
D. La Fondazione promuove la ricerca anche attraverso il miglioramento dell’accesso da parte della
comunità scientifica a strumentazioni e tecnologie. Ci racconta l’esperienza più significativa?
R. Direi che l’esperienza che ha fatto scuola non solo in Fondazione Cariplo ma anche all’esterno
è stato il progetto NOBEL (Network Operativo per la Biomedicina di eccellenza in Lombardia). Il
progetto era ed è un programma di accesso a piattaforme tecnologiche, ormai concluso da qualche
anno, che ha aperto una strada (si chiamava NOBEL perché fu disegnato con l’allora membro della
Commissione Centrale, Renato Dulbecco). Il programma si prefiggeva di creare piattaforme che
offrissero servizi e accesso a servizi da parte della comunità scientifica, e fruibili dalla comunità stessa,
al fine di migliorarne la propositività. L’iniziativa è partita nel 2003, ha avuto un percorso di almeno
5-6 anni, estremamente importante per attirare il dibattito su questo tema. Attualmente siamo in
procinto di pubblicare un lavoro sulle infrastrutture di ricerca in tutt’Italia, che abbiamo sviluppato in
collaborazione con altri Enti.
D. Fondazione Cariplo e Paesi in via di sviluppo: ci illustra il progetto FIRST?
R. L’acronimo FIRST (French-Italian Rice Science and Technology), interessante perché comporta
che ci sia un first, un second ecc., indica un programma di ricerca internazionale che si sostanzia in
un bando internazionale di ricerca ed è il primo strumento messo a punto nell’ambito dell’accordo
tra Fondazione Cariplo e Fondazione Agropolis a Montpellier, una fondazione molto importante in
Francia che opera nella ricerca agroalimentare. FIRST in questo ambito specifico si è concentrato
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sul tema della ricerca per il miglioramento della produzione del riso. La caratteristica di questo
programma, che poi ha visto un successivo bando denominato CERES, sempre sui cereali e che è in
corso di valutazione, è quella di avviare la collaborazione tra gruppi di ricerca italiani e francesi nello
specifico, con il vincolo che tali gruppi di ricerca debbano coinvolgere ricercatori provenienti anche
da Paesi in via di sviluppo. Questo con la duplice convinzione che: i) è importante investire in ricerca
coinvolgendo Paesi in via di sviluppo su tematiche, come quelle legate ai cereali, che costituiscono
un concetto nell’agroalimentare molto orientato al bene comune, ii) è importante il coinvolgimento
dei Paesi in via di sviluppo perché la ricerca non deve essere appannaggio solo di chi può permettersi
di investire in ricerca; è un discorso di inclusione – c’è chi lo ha chiamato “democratizzazione della
scienza” – nei percorsi di produzione scientifica nell’ambito specifico.
D. Sviluppo del capitale umano dedicato alla scienza anche attraverso il sostegno di giovani ricercatori
africani. Ci parla dell’iniziativa Neglected Tropical Diseases?
R. Neglected Tropical Diseases, o anche NTD, è un’iniziativa di cui non siamo coordinatori, ma partner,
essendo coordinata dalla Fondazione Volkswagen Stiftung con sede in Hannover. Il programma vede
la presenza di Volkswagen, Fondazione Cariplo, Fondazione Nuffield nel Regno Unito, Fondazione
Mérieux in Francia, Fondazione Gulbenkian in Portogallo. Alla base vi è l’obiettivo di investire in
capitale umano africano e creare allo stesso tempo una rete di collaborazioni transnazionale contro
le neglected tropical diseases, un gruppo di malattie trascurate che colpiscono in particolare i Paesi
poveri con un’elevata incidenza. I ricercatori locali africani, attraverso questo programma, riescono a
migliorare e a integrarsi nei percorsi di produzione scientifica anche internazionale. Il tutto è frutto
anche di queste collaborazioni internazionali, che noi da soli non riusciremmo a realizzare ma che in
questo modo diventano delle realtà. Dalle collaborazioni c’è sempre da imparare.
D. Filantropia e volontariato sono altre missions della Fondazione. Si può quindi affermare che la Fondazione
è impegnata nel sociale a 360 gradi? Se sì, cosa può aspettarsi la società dalla Fondazione nel futuro?
R. La Fondazione è una grande Istituzione nel senso che opera nell’ambito dell’attività scientifica, del
sociale, dell’ambiente, dei beni comuni, dell’arte e della cultura. L’interpretazione che è stata fatta in
occasione della messa a punto del nostro programma strategico di intervento per i prossimi 7 anni è
proprio quella di superare il confine tra i settori, cercando di avere una declinazione veramente a 360
gradi sulle varie tematiche, mettendo i fabbisogni al centro. Ci sono tematiche che riguardano la ricerca,
la tecnologia, il sociale, l’housing sociale piuttosto che altri ambiti specifici come l’ambiente ecc. L’idea è
proprio quella che Fondazione Cariplo costituisca una sorta di laboratorio filantropico per intervenire su
tematiche estremamente trasversali, affrontandole in una logica integrata di welfare di comunità.
D. Attualmente la ricerca scientifica focalizzata sulla terapia del dolore è in grande espansione (soprattutto
in Italia, dove è appena stato vinto un grant europeo dedicato proprio alla genetica del dolore), ma non
vi sono ancora molti grant specifici su questo tema nonostante la grande rilevanza socio-sanitaria. La
Fondazione ha in programma nei prossimi anni di favorire la ricerca di giovani ricercatori in tale ambito,
come ha fatto per la ricerca biomolecolare?
R. Il tema, come dicevo prima, rientra sicuramente in un concetto molto trasversale, che noi
pensiamo sia legato a uno dei tre obiettivi della Fondazione e cioè quello del benessere della persona.
Non so se faremo mai un bando dedicato a questo; certamente intraprenderemo delle linee in questo
ambito dove il tema della persona con la sua sfera fisica, psicologica, sociale entra a pieno titolo nella
definizione del concetto di benessere, e ciò addirittura prescindendo, come dice l’Organizzazione
Mondiale della Sanità, dalla presenza/assenza di patologie, ma considerando le persone
semplicemente nelle diverse stagioni della vita. Questo discorso sarà probabilmente una sorta di talea
che innerverà le iniziative che verranno intraprese. Anche noi, nel corso di anni precedenti, abbiamo
finanziato progetti che riguardavano le tematiche legate al dolore soprattutto nelle fasi più delicate
dell’esistenza umana, ossia le cure palliative.
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D. In riferimento a quanto diceva prima a proposito del superamento del confine tra settori, il dolore
cronico, definito dall’Organizzazione Mondiale della Sanità come dolore globale perché interferisce con
vari aspetti non solo umani e psicologici, ma anche sociali ed economici, è un esempio emblematico di
sovrapposizione di ambiti. Si può affermare che si sia addirittura passati da un problema esclusivamente
medico a un problema sociale. Cosa pensa al riguardo?
R. Sono d’accordo, non a caso parlando delle tre sfere della persona – fisica, psicologica e sociale –
esse si integrano in modo importante e con enfasi addirittura maggiore quando ci sono situazioni
di difficoltà; comunque noi sappiamo che le problematiche riguardanti questi aspetti specifici
comportano il fatto che non sia, come dire, l’“individuo” a patire di queste patologie ma la “persona”,
intendendo come persona l’individuo con tutta la sua sfera di relazioni interpersonali, sociali,
familiari, e con questo si tocca anche tutto il tema estremamente ampio dei caregiver.
D. Il dolore interferisce anche con le abilità lavorative, quindi ha implicazioni anche economiche; è un tema
che raccoglie effettivamente a 360 gradi i punti di cui abbiamo parlato.
R. Certo, sono assolutamente d’accordo.
D. Il programma europeo Horizon 2020 dedica ampio spazio al dolore nell’anziano. La Fondazione ha
dei programmi di ricerca e un interesse nel dolore dell’anziano e nel tema dell’invecchiamento?
R. Il tema dell’invecchiamento è un tema importante per tanti ordini di motivi, non solo quelli demografici
che ci richiamano a una riflessione sulla criticità e sulla rilevanza che ha una tematica di questo tipo.
In questo ambito, in tutte le declinazioni che riguardano le patologie legate all’anziano, noi siamo
non solo interessati ma abbiamo dedicato una parte importante del nuovo programma di ricerca
medica, legato proprio alla comprensione delle patologie legate all’invecchiamento. Nello specifico,
i macro-ambiti di intervento saranno due: il primo legato al tema delle patologie neurodegenerative
nell’anziano, il secondo alle patologie cardiovascolari.
Tutto questo, continuo a dire, mettendo la persona al centro, e quindi con un “taglio” in linea con
quello di cui parlavo prima e cioè a 360 gradi sulla persona.
D. Ci illustra il bando congiunto di ricerca di frontiera in ambito oncologico, denominato TRIDEO
(TRansforming IDEas in Oncological research award), che vede la collaborazione della Fondazione
Cariplo con l’Associazione Italiana per la Ricerca sul Cancro (AIRC)?
R. L’abbiamo presentato proprio questa mattina; i vertici delle due Fondazioni si sono incontrati,
hanno stipulato questa alleanza che durerà almeno due anni e che partirà quest’anno. Noi finanziamo
ricerche prodotte da “giovani ricercatori” con età massima di 40 anni (secondo i canoni italiani).
In ambito oncologico, quello che cerchiamo di stimolare non è l’attività che le nostre Agenzie già
in parte finanziano (noi, e AIRC maggiormente, cioè progetti di ricerca esclusivamente sui tumori
nel caso di AIRC, su tumori e altre patologie nel nostro caso). Quello che abbiamo voluto fare è una
cosa che nel nostro Paese non viene fatta molto spesso e cioè finanziare una ricerca trasformativa,
innovativa, non convenzionale, un po’“rivoluzionaria” se vogliamo (per essere più efficaci in termini
di comunicazione), una ricerca che certamente ha delle caratteristiche di rischio e di innovazione,
che molto spesso non trova le Agenzie di finanziamento pronte a sostenere questi progetti. Poiché
riteniamo che sia un vero peccato che alcuni progetti, proprio a causa dell’estrema innovatività dei
temi proposti, vengano rigettati dalle Agenzie, noi siamo a disposizione per finanziare programmi di
ricerca estremamente innovativi nell’ambito dei quali, pur su un robusto impianto di ricerca, non si
hanno tutti i dati preliminari messi a punto completamente proprio perché alcune di queste ricerche
sono dei trampolini di lancio. A noi pare corretto stimolare questa propositività non convenzionale,
magari un po’ visionaria in ambito oncologico, ma si tratta di un tema che impone, anche in virtù
dell’invecchiamento della popolazione, una serie di riflessioni.
Questo è TRIDEO, il nostro accordo con AIRC; in più va detto che collaborare con altre agenzie di
finanziamento per noi è un elemento importante, pregnante: ben vengano queste partnership.
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D. Il dolore cronico non è ancora riconosciuto come malattia genetica e quindi la ricerca in tale ambito
non può avvalersi del supporto di Fondazione Telethon, una delle principali charities italiane. Proprio in
merito a progetti sul dolore, la Fondazione ha un’apertura, ha già qualcosa in programma?
R. Premetto che noi non ragioniamo sulla base di preconcetti, quello che conta sono le evidenze
scientifiche di quello che noi intendiamo finanziare. È un po’ difficile che questi progetti rientrino
in alcuni programmi, ma generalmente non vi sono preclusioni da parte di Fondazione Cariplo.
Nel caso in cui ci trovassimo con dei progetti meritevoli e coerenti con le nostre linee di intervento,
perché no? Non abbiamo preclusioni di sorta del tipo “non ci interessa il tema”.
D. Quindi non avete programmi specifici o progetti sul dolore, però siete aperti comunque al tema?
R. Sì, noi siamo aperti al tema, in particolare con riferimento a quanto dicevo prima sul benessere
della persona, con i programmi e le valenze che le ho riportato.
D. Quali sono i programmi scientifici più importanti realizzati in passato dalla Fondazione?
R. È difficile, si rischia sempre di dimenticare qualcosa, prima abbiamo citato NOBEL che è stata
un’importante realizzazione di questa Fondazione; le riporto anche un altro tema importante che
riguarda il nostro progetto AGER (Agroalimentare e Ricerca) in collaborazione con altre Fondazioni
di origine bancaria; abbiamo parlato anche del progetto NTD e quello con Agropolis, due programmi
molto rilevanti; ce ne sono molti altri e non vorrei dimenticarne qualcuno.
D. Quali invece i programmi scientifici in cui la Fondazione sta impiegando le sue risorse ora?
R. Il tema giovani è importantissimo. Rinnoveremo l’Accordo Quadro con la Regione Lombardia per
i percorsi che coinvolgono i giovani nell’ambito, per esempio, della collaborazione con l’Università e le
imprese, ma in questo senso anche tutto il tema degli istituti tecnici professionali: questo per noi è un
aspetto decisamente rilevante e su questo focalizzeremo importantissime risorse.
Se parliamo di programmi scientifici, due probabilmente sono i filoni più importanti: uno è
sicuramente il tema legato ai giovani, l’altro è quello legato al benessere della persona inteso come
situazioni in presenza di patologie, disabilità o altro oppure collegato a una condizione particolare,
momentanea, anche solamente una stagione della vita; in questo ambito rientra l’impegno della
nostra Fondazione anche in futuro nel campo della riabilitazione psicomotoria piuttosto che con altri
interventi che potremo prendere in considerazione.
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by the editorial staff
Fondazione Cariplo is a banking foundation committed to social, cultural and economic
development in the fields of environment, arts and culture, scientific research, and social
services. Since its inception, Fondazione Cariplo has translated this commitment into
numerous important projects undertaken both independently and in partnership with
Italian and foreign foundations.
Fondazione Cariplo’s dedication to research and strong social commitment perfectly
match the intent of Fighting Pain: to address and provide insight into the issue of pain
through expert scientific knowledge, while addressing how pain fits into a social context
by virtue of more than its clinical and therapeutical implications. It is in this spirit that
we interviewed Carlo Mango, Director of the Scientific Research and Technology Area
of Fondazione Cariplo.
Q. Fondazione Cariplo has a strong tradition in scientific research. How did this interest come about?
A. Fondazione Cariplo has always had an interest and been actively involved in scientific research,
thanks in no small part to support from universities across Lombardy and Eastern Piedmont. The
strong presence of universities in these areas is reflected in the high-level expertise of some of the
figures that have worked for the Foundation over the years. Two such figures were Renato Dulbecco
and Carlo Rubbia, who served on the Steering Committee and were awarded the Nobel Prize. So,
yes, I would say that indeed we have a strong tradition in scientific research, it being one of the four
fields, in addition to the environment, arts and culture and social services, to which Fondazione
Cariplo is devoted. It’s safe to say that our organization cares very deeply about scientific research.
Q. Fondazione Cariplo promotes initiatives in support of young researchers, an activity of high ethical value
considering that, because of the lack of funding, oftentimes important projects are not carried to fruition.
Can you tell us more about the Foundation’s work in this area?
A. Firstly, it is important to point out that Fondazione Cariplo has always had an eye toward young
researchers. And it continues and will continue to do so in the future. In May 2013, the Foundation
elected all new members to its governing bodies and three important objectives were established in
each one of its areas of activity. Foremost among these objectives, together with the welfare of the
community and the wellbeing of individuals, is to provide support to young researchers. In terms of
scientific research specifically, there is certainly an ethical commitment and certainly a lack of funds.
No doubt, we need to offer our young researchers opportunities for growth, also taking into account
their vocations and expectations as they move into the job market. What we offer in the way of research
must meet expectations, but must also contribute to the achievement of excellence in personal and
professional development. That’s what research is and that is what we most need to focus on.
What is our plan of action? Essentially, our strategy is to launch programs. Today we launched a cancer
research program, which I will talk more about later, called TRIDEO (TRansforming IDEas in Oncological
research award). We have also established a program in collaboration with Regione Lombardia as part
of the Human Capital Framework Agreement through which we nurture the professional growth of
young people within the context of partnerships between universities and businesses. In this case, we
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financed 17 projects amounting to more than €12.5 million. Another program within the scope of our
collaboration with Regione Lombardia saw the recruitment of foreign researchers of international fame
whom we brought to Italy to ‘raise’ our brightest young researchers, thereby creating opportunities in Italy.
Another scientific initiative in which the Foundation takes part is the annual Lindau Nobel Laureate
Meeting held at Lake Constance. During this ‘intense’ week-long event some fifty Nobel laureates
meet with 600 young researchers. Until a few years ago, the event was not open to young Italian
researchers, but since 2009 they now have the opportunity to attend through an application process
that undergoes a peer review.
Q. Why was this meeting not open to young Italian researchers?
A. Because none of the Italian partners were willing to fund scholarships so that they could attend.
Fondazione Cariplo played a pivotal role in this and even involved other entities which were willing
to provide co-financing so that young Italians could attend the meeting. For instance, our agreement
with Fondazione della Cassa di Risparmio di Padova made it possible to make the event available to
worthy young researchers.
Another key youth-oriented initiative is the Cariplo-Microsoft Framework Agreement. Since the
project is financed by Microsoft Corporate, Cariplo had to apply for the grant through a call for
proposals, which it won two years in a row. Through this project, we have been able to support
countless young people – in the first year alone (2012), we provided support to 17,000 youth and for
the next call we expect to achieve similar results – and guide them along the way to the creation of an
innovative start-up. The project is very interesting and is making an important contribution.
Another point worthy of note is that starting this year, our call for proposals on biomedical research
led by young researchers (Bando Ricerca Biomedica Condotta da Giovani Ricercatori) will in part (€3
million) be allocated to young researchers not only on the basis of merit, a principle upheld for all of the
Foundation’s programs, but also based on an additional element also shared by the European Research
Council. Essentially, the researchers will be responsible for the scientific aspects of the projects that they
present and the content of their projects can be ‘carried over’. In other words, if the conditions are not
ideal to realize the project, the researchers can keep the grant and develop their project elsewhere.
Q. The academic world is often far too removed from the business world. Can you tell us about TTVenture,
the joint-venture between universities and businesses?
A. TTVenture (a technology transfer fund) is an Italian closed-end fund that invests in research-intensive
businesses and start-ups and has become a key player in the venture capital market in Italy. TTVenture has
raised some €67 million thanks to a group of banking foundations and the Milan Chamber of Commerce.
In this context, numerous grant applications have been received – nearly a thousand since the fund was
established in 2007; the applications are selected and the entrepreneurs receive strategic guidance.
Obviously, we are dealing with very small numbers, but ones that make up a reality and result in the creation
of businesses based on intellectual (research-intensive) activity and therefore on the capitalization of
knowledge within this reality; therefore the goal is not just to create businesses.
The subject-matter is very unique because it combines investment logic and the grant-making logic we
develop in other programs. In the case of TTVenture, we invest money in an effort to show that there can
be a return in investing in scientific companies. Ultimately, this is the main feature of the program.
Q. In addition to scientific research in general and furthering applied research, the Foundation is also
committed to the dissemination and diffusion of science. In what way does the Foundation encourage the
exchange and circulation of scientific knowledge?
A. The Foundation certainly has various ways of disseminating and furthering research and therefore
spreading scientific knowledge. One point we do wish to underscore is that over the years our Foundation
has put specific policies in place in this area that deal with two key aspects.
The first concerns our policy on intellectual property, which, unlike the policies currently in force in
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other areas, requires the co-registration of patented research findings, not for the purpose of obtaining
investment returns or economic revenues, but so that we can trace and monitor the outcome of
our research projects. We therefore become a part of the value enhancement process by requiring
co-registration and the provision of information to the Foundation on matters specific to the value
enhancement process, but without achieving any economic gain. This enables us to be abreast of the end
results of our contributions to a specific research field. This is a crucial point: imagine a research project
that lasts 2-3 years plus 2-3 years of value enhancement work; typically, the research funders are not
informed of the outcome of the project once it is over. We want to know the end result and what it leads to.
This not only because we measure the results of our research projects, but also because we want to ensure
the preservation of our Foundation’s ethical principles and commitment. The second important aspect in
terms of policy concerns the dissemination and open access of the results. Our policy allows researchers
the freedom – and this is important – to choose how best to further the results of their scientific research.
They can publish in international publications such as Nature, Science etc. or make the results available via
open access delivery. Our only requirement is if the first option is chosen, upon expiration of the publisher’s
embargo period, that the researchers’ publications as well as the data and meta-data be disseminated via
open access. We cannot start from square one every time, and doing so would be a disservice to society.
Our commitment to these issues is steadfast and is reflected in our very specific, long-standing policies.
Q. The Foundation also promotes research by making tools and technology more readily available to the
scientific community. Can you tell us about the most significant experience?
A. I would say that the project that provided the best learning experience to Fondazione Cariplo and
externally was the NOBEL project (Network Operativo per la Biomedicina di Eccellenza in Lombardia).
The project was a program that gave access to technology platforms. The project was concluded a few
years ago and opened a new road (it was called NOBEL because it was designed by the then member of
the Steering Committee, Renato Dulbecco). The program set out to create platforms that would offer
the scientific community services and access to services which the community could take advantage of
in order to improve proactivity. The initiative was launched in 2003 and lasted for 5-6 years; it played a
pivotal role in attracting debate to this issue. We are now in the process of publishing a work on research
infrastructures across Italy, which we developed in joint collaboration with other entities.
Q. Fondazione Cariplo and developing Countries. Can you tell us more about the FIRST project?
A. The acronym FIRST (French-Italian Rice Science and Technology), implying that this will be the
first of many, stands for an international research program based on an international research call
for proposals and is the first tool developed under the agreement between Fondazione Cariplo and
Agropolis Foundation in Montpellier, a very important foundation in France operating in farming
and food research. In this specific area, FIRST concentrates on research for the improvement of rice
production. The program, which saw a subsequent call for proposals named CERES (also concerning
itself with cereals and in the process of being evaluated), aimed to promote partnerships between Italian
and French research groups, requiring them to call in researchers from developing Countries. This in
the belief that: a) it is important to invest in research and involve developing Countries in issues, such as
those regarding the production of cereals, that embrace a food and farming concept that benefits the
entire community, and b) it is important to involve developing countries because research should not be
exclusive only to those that can afford to invest in it. It is a matter of inclusion – some have called it the
‘democratization of science’ – in specific scientific production processes.
Q. The Foundation also fosters the development of human capital dedicated to science by lending its support to
young African researchers. Can you talk to us about the Neglected Tropical Diseases initiative?
A. Neglected Tropical Diseases, or NTD, is an initiative coordinated by Volkswagen Stiftung
headquartered in Hannover. The program teams up Volkswagen, Fondazione Cariplo, Nuffield Foundation
in the UK, Mérieux Foundation in France, and Gulbenkian Foundation in Portugal. The main aim is to
23
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invest in African human capital and create a transnational partnership network against neglected tropical
diseases, a group of aggressive neglected diseases widespread in poor countries. Through this program,
local African scientists are able to improve and become involved in scientific production processes in an
international arena. Alone we would not be able to achieve these objectives, but through this partnership,
these goals can become reality. Working together always provides learning opportunities.
Q. Philanthropy and volunteerism are also among the Foundation’s missions. Can we say that the Foundation is
committed to social issues on a 360° scale? If so, what future social impacts can we expect the Foundation to make?
A. The Foundation is one big Institution in that it operates in the fields of scientific research, social services,
environment, and arts and culture. As we were finalizing our strategic plan for the next seven years, we
became aware that it was important to blur the boundaries between these fields and operate across-theboard, putting needs first. Research, technology, social, social housing issues and other specific areas like
the environment all require attention. The idea is for Fondazione Cariplo to become a sort of philanthropic
laboratory able to operate across a wide range of areas based on an integrated logic of community welfare.
Q. Today’s scientific research is becoming more and more focused on pain therapy (especially in Italy, which recently won
a European grant dedicated to the genetics of pain), but there aren’t many other specific grants on this issue despite the
importance of this issue in a social and public healthcare context. Does the Foundation have any forthcoming plans to
encourage young researchers in this field, as it has done in the past for biomolecular researchers?
A. As I said before, the issue is an undoubtedly broad one and in our opinion is linked to one of the
Foundation’s three objectives: the wellbeing of the individual. I don’t know if we’ll ever launch a call for
proposals on this specific issue, but we certainly will move in this direction. The individual and his/her
physical, psychological and social sphere fall four-square within the definition of wellbeing provided
by the World Health Organization, despite the presence/absence of pathologies and considering the
individual simply in the various stages of his/her life. This issue will likely fuel future initiatives. In the
past, we too have financed projects linked to pain, especially pain experienced in the most delicate
phase of human existence, during palliative treatment.
Q. In reference to your previous comments on blurring the boundaries between the various fields, chronic pain,
defined by the World Health Organization as global pain because it interferes with human and psychological
aspects as well as social and economic ones, is a prime example of overlapping boundaries. One could say that
the issue was once a solely medical problem and is now a social problem. What are your thoughts?
A. I agree. This is why when we speak of the three spheres of the individual – physical, psychological
and social – we acknowledge that they overlap even more so in situations of suffering. In any case, we
know that the problems surrounding these specific aspects do not affect the ‘individual’ but rather
the ‘person’, understood as the individual and his/her sphere of interpersonal, social and family
relationships. Related to this is the enormously broad issue of caregivers.
Q. Pain interferes with an individual’s ability to work and therefore poses economic implications. The issue
effectively encompasses all of the points we’ve discussed.
A. Of course, I completely agree.
Q. The European program Horizon 2020 devotes considerable attention to pain as it relates to the elderly.
Does the Foundation have research programs for or an interest in this issue or the issue of aging in general?
A. Aging is an important issue for many reasons, and not just in terms of demographics, which require
reflection on the challenges and impact of this issue.
We are not only interested in all areas of age-related diseases, but we have dedicated a big part of our
new medical research program to understanding pathologies linked to aging. More specifically, our
work covers two macro fields: the first linked to neurodegenerative diseases in the aging population and
the second to cardiovascular diseases.
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All the while, we put the individual first, in keeping with the idea of what we discussed earlier
regarding the various spheres of the individual.
Q. Can you tell us more about the joint call for proposals TRIDEO (TRansforming IDEas in Oncological research
award) launched by Fondazione Cariplo and Associazione Italiana per la Ricerca sul Cancro (AIRC)?
A. We presented it this morning, actually. The heads of the two Foundations met and agreed on a
two-year partnership that will start this year. We fund research projects by ‘young researchers’ aged 40
years or younger (young by Italian standards). From an oncological standpoint, it is not our intention to
stimulate activity that we already partially finance (in other words, research projects related exclusively to
tumors in the case of AIRC and tumors and other pathologies in our case). What we wanted to do instead
was something that doesn’t occur very often in Italy, and that is to finance research that is transformative,
ground-breaking, unconventional, and ‘revolutionary’, if you will. Research projects that embrace risk and
innovation very often do not have access to financing. Because we feel that it would be a shame for certain
projects to be rejected simply because of their highly innovative subject-matter, we have made financing
available to these projects. While these projects have sophisticated research facilities available, conclusive
preliminary data is not always available since some research projects serve as launch pads. We believe that
these unconventional and visionary proposals in the field of cancer research should be supported. And on
account of our aging population, this issue requires serious reflection.
This is what TRIDEO and our partnership with AIRC are all about. Collaborating with other funding
agencies is important to us and we welcome these alliances.
Q. Chronic pain has not yet been recognized as a genetic disease and research in this area does not have the
support of Fondazione Telethon, one of Italy’s biggest charities. With regard to projects on the issue of pain
and the Foundation’s openness toward the subject, does the Foundation have anything in the pipeline?
A. We do not operate on the basis of preconceptions. What matters to us is the scientific evidence
behind the projects we intend to finance. It is unlikely that these projects will fall into any of our
programs, but, generally, Fondazione Cariplo does not preclude any possibility. If we were to be
presented with worthy projects that are in line with our ethos, then why not? We do not rule anything
out simply because ‘the issue does not interest us’.
Q. So there are no specific programs or projects regarding pain per se, but you are open to the possibility?
A. Yes, we are open to the possibility. Particularly in relation to what we discussed before on the
wellbeing of the individual and the programs and value enhancement processes I mentioned earlier.
Q. What are some of the most important scientific programs that have been brought to fruition by the Foundation?
A. It’s hard to say, and I don’t want to exclude any. Earlier, I mentioned NOBEL and I would say that
that was an important program for the Foundation. Another would be our AGER project (Farming,
Food and Research) in collaboration with other banking foundations. I also spoke about NTD and
Agropolis, two other very important initiatives. There are many others and I don’t want to forget any.
Q. On which scientific programs is the Foundation currently focusing its efforts?
A. The issue of young people is very important. We will renew our Framework Agreement with
Regione Lombardia supporting youth through initiatives like establishing collaborations between
businesses and universities, and even professional trade schools. This is a key issue for us and one to
which we intend to allocate significant resources.
In terms of scientific programs, our focus is on two crucial areas: the first certainly relates to young
people, and the other is linked to the wellbeing of the individual affected by pathologies, disabilities or
other illnesses, or linked to a specific, momentary condition that arises during a certain stage of life. The
Foundation’s commitment, even in the future, to the field of psychomotor rehabilitation and other initiatives
we might take into consideration also fall within these areas.
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Fondazione Cariplo e sostegno dei giovani talenti: breve storia di un’esperienza unica e indimenticabile
Manuela De Gregori, Responsabile studi di genetica e dolore, Servizio di Terapia del Dolore, Fondazione IRCCS Policlinico
San Matteo, Pavia
Nell’anno 2011, grazie all’Università degli Studi di Pavia
Ada Yonath vinse il Premio Nobel per la chimica nel
che ha sostenuto la mia candidatura, ho avuto l’onore di
2009 insieme a Thomas Arthur Steitz e a Venkatraman
essere selezionata da Fondazione Cariplo per partecipare
Ramakrishnan per gli studi sulla struttura e sulla funzione
al 61° Lindau Nobel Laureate Meeting, nella settimana
dei ribosomi. Ha intitolato la sua presentazione: “Climbing
dal 26 giugno fino al primo luglio insieme a 570 giovani
the Everest beyond the Everest” e ha mostrato commossa
ricercatori provenienti da 80 Paesi.
un’immagine della sua nipotina che fiera della nonna
Il meeting, che ha avuto luogo a Lindau, in Germania, è stato
un’occasione unica di incontro e confronto con 23 premi
Nobel provenienti da tutto il mondo: Agre, Arber, Blackburn,
racconta alle amiche di avere una nonna sempre molto
occupata, ma che riesce a trovare del tempo per giocare
con lei.
Ciechanover, de Duve, Evans, Fischer, Hershko, Huber, Kroto,
Tutti i Premi Nobel sottolineavano che il futuro è nelle
Lehn, Michel, Murad, Negishi, Neher, Sakmann, Smith,
mani di noi giovani, che abbiamo tutte le possibilità per
Smithies, Steitz, Tsien, Wiesel, Yonath, zur Hausen.
costruirlo al meglio grazie alla passione per la ricerca – che
Questa possibilità mi ha reso fiera della strada che ho percorso
finora nell’ambito della ricerca scientifica e ha rappresentato
una delle soddisfazioni più grandi che abbia mai avuto.
I premi Nobel si sono resi disponibili per tutta la settimana
a interagire direttamente con noi giovani ricercatori, sia
durante gli incontri ufficiali mattutini e pomeridiani, sia nelle
non deve però rimanere l’unica passione nella nostra vita –
alla voglia di scoprire, sapere, imparare.
Ricorderò questa meravigliosa esperienza per sempre,
ringraziando la Fondazione Cariplo e continuando a
occuparmi di ricerca per la personalizzazione della terapia
del dolore tramite l’identificazione di marcatori molecolari.
brevi pause nel corso del giorno e durante le cene. Le giornate
erano sempre ricchissime di eventi: era possibile partecipare a
colazioni di lavoro con i Nobel Laureates, seguite da sessioni
plenarie e incontri pomeridiani a piccoli gruppi, per poter
direttamente interagire con uno di loro. Durante le cene il
clima diventava molto familiare e i professori rimanevano in
compagnia di noi giovani molto volentieri.
Rivivo tuttora un entusiasmo fortissimo al pensiero di aver
vissuto questa fantastica esperienza, grazie all’Università
degli Studi di Pavia e alla Fondazione Cariplo, che ha
permesso che questo viaggio si realizzasse, provvedendo
alla completa organizzazione di tutto.
Durante il meeting i premi Nobel hanno esposto in modo
originale e appassionato a noi giovani ricercatori i risultati
delle loro ricerche, unendo alla descrizione scientifica
dei metodi adottati per ottenerli aneddoti divertenti e
spiegando come avessero combinato la passione per la
ricerca scientifica con le altre passioni della loro vita.
Le voci dei premi Nobel rimarranno per lungo tempo nella
mia memoria, così come molte delle loro frasi e dei loro
concetti chiave.
Manuela De Gregori e altri giovani ricercatori con Aaron Ciechanover,
Premio Nobel per la Chimica nel 2004.
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27
Dolore cronico: un’entità
nosologica complessa
William Raffaeli1, Cristina E. Minella2
1
ISAL Foundation, Institute for Research on Pain, Rimini, Italy
2
Pain Therapy Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
Abstract
Chronic pain is an enormous medical-health problem. It does occur in the context of
numerous diseases, syndromes or it is itself a disease process. It seriously affects patients’
quality of social- and work-life and often it is underdiagnosed and undertreated. Current
European statistics estimate that approximately 20% of the adult population is affected
by a syndrome associated with chronic pain. Moreover chronic pain is a major cost driver
because of its management and loss of productivity.
Recently the concept that chronic pain is a disease in its own right has gained ground,
because of mounting evidence that it is related to functional and structural changes in
the brain. Even if this theory is still object of intense debate in the scientific community,
it suggests the high complexity of the entity ‘pain’ and the difficulties in understanding its
pathophysiology and management.
The neurobiological mechanisms responsible for different types of pain are beginning
to be defined and medical treatments are switching from empirical approaches to
approaches targeted to the possible underlying pathophysiological mechanisms, and are
monitored using specific indicators. Along these lines we suggest that the management of
patients affected by pain should be based on the knowledge of complex and multiple pain
mechanisms, patients’ characteristics and pharmacological treatments, identifying a specific
clinical pathway for pain control.
fighting pain – combattere il dolore, 1(2)2014: 27-30
Introduzione
Dal punto di vista neurofisiopatologico il “dolore” è la manifestazione clinica di un evento elettrico
neurologico molto complesso, che ha il fine di avvertire l’organismo dell’esistenza di un elemento nocivo (interno o esterno) che ne pregiudica l’omeostasi. Ma qual è la sua specificità nosologica?
Il dolore è definito dalla International Association for the Study of Pain (IASP) come “un’esperienza
sensoriale ed emotiva spiacevole, associata ad un danno tessutale attuale o potenziale, o riferita in
tali termini” (1). Tale definizione riconosce, quindi, la composizione multifattoriale della “percezione ed espressione soggettiva” che è il frutto di un fattore di proiezione ed elaborazione cerebrale
dell’evento che genera dolore, elaborato all’interno di processi di caratterizzazione che derivano da
un substrato fisiologico e antropologico-culturale; questi fattori congiunti danno luogo alla percezione di una sensazione descritta come “dolorosa”, che avviene perché vi è un fattore biologico organicistico lesivo in atto o perché un evento interno-esterno noto viene percepito, per l’esperienza
Indirizzo per la corrispondenza:
William Raffaeli
E-mail: [email protected]
28
psico-sensoriale maturata, quale fattore lesivo dell’integrità
e quindi doloroso. Questo identifica perché un comportamento secondario a fattori dolorosi o ritenuti fonte di dolore generi espressioni cliniche e psicologiche differenti nelle
persone per intensità e significato socio-individuale, senza
tuttavia inficiare il fatto che la sensazione sia reale nella sua
identità biologica di sofferenza (2).
È interessante notare come già nel 1773 il conte Pietro
Verri nel suo “Discorso sull’indole del piacere e del dolore”, che fa parte delle “Opere filosofiche ed economiche”,
ci introducesse al tema con queste parole: “La sensibilità
dell’uomo, il grande arcano, al quale è stata ridotta come a
generale principio ogni azione della fisica sopra di noi, si divide, e scompone, in due elementi, e sono amor del piacere
e fuga del dolore…”.
Nell’era moderna è stato reso evidente come l’esperienza dolorosa consti di una parte percettiva (nocicezione), che
costituisce la modalità sensoriale e permette la ricezione e
il trasporto di stimoli potenzialmente lesivi per l’organismo
al sistema nervoso centrale, e di una parte esperienziale (individuale), la componente psichica (o meglio di elaborazione
individuale-culturale-emotiva), connessa alla percezione di
una sensazione spiacevole.
È ampiamente noto come il dolore abbia un ruolo fondamentale nel preservare l’integrità di un individuo, giacché
lo protegge da ogni elemento nocivo interno e/o esterno;
esso rappresenta un indispensabile “campanello d’allarme”
dell’aggressione all’omeostasi dell’individuo; ma è certo che
questo sia sempre vero? o meglio che sia esaustivo di ogni
funzione del dolore?
Il dolore può essere esso stesso fattore di lesività delle
funzioni biologiche senza che alcun elemento aggredisca
e danneggi l’individuo, divenendo dunque un elemento di
patologia? È questo un tema introdotto nel dibattito alla fine
degli anni ’90, ma che già era stato da noi affrontato nel 1992
(3-5), interrogandoci sulla necessità di rimodellare il pensiero
corrente che vedeva il dolore nell’unicità di sintomo di danno, reputando che le acquisizioni sull’endogenicità del sistema oppioide e sulla sua complessità di relazioni endocrinoimmunitarie obbligassero a una riflessione su quanto fosse
necessario ricercare il principio di disfunzione con esito in
malattia autonoma del dolore. Un tassello di autonomia nosologica che andava a integrare le condizioni di neurolesività
esterna-interna secondarie a patologia (6).
Il dolore è fisiologico quando rappresenta una corretta risposta di adattamento, essenziale per evitare danni tissutali;
diventa patologico quando vi è un’alterata risposta di adattamento a un insulto tissutale, nervoso o non nervoso (7,8).
Il tema della persistenza cronica del dolore obbliga a una
diagnostica molto precisa nel descriverne le qualità e caratte-
ristiche per giungere a diagnosi differenziali tra evento in cui
persiste una causa primaria ed evento senza più alcuna causa
da ricercare; nel primo caso la cura del dolore dura il tempo
della guarigione della causa primaria, nel secondo caso è la
patologia dolorosa unica sindrome da curare per tutto il tempo in cui la stessa influisce sull’autonomia funzionale, emozionale e sociale del soggetto malato.
Questo comporta che il clinico prenda consapevolezza
della sua nuova missione, che non si esaurisce nella competenza tecnica di una procedura, ma nell’indagare, con una
semeiotica e laboratoristica specialistica, i processi di diagnosi e cura, per una gestione clinica che detti comportamenti
di presa in carico su cui s’inseriscono la rimodulazione del
concetto di esito, gli strumenti di monitoraggio sulle azioni
terapeutiche e la consapevolezza di una condivisione di ogni
scelta tra tutti i soggetti che devono viverne le conseguenze
per il lungo tempo della malattia. È il dolore cronico la pietra
angolare di misura del nostro sapere, la condizione morbosa
cui si devono rivolgere le nostre attenzioni nel costruire una
scuola di disciplina specialistica: patologia che genera comorbidità e dunque una condizione morbosa a impatto sia
individuale che sociale (9).
Il dolore cronico: complessità socio-economicoculturale
Il dolore cronico rappresenta un complesso problema
socio-sanitario, ed è una delle condizioni più costose e
studiate nella nostra società (10-12). Tuttavia, la gestione
del dolore è per lo più inadeguata, e ciò è dovuto sia a
motivi medici ma anche, e soprattutto, socio-culturali,
quali lo scarso riconoscimento del dolore come problema
sanitario, i pregiudizi che limitano un accesso adeguato e
corretto all’utilizzo dei farmaci oppioidi e, non da ultimo,
la non adeguata formazione accademica.
A testimonianza di ciò un’indagine condotta nel 2006 ha
portato alla luce dati preoccupanti: circa il 19% della popolazione adulta europea riferiva di soffrire di dolore cronico,
della durata superiore ai 5 mesi, di intensità moderata (NRS >
5), e circa il 40% dei pazienti riferiva un non adeguato trattamento della propria sintomatologia dolorosa (13).
Reid e colleghi, nel confermare i dati di prevalenza del dolore cronico e il suo enorme impatto socio-economico (14),
hanno anche evidenziato la mancanza di dati di alta qualità
sulla prevalenza e sui costi del dolore cronico in Europa e
questo è in parte dovuto al fatto che il dolore cronico molto
spesso non è considerato una patologia a sé stante, ma meramente un sintomo.
Infine il “peso” esercitato dal dolore cronico sulla società
deriva anche dai costi diretti e indiretti che esso genera; ad
esempio, è stato stimato che la lombalgia cronica determini
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una spesa di 1096 €/persona/anno in Germania e 1431 €/
persona/anno in Francia (15).
Tutti questi dati non solo delineano l’enormità del problema, ma anche la sua complessità; infatti un trattamento inadeguato e costoso origina prevalentemente dalla difficoltà insita nella corretta diagnosi fisiopatologica del dolore cronico,
ma anche dall’incompleta conoscenza dei farmaci analgesici.
Dolore cronico: complessità diagnostico-terapeutica
Il dolore cronico riconosce diversi e complessi meccanismi fisiopatologici la cui individuazione richiede specifiche
competenze e conoscenze.
Il trattamento, inoltre, si deve necessariamente avvalere di
approfondite conoscenze farmacologiche che permettano di
fare ricorso a un approccio che nella maggior parte dei casi
è multimodale e rivolto ai diversi meccanismi fisiopatologici
sottostanti una specifica sindrome dolorosa.
Scopo primario dell’intervento terapeutico non deve essere
tanto un esito favorevole, ossia il sollievo dal dolore, ma termometro del nostro agire è la capacità di “gestire” il paziente nella
sua interezza e complessità, nell’evoluzione della patologia, con la
capacità di affrontare recrudescenze ed evoluzioni della patologia
stessa al fine di garantire un “outcome” positivo in termini di sintomatologia, qualità di vita, funzionalità psicologica e sociale.
Un ulteriore fattore di complessità gestionale risiede
nel fatto che la letteratura mostra che esistono aree di so-
29
vrapposizione anatomica tra le strutture cerebrali coinvolte
nel processo nocicettivo e alcune regioni corticali deputate all’elaborazione dell’informazione in specifici domini
cognitivi (16-18). Tuttavia, gli esiti delle ricerche non consentono la definizione di un rapporto di causalità diretta tra
dolore e deficit cognitivi in ragione dell’interazione di altri
fattori quali la durata, il tipo, la localizzazione e l’intensità
del dolore stesso, la comorbidità con diverse psicopatologie
(es. depressione, ansia), l’eventuale assunzione di farmaci,
nonché il contributo di variabili demografiche di rilievo
come l’età e il livello di istruzione (19).
E infine un interessante corollario della problematica
dolore-cognizione è rappresentato dai possibili effetti collaterali di natura neuropsicologica conseguenti all’assunzione di farmaci oppioidi impiegati nel trattamento del dolore
cronico. Le differenze nella struttura chimica, l’affinità verso specifici recettori e le caratteristiche farmacocinetiche
dei diversi oppioidi potrebbero determinare effetti collaterali clinicamente differenti, inclusi quelli inerenti alla sfera
cognitiva (20).
A testimonianza della complessità diagnostico-terapeutica sopra delineata possiamo citare il dolore centrale
post-ictale, che presenta ancora oggi una forte disomogeneità di letteratura per ciò che riguarda sia la sua incidenza
epidemiologica sia la caratterizzazione del quadro clinico;
questo avviene sia perché l’analisi della patologia è effettua-
30
ta in tempi differenti della malattia, da specialisti diversi che
tendono a caratterizzare le componenti cliniche a loro più
familiari, sia perché la variabilità del quadro, a seconda del
tempo di valutazione, può determinare la presenza o meno
di alcune condizioni di patologia dolorosa (21,22).
I dolori muscoloscheletrici nella popolazione anziana
rappresentano un’altra impegnativa sfida diagnostica e
gestionale; in questa fragile categoria di pazienti, in considerazione della notevole prevalenza di problemi sociali,
psicologici, affettivi, cognitivi, risulta evidente come un
approccio basato esclusivamente sulla valutazione del sintomo dolore e della singola malattia risulti inadeguato, ma
sia necessaria una valutazione globale di tutte le aree problematiche del paziente.
Il fisiologico declino delle funzioni di alcuni organi,
quali reni e fegato, può comportare un’alterazione della
farmacologia degli analgesici e quindi dell’inizio di azione,
dell’eliminazione e dell’emivita dei farmaci. Comorbidità e
politrattamenti farmacologici aumentano la possibilità di
interazioni tra farmaci e di eventi avversi, quali confusione
e depressione respiratoria, che possono avere conseguenze
serie in un paziente già fragile (23).
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2. Tsuji T, Inui K, Kojima S, Kakigi R. Multiple pathways for noxious
information in the human spinal cord. Pain. 2006;123(3):322-31.
3. Raffaeli W. Livelli plasmatici di β-endorfina in dipendenti
da oppiacei. Giornale di Neuropsicofarmacologia 1983; 2.
4 Provinciali M, Di Stefano G, Raffaeli W, et al. Evaluation of
NK and LAK cell activities in neoplastic patients during treatment
with morphine. Int J Neurosci. 1991;59(1-3):127-33.
5. Raffaeli W. Oppioidi: meccanismi d’azione ed effetti su altre funzioni biologiche. International Journal of Pain Therapy
1994;4:135-46.
6. Raffaeli W. Il dolore. L’antalgologia: storia di una scienza
medica. Atti II Congresso Nazionale SICD, 1992.
7. Cruccu G, Raffaeli W, Sabato A, Zucco F. Il dolore e le sue componenti. Milano: Medica Editoria e Diff usione Scientifica, 2002.
8. Raffaeli W. Il dolore come Malattia. Rimini: Edizioni ISAL, 1997.
9. Mannion RJ, Woolf CJ. Pain mechanisms and management:
a central perspective. Clin J Pain. 2000;16 (3 Suppl):S144-56.
10. Pizzo PA, Clark NM. Alleviating suffering 101-pain relief in
the United States. N Engl J Med. 2012;366(3):197-9.
11. Gupta A, Mehdi A, Duwell M, Sinha A. Evidence-based
review of the pharmacoeconomics related to the management of
chronic nonmalignant pain. J Pain Palliat Care Pharmacother.
2010;24(2):152-6
12. Dagenais S, Caro J, Haldeman S. A systematic review of low
back pain cost of illness studies in the United States and internationally. Spine J. 2008;8(1):8-20.
13. Breivik H, Collett B, Ventafridda V, et al. Survey of chronic
Conclusioni
Il dolore in generale, e il dolore cronico in particolare,
rappresentano dunque un problema socio-culturale e sanitario importante e attuale; la comprensione di questa entità nosologica, dei suoi meccanismi, delle sue interazioni
richiede competenze e conoscenze specifiche ma anche lo
schieramento di forze multidisciplinari in fase sia diagnostica sia terapeutica per una corretta visione del paziente nella
sua interezza e una gestione efficace.
oral communications
31
Proceedings of the
th
h
6 Meeting SIMPAR (Study in
Multidisciplinary Pain Research)
Rome, March 28-29, 2014
Oral Communications
BASIC SCIENCE
01. Adrenergic Pain Pathway: Central Role of COMT
Inna Belfer
Departments of Anesthesiology and Human Genetics,
University of Pittsburgh, Pittsburgh, PA, USA
Adrenergic pathways play an important role in
pathophysiology of pain and analgesia. Cutaneous
adrenergic receptors (ARs) contribute to sympathetically
maintained pain (e.g., Complex Regional Pain Syndrome,
post-herpetic neuralgia), alpha-2-adrenoceptor agonists
can activate regional and spinal analgesia, and chronic
administration of β-adrenergic receptor antagonist
propranolol reduces the severity of arthritis and joint
responses to injury. β2- and β3ARs are uniquely positioned
to promote peripheral and central sensitization by way of
proinflammatory cytokines and nitric oxide. Although
the complex network of relationships that exists between
peripheral, spinal, and central βARs and downstream
signaling molecules and their relevance to persistent pain
is not fully understood, key players in these adrenergic
pathways have been identified. Evidence from animal
and human studies shows that enzymes regulating the
bioavailability of catecholamines influence persistent pain.
One of them is catechol-O-methyltransferase (COMT)
that metabolizes epinephrine, norepinephrine, and
dopamine, and is involved in several biological functions,
including pain perception and stress response. Complex
persistent pain conditions are due, in large part, to
diminished activity of COMT, which results in elevated
levels of catecholamines and increased activity of β2/3adrenergic receptors. Low COMT activity also leads to
increased sensitivity to experimental painful stimulation,
for example, depressed COMT activity results in enhanced
mechanical and thermal pain sensitivity. This phenomenon
is completely blocked by the nonselective β-adrenergic
antagonist propranolol or by the combined administration
of selective β2- and β3-adrenergic antagonists, while
administration of β1-adrenergic, α-adrenergic, or
dopaminergic receptor antagonists fail to alter COMTdependent pain sensitivity. Thus, β2/3-adrenergic
mechanism is most likely underlying the influence of
COMT on pain.
The gene encoding the COMT enzyme (COMT) has
functional polymorphisms that contribute to the interindividual variability in human pain phenotypes such as
pain sensitivity, chronicity, severity and response to pain
medicine. The most studied SNP in the COMT gene is the
rs4680, also known as Val158Met that leads to a three- to
four-fold reduced activity of the COMT enzyme. The Met
allele is associated with low enzymatic activity and low
protein stability. There are three very common haplotypes
consisting of four SNPs (rs6269, rs4633, rs4818 and rs4680
– Val158Met) covering almost entirely COMT region and
accounting for 96% of its genetic diversity. These haplotype
alleles correlate with even more profound change in COMT
activity (up to twenty-fold difference). Studies showed
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that COMT functional genetic variation is associated with
fibromyalgia, Temporomandibular Joint Disorder onset,
experimental pain sensitivity and morphine efficacy in
cancer pain treatment. Current hypothesis suggests that
high COMT activity is a risk factor for neuropathic pain
while low COMT activity is a risk factor for nociceptive
pain. Therefore COMT genotype might be a predictor for
the development of each type of pain. Recent evidence
demonstrated that COMT effects on pain (both in animals
and humans) are modality- and sex-specific. Moreover, there
is an interaction between COMT haplotypes, gender and
stress affecting response to pain that may explain previous
negative findings or replication failures. These findings are
particularly important for future studies that will aim to
investigate the effect of COMT haplotypes on different pain
phenotypes. They may also have clinical relevance in terms
of prediction of risk of painful disorders and prevention in
target patients.
Since COMT contributes to pain via β2/3-adrenergic
mechanism it is plausible to suggest that pain conditions
resulting from low COMT activity and/or elevated
catecholamine levels can be treated with pharmacological
agents that block both β2- and β3-adrenergic receptors.
Furthermore, COMT genotype may predict who is going
to benefit from such treatment. To test this hypothesis, a
double-blind, placebo-controlled, two-period crossover
pilot study of efficacy of propranolol, a nonselective
β-adrenergic antagonist that is widely used clinically
for treatment of hypertension, was conducted in female
patients with chronic orofacial pain. A considerable
beneficial effect of propranolol on pain perception was
noted in subjects not carrying ‘COMT high activity’
haplotype alleles, a diminished benefit was observed
in the heterozygotes, and no benefit was noted in the
homozygotes for this allele. These findings corroborate
that COMT gene polymorphisms contribute to the variable
pharmacodynamic responses to propranolol in patients
with chronic musculoskeletal pain, probably as a result of
variation in baseline levels of β2/β3-adrenergic signaling.
Furthermore, β2/β3-adrenergic receptor antagonists will
probably be effective in treating other human chronic pain
conditions, based on patient’s COMT genetic makeup and
resulting COMT enzyme activity.
The contribution of β2ARs to enhanced pain sensitivity
is in line with results from previous studies demonstrating
that epinephrine activates β2ARs located on primary
afferent nociceptors and produces hyperalgesia. Common
variants of the human β2AR gene (ADRB2), coding for
differences in receptor expression and internalization, are
associated with the development of chronic orofacial pain.
2ARs also contribute to the development of opioid-induced
hyperalgesia, a syndrome characterized by increased
sensitivity to noxious stimuli following acute and chronic
opioid administration. β2-adrenergic receptor stimulation
mechanism may explain the observed alterations in
COMT-dependent pain sensitivity and μ-opioid responses.
Overall, suppressing β2/3-adrenergic systems attenuates
pain by reducing the activity of catecholamines that
engage peripheral and/or central processes to promote
mechanical allodynia and thermal hyperalgesia and the
development of acute COMT-dependent pain sensitivity.
Elevated levels of norepinephrine and epinephrine,
resulting from depressed COMT activity, activate β2/3ARs
to produce heightened pain sensitivity. These findings
have important clinical implications, suggesting that β2and β3AR antagonists may benefit patients suffering from
pain conditions resulting from low COMT activity and/or
elevated catecholamine levels.
02. Chronic Pain as a Complex Disease: How We Can
Find New Targets
Inna Belfer
Departments of Anesthesiology and Human Genetics, University of
Pittsburgh, Pittsburgh, PA, USA
Chronic and persistent pain costs approximately $1
trillion per year in medical treatment, loss of productivity
and disability payments in developed countries. It results
in more than 20% of visits to physicians and 10% of drug
sales. Chronic pain is a complex disease rather than a
symptom since its development and maintenance often do
not correlate with “causing pathology”, have own risk factors
and multifactorial nature. Studies showed that chronicity of
pain is influenced by many factors including psychological
and personality-related (e.g., previous pain experiences,
emotionality, temperament, cognition, somatization and
catastrophizing, presence of acute and chronic stressful life
events, fatigue, anxiety, fear, boredom and anticipation of
more pain), socioeconomic (e.g., social support, acceptance,
incentives, education, occupation and quality of life),
cultural (e.g., ethnicity/race, religion), demographic (e.g.,
age, gender, life style and habits), clinical and medical
(e.g., patient’s knowledge of the diagnosis, disease-related
variables, treatment outcome, operative procedures or the
degree of tissue trauma). The relationships among these
factors are also multifaceted and largely understudied.
Treatment of chronic pain is always challenging due to
the diversity of underlying mechanisms for each chronic
pain condition, unpredictability of pain course and intensity
oral communications
and great inter-individual variability in pain perception
and response to analgesia. Large epidemiological studies
evaluated the role of many "environmental” factors as
predictors of chronic pain and discovered some of them
independently and/or through interaction predicting
the likelihood of chronic pain onset or severity in certain
patients’ groups. Unfortunately, results of treatment
interventions targeting these risk factors have yielded
mixed picture suggesting that there may be other important
factors that have not been examined.
Genetic approaches applied to pain research may help
identify important biological factors that may contribute
to the risk for or protection against pain chronicity and
recurrence. Indeed, many “pain candidate genes” have been
established using animal studies and then tested in human
pain research. Moreover, some of the identified genetic
risk factors contributing to pain phenotypes in humans
are maintained across multiple species demonstrating
extraordinary conservation of nociception and pain
behavior. Another line of evidence on genetic mechanisms
controlling pain comes from animal and human (twin)
studies on heritability of experimental pain phenotypes
and clinical painful conditions. It was found that most types
of chronic clinical pain have high heritability estimates
indicating a large portion of variance in pain phenotypes
due to genetic influence (e.g., 50% heritability for migraine,
tension-type headache and chronic widespread pain,
more than 35% for back and neck pain, and around 25%
for irritable bowel syndrome). High heritability of pain
phenotype can either result from large contributions of one
or several “major genes”, or small contributions of many.
Genetic studies of common chronic painful conditions
over the last decade have utilized mostly candidate gene
approach based on previous research in animal models and
human linkage studies of rare “Mendelian” pain disorders.
These studies revealed over hundred novel targets for future
painkillers. Since genes encoding these promising target
molecules may have sex- and modality-specific effects on
pain and analgesia, these findings provide a new rationale
for personalized pain medicine and pain management
based on individual genetic makeup. Due to the complex
nature of chronic pain new standards for pain assessment
and characterization have been implemented in genetic
studies that reduce sample phenotypic heterogeneity and
allow uncovering hidden genetic contributions. Deep and
comprehensive phenotyping of chronic pain patients as
well as advanced analytical methods may solve the old
problem of non-replication of genetic association studies
and help the correct interpretation of genetic data. These
studies provide both rationale and methodology for the
33
only unbiased genetic approach, genome-wide association
studies (GWAS) that will lead to identification of “human
pain genome” with all key players, their interactions and
signaling pathways.
Recent studies demonstrate that interactions among
genes, psychosocial and psychophysical factors shape
chronic pain experience and analgesic response, and
genetic and psychological combinations are predictive of
chronic pain phenotypes. Such combinations represent
another novel target for treatment in patients at risk.
This is especially true for pain phenotypes for which the
physical causes are clear, such as pain caused by laboratory
stimuli, surgery or nerve injury. A longer-term goal of
large-scale genetic epidemiology studies is to unravel
the causes of common pain conditions for which there
are no obvious structural lesions, such as fibromyalgia,
chronic tension-type headache, irritable bowel syndrome,
temporomandibular disorders and low back pain. A
systematic approach to the molecular epidemiology of pain
might accelerate the development of new treatments for
pain and its co-morbidities, including depression, anxiety,
insomnia and cognitive dysfunction. Modern genetics
and genomics provide with powerful tools allowing to
investigate shared biological processes that are common to
all individuals (e.g., molecular pathways of nociception), and
to dissect the genetic basis for inter-individual differences
in pain susceptibility, chronicity, behavior, and pathology.
Understanding the genetic basis of these differences is
critical to elucidating the molecular basis of pain sensitivity,
variable responses to analgesic drugs, and, ultimately,
to individualized treatment of pain and improved public
health.
03. Pharmacokinetic and Drug Response Predictability
in Pain Management
Pål Klepstad
Department of Intensive Care Medicine, St Olav’s University
Hospital, Trondheim, Norway
Opioids are the primary medications used to
relieve severe cancer pain. The pharmacology, both
pharmacokinetics and pharmacodynamics, of opioid
analgesics is complicated. This relates to large
interindividual variability in opioid metabolisms, to that
some metabolites are active while some are inactive, to
variability in drug distribution, to variability in absorption,
and, finally, to that opioid pharmacodynamics vary. Also to
define the clinical outcome for which opioid pharmacology
should be assessed in relation to is problematic.
oral communications
34
Opioids metabolism shows a large interindividual
variability. In cancer pain patients the variability of serum
concentrations of morphine is 10-fold the variability
in morphine doses 1. Similar variability exists for other
opioids 2. The variable metabolism of the opioids may
be caused by several factors. Morphine renal function
strongly influences the elimination of the active metabolite
morphine-6-glucuronide. Other factors such as age,
weight and concomitant medications may also influence
morphine metabolism, but the findings are inconsistent
across studies. For most other opioids, such as fentanyl
and oxycodone, renal function is not important, while
drug-drug interactions influencing the CYP-450 enzyme
activity alter drug metabolism 3. The clinical implications
are less studied, but physicians should be aware of some
specific drugs; antifungal agents and macrolides are two
examples for which start or stop the medication can change
opioid pharmacokinetics and effects. However, despite
knowledge about several potential factors influencing
opioid metabolism, generally, in studies on opioid
pharmacokinetics the observed clinical factors only explain
a minor part of the variability of metabolism. Thus, other
hereto-unknown factors are important determinants for
opioid metabolism.
The influence from variable metabolism is different for
different opioids. For most opioids such as fentanyl and
oxycodone the drug is metabolized to inactive substances.
Thus, increased metabolism gives less clinical efficacy.
However, for some opioids, morphine and codeine as the
most frequently used examples, the metabolites, morphine6-glucuronide and morphine, respectively, are more active
than the given drug. For these opioids increased metabolism
will result in increased clinical effects.
In order to use serum concentrations of a drug to predict
response two conditions must be met. First, the clinical
relevant outcome must be defined. Second, there has to be
a robust relationship between serum concentrations and
the selected clinical outcome.
The clinical outcome for drug response prediction
after administration of opioids is not obvious. Despite
that pain seems to be the obvious choice, this still renders
much discussion about which target should be chosen.
What should be the instrument for measuring pain; verbal
descriptors, numeric scales or pain items included in
health-related quality of life questionnaires? What should
be the time frame for assessing pain; pain now, pain last 24
hours or pain last week? What should be defined as clinical
acceptable pain relief; less than 4 on a 0-10 numeric rate
scale, patient global satisfaction or another measure? Should
episodic pain be measured? 4 Furthermore, patients may fail
to obtain pain relief not because of lack of analgesic efficacy
after achieving a defined effective serum concentration level
but due to the fact that the needed dose increments are not
possible due to adverse effects. Therefore, meaningful drug
monitoring and prediction of clinical opioid efficacy must
also address opioid effects other than pain.
The other limiting factor related to a potential drug
monitoring for opioids is that there is no clear relationship
between serum concentrations and clinical effects 5. Studies
repeatedly show that there are large pharmacodynamic
variabilities and that clinical or demographic factors fail to
explain most of these variations. This variability suggests that
patients have in-born properties that give variable response
to opioids. However, while early studies showed promising
results, later large scale studies and meta-analysis failed to
find a basis for pharmacogenetic guided opioid dosing 6, 7.
In conclusion, the evidence for applying pharmacokinetic
knowledge in order to plan opioid therapy is limited. Some
exceptions exist such as the profound influence from
renal failure on the elimination of the active morphine
metabolite, morphine-6-glucuronide, which argue against
the use of morphine in patients with renal failure, and the
known influence from variability in the CYP2D6 gene on
codeine efficacy.
References
1. Klepstad P, Dale O, Kaasa S, et al. Influences on serum
concentrations of morphine, M6G and M3G during routine clinical
drug monitoring: A prospective survey in 300 adult cancer patients.
Acta Anaesthesiol Scand. 2003;47:725-31.
2. Andreassen TN, Klepstad P, Davies A, et al. Influences on the
pharmacokinetics of oxycodone: a multicentre cross-sectional study
in 439 adult cancer patients. Eur J Clin Pharmacol. 2011;67:493-506.
3. Fladvad T, Klepstad P, Langaas M, et al. Variability in
UDP-glucuronosyltransferase genes and morphine metabolism.
Observations from a cross-sectional multicenter study in advanced
cancer patients with pain. Pharmacogenet Genomics. 2013; 23; 117-26.
4. Kaasa S, Apolone G, Klepstad P, et al. Expert conference on
cancer pain assessment and classification--the need for international
consensus: working proposals on international standards. BMJ
Support Palliat Care. 2011;1:281-7.
5. Klepstad P, Borchgrevink PC, Dale O, et al. Routine drug
monitoring of serum concentrations of morphine, morphine-3glucuronide and morphine-6-glucuronide do not predict clinical
observations in cancer patients. Palliat Med. 2003; 17:679-87.
6. Klepstad P, Fladvad T, Skorpen F, et al. Influence from genetic
variability on opioid use for cancer pain: a European genetic association
study of 2294 cancer pain patients. Pain. 2011;152:1139-45.
7. Walter C, Lötsch J. Meta-analysis of the relevance of the OPRM1
118A>G genetic variant for pain treatment. Pain. 2009; 146:270-5.
oral communications
04. GABAergic Control of Chronic Pain States
Hanns Ulrich Zeilhofer
Institute of Pharmacoloy and Toxicology, University of Zurich,
Institute of Pharmaceutical Sciences, ETH Zurich, Switzerland
Increasing evidence indicates that diminished synaptic
inhibition in the spinal cord contributes to chronic pain
syndromes through a variety of different mechanisms.
Drugs facilitating the activation of GABA A receptors
should be well-suited to correct for this loss of inhibition.
Such drugs have turned out to be extremely successful
in a variety of CNS diseases including anxiety, epilepsy,
sleep disorders, and spasticity. However, attempts to use
such drugs as analgesics have not been successful so far.
Over the last ten years, we have dissected the molecular
details of the spinal control of nociception by GABA A
receptors. GABA A receptors are heteropentameric
ligand gated chloride permeable ion channels. Nineteen
mammalian genes encode GABA A receptor subunits.
Most GABA A receptors are composed of two α subunits,
two β subunits and one γ2 subunit. The mammalian
genome contains six genes encoding GABA A receptor
α subunits, three genes encoding β subunits and three
genes for γ subunits. The benzodiazepine-sensitivity
of GABA A receptors is determined by the type of α
subunit harbored in the receptor. Benzodiazepinesensitive GABA A receptors contain an α1, α2, α3, or α5
subunit, while benzodiazepine-insensitive receptors lack
these subunits and contain instead α4 or α6. We have
used GABA A receptor point-mutated mice, in which
one or more of these α subunits have been rendered
benzodiazepine-insensitive, to assess whether specific
activation of certain GABA A receptor subtypes can induce
analgesic or antihyperalgesic effects and whether such an
effect can be separated from undesired effects of classical
GABAergic drugs.
We have verified this concept in a large series of ex vivo
electrophysiological and in vivo behavioral experiments
involving GABA A receptor mutated mice and different
models of chronic neuropathic and inflammatory pain.
Proof of concept evidence for the feasibility of our
approach has in addition been obtained from in vivo
experiments using GABAergic drugs (benzodiazepine
site agonists) with an improved (yet still not optimal)
selectivity profile.
In wild-type mice, we found that injection of
benzodiazepines into the spinal canal reduces thermal
and mechanical hyperalgesia, and allodynia in mice with
neuropathic pain (neuropathy induced through a peripheral
nerve injury) or inflammatory pain (cutaneous inflammation
35
induced with zymosan A). This antihyperalgesic action
occurred without confounding sedative effects. Using
GABA A receptor point-mutated mice, in which one subunit
has been rendered benzodiazepine-insensitive, we found
that diazepam-induced antihyperalgesic action requires
α2-GABA A receptors (GABA A receptors containing α2
subunits). α3-GABA A receptors and α5-GABA A receptors
also contributed but to lesser extents. Importantly, α1GABA A receptors, which mediate the sedative and amnestic
effects, did not contribute.
The strong antihyperalgesic action by α2-GABA A
receptors achieved in our preclinical studies contrasts
to the lack of clear analgesic/antihyperalgesic actions
of classical benzodiazepines in human patients. To
address this apparent discrepancy we examined the dose
dependence of sedation mediated by α1-GABA A receptors
in the brain and antihyperalgesia occurring through
spinal α2-GABA A receptors. To this end, we compared
the dose and receptor occupancy dependence of sedation
in mice, in which only α1-GABA A receptors were left
benzodiazepine-sensitive, with that of antihyperalgesia
in mice, in which only α2-GABA A receptors remained
benzodiazepine-sensitive. Sedation and antihyperalgesia
differed dramatically in their dose dependences and
in the degree of receptor occupancy required to elicit
both actions. Significant antihyperalgesia was only
reached at doses (receptor occupancies) which cause
an almost saturating sedative effect. Antihyperalgesic
doses of classical benzodiazepines would therefore
cause maximum sedation before eliciting significant
antihyperalgesia. Clinically useful antihyperalgesia will
therefore only be achievable with benzodiazepine site
agonists exhibiting a high selectivity for α2- over α1GABA A receptors.
We have meanwhile tested a number of different
benzodiazepine site agonists with improved subtype
selectivity/reduced sedative effects in a variety of pain
models. These include L-838,417, SL-651498, and HZ166. Other groups have tested additional compounds such
as NS11394. Collectively, the results from these studies
indicate that compounds with full agonistic activity at
α2-GABA A receptors and a high α2- over α1-GABA A
receptor selectivity exert significant antihyperalgesia in
the absence of sedation.
In summary, it is hence likely that drugs specifically
targeting α2-GABA A receptors will exert analgesic (and
anxiolytic) effects in vivo without inducing sedation or
amnesia, and that such drugs should not be liable to
tolerance development. It can be expected that these
drugs will in addition probably also exert muscle relaxant
oral communications
36
effects, which, like the anxiolytic actions, might be
beneficial in chronic pain patients.
References
Di Lio A, Benke D, Besson M, et al. HZ166, a novel GABA A
receptor subtype-selective benzodiazepine site ligand, is
antihyperalgesic in mouse models of inflammatory and neuropathic
pain. Neuropharmacol. 2011;60:626-32.
Knabl J, Witschi R, Hösl K, et al. Reversal of pathological
pain through specific spinal GABA A receptor subtypes. Nature.
2008;451:330-4.
Knabl J, Zeilhofer UB, Crestani F, et al. Genuine antihyperalgesia
by systemic diazepam revealed by experiments in GABA A receptor
point-mutated mice. Pain. 2009:141:237-43.
Paul J, Yévenes GE, Benke D, et al. Antihyperalgesia by 2-GABA A
receptors occurs via a genuine spinal action and does not involve
supraspinal sites. Neuropsychopharmacology. 2014;39(2):477-87.
Witschi R, Punnakkal P, Paul J, et al. Presynaptic α2-GABA A
receptors in primary afferent depolarization and spinal pain control.
J Neurosci. 2011;31:8134-42.
05. New Neuroimaging Diagnosis of Low Back Pain
Dino Samartzis
Department of Orthopaedics and Traumatology, The University
of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, China
Low back pain is the world’s most debilitating condition,
affecting every population. Treatment of low back pain can
entail conservative measures or surgical interventions,
often with dubious outcomes. Although the development
of low back pain is multifactorial, potential for ‘imaging
pain’ may hold substantial clinical applications and impact.
The following lecture will address the complexities of low
back pain diagnosis, and the current and novel imaging
technologies that have been developed that further
elaborate upon the development of low back pain, pain
generators and predictive utility of such imaging for future
pain development/severity.
06. Glycomics and Glycoproteomics as a Tool to
Diagnose Pain
Gordan Lauc
University of Zagreb, Faculty of Pharmacy and Biochemistry
& Genos Glycobiology Laboratory, Zagreb, Croatia
Glycosylation is an essential posttranslational modification1
generated by a complex biosynthetic pathway comprising
hundreds of glycosyltransferases, glycosidases, transcriptional
factors, ion channels and other proteins2. This process
results in the creation of branched oligosaccharide chains,
called glycans, which become integral part of proteins and
significantly contribute to their structure and function3.
Since glycans are created without the genetic template,
alternative glycosylation creates an additional layer of protein
complexity by combining genetic variability with past and
present environmental factors4. Despite the absence of a
direct genetic template, the proportion of different glycan
structures in the total plasma glycome is up to 50% heritable5.
Individual variability in glycome composition is very large5-7,
but glycosylation of an individual protein seems to be under
strong genetic influence, with the heritability of the IgG
glycome (the only glycoprotein for which heritability has
been investigated) being up to 80%8. Structural details of the
attached glycans are of great physiological significance and
many pathological conditions are associated with various
types of glycan changes9, 10.
Since the onset of genome wide association studies
(GWAS) some 6 years ago, thousands of genetic loci
have been associated with different diseases and traits.
Pain was not an exception and several studies identified
a number of genetic loci which associated with
different forms of pain. However, in the last few years,
and particularly after recent publication of the results
from the ENCODE project, it is becoming increasingly
clear that GWAS studies are only a beginning of
understanding complex human diseases. Hypotheses
generated in these studies (associations between
genetic loci and diseases) need to be put in the context
of the complex biology of life and a more complex
approach that combines different ‘omics phenotyping
technologies is needed to understand mechanisms
behind chronic pain and perform patient stratification
that transcends genomics.
Generation and transmission of pain signals, as well
as the response to pain alleviating drugs depend on the
action of various membrane receptors. Nearly all these
receptors are glycosylated and glycans significantly
affect their action. Individual variation in glycosylation of
membrane receptors has not been adequately addressed,
but if it mirrors variation in the soluble proteins, it is
expected to significantly affect generation, progression
and alleviation of pain. Since glycans are not directly
encoded in the genome, both genetic and environmental
factors are expected to participate in the creation of
an individual predisposition and sensitivity to pain.
Through a recently initiated PAIN-Omics initiative
within the 7th European Framework Programme for
Research and Innovation, we are performing multiple
oral communications
‘omics phenotyping of a large number of patients aiming
to develop methods for their efficient stratification.
References
1. Opdenakker G, Rudd PM, Ponting CP, Dwek RA. Concepts and
principles of glycobiology. FASEB J. 1993;7:1330-7.
2. Moremen KW, Tiemeyer M, Nairn AV. Vertebrate protein
glycosylation: diversity, synthesis and function. Nat Rev Mol Cell
Biol. 2012;13:448-62.
3. Skropeta D. The effect of individual N-glycans on enzyme
activity. Bioorg Med Chem. 2009;17:2645-53.
4. Lauc G, Zoldoš V. Protein glycosylation – an evolutionary
crossroad between genes and environment. Mol Biosyst.
2010;6:2373-9.
5. Knežević A, Polasek O, Gornik O, et al. Variability, heritability
and environmental determinants of human plasma N-glycome.
J Proteome Res. 2009;8:694-701.
6. Pucic M, Knezević A, Vidic J, et al. High throughput isolation
and glycosylation analysis of IgG-variability and heritability of the IgG
glycome in three isolated human populations. Mol Cell Proteomics.
2011: 10:M111.010090.
7. Pučić M, Pinto S, Novokmet M, et al. Common aberrations
from normal human N-glycan plasma profi le. Glycobiology. 2010:
20, 970-5.
8. Menni C, Keser T, Mangino M, et al. Glycosylation of
Immunoglobulin G: Role of genetic and epigenetic influences. PLoS
One, 2013;8(12):e82558.
9. Alavi A, Axford JS. Sweet and sour: the impact of sugars on
disease. Rheumatology (Oxford) 2008;47:760-70.
10. Gornik O, Pavic T, Lauc G. Alternative glycosylation modulates
function of IgG and other proteins – Implications on evolution and
disease. Biochim Biophys Act. 2012: 1820:1318-26.
07. Strategies for New Target Development of Pain
Therapeutics
Stephen P. Arneric
Neuroscience Discovery, Eli Lilly & Company, Indianapolis,
IN, USA
Two cornerstones of drug development are: 1) medicines
are intended to restore and improve Quality of Life
(QoL) for patients; and 2) patient QoL is influenced by a
medication’s impact on efficacy, safety, and activities [i.e.,
capabilities] of daily living (ADLs). Increasingly, regulators
shape the definition of an ‘effective’ medicine, and require
objective scientific evidence for this ‘effectiveness’ via health
technology assessments [Health Outcome ‘Effectiveness’
= Efficacy + Safety + QoL]. Third Party Payers (TPPs) are
gatekeepers to the access of new ‘valued medicine’ where
37
value = health outcome effectiveness/costs to deliver the
outcomes. A major challenge remains on how to objectively
measure outcomes related to QoL (currently not allowed
in label claims as they are often patient reported, and nonverifiable) and subjective efficacy outcomes (e.g., fatigue,
mood, and pain).
One of the major challenges to the field of developing
new valued medicines is overcoming the difficulty in
assessing subjective efficacy measures and gauging its
direct effect on QoL of the elderly with chronic pain 1.
The elderly (> 65 yrs old) are the fastest growing segment
of the global population 2 , yet very few of the drugs used
to treat patients in this age segment have been adequately
studied in well controlled clinical studies. By 2030 our
increased life expectancy will result in a ‘tsunami’ of
elderly that will flood the global health care systems
requiring treatment relief options commensurate with
their unique needs, and tailored to improve the quality
of their extended life. By 2040 nearly 25% of the US
population will be over age 65, with similar trends in
other major markets.
Analgesic development today should begin with a
clear vision of what pain relief should look like in 2030.
Key activities required to delivering valued analgesics
include: 1) creating clinical instruments that objectively
verify effectiveness 3; 2) overcoming factors contributing
to failed clinical trials; 3) advancing our understanding
of the physiologic basis of patient stratification and
treatment tailoring; and 4) leveraging the recent
molecular advances in understanding pain signaling. A
cogent example is the biased ligand signaling for opioid
receptors4 derived from the Nobel Prize winning work of
Robert Lefkowitz 5.
References
1. Arneric SP, Laird JM, Chappell AS, Kennedy JD. Tailoring
chronic pain treatments for the elderly: are we prepared for the
challenge? Drug Discov Today. 2014;19(1):8-17.
2. Vos T. et al. Years lived with disability (YLDs) for 1160 sequelae
of 289 diseases and injuries 1990–2010: a systematic analysis for the
Global Burden of Disease Study 2010. Lancet 2012;380:2163-96.
3. Kaye JA, Maxwell SA, Mattek N, et al. Intelligent Systems for
Assessing Aging Changes: home-based, unobtrusive and continuous
assessment of aging. J Gerontol B Psychol Sci Soc Sci. 2011;66
(Suppl. 1):i180-i90.
4. Raehal KM, Schmid CL, Groer CE, Bohn LM. Functional
selectivity at the μ-opioid receptor: implications for understanding
opioid analgesia and tolerance. Pharmacol Rev. 2011;63(4):1001-19.
5. Lefkowitz RJ. A brief history of G-protein coupled receptors
(Nobel Lecture). Angew Chem Int Ed Engl. 2013;52:6366-78.
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08. Opioid Receptor Isoforms: Structure and Function
M. Convertino1, A. Samoshkin2, W. Maixner2, L. Diatchenko2,3,
N.V. Dokholyan1,2
1
Department of Biochemistry and Biophysics, University of
North Carolina at Chapel Hill, Chapel Hill, NC, USA; 2Center of
Neurosensory Disorders, University of North Carolina at Chapel
Hill, Chapel Hill, NC, USA; 3Alan Edwards Centre for Research
on Pain, McGill University, Montreal, Quebec, Canada
Opioids are the most prescribed and effective drugs for
treatment of moderate and severe pain. They act as agonists
towards μ-opioid receptor (mOR), a G Protein-Coupled
Receptor (GPCR) that mediates the perception of noxious
stimuli at the level of the central nervous system.1 More than
30% of patients treated with opioids do not show adequate
pain relief,2,3 thus there is a compelling need of novel, safe
and effective analgesic drugs. An accurate description of the
interactions occurring at the molecular level between mOR
and classical opioids, i.e. morphine, can provide valuable
insights about the structural and dynamical mechanisms
underlying the activation of the receptor. Moreover, such
information can be effectively exploited to initiate new
drug discovery endeavors. With this aim, starting from
the recently available crystallographic coordinates of
mOR chimera,4 we have reconstructed the structure of
the receptor using discrete molecular dynamics (DMD)
simulations. 5,6 Docking calculations7,8 and extensive
molecular dynamics (MD) simulations9 have been adopted
to identify a stable binding mode of morphine in mOR (Fig.
1A). Our computational model of morphine-mOR complex
has been validated by site-directed mutagenesis coupled
with radioligand binding and functional assays.10
Further, we have observed a ligand-dependent increase
in the conformational flexibility of third intracellular loop of
mOR. These findings are consistent with the notion of the
critical role of mOR intracellular loop in coupling with the
intracellular trimeric G protein complex, and in the initiation
of the signaling cascade. We have also used our structural
model of mOR to blindly screen a library of ~1.2 million
compounds from the ZINC database11. Using AutoDock
docking algorithm12 and our in-house developed physicsbased scoring function MedusaScore,8 we retrieved 34
compounds predicted to be strong binders. The top three
candidates have been examined using biochemical assays.
One compound has shown high efficacy and potency. Post
hoc testing have revealed this compound to be nalmefene, a
potent mOR antagonist, currently used in clinic, thus further
validating our computational approach and structural model
of opioids receptor. However, clinical and pharmacological
studies have revealed that, despite their pharmacological
efficacy, the use of opioids in therapy is compromised by the
onset of severe side effects, the most important one being the
opioid-induced hyperalgesia (OIH).1 A recently discovered
spliced isoform of mOR is directly involved in the generation
of an excitatory cellular response, leading to the onset of
OIH.13,14 It consists of six trans-membrane helices (6TMmOR) and it is localized at the level of endoplasmic reticulum.
We have developed a structural model of 6TM-mOR and
have performed extensive MD simulations9 of the apo- and
morphine-bound isoform. Antithetically to what observed in
wild-type mOR, the G-protein-interacting intracellular loop
of 6TM-mOR does not undergo ligand-dependent increase
of conformational flexibility. Moreover, because of the lack
of the N-terminal helix, 6TM-mOR cannot translocate from
the endoplasmic reticulum to the cell surface. Therefore,
we speculate that monomeric 6TM-mOR is not able to
activate any intracellular response. However in response
to morphine exposure, a strong increase in intracellular
calcium concentration is registered in cell over-expressing
6TM-mOR and β2 adrenergic receptor (b2AR).14 Using
immunofluorescence microscopy, we have observed that
6TM-mOR migrates from intracellular compartments to the
cell surface together with b2AR, upon prolonged exposure
to morphine. In addition, after administration of a b2AR
agonist (i.e., propranolol), 6TM-mOR undergoes agonist–
induced internalization jointly with b2AR. We hypothesize
that, upon chronic exposure to membrane-permeable
opioids, 6TM-mOR is able to heterodimerize with b2AR;
the newly formed 6TM/b2AR heterodimer migrates to
the cell surface and stimulates a non-G-protein-dependent
signaling pathway resulting in an increment of intracellular
calcium concentration and, ultimately, in an excitatory
cellular response. Using protein-protein docking15 and DMD
simulations, 5,6 we have developed a structural model of 6TMmOR/b2AR heterodimer that has been validated by means
of site-directed mutagenesis and immunofluorescence.
According to our structural model of 6TM-mOR/b2AR
heterodimer, helices five and six of the two GPCRs constitute
the surface of dimerization and allow the parallel alignment
of longitudinal axes and binding pockets of the two receptors.
The resulting geometry of the two receptors is consistent
with the general paradigm of activation of intracellular
signaling pathways upon binding of small molecules in the
extracellular binding sites. In conclusion, the development of
wild type and spliced mOR isoforms, as well as 6TM-mOR/
b2AR structural models, provides an effective elucidation of
the structural and dynamical mechanism of ligand-initiated
cell signaling leading to the development of OIH and serves
as a powerful tool for screening novel, more effective and
safer analgesics.
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39
Figure 1. μ-Opioid receptor (mOR) isoforms: structure and function.
(A) Stable binding mode of morphine in mOR as
determined by docking calculations and MD simulations.
(B) Virtual Screening strategy and results (adapted from
Ref.10). (C) Effect of the binding of morphine on the
stability of wild type and 6TM-mOR. (C,top) The binding
of morphine stabilizes the structure of wild type mOR
while increasing the motion of its third intracellular
loop (i3), which is known to interact with the G protein.
(C,low) 6TM-mOR results more stable than the wild type
isoform, and the binding of morphine further stabilizes
its structure. (D) Structural model of 6TM-mOR/b2AR
heterodimer as obtained by protein-protein docking.
6TM-mOR and b2AR are represented in green and
magenta, respectively.
References
1. Reisine T, Pasternak G. Opioid analgesics and antagonists.
In: Hardman JG, Limbird LE, Molinoff PB, et al. (eds). The
Pharmacological Basis of Therapeutics. 9th edn. New York: McGraw
Hill, 1996: 528-32.
2. Ballantyne JC, Shin NS Efficacy of opioids for chronic pain: a
review of the evidence. Clin J Pain. 2008;24:469-78.
3. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid
management for chronic noncancer pain. Cochrane Database Syst
Rev. 2010 Jan 20(1):CD006605;
4. Manglik A, Kruse AC, Kobilka TS, et al. Crystal structure of
the μ-opioid receptor bound to a morphinan antagonist. Nature
2012;485:321-5.
5. Dokholyan NV, Buldyrev SV, Stanley HE, Shakhnovich EI..
Discrete molecular dynamics studies of the folding of a protein-like
model. Fold Des. 1998;3:577-87.
6. Shirvanyants D, Ding F, Tsao D, et al. Discrete molecular
dynamics: an efficient and versatile simulation method for fine
protein characterization. J Phys Chem B. 2012;116:8375-82.
7. Ding F, Yin S, Dokholyan NV. Rapid flexible docking
using a stochastic rotamer library of ligands. J Chem Inf Model.
2010;50:1623-32.
8. Yin S, Biedermannova L, Vondrasek J, Dokholyan NV.
MedusaScore: an accurate force field-based scoring function for
virtual drug screening. J Chem Inf Model. 2008;48:1656-62.
9. Van der Spoel D, Lindahl E, Hess B, et al. GROMACS: fast,
flexible, and free. J Comput Chem. 2005;26:1701-18.
10. Serohijos AW, Yin S, Ding F, et al. Structural basis for μ-opioid
receptor binding and activation. Structure. 2011;19:1683-90.
11. Irwin JJ, Shoichet BK. ZINC--a free database of commercially
available compounds for virtual screening. J Chem Inf Model.
2005;45:177-82.
12. Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and
AutoDockTools4: Automated docking with selective receptor
flexibility. J Comput Chem. 2009;16:2785-91.
13. Shabalina SA, Zaykin DV, Gris P, et al. Expansion of the human
mu-opioid receptor gene architecture: novel functional variants.
Hum Mol Genet. 2009;18:1037-51.
14. Gris P, Gauthier J, Cheng P, et al. A novel alternatively spliced
isoform of the mu-opioid receptor: functional antagonism. Mol Pain.
2010;2:6-33.
15. Mintseris J, Pierce B, Wiehe K, et al. Integrating statistical
pair potentials into protein complex prediction. Proteins. 2007;69:
511-20.
09. A New Drug: What is Required to Make it
Possible. Bringing Patient Needs, Academic
Contributions, Outcome Selection and Regulatory
Guidance to Clinical Practice
René Allard
Global Clinical Development Grünenthal GmbH, Aachen, Germany
Two decades ago, systemic drugs indicated for pain
were assigned to mechanistic classes: the opioids, NSAIDs,
anticonvulsants 1. Opioids have been used for thousands
of years for the treatment of pain 2 and subject to narcotic
scheduling 3. Morphine is the archetypal analgesic for use in
oral communications
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moderate to severe pain 4. However, approximately 80% of the
world’s population does not have access to morphine for their
pain 3. In 20 to 40% of patients that are prescribed morphine
there are dose limiting side-effects with incompletely
controlled analgesia 5. There are many similarities between
morphine and the other μ-agonists but there is evidence that
their mode of action is not identical 6. As a consequence the
continued research into and further development of opioids
and other analgesics is essential in the understanding of
effective pain medication management.
From a clinical development perspective the generation
of data for marketing authorization requires multiple
questions to be satisfactorily addressed before regulators
issue a marketing authorization. Regulatory agency
decisions directly impact clinical development plans as
well as clinical practice. An example is the dichotomous
fibromyalgia decisions reached in the USA (NDA 22148) and Europe (Doc Ref EMEA/551181/2008). A CTD
(Common Technical Document) is compiled for regulatory
review before a new opioid is approved. Quality-of-life
evidence is collected for the Core Value Dossier prepared
for health technology assessments. Pain as the 5th vital sign
emphasized the importance of effectively managing pain 7
and pain is both a measure as part of the quality-of-life
questionnaires as well as for the indication. The 0 to 10
numerical rating scale being frequently used in hospitals.
However, even when pain is routinely captured in clinical
practice only 76 of 288 patients responded in a survey
regards their satisfaction with treatment 8. Recently it
has been postulated that the exclusive focus on pain relief
may paradoxically hinder pain treatment 9. How pain data
collection is incorporated in diabetes, in the UK, is via the
annual foot examination (National Institute for Clinical
Excellence – Clinical guideline 119; 2011).
Opioid availability across the globe is diverse (www.
painpolicy.wisc.edu). On a global level it is adventurous
to attempt any conclusion regarding opioid treatments
and how healthcare systems embrace opioid prescribing.
This highlights meticulous logistical planning of trials.
Societies have their own national narcotic drug policies
that cover aspects ranging from procurement, licensing and
distribution and dispensing to patients 10. Furthermore, for
the pharmacological treatment of dependence syndrome
only 70 countries have services that are operational, while
globally only 8% of injecting drug users receive therapy 3.
Clinical development plans attempt to incorporate as
many stakeholder aspects as possible. As with clinical
practice opioid development faces dynamic changes.
It is likely that pharmaco-genomics and other ‘-omics’
will eventually become routine. Both the EMA and
the FDA have issued guidelines for the incorporation
of pharmacogenomics into both clinical development
plans, e.g. EMA/CHMP/37646/2009, as well as the
post-marketing surveillance in the past 12 months
(Guideline on good pharmacovigilance practices Module V
EMA/838713/2011). A phenotype and genotype approach
in patient management highlighting the complementary
aspects of such an approach with the current state of
knowledge may serve as an example of how comprehensive
patient management could become 11. Genomic and other
biomarkers will continue to play an evolving role in drug
discovery and development. No one sponsor is likely to have
all the information necessary to characterize the utility of
a given biomarker (or set of markers). Regulatory agencies
may bring together multiple parties to discuss global issues
surrounding biomarkers of mutual interest 12. Within
opioid therapy this discussion is ongoing and is highlighted
by the multitude of publications on the polymorphism
of the OPRM1 A118G variant and others, where issues
concerning reproducibility and multiple endpoints are
unresolved. A clinical development approach that validates
biomarkers server multiple interest groups has been
proposed 13. This would be similar to OPPERA 14 and other
excellent academic initiated projects. However, the lack
of reproducibility of published drug target data is a major
concern to pharmaceutical companies as this consumes
vast internal resources and hinders rapid effective decision
in drug development 15.
In scientific discussions the focus is often on a particular
trial and specific outcomes. The discussion of individual trials
can be viewed from different perspectives but the discourse
highlights that there is a need to establish a platform to enable
knowledge sharing as well as a common understanding to
ensure best resource utilization in the healthcare system. In
several countries Health Technology Assessors, i.e. payers,
need to have additional requirements. An EMA workshop
to address the scientific needs of both the regulators and
the payers took place on November 26, 2013. Additional
initiatives are underway to close current gaps. An astute
awareness for the primary reason for a trial is paramount for
anyone interpreting or wishing to use the data for external
analyses. The introduction of innovations and tracking as
per commonly agreed principles are necessary to achieve a
successful shift from the solution-driven ‘bench to bedside’
to the need-driven ‘bedside to bench’ and back 16.
References
1. Chaplan SR et al. Drug Discovery and Development for Pain.
In: Kruger L, Light AR, editors. Translational Pain Research from
Mouse to Man. Boca Raton, FL: CRC Press, 2010.
oral communications
2. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology.
Pain Physician. 2008;11 (Suppl. 2):S133-S53.
3. WHO. Ensuring balance in national policies on controlled
substances. Guidance for availability and accessibility of controlled
medicines. Geneva, 2011.
4. Comerford D. Techniques of opioid administration. Anesthesia
and Intensive Care Medicine. 2007;9(1):21-6.
5. Davis MP, Walsh D, Lagman R, LeGrand SB. Controversies in
pharmacotherapy of pain management. Lancet Oncol. 2005;6:696-704.
6. Ross JR, Rutter D, Welsh K, et al. Clinical response to
morphine in cancer patients and genetic variation in candidate
genes. Pharmacogenomics J. 2005;5:324-36.
7. Joel LA. The fifth vital sign: pain. Am J Nurs. 1999;99(2):9.
8. Phillips S, Gift M, Gelot S, et al. Assessing the relationship
between the level of pain control and patient satisfaction. J Pain Res.
2013;6:683-89.
9. Lauwerier E, Van Damme S, Goubert L, et al. To control or
not? A motivational perspective on coping with pain. Acta Neurol
Belg. 2012;112(1):3-7.
10. Joranson DE, Ryan KM. Ensuring opioid availability: methods
and resources. J Pain Symptom Manage. 2007;33(5):527-32.
11. Ashley EA, Butte AJ, Wheeler MT, et al. Clinical assessment
incorporating a personal genome. Lancet. 2010;375(9725):1525-35.
12. Goodsaid FM, Amur S, Aubrecht J, et al. Voluntary exploratory
data submissions to the US FDA and the EMA: experience and
impact. Nat Rev Drug Discov. 2010;9(6):435-45.
13. Merlin T, Farah C, Schubert C, et al. Assessing personalized
medicines in Australia: a national framework for reviewing
codependent technologies. Med Decis Making. 2013;33(3):333-42.
14.Ohrbach R, Fillingim RB, Mulkey F, et al. Clinical findings and
pain symptoms as potential risk factors for chronic TMD: descriptive
data and empirically identified domains from the OPPERA casecontrol study. J Pain. 2011;12(11 Suppl):T27-45.
15. Prinz F, Schlange T, Asadullah K. Believe it or not: how much
can we rely on published data on potential drug targets? Nat Rev
Drug Discov. 2011;10(9):712.
16. Stone VI, Lane JP. Modeling technology innovation: how
science, engineering, and industry methods can combine to generate
beneficial socioeconomic impacts. Implement Sci. 2012;7:44.
10. OPRM1 in Clinical Pain Therapy
Viola Spahn
Department of Anesthesiology and Operative Intensive Care
Medicine, Charité Campus Benjamin Franklin, Berlin, Germany
Opioids are the gold standard for the treatment of severe
acute pain associated with trauma or surgery as well as
cancer pain. Most clinically used opioids act at mu-opioid
receptors (OPRM1), which belong to the family of G-protein
41
coupled receptors (GPCRs). Activation of OPRM1 results in
a dissociation of the inhibitory Gi/o-protein complex into
the Gα- and Gβγ-subunit, which then influence different
signaling cascades and effector proteins. Prominent
examples are the reduced activity of adenylyl cyclases (ACs),
calcium channels and sodium channels, and activation
of potassium channels, resulting in an inhibition of the
generation and transmission of impulses in nociceptive
peripheral and central neurons. Opioid receptors are
localized and can be activated along all levels of the neuraxis
including peripheral and central processes of primary
sensory neurons (nociceptors), spinal cord (interneurons,
projection neurons), brainstem, midbrain, and cortex.
The commonly available and clinically used opioid
drugs are mainly OPRM1 agonists (e.g. morphine, codeine,
methadone, fentanyl and its derivatives). Beside the beneficial
analgesic effect of OPRM1 activation there are some severe
side effects like respiratory depression, sedation, reward/
euphoria, nausea, urinary retention, biliary spasm and
constipation. Moreover, tolerance and physical dependence
may occur with prolonged administration of pure agonists,
and abrupt cessation or antagonist administration can
result in a withdrawal syndrome. This presents challenges
in the context of the treatment of chronic or longer lasting
pain states. Tolerance, for example, is characterized by
decreased drug efficacy with repeated administration of
the same dose, or by increasing doses needed to produce
the same effect. These opioid-induced adaptations occur at
multiple levels in the nervous system, beginning with direct
modulation of opioid receptor signaling and extending to
complex neuronal networks including learned behavior.
Another contemporary issue is the so called opioid induced
hyperalgesia. It is still under debate whether the associated
pain hypersensitivity is directly induced by opioids. A deeper
look into the available data reveals that most studies have in
fact shown withdrawal-induced hyperalgesia, a well-known
phenomenon following the abrupt cessation of opioids. At
ultra-high doses, occasionally encountered in extreme cancer
pain, singular cases of allodynia have been observed and
attributed to neuroexcitatory effects of opioid metabolites.
There is no conclusive evidence that hyperalgesia occurs
during the perioperative or chronic administration of regular
opioid doses in patients.
The clinical choice of a particular OPRM1 agonist or its
formulation is based on pharmacokinetic considerations
(route of administration, desired onset or duration,
lipophilicity) and on side effects associated with the
respective route of drug delivery. Systemically and spinally
administered opioids can produce similar side effects,
depending on dosage and rostral/systemic redistribution.
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For intrathecal application lipophilic drugs are preferred
because they are trapped in the spinal cord and less likely
to migrate to the brain within the cerebrospinal fluid. The
peripheral application of opioids (and other analgesics)
is an area of considerable interest because many chronic
pain syndromes depend to some degree on the peripheral
activation of primary afferent neurons.
Topically applied or locally injected opioids produce
analgesia by activating opioid receptors on primary afferent
neurons. This inhibits the excitability of nociceptors,
the propagation of action potentials and the release of
proinflammatory neuropeptides from sensory nerve
endings, resulting in analgesia and/or antiinflammatory
effects. Possible mechanisms underlying the efficacy
of peripheral opioids in inflammatory pain include
upregulation and accelerated centrifugal transport of
opioid receptors in sensory neurons, enhanced G-protein
coupling of peripheral opioid receptors, and disruption of
the perineural barrier facilitating access of opioid receptor
agonists to their receptors. Interestingly, endogenous
opioid peptides from immune cells within inflamed tissue
appear to produce additive/synergistic interactions rather
than tolerance at peripheral opioid receptors. Thus, it
would be attractive to develop novel opioid receptor ligands
acting exclusively in the peripheral nervous system without
centrally mediated side-effects. A common approach is
the use of hydrophilic compounds with minimal capability
to cross the blood–brain barrier. Peripheral restriction
was also achieved with glucuronidation, arylacetamide,
morphinan-based, triazaspiro and peptidic compounds.
In clinical studies peripherally restricted opioids
(morphine-6-glucuronide) have been shown to reduce
visceral and postoperative pain with limited central sideeffects and similar efficacy as conventional opioids. Current
research pursues the development of systemically applicable
opioids that do not permeate blood–brain or placental
barriers, aiming at the selective activation of peripheral opioid
receptors. Peripheral opioid administration is regularly used
and well documented in the case of perioperative intraarticular
morphine. Intraarticular morphine also produces analgesia
in chronic rheumatoid and osteoarthritis where its effect
was shown to be similarly potent to standard intraarticular
steroids and long lasting, possibly due to morphine's antiinflammatory activity. In numerous small clinical studies,
locally applied opioids (e.g. dermal formulations, gels) have
shown analgesic efficacy in the treatment of skin ulcers,
cystitis, cancer-related oral mucositis, corneal abrasion,
neuropathic pain and bone injury. No significant adverse
effects have been reported so far.
(Reviewed in and modified from Stein, 2013).
11. Human Genetics for Pain Drug Target Development
Luda Diatchenko
Alan Edwards Centre for Research on Pain, McGill University,
Montreal, Canada
Complex pain conditions are by definition attributable
to multiple genetic and environmental influences. Several
risk factors have been associated with these conditions. In
addition to demographic factors, two intrinsic phenotypic
domains associated with the risk of developing painful
musculoskeletal conditions include a pain amplification
domain (i.e., increased pain sensitivity) and a psychological
distress domain.
The relative importance of genetic factors in human
musculoskeletal pain conditions is becoming clearer
with reported heritability that is comparable to other
common disorders. For example, the heritability of neck
pain is estimated to be 44%, pain reported at any bodily
site is 46%, and clustering of symptoms associated with
fibromyalgia is 51%. Thus, it appears that about 50% of the
risk of developing common chronic pain conditions can be
substantially attributed to a patient’s genetic background.
Identification of genotypic markers of chronic pain has
substantial translational value. Findings from complex
cardiovascular disorders show that there is a substantial
overlap of the genetic loci of rare mutations causing
familial cardiovascular disorders with common genetic
variants identified in association studies from related
common cardiovascular disorders, and genetic variants
in pathways implicated in pharmacotherapy for these
disorders. An illustration of how the results from human
genetic associations can contribute to the understanding
and treatment of a common pain condition is presented
in Figure 1. Catechol-O-methyltransferase (COMT),
an enzyme responsible for degrading catecholamines,
represents a critical component regulating homeostasis in
response to physical and psychological stressors. A series
of recent human and animal studies have linked COMT
to pain perception. A genetic variation in the COMT gene
correlates with sensitivity to noxious stimuli in both human
and mouse, as well as the risk and severity of chronic pain
conditions. These findings have led to the discovery of new
drug targets in animal models that have been translated
into a novel pharmacological treatment for TMD.
Specifically, three major haplotypes of COMT, designated
as low pain sensitive (LPS), average pain sensitive (APS), and
high pain sensitive (HPS) have been identified based on a
carrier’s response to experimental pain stimuli. These three
haplotypes account for 11% of the variability to experimental
pain sensitivity in young women and are predictive of the
oral communications
risk of onset of a common musculoskeletal pain disorder
(i.e., temporomandibular disorder, or TMD). The LPS
haplotype produces higher levels of COMT enzymatic
activity than the APS or HPS haplotypes. Recent literature
review revealed that COMT haplotypes are consistently
associated with pain sensitivity in multiple studies.
The pharmacological inhibition of COMT in rats results
in mechanical and thermal hypersensitivity that is reversed
by the nonselective β-adrenergic antagonist propranolol,
or by the combined administration of selective β2- and
β3-adrenergic antagonists. In contrast, the administration
of β1-adrenergic, α-adrenergic, or dopaminergic receptor
antagonists fail to alter COMT-dependent pain sensitivity.
These data provide the first direct evidence that low
COMT activity leads to increased pain sensitivity via a β2/3adrenergic mechanism, and suggests that pain conditions
associated with low COMT activity and/or elevated
catecholamine levels can be treated with pharmacological
agents that block both β2- and β3-adrenergic receptors.
This finding led to the hypothesis that propranolol, a nonselective β-adrenergic antagonist which is widely used for
treatment of hypertension, may be an effective treatment
for chronic pain conditions in a manner that is dependent
on the subject’s COMT diplotype.
To test this hypothesis, a double-blind, placebocontrolled, two-period crossover pilot study of efficacy of
propranolol in 40 female patients suffering from TMD was
conducted. The outcomes of this study demonstrated that
propranolol, independent of COMT genotype, significantly
43
reduced a composite measure of clinical pain and showed
a trend towards decreasing experimental pressure and
heat pain ratings compared to placebo. When stratified
by the COMT high activity haplotype (LPS), a significant
beneficial effect of propranolol on pain perception was
noted in subjects not carrying this haplotype, a diminished
benefit was observed in the heterozygotes, and no benefit
was noted in the homozygotes. These findings corroborate
that COMT gene polymorphism contributes to the variable
pharmacodynamic responses to propranolol in patients
with chronic musculoskeletal pain.
Together, this sequence of discoveries provides an
excellent illustration of how a genetic marker identified in
human association studies can be investigated in cellular
molecular studies and confirmed in animal models, to
identify a putative drug that can be tested in a human
clinical trial for safety and efficacy. This process not only
identified selective ADRB2-ADRB3 antagonists as a new
target for treatment of chronic pain conditions, but also
provided evidence that COMT haplotypes can serve as
genetic predictors of treatment outcomes and permits the
identification of subgroups of patients who will benefit
from propranolol therapy. Although the initial clinical
pharmacogenetics studies have been conducted on a
TMD population, ADRB2-ADRB3 antagonists are very
likely to be effective in treating other musculoskeletal pain
conditions, and thus this approach may represent a general
example of how to identify novel drug targets and genetic
markers in future human musculoskeletal pain research.
Figure 1. The translational clock – a schematic representation of a novel and rapid approach to identification of new
therapeutic targets in commonly observed persistent pain conditions.
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44
12. New Developments in Inflammation: TRPV1
Mark A. Schumacher
Department of Anesthesiology & Perioperative Care, UCSF
School of Medicine and Medical Center, San Francisco, CA, USA
Physicians of ancient times faced challenges in pain
management that continue today. How to effectively
manage painful conditions arising from a range of
conditions and locations. Should treating the pain of a
tooth abscess be approached in the same way as that of
arthritis or trauma? Surprisingly, physicians of that era,
whether in Europe, Asia or the Americas, adopted the
use of similar plant derivatives based on their clinical
effectiveness that are now in the forefront of modern
analgesic development in the treatment of inflammatory
pain. Crude plant extracts or plant derived balms applied
to an inflamed tooth or joint of ancient times can still
be shown to provide pain relief today. We now know
that many of these preparations shared a common
feature; they contained the chemical entity (capsaicin
or resiniferatoxin) capable of activating/inactivating the
capsaicin receptor (TRPV1) as well as other nociceptive
functions of sensory nerves. Since those early days, our
knowledge has grown to the point that the molecular
basis of inflammatory pain transduction is within our
reach. This is exciting given its foundation was built on
clinical observations recorded thousands of years ago.
Fostered by the isolation of TRPV1 more than a decade
ago, subsequent experiments conducted on rodent
sensory neurons, cell lines expressing cloned TRPV1
and genetically modified mice have collectively revealed
the critical role TRPV1 serves in the development of
inflammatory pain. This review will provide a framework
to look beyond TRPV1 activation/desensitization by
capsaicin and examine how channel activation is also
modulated by a wide range of endogenous inflammatory
compounds and agents released in response to
cellular injury. They include an increasingly long list
of compounds representing many of the prominent
categories: Bradykinin, H+, ATP, Fatty acid derivatives,
products of arachidonic acid metabolism especially via
the lipoxygenase pathways, growth factors and reactive
aldehydes and oxygen species. Since these agents can
directly activate or sensitize nociceptors by activating/
lowering the thermal activation threshold of TRPV1
(from 43-45 oC to 34-37 oC), we will examine how the
development of selective high-affinity TRPV1 antagonists
represents a unique way to block nociceptor activation
under conditions of inflammation. New developments
in structural biology and pharmaceutical chemistry have
reinvigorated efforts to target TRPV1 for the development
of the next generation of analgesics. Moreover, in addition
to the blockade of de-novo endogenous inflammatory
molecules capable of activating and/or sensitizing TRPV1,
another emerging area of therapeutic targeting involves
limiting or blocking increased expression of nociceptive
receptors such as TRPV1 that may develop during
inflammation. Thus, inflammation-induced changes
in spinal and sensory neuronal plasticity that drive the
persistence of certain types of inflammatory pain could
be blocked or reversed with genomic targeting. Finally,
we will conclude by examining a model that integrates
what is known about TRPV1 structure, activation,
pharmacology and genomics to propose an innovative
plan for the treatment of inflammatory pain.
PERIOPERATIVE CARE
13. Current Challenges and Future Directions for
Outcomes Research in Perioperative Medicine
Edward R. Mariano
Department of Anesthesiology, Perioperative and Pain
Medicine; Stanford University School of Medicine,
Stanford, California, USA; and Department of Anesthesia,
Anesthesiology and Perioperative Care Service, VA Palo Alto
Health Care System, Palo Alto, CA 94304, USA
Since 2012, the American Society of Anesthesiologists
has promoted the Perioperative Surgical Home model
in which anesthesiologists function as leaders in the
coordination of perioperative care for surgical patients
to improve outcomes.1,2 While anesthesiologists
globally have had similar interests over the years, the
unifying challenge continues to be the selection of
outcomes and demonstration of improvement due to
the anesthesiologist’s role and/or choice of anesthetic
or analgesic technique. Since the types of outcomes and
frequency of occurrence vary widely, a comprehensive
discussion of perioperative outcomes is beyond the scope
of this summary. Therefore, this review will focus on
select anesthesiologist-driven factors related to acute pain
management and anesthetic technique on perioperative
outcomes and potential research directions.
Rare Outcomes and Big Data
For anesthesiologists, avoiding adverse events of
the lowest frequency (death, recall, and nerve injury)
receives highest priority with death ranking first among
oral communications
complications to avoid.3 Studies involving rare outcomes,
positive or negative, will invariably require accumulation
of ‘big data’. Such studies must either involve multiple
institutions over a long study period (if prospective) or access
data involving a large cohort of patients for retrospective
studies; these study designs involving longitudinal data
may also require advanced statistical methods.4 For
example, Memtsoudis and colleagues sought to evaluate
postoperative morbidity and mortality for lower extremity
joint arthroplasty patients in a recent study. 5 They utilized
a large nationwide administrative database maintained by
Premier Perspective, Inc. (Charlotte, NC, USA); the study
data were gathered from 382,236 patients in approximately
400 acute care hospitals throughout the United States over
4 years. 5 Other retrospective cohort studies comparing
the occurrence of perioperative complications such as
surgical site infections, cardiopulmonary morbidity, and
mortality have used the American College of Surgeons
National Surgical Quality Improvement Project (NSQIP).6-8
NSQIP originally started within the Veterans Health
Administration (VHA) system in the 1980s with a small
sample of hospitals; this project, which included public
reporting of outcomes data, eventually expanded to include
all VHA surgical facilities and others outside the VHA
system.9 Multi-center prospective registries such as the
SOS Regional Anesthesia Hotline10,11 and AURORA12,13
have been developed for outcomes research and have
reported the occurrence rates of rare complications related
to regional anesthesia. The disadvantages of these datadriven studies include lack of randomization introducing
potential bias, missing or incorrectly coded data, inability
to draw conclusions regarding causation, and restrictions
to access such as information security issues and/or cost
(e.g., the Premier database). However, these retrospective
cohort database studies may offer large samples sizes
and administrative data from actual ‘real world’ patients
over a longer period of time and may identify important
associations that influence clinical practice and generate
hypotheses for future prospective studies.
Anesthesia Type and Perioperative Mortality
Based on the study by Memtsoudis and colleagues,
overall 30-day mortality for lower extremity arthroplasty
patients is lower for patients who receive neuraxial and
combined neuraxial-general anesthesia compared to
general anesthesia alone. 5 In most categories, the rates of
occurrence of in-hospital complications are also lower for
the neuraxial and combined neuraxial-general anesthesia
groups vs. the general anesthesia group, and transfusion
requirements are lowest for the neuraxial group
45
compared to all other groups. 5 Studies using NSQIP have
reported no difference in 30-day mortality for carotid
endarterectomy patients associated with anesthetic
technique although regional anesthesia patients are
more likely to have a shorter operative time and nextday discharge;8 similarly, there is no difference in 30day mortality for endovascular aortic aneurysm repair
although general anesthesia patients are more likely to
have longer length of stay and pulmonary complications.14
Perioperative Analgesia and Cancer Recurrence
In a relatively small matched retrospective study,
Exadaktylos and colleagues have reported lower
rates of recurrence and metastasis for breast cancer
surgery patients who receive paravertebral analgesia
vs. conventional systemic opioids.15 Although the exact
mechanism was not well-understood at that time
(regional anesthesia vs. reduction in the use of anesthetic
agents and opioids), clinical and basic science research
in this area has grown rapidly and has demonstrated
mixed results. A follow-up study involving 503 patients
who underwent abdominal surgery for cancer and were
previously enrolled in a large multi-center clinical trial16
and a retrospective database study of 424 colorectal
cancer patients who underwent laparoscopic resection17
have not shown a difference in recurrence-free survival or
mortality. A recent meta-analysis including 14 prospective
and retrospective studies involving cancer patients
(colorectal, ovarian, breast, prostate, and hepatocellular)
demonstrates a positive association between epidural
analgesia and overall survival but no difference in
recurrence-free survival compared to general anesthesia
with opioid analgesia.18
Analgesic Technique and Persistent Postsurgical Pain
Chronic pain may develop after many common
operations including breast surgery, hernia repair,
thoracic surgery, and amputation and is associated with
severe acute pain in the postoperative period.19 While
regional analgesic techniques are effective for acute pain
management, currently-available data are inconclusive
with regard to their ability to prevent the development of
persistent postsurgical pain.20-22 There is an opportunity
to use larger databases to investigate this issue further.
Ultrasound and Patient Safety
In 2010, the American Society of Regional Anesthesia
and Pain Medicine published a series of articles
presenting the evidence basis for ultrasound in regional
anesthesia.23 According to the article focused on patient
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46
safety, evidence at the time suggested that ultrasound
may decrease the incidence of minor adverse events (e.g.,
hemidiaphragmatic paresis from interscalene block or
inadvertent vascular puncture), but serious complications
such as local anesthetic systemic toxicity (LAST) and
nerve injury did not occur at different rates based on
the nerve localization technique.24 Since then, a large
prospective multi-center registry study has shown that the
use of ultrasound in regional anesthesia does reduce the
incidence of LAST compared to traditional techniques.13
Similar methodology may be applied to other rare
complications associated with anesthetic interventions.
Perioperative Medicine and Health Care Costs
Approximately 31% of costs related to inpatient
perioperative care is attributable to the ward admission.25
Anesthesiologists as perioperative physicians have an
opportunity to influence the cost of surgical care by
decreasing hospital length of stay through effective pain
management and by developing coordinated multidisciplinary clinical pathways.26,27
References
1. Vetter TR, Goeddel LA, Boudreaux AM, et al. The Perioperative
Surgical Home: how can it make the case so everyone wins? BMC
Anesthesiology. 2013;13:6.
2. Vetter TR, Ivankova NV, Goeddel LA, et al. An analysis
of methodologies that can be used to validate if a Perioperative
Surgical Home improves the patient-centeredness, evidence-based
practice, quality, safety, and value of patient care. Anesthesiology.
2013;119(6):1261-74.
3. Macario A, Weinger M, Truong P, Lee M. Which clinical
anesthesia outcomes are both common and important to avoid? The
perspective of a panel of expert anesthesiologists. Anesth Analg.
1999;88(5):1085-91.
4. Ma Y, Mazumdar M, Memtsoudis SG. Beyond repeatedmeasures analysis of variance: advanced statistical methods for the
analysis of longitudinal data in anesthesia research. Reg Anesth Pain
Med. 2012;37(1):99-105.
5. Memtsoudis SG, Sun X, Chiu YL, et al. Perioperative
comparative effectiveness of anesthetic technique in orthopedic
patients. Anesthesiology. 2013;118(5):1046-1058.
6. Liu J, Ma C, Elkassabany N, et al. Neuraxial anesthesia decreases
postoperative systemic infection risk compared with general
anesthesia in knee arthroplasty. Anesth Analg. 2013;117(4):1010-16.
7. Radcliff TA, Henderson WG, Stoner TJ, et al. Patient risk factors,
operative care, and outcomes among older community-dwelling male
veterans with hip fracture. J Bone Joint Surg Am. 2008;90(1):34-42.
8. Schechter MA, Shortell CK, Scarborough JE. Regional versus
general anesthesia for carotid endarterectomy: the American College
of Surgeons National Surgical Quality Improvement Program
perspective. Surgery. 2012;152(3):309-14.
9. Ingraham AM, Richards KE, Hall BL, Ko CY. Quality
improvement in surgery: the American College of Surgeons National
Surgical Quality Improvement Program approach. Adv Surg.
2010;44:251-67.
10. Auroy Y, Benhamou D, Bargues L, et al. Major complications
of regional anesthesia in France: The SOS Regional Anesthesia
Hotline Service. Anesthesiology. 2002;97(5):1274-80.
11. Auroy Y, Narchi P, Messiah A, et al. Serious complications
related to regional anesthesia: results of a prospective survey in
France. Anesthesiology. 1997;87(3):479-86.
12. Barrington MJ, Watts SA, Gledhill SR, et al. Preliminary
results of the Australasian Regional Anaesthesia Collaboration: a
prospective audit of more than 7000 peripheral nerve and plexus
blocks for neurologic and other complications. Reg Anesth Pain
Med. 2009;34(6):534-41.
13. Barrington MJ, Kluger R. Ultrasound guidance reduces the
risk of local anesthetic systemic toxicity following peripheral nerve
blockade. Reg Anesth Pain Med. J 2013;38(4):289-97.
14. Edwards MS, Andrews JS, Edwards AF, et al. Results of
endovascular aortic aneurysm repair with general, regional, and
local/monitored anesthesia care in the American College of
Surgeons National Surgical Quality Improvement Program database.
J Vasc Surg. 2011;54(5):1273-82.
15. Exadaktylos AK, Buggy DJ, Moriarty DC, et al. Can anesthetic
technique for primary breast cancer surgery affect recurrence or
metastasis? Anesthesiology. 2006;105(4):660-4.
16. Myles PS, Peyton P, Silbert B, et al. Perioperative epidural
analgesia for major abdominal surgery for cancer and recurrencefree survival: randomised trial. BMJ. 2011;342:d1491.
17. Day A, Smith R, Jourdan I, et al. Retrospective analysis
of the effect of postoperative analgesia on survival in patients
after laparoscopic resection of colorectal cancer. Br J Anaesth.
2012;109(2):185-90.
18. Chen WK, Miao CH. The effect of anesthetic technique on
survival in human cancers: a meta-analysis of retrospective and
prospective studies. PloS one. 2013;8(2):e56540.
19. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain:
risk factors and prevention. Lancet. 2006;367(9522):1618-25.
20. Kairaluoma PM, Bachmann MS, Rosenberg PH, Pere PJ.
Preincisional paravertebral block reduces the prevalence of chronic
pain after breast surgery. Anesth Analg. 2006;103(3):703-8.
21. Schnabel A, Reichl SU, Kranke P, et al. Efficacy and safety of
paravertebral blocks in breast surgery: a meta-analysis of randomized
controlled trials. Br J Anaesth. 2010;105(6):842-52.
22. Wildgaard K, Ravn J, Kehlet H. Chronic post-thoracotomy
pain: a critical review of pathogenic mechanisms and strategies for
prevention. Eur J Cardiothorac Surg. 2009;36(1):170-80.
23. Neal JM, Brull R, Chan VW, et al. The ASRA evidence-based
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medicine assessment of ultrasound-guided regional anesthesia
and pain medicine: Executive summary. Reg Anesth Pain Med.
2010;35(2 Suppl):S1-9.
24. Neal JM. Ultrasound-guided regional anesthesia and patient
safety: An evidence-based analysis. Reg Anesth Pain Med. 2010;35(2
Suppl):S59-67.
25. Macario A, Vitez TS, Dunn B, McDonald T. Where are the
costs in perioperative care? Analysis of hospital costs and charges for
inpatient surgical care. Anesthesiology. 1995;83(6):1138-44.
26. Ilfeld BM, Mariano ER, Williams BA, et al. Hospitalization
costs of total knee arthroplasty with a continuous femoral nerve
block provided only in the hospital versus on an ambulatory basis: a
retrospective, case-control, cost-minimization analysis. Reg Anesth
Pain Med. 2007;32(1):46-54.
27. Jakobsen DH, Sonne E, Andreasen J, Kehlet H. Convalescence
after colonic surgery with fast-track vs conventional care. Colorectal
Dis. 2006;8(8):683-7.
14. Use of Regional Anesthesia Techniques to
Improve Rehabilitation Outcomes following Lower
Extremity Joint Replacement
Edward R. Mariano
Department of Anesthesiology, Perioperative and Pain Medicine;
Stanford University School of Medicine, Stanford, California,
USA; and Department of Anesthesia, Anesthesiology and
Perioperative Care Service, VA Palo Alto Health Care System,
Palo Alto, CA 94304, USA
Among Medicare beneficiaries in the United States,
the number of primary total knee arthroplasty (TKA)
procedures from 1991 to 2010 increased by 161.5%.1
Postoperative pain remains one of patients’ top concerns
when undergoing elective surgery 2 and can limit patients’
functional ability in the early postoperative period.3
Providing effective perioperative pain control has potential
longer-term implications since early rehabilitation may lead
to improvements in functional outcomes later on.4 With the
ability to select specific targets for local anesthetic injection
and infusion, regional anesthesia techniques, neuraxial and
peripheral, are commonly included in the perioperative
analgesic protocol for joint arthroplasty patients. 5-11 While
the data supporting the analgesic efficacy of regional
anesthesia techniques in this setting are strongly positive,
studies attempting to attribute functional outcome benefits
to regional anesthesia demonstrate mixed results.
The main challenge in assessing functional outcomes
following joint replacement is the selection of outcomes;
these can be divided into performance-based outcomes and
self-reported outcomes.12,13 Performance-based outcomes
47
are measurable and arguably more objective, although often
subject to effort. Examples of these outcomes and their
units of measure include joint range of motion in degrees
(e.g., flexion, extension, rotation); timed walking tests in
meters (e.g., 6 minute walking test [6MWT], 2 minute
walking test [2MWT]); muscle strength in units of force
using a dynamometer (e.g., maximum voluntary isometric
contraction [MVIC]); and timed up-and-go (TUG) in
minutes.12,13 Self-reported outcomes are typically surveybased; examples include the Western Ontario McMaster
Universities Osteoarthritis Index (WOMAC), Knee
Society Score, and Lower Extremity Functional Scale.12,13
Since patient perception of successful rehabilitation is
an important factor, self-reported outcomes should be
reported with performance-based outcomes.12 Another
important challenge when measuring and comparing
functional outcomes is that clinical pathways for joint
arthroplasty that integrate pain management (including
regional analgesia), physical therapy, nursing, and surgical
care are often specific to individual institutions, and
institutions may vary with respect to rehabilitation goals
and the timeline to achieve them.
Epidural Analgesia
Epidural analgesia has been used for perioperative
pain management in joint replacement patients since at
least the 1980s.14,15 In 1987, Raj and colleagues compared
postoperative systemic opioid analgesia to continuous
epidural analgesia (bupivacaine 0.25% at 6-15 ml/hr) for
TKA patients in a prospective non-randomized study.14
Although pain scores were lower in the epidural group,
not surprisingly a high proportion of these patients
experienced complete motor block of the lower extremities;
although the authors mention “rigorous passive exercises”,
specific rehabilitation outcomes were not reported.14 Later
studies have reported functional benefits associated with
continuous epidural analgesia, such as shorter time to
achieve ambulation distance and range of motion goals,
when compared to parenteral opioids alone.16 At institutions
where continuous epidural analgesia is currently employed
as part of a multimodal analgesic protocol, very low doses
of local anesthetic (e.g., 0.06% bupivacaine) in combination
with opioid are used in order to minimize motor block.17
Peripheral Nerve Blocks
The innervation of the knee is complex and involves
contributions from both the lumbar and sacral plexuses.
While epidural analgesia is effective, it is also associated with
clinically-significant side effects (e.g., nausea/vomiting and
motor block of the non-operative limb)5,18 and the potential
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48
for neuraxial hematoma in patients on pharmacologic
thromboprophylaxis.19 Thus, peripheral nerve block
options, either single-injection or continuous infusions,
have been explored for postoperative pain management.
Two early studies by Capdevila6 and Singelyn 20
have shown continuous femoral nerve block (FNB) to
provide comparable analgesia and physical therapy
outcome achievement with fewer side effects when
compared to epidural analgesia. Both of these studies
also demonstrated shorter hospital length of stay for the
regional anesthesia groups compared to an opioid-only
group,6,20 but hospitalization duration for these studies
was, on average, greater than what has been reported
in other studies.21 Triple-masked, placebo-controlled
randomized clinical trials have shown that CPNB can
shorten the time to achieve discharge criteria, including
100 m ambulation distance, for TKA 10,22 and total hip
arthroplasty (THA)9 patients, but actual hospital duration
was similar in these studies.
One of the interesting findings from the Singelyn study
was that regional anesthesia patients maintained a knee
flexion advantage over the opioid-only group at 6 week
follow-up;20 although this advantage did not remain at
3 months, this finding supported the potential for longterm functional improvement resulting from effective pain
management and early rehabilitation in the immediate
perioperative period.4 In a randomized comparison of
continuous FNB to local infiltration analgesia (LIA) for
TKA, the FNB group spent more time out of bed walking;
at 6 weeks, the FNB group showed more improvement in
performance-based (6MWT) and self-reported functional
outcome assessments.23 In contrast, the one year followup studies of randomized clinical trial subjects9,10,22 using
self-reported outcome measures for functional status
(WOMAC) did not show long-term improvement associated
with regional anesthesia techniques.24-27
The rehabilitation outcome measured in the immediate
postoperative period that correlates best with long-term
functional improvement is not yet established. Ambulation
distance is often measured by physical therapists and
included in discharge criteria.9,10,22 For institutions that
emphasize ambulation in their clinical pathway for lower
extremity joint arthroplasty, a major concern raised with
regard to FNBs is the potential association with increased
fall risk.28,29 In-hospital falls can lead to prolonged hospital
stays with higher costs and are associated with more
frequent postoperative complications, including serious
organ system dysfunction and death.30 With currentlyavailable local anesthetic solutions and typical doses,
perineural infusion does produce clinically-significant
quadriceps weakness when administered near the femoral
nerve or lumbar plexus.31,32 Since the local anesthetics
themselves cannot select sensory over motor nerves, 33
anesthesiologists have started exploring alternate nerve
block locations to minimize the risk of motor block and
maximize patient rehabilitation.
For TKA, a more distal nerve block location in
the adductor canal can provide effective analgesia
postoperatively34 and has been shown to better preserve
quadriceps strength compared to a FNB in both volunteers35
and clinical patients.11 While regional analgesic techniques
are often included in multimodal analgesic protocols along
with non-steroidal anti-inflammatory drugs (NSAIDs),
acetaminophen, and low-dose opioids,36 there is a growing
body of evidence to support the adductor canal block as
the regional analgesic technique of choice for promoting
postoperative ambulation.37,38
References
1. Cram P, Lu X, Kates SL, et al. Total knee arthroplasty volume,
utilization, and outcomes among Medicare beneficiaries, 1991-2010.
JAMA. 2012;308(12):1227-36.
2. Macario A, Weinger M, Carney S, Kim A. Which clinical
anesthesia outcomes are important to avoid? The perspective of
patients. Anesth Analg. 999;89(3):652-8.
3. Holm B, Kristensen MT, Myhrmann L, et al. The role of pain
for early rehabilitation in fast track total knee arthroplasty. Disabil
Rehabil. 2010;32(4):300-6.
4. Munin MC, Rudy TE, Glynn NW, et al. Early inpatient
rehabilitation after elective hip and knee arthroplasty. JAMA.
1998;279(11):847-52.
5. Barrington MJ, Olive D, Low K, et al. Continuous femoral
nerve blockade or epidural analgesia after total knee replacement:
a prospective randomized controlled trial. Anesth Analg.
2005;101(6):1824-9.
6. Capdevila X, Barthelet Y, Biboulet P, et al. Effects of
perioperative analgesic technique on the surgical outcome and
duration of rehabilitation after major knee surgery. Anesthesiology.
1999;91(1):8-15.
7. Chelly JE, Greger J, Gebhard R, et al. Continuous femoral
blocks improve recovery and outcome of patients undergoing total
knee arthroplasty. J Arthroplasty. 2001;16(4):436-45.
8. Hebl JR, Dilger JA, Byer DE, et al. A pre-emptive multimodal
pathway featuring peripheral nerve block improves perioperative
outcomes after major orthopedic surgery. Reg Anesth Pain Med.
2008;33(6):510-7.
9. Ilfeld BM, Ball ST, Gearen PF, et al. Ambulatory continuous
posterior lumbar plexus nerve blocks after hip arthroplasty: a
dual-center, randomized, triple-masked, placebo-controlled trial.
Anesthesiology. 2008;109(3):491-501.
oral communications
10. Ilfeld BM, Le LT, Meyer RS, et al. Ambulatory continuous
femoral nerve blocks decrease time to discharge readiness after
tricompartment total knee arthroplasty: a randomized, triple-masked,
placebo-controlled study. Anesthesiology. 2008;108(4):703-13.
11. Jaeger P, Zaric D, Fomsgaard JS, et al. Adductor canal block
versus femoral nerve block for analgesia after total knee arthroplasty:
a randomized, double-blind study. Reg Anesth Pain Med.
2013;38(6):526-32.
12. Choi S, Trang A, McCartney CJ. Reporting functional outcome
after knee arthroplasty and regional anesthesia: a methodological
primer. Reg Anesth Pain Med. 2013;38(4):340-9.
13. Bernucci F, Carli F. Functional outcome after major
orthopedic surgery: the role of regional anesthesia redefi ned. Curr
Opin Anaesthesiol. 2012;25(5):621-8.
14. Raj PP, Knarr DC, Vigdorth E, et al. Comparison of continuous
epidural infusion of a local anesthetic and administration of systemic
narcotics in the management of pain after total knee replacement
surgery. Anesth Analg. 1987;66(5):401-6.
15. Pettine KA, Wedel DJ, Cabanela ME, Weeks JL. The use of
epidural bupivacaine following total knee arthroplasty. Orthop Rev.
1989;18(8):894-901.
16. Mahoney OM, Noble PC, Davidson J, Tullos HS. The effect of
continuous epidural analgesia on postoperative pain, rehabilitation,
and duration of hospitalization in total knee arthroplasty. Clin
Orthop Relat Res. 1990(260):30-7.
17. YaDeau JT, Cahill JB, Zawadsky MW, et al. The effects of femoral
nerve blockade in conjunction with epidural analgesia after total knee
arthroplasty. Anesth Analg. 2005;101(3):891-5, table of contents.
18. Zaric D, Boysen K, Christiansen C, et al. A comparison
of epidural analgesia with combined continuous femoralsciatic nerve blocks after total knee replacement. Anesth Analg.
2006;102(4):1240-6.
19. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional
anesthesia in the patient receiving antithrombotic or thrombolytic
therapy: American Society of Regional Anesthesia and Pain Medicine
Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med.
2010;35(1):64-101.
20. Singelyn FJ, Deyaert M, Joris D, et al. Effects of intravenous
patient-controlled analgesia with morphine, continuous epidural
analgesia, and continuous three-in-one block on postoperative
pain and knee rehabilitation after unilateral total knee arthroplasty.
Anesth Analg. 1998;87(1):88-92.
21. Salinas FV, Liu SS, Mulroy MF. The effect of single-injection
femoral nerve block versus continuous femoral nerve block after total
knee arthroplasty on hospital length of stay and long-term functional
recovery within an established clinical pathway. Anesth Analg.
2006;102(4):1234-9.
22. Ilfeld BM, Mariano ER, Girard PJ, et al. A multicenter,
randomized, triple-masked, placebo-controlled trial of the effect of
ambulatory continuous femoral nerve blocks on discharge-readiness
49
following total knee arthroplasty in patients on general orthopaedic
wards. Pain. 2010;150(3):477-84.
23. Carli F, Clemente A, Asenjo JF, et al. Analgesia and functional
outcome after total knee arthroplasty: periarticular infi ltration vs
continuous femoral nerve block. Br J Anaesth. 2010;105(2):185-95.
24. Ilfeld BM, Shuster JJ, Theriaque DW, et al. Long-term pain,
stiff ness, and functional disability after total knee arthroplasty with
and without an extended ambulatory continuous femoral nerve
block: a prospective, 1-year follow-up of a multicenter, randomized,
triple-masked, placebo-controlled trial. Reg Anesth Pain Med.
2011;36(2):116-20.
25. Morin AM, Kratz CD, Eberhart LH, et al. Postoperative
analgesia and functional recovery after total-knee replacement:
comparison of a continuous posterior lumbar plexus (psoas
compartment) block, a continuous femoral nerve block, and the
combination of a continuous femoral and sciatic nerve block. Reg
Anesth Pain Med. 2005;30(5):434-45.
26. Ilfeld BM, Ball ST, Gearen PF, et al. Health-related quality
of life after hip arthroplasty with and without an extended-duration
continuous posterior lumbar plexus nerve block: a prospective, 1-year
follow-up of a randomized, triple-masked, placebo-controlled study.
Anesth Analg. 2009;109(2):586-91.
27. Ilfeld BM, Meyer RS, Le LT, et al. Health-related quality of
life after tricompartment knee arthroplasty with and without an
extended-duration continuous femoral nerve block: a prospective,
1-year follow-up of a randomized, triple-masked, placebo-controlled
study. Anesth Analg. 2009;108(4):1320-5.
28. Feibel RJ, Dervin GF, Kim PR, Beaule PE. Major complications
associated with femoral nerve catheters for knee arthroplasty: a word
of caution. J Arthroplasty. 2009;24(6 Suppl):132-7.
29. Ilfeld BM, Duke KB, Donohue MC. The association between
lower extremity continuous peripheral nerve blocks and patient falls
after knee and hip arthroplasty. Anesth Analg. 2010;111(6):1552-4.
30. Memtsoudis SG, Dy CJ, Ma Y, Chiu YL, Della Valle AG,
Mazumdar M. In-hospital patient falls after total joint arthroplasty:
incidence, demographics, and risk factors in the United States.
J Arthroplasty. 2012;27(6):823-8 e 821.
31. Charous MT, Madison SJ, Suresh PJ, et al. Continuous
femoral nerve blocks: varying local anesthetic delivery method (bolus
versus basal) to minimize quadriceps motor block while maintaining
sensory block. Anesthesiology. 2011;115(4):774-81.
32. Ilfeld BM, Moeller LK, Mariano ER, et al. Continuous
peripheral nerve blocks: is local anesthetic dose the only factor, or
do concentration and volume influence infusion effects as well?
Anesthesiology. 2010;112(2):347-54.
33. Ilfeld BM, Yaksh TL. The end of postoperative pain--a fastapproaching possibility? And, if so, will we be ready? Reg Anesth
Pain Med. 2009;34(2):85-7.
34. Lund J, Jenstrup MT, Jaeger P, Sorensen AM, Dahl JB.
Continuous adductor-canal-blockade for adjuvant post-operative
oral communications
50
analgesia after major knee surgery: preliminary results. Acta
Anaesthesiol Scand. Jan 2011;55(1):14-19.
35. Jaeger P, Nielsen ZJ, Henningsen MH, Hilsted KL, Mathiesen
O, Dahl JB. Adductor Canal Block versus Femoral Nerve Block and
Quadriceps Strength: A Randomized, Double-blind, Placebocontrolled, Crossover Study in Healthy Volunteers. Anesthesiology.
2013;118(2):409-15.
36. Practice guidelines for acute pain management in the
perioperative setting: an updated report by the American Society
of Anesthesiologists Task Force on Acute Pain Management.
37. Perlas A, Kirkham KR, Billing R, et al. The impact of analgesic
modality on early ambulation following total knee arthroplasty. Reg
Anesth Pain Med. 2013;38(4):334-9.
38. Mudumbai SC, Kim TE, Howard SK, et al. Continuous
adductor canal blocks are superior to continuous femoral nerve
blocks in promoting early ambulation after TKA. Clin Orthop Relat
Res. 2013 Jul 30. [Epub ahead of print].
15. Anticoagulation and Regional Anesthesia
Honorio T. Benzon
Northwestern University Feinberg School of Medicine, Chicago,
IL, USA
Antiplatelet therapy
Studies demonstrated the relative safety of neuraxial
blockade in combination with antiplatelet therapy1.
The case reports of intraspinal hematoma in patients
on aspirin and NSAIDs showed complicating factors
including concomitant heparin administration, epidural
angioma and technical difficulty in the performing the
procedure 2 . Clopidogrel is a prodrug, causes 65% platelet
inhibition, and has a good safety profile. There have been
reports of spinal hematoma in patients on clopidogrel2 .
The ASRA and the European guidelines concluded that
neuraxial blocks maybe performed in patients on aspirin1,3.
The Scandinavian guidelines recommended that aspirin be
discontinued for a week if the dose is greater than 1 gram a
day 4. For clopidogrel, the drug is to be discontinued for 7
days. There are case reports of neuraxial injection 5 days
after clopidogrel was stopped 5. If a neuraxial injection is to
be performed in a patient on clopidogrel before 7 days of
stoppage then a P2Y12 assay, or another point-of-care assay
of antiplatelet activity is recommended5.
Oral anticoagulants
Neuraxial procedure can be done within 24 hours of
warfarin intake1. A study showed that Factor VII levels are
acceptable, even with INRs up to 1.9, 12-14 hours after
warfarin is started6. Another study showed that it may
be acceptable to remove the epidural catheter on POD3
or 3 days after the warfarin is started, in the presence
of elevated INRs7. Unfortunately, concentrations of the
clotting factors were not determined7.
Intravenous heparin
Risk factors for the development of spinal hematoma
in patients who had lumbar puncture and subsequent
heparinization include the presence of blood during the
procedure, concomitant aspirin therapy, and heparinization
within 1 hour8. When intraoperative anticoagulation is
planned, there should be a 1 hour delay between needle
placement and heparin administration 1. The catheter should
be removed 1 hour before subsequent heparin administration
and 2 to 4 hours after the last heparin dose.
Subcutaneous heparin
Neuraxial techniques are not contraindicated during
subcutaneous mini-dose prophylaxis but the risk of bleeding
may be reduced by delay of the heparin administration until
after the block1. Three times a day s.c. heparin9 may result
in increased risk of bleeding10. In view of this increased
bleeding and in the absence of prospective studies, the ASRA
guidelines recommended that patients not receive TID s.c.
heparin when on epidural infusions1.
Low molecular weight heparin
Needle/catheter placement (or catheter removal)
should be performed at least 12 hours after the last
prophylactic dose of enoxaparin or 24 hours after higher
doses of enoxaparin (1 mg/kg every 12 hours), and 24
hours after dalteparin or tinzaparin1. The LMWH may
be administered 2 hours after the epidural catheter is
removed. However, a November 2013 FDA statement
recommended a 4 hour interval for enoxaparin; this was
based on internal reports from the drug manufacturer.
Fondaparinux
Fondaparinux is a synthetic anticoagulant that inhibits
Factor Xa. It has a half-life of 17 to 21 hours. ASRA
recommends against the use of fondaparinux in the presence
of an indwelling epidural catheter. Performance of neuraxial
techniques should occur under conditions utilized in clinical
trials (single needle pass, atraumatic needle placement,
avoidance of indwelling neuraxial catheters)1. A study showed
no complications in patients who had neuraxial injections11.
In this study, the catheters were removed 36 hours after the
last dose of fondaparinux and dosing was delayed for 12 hours
after the catheter was removed.
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51
Newer anticoagulants
Interval between stoppage of drug and neuraxial procedure
Rosencher recommended a two half-life interval
to have residual anticoagulation12 . The European and
Scandinavian guidelines recommended a two half-life
interval between the stoppage of the drug and neuraxial
injection3,4. It should be noted that after a drug is
administered, the following percentages of the drug
remain in the body at 1, 2, 3, 4, 5, and 6 half-lives: 50,
25, 12.5, 6.25, 3.125, and 1.5625% respectively13. Others
recommended five half-lives to assure almost complete
elimination of drug14-16. If necessary, LMWH bridge
therapy can be instituted and stopped 24 hours before
the neuraxial procedure.
For antiplatelets, 10 to 15% of the circulating platelet
pool is formed every day17, therefore there should be
adequate platelets 5 to 7 days after stopping the drug.
Resumption of drug after neuraxial procedure or removal of
epidural catheter
The European and Scandinavian guidelines recommended
8 hours, a time they considered for a clot to stabilize, minus
the peak effect of the drug3,4,12. Others recommended a 24- or
48-hour interval14,15,18,19.
Dabigatran etexilate
Dabigatran is an oral direct thrombin inhibitor. Peak
plasma levels occur in 2 hours, it has a half-life of 12-17
hours that may be doubled in patients with end-stage
renal disease. The 2 and 5 half-lives of the drug are 34h
(2d), and 85h (4d) respectively14. The PTT, dilute TT and
ECT are the recommended tests to monitor dabigatran’s
anticoagulant activity16,20,21. It can be reversed by charcoal
if given within 2 hours and by dialysis; an antibody is
under development.
Rivaroxaban
Rivaroxaban is an oral Factor Xa inhibitor. Its peak
effect occurs after one hour; duration of effect is 12 hours;
and half-life is 9 to 13 hours. The 2 and 5 half-lives of
the drug are 26h (1-2d), and 65h (3d) respectively14. PT
and Factor Xa assay can monitor rivaroxaban’s effect16,20.
Charcoal may be effective if given within 8 hours, 4-factor
PCC was shown to be effective in volunteers.
Apixaban
Apixaban is a Factor Xa inhibitor. Its peak effect is 1-2 hours,
half-life is 15 ± 8 hours. The 2 and 5 half-lives of the drug are
30h (2d), and 75h (3-4d) respectively14. Factor Xa assay and
dilute PT are the tests to monitor apixaban’s activity16,20,22,
there is no known reversal for apixaban at this time.
Prasugrel
Prasugrel is a prodrug similar to clopidogrel. Maximum
percent inhibition is 90% compared to 65% for clopidogrel.
It is less prone to drug-drug interactions and genetic
polymorphisms. The European guidelines recommended
7-10 days while the Scandinavian guidelines noted that 5
days is adequate3,4.
Ticagrelor
Unlike clopidogrel and prasugrel, ticagrelor is directacting and its antiplatelet effect is reversible. It causes
90% inhibition of the platelets. The European guidelines
recommended a 5 day interval between discontinuation of
the drug and subsequent neuraxial injection3.
Table. Time interval between discontinuation (dc) of drug and neuraxial injection and between catheter removal/manipulation
and resumption of drug
Drug
Drug dc & neuraxial injection Drug dc & neuraxial injection – Catheter removal & drug
– European guidelines
Scandinavian guidelines
resumption – European
guidelines
Catheter removal & drug
resumption – Scandinavian
guidelines
Dabigatran
Contraindicated
according to manufacturer
Data not available
6h
6h
Rivaroxaban
22-26h (1d)
18h (1d)
4-6h
4-6h
Apixaban
26-30h (2d)
Data not available
4-6h
6h
Prasugrel
7-10d
5d
6h
After catheter removal
Ticagrelor
5d
No recommendation
6h
After catheter removal
The European and Scandinavian guidelines were based on two half-lives of the drug wherein 25% of the drug still remains. A 5 half-life is
probably safer (see text). For resumption of drugs, others recommend 24 hours 15,18.
oral communications
52
References
1. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional
anesthesia in the patient receiving antithrombotic or thrombolytic
therapy: American Society of Regional Anesthesia and PainMedicine evidence-based guidelines (third edition). Reg Anesth Pain
Med. 2010;35:64-101.
2. Benzon HT, Wong HY, Siddiqui T, Ondra S. Caution in
performing epidural injections in patients on several antiplatelet
drugs. Anesthesiology. 1999;91:1558-9.
3. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional
anaesthesia and antithrombotic agents: recommendations of
the European Society of Anaesthesiology. Eur J Anaesthesiol.
2010;27:999-1015.
4. Breivik H, Bang U, Jalonen J, et al. Nordic guidelines for
neuraxial blocks in disturbed haemostasis from the Scandinavian
Society of Anaesthesiology and Intensive Care Medicine. Acta
Anaesthesiol Scand. 2010;54:16-41.
5. Benzon HT, McCarthy R, Benzon HA, et al. Determination of the
residual antiplatelet activity of clopidogrel. Br J Anaesth. 2011;107:966-71.
6. Benzon HT, Benzon HA, Kirby-Nolan M, et al. Factor VII levels
and risk factors for increased international normalized ratio in the
early phase of warfarin therapy. Anesthesiology. 2010;112:298-304.
7. Liu SS, Buvanendran A, Viscusi ER, et al. Uncomplicated
removal of epidural catheters in 4365 patients with International
Normalized Ratio greater than 1.4 during initiation of warfarin
therapy. Reg Anesth Pain Med. 2011;36:231-5.
8. Ruff DL, Dougherty JH. Complications of anticoagulation
followed by anticoagulation. Stroke. 1981;12:879-81.
9. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of
venous thromboembolism. American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines (8th Edition). Chest.
2008;133:381S-453S.
10. King CS, Holley AB, Jackson JL, et al. Twice versus three
times daily heparin dosing for thromboembolism prophylaxis in the
general population: A meta-analysis. Ches. 2007;131:507-16.
11. Singelyn FJ, Verheyen CC, Piovella F, et al. EXPERT Study
Investigators. The safety and efficacy of extended thromboprophylaxis
with fondaparinux after major orthopedic surgery of the lower limb
with or without a neuraxial or deep peripheral nerve catheter: the
EXPERT Study. Anesth Analg. 2007;105:1540-7.
12. Rosencher N, Bonnet MP, Sessler DI. Selected new
antithrombotic agents and neuraxial anesthesia for major orthopedic
surgery: management strategies. Anaesthesia. 2007;62:1154-60.
13. Greenblatt DJ. Elimination half-life of drugs. Value and
limitations. Ann Rev Med. 1985;36:421-7.
14. Benzon HT, Benzon HT, Avram J, et al. New oral anticoagulants
and regional anaesthesia. Br J Anaesth. 2013;111 Suppl 1:i96-i113.
15. Connolly G, Spyropoulos AC. Practical issues, limitations,
and periprocedural management of the NOAC’s. J Thromb
Thrombolysis. 2013;36:212-22.
16. Garcia D, Barrett YC, Ramaciotti E, Weitz JI. Laboratory
assessment of the anticoagulant effects of the next generation of oral
anticoagulants. J Thromb Haemost. 2013;11:245-52.
17. George JN. Platelets. Lancet 2000;335:1531-9.
18. Liew A, Douketis J. Perioperative management of patients
who are receiving a novel oral anticoagulant. Intern Emerg Med.
2013;8(6):477-84.
19. Baron TH, Kamath PS, McBane RD. Management of
antithrombotic therapy in patients undergoing invasive procedures.
N Engl J Med. 2013;368:2113-24.
20. Tripodi A. The laboratory and the direct oral anticoagulants.
Blood. 2013;121:4032-5.
21. Siegal DM, Cuker A. Reversal of novel oral anticoagulants in
patients with major bleeding. J Thromb Thrombolysis. 2013;35:391-8.
22. Siegal DM, Crowther MA. Acute management of bleeding in
patients on novel oral anticoagulants. Eur Heart J. 2013;34:489-500.
16. Regional Analgesia and Cancer Outcomes: What
are We Missing?
Juan Pablo Cata and Maria Fernanda Ramirez
Department of Anesthesiology and Perioperative Medicine. The
University of Texas, MD Anderson Cancer Center, Houston, TX, USA
Surgery remains as one of the first line treatment for
solid cancers. Although, tumor recurrences are related
to biology of the tumor, poor tumor responsiveness to
chemotherapy and/or radiation, micrometastasis and
circulating malignant cells present in the blood stream
before, during and after surgery 1, 2 . The only source of
defense against minimal residual disease proliferation
during the perioperative period is the immune system
because postoperative adjuvant therapy is given weeks
after surgery, thus leaving the patient vulnerable to
the growth and spread of minimal residual disease
during and immediately after surgery (the perioperative
period). Intra- and postoperatively there is an increased
release of angiogenesis factors, inflammatory mediators,
corticosteroids and catecholamines that will result in
diminished immune surveillance against cancer growth
and spread 3.
The immune system protects the host from tumor
development by modulation of a complex system of cells
and soluble mediators. For instance, the prostaglandin E2
plays a role in growth and invasiveness, therefore COX-2
inhibitors have been proposed as a new therapeutic tool
in neutralizing the tumorigenicity of cancer cells4. In
the perioperative period the administration of the COX
inhibitor etodolac to animals having surgery diminished
the number of metastasis 5. Interleukins can induce
oral communications
cancer cells death directly but most importantly they can
amplify the cell-mediated immunity by modulating the
function of natural killer (NK) cells, cytotoxic lymphocytes
(CD8), NK-T cell lymphocytes, antigen presenting cells
(APC) and helper lymphocytes (Th). A typical Th1 cell
response is characterized by production of interferonalpha (IFN-α), IL-2, tumor necrosis factor (TNF-α) and
it is highly effective in enhancing cellular immunity
necessary for tumor cell destruction. By contrast, a Th2
cell response is seen as an increase in IL-4, IL-5, IL-10
and IL-13, which mediate humoral response and promote
tumoral growth. In the perioperative period there is a
predominant response towards Th2 which might favor
tumor growth 6.
The innate immunity is also impaired after cancer
surgery. Our group and others have shown that the natural
killer (NK) cell function is decreased postoperatively
after cancer surgery 7. Opioids, volatile anaesthetics
and mediators of surgical stress are known to impair
the function of NK cells 3. All these findings indicate
that the perioperative period may be a key moment for
intervention and perhaps modifications of prognosis of
cancer patients.
Potential benefits of regional anesthesia
Regional anesthesia is associated with a decreased
consumption of opioids, volatile anesthetics and
partial control of the stress response depending
on the magnitude of the surgical insult. This
protective effect of regional anesthesia has been well
documented in some clinical scenarios such as lower
abdominal surgery but it seems to be insufficient to
blunt neuroendocrine response in upper abdominal
surgery which could be explained by the incomplete
neural blockage of afferent somatic pathways 8 . Local
anesthetics are the main drugs used in regional
anesthesia and analgesia for postoperative pain
management of orthopedic oncological patients 9.
These drugs have effect on cancer cells. For instance,
lidocaine decreases the ability of fibrosarcoma and
osteosarcoma cells to invade and form metastases 10.
Despite accumulated basic science data suggesting
the benefits of regional anesthesia in cancer, the
clinical evidence is conflicting. The studies that have
shown a clinical benefit in terms of cancer recurrence
are retrospective and suffer all possible bias of the
observational studies 11. Exadaktylos et al. suggested
that paravertebral anesthesia was associated with a
reduced cancer recurrence after breast cancer surgery 12 .
Similar results were found by Biki et al. in patients
53
with prostate cancer and regional analgesia 13. The
results of Cumming et al. and Gottschalk et al.
add important information to the debate because
they did not find any association between epidural
analgesia and cancer recurrence in patients with colon
cancer 14,15. A recent work from our group also indicates
no association between regional analgesia and improved
recurrence-free and overall survival 16. A recent metaanalysis concluded that epidural analgesia/anesthesia
is associated with improved overall survival in patients
with solid cancer specially in colon cancer patients,
however it did not found an association between
epidural anesthesia and cancer recurrence 17. These
findings are disappointing but not surprising due to
the fact that probably the benefit depends on multiple
variables including the type of cancer and the stage of
the disease among others.
At this point there are questions to be addressed
by the investigators of this fascinating topic. Certainly
could anesthesiologist seek a way to effectively change
cancer outcomes? Do all cancer patients benefit from this
intervention? Does the benefit depend on type of cancer,
stage or site of the primary tumor? Does the timing of
anesthetic/analgesic exposure matter? It is difficult to
speculate that regional anesthesia might in fact have
an impact on cancer recurrence, if such a phenomenon
actually occurs it is perhaps in early stages of cancer in
which the tumor burden is minimal and when the immune
system is able to accomplish its surveillance function at
best. Clearly randomized controlled trials are needed to test
the hypothesis whether regional anesthesia and analgesia
would improve recurrence-free and overall survival after
oncological surgery. Based on the current clinical evidence,
we cannot recommend the use of any particular anesthesia
technique to reduce cancer recurrence, however we would
urge surgeons and anesthesiologists to use regional
anesthesia to improve other perioperative outcomes such
as pain control, mobilization and opioid-related side effects
particularly in the early postoperative period.
Reference s
1. Bielack SS, Kempf-Bielack B, Delling G, et al. Prognostic
factors in high-grade osteosarcoma of the extremities or
trunk: an analysis of 1,702 patients treated on neoadjuvant
cooperative osteosarcoma study group protocols. J Clin
Oncology. 2002;20: 776-90 .
2. Wong IH, Chan AT, Johnson PJ. Quantitative analysis
of circulating tumor cells in peripheral blood of osteosarcoma
patients using osteoblast-specific messenger RNA markers: a pilot
study. Clin Cancer Res. 2000;6:2183-8.
oral communications
54
3. Cata JP, Gottumukkala V, Sessler DI. How regional analgesia
might reduce postoperative cancer recurrence. Eur J Pain Suppl.
2011;5:345-55.
4. Naruse T, Nishida Y, Hosono K, Ishiguro N. Meloxicam
inhibits osteosarcoma growth, invasiveness and metastasis by
COX-2-dependent and independent routes. Carcinogenesis.
2006;27:584-92 .
5. Goldfarb Y, Sorski L, Benish M, et al. Improving
postoperative immune status and resistance to cancer metastasis:
a combined perioperative approach of immunostimulation and
prevention of excessive surgical stress responses. Ann Surg. 2011;
253:798-810.
6. Ishikawa M, Nishioka M, Hanaki N, et al. Perioperative
immune responses in cancer patients undergoing digestive
surgeries. World J Surg Oncol. 2009;7:7.
7. Cata JP, Bauer M, Sokari T, et al. Effects of surgery, general
anesthesia, and perioperative epidural analgesia on the immune
function of patients with non-small cell lung cancer. J Clin Anesth.
2013;25(4):255-62 .
8. Yokoyama M, Itano Y, Katayama H, et al. The effects
of continuous epidural anesthesia and analgesia on stress
response and immune function in patients undergoing radical
esophagectomy. Anesth Analg. 2005;101:1521-7.
9. Weinbroum AA. A single small dose of postoperative
ketamine provides rapid and sustained improvement in morphine
analgesia in the presence of morphine-resistant pain. Anesth
Analg. 2003;96:789-95, table of contents .
10. Mammoto T, Higashiyama S, Mukai M, et al. Infiltration
anesthetic lidocaine inhibits cancer cell invasion by modulating
ectodomain shedding of heparin-binding epidermal growth factor-like
growth factor (HB-EGF). J Cell Physiol. 2002;192:351-8.
11. Cata JP, Hernandez M, Lewis VO, Kurz A. Can regional
anesthesia and analgesia prolong cancer survival after orthopaedic
oncologic surgery? Clin Orthop Relat Res. 2013 Oct 1. [Epub
ahead of print].
12. Exadaktylos AK, Buggy DJ, Moriarty DC, et al. Can
anesthetic technique for primary breast cancer surgery affect
recurrence or metastasis? Anesthesiology. 2006;105:660-4.
13. Biki B, Mascha E, Moriarty DC, et al. Anesthetic technique
for radical prostatectomy surgery affects cancer recurrence: a
retrospective analysis. Anesthesiology. 2008;109:180-7.
14. Cummings KC, Xu F, Cummings LC, Cooper GS. A
comparison of epidural analgesia and traditional pain management
effects on survival and cancer recurrence after colectomy: a
population-based study. Anesthesiology. 2012:116:797-806.
15. Gottschalk A, Ford JG, Regelin CC, et al. Association
between epidural analgesia and cancer recurrence after colorectal
cancer surgery. Anesthesiology. 2010;113:27-34.
16. Cata JP, Gottumukkala V, Thakar D, et al. Effects of
postoperative epidural analgesia on recurrence-free and overall
survival in patients with nonsmall cell lung cancer. J Clin Anesth.
2013 Oct 4. [Epub ahead of print].
17. Chen WK, Miao CH. The effect of anesthetic technique on
survival in human cancers: a meta-analysis of retrospective and
prospective studies. PloS one. 2013;8(2):e56540.
17. Chronic Persistent Postoperative Pain:
What are the Risk Factors and the Role of the
Anaesthesiologist?
Henrik Kehlet
Section of Surgical Pathophysiology, Rigshospitalet, Copenhagen
University, Copenhagen, Denmark
Based upon plenty of studies from single and
multicentre nationwide data, there is a general agreement
that persistent postsurgical pain (PPP) is a significant
clinical problem. Although most data have come from
groin hernia repair, thoracic surgery, breast cancer
surgery and knee replacement, PPP has been documented
from all types of surgery.
The pathogenic mechanisms are multifactorial divided
into preoperative risk factors (genetic, anxiety, psycho-social,
nociceptive function, etc.), intraoperative factors (nerve injury)
and postoperative factors (analgesic management). There
is a general agreement that PPP is mostly characterised by
‘neuropathic pain’ and most data suggest that minimal nervesparing techniques may reduce the risk of PPP.
Regarding the role of anaesthesia and especially
postoperative analgesic techniques, the literature is
controversial both regarding regional anaesthetic techniques
and single or multimodal specific analgesic therapies.
Although the hypothesis of ‘preventive’ analgesia should not
be discarded, there is an urgent need for better design of
studies probably with interventions that target different levels
of the nociceptive system and then with sufficient prolonged
therapy until the peripheral surgical inflammatory response
has declined. So far, there is no clear evidence that anaesthetic
or analgesic techniques may significantly reduce the risk of
PPP. Also, future studies should focus on the potential value
of drugs reducing the central (microglia) neuro-inflammatory
responses which may be involved in the development of PPP.
References
Andersen KG, Kehlet H. Persistent pain after breast cancer
treatment: a critical review of risk factors and strategies for
prevention. J Pain. 2011;12:725-46.
Andreae MH, Andreae DA. Regional anaesthesia to prevent
chronic pain after surgery: a Cochrane systematic review and
meta-analysis. Br J Anaesth. 2013;111:711-20.
oral communications
Chaparro LE, Smith SA, Moore RA, et al. Pharmacotherapy for
the prevention of chronic pain after surgery in adults. Cochrane
Database Syst Rev 2013;7:CD008307.
Clarke H, Bonin RP, Orser BA, et al. The prevention of chronic
postsurgical pain using gabapentin and pregabalin: a combined
systematic review and meta-analysis. Anesth Analg. 2012;115:428-42.
Deumens R, Steyaert A, Forget P, et al. Prevention of chronic
postoperative pain: Cellular, molecular, and clinical insights for
mechanism-based treatment approaches. Prog Neurobiol, 2013; 104:1-37.
Ellis A, Bennett DL. Neuroinflammation and the generation of
neuropathic pain. Br J Anaesth, 2013; 111:26-37.
Gilron I, Kehlet H. Prevention of chronic pain after surgery:
New insights for future research and patient care. Can J Anaesth.
2014;61(2):101-11
Haroutiunian S, Nikolajsen L, Finnerup NB, et al. The
neuropathic component in persistent postsurgical pain: a
systematic literature review. Pain. 2013; 154:95-102.
Johansen A, Schirmer H, Stubhaug A, Nielsen CS. Persistent
post-surgical pain and experimental pain sensitivity in the Tromso
study: Comorbid pain matters. Pain. 2014;155(2):341-8.
Kalso E. IV. Persistent post-surgery pain: research agenda for
mechanisms, prevention, and treatment. Br J Anaesth. 2013;111:9-12.
Kehlet H, Roumen RM, Reinpold W, et al. Invited commentary:
persistent pain after inguinal hernia repair: what do we know and
what do we need to know? Hernia. 2013;17:293-7.
Schmidt PC, Ruchelli G, Mackey SC, et al. Perioperative
gabapentinoids: choice of agent, dose, timing, and effects on
chronic postsurgical pain. Anesthesiology. 2013;119:1215-21.
Vandenkerkhof EG, Peters ML, Bruce J. Chronic pain after
surgery: time for standardization? A framework to establish core
risk factor and outcome domains for epidemiological studies. Clin
J Pain. 2013; 29:2-8.
18. Perioperative Care of the Cancer Patient:
Beyond Optimal Pain Control
Vijaya Gottumukkala
Department of Anesthesiology & PeriOperative Medicine,
The University of Texas, MD Anderson Cancer Center,
Houston, TX, USA
The incidence of cancer is increasing at a rapid pace
due to environmental factors, chronic infectious etiology,
unhealthy life style choices, and longer life expectancies.
Cancer currently is the leading cause of death in the
developing nations, and ranks next to cardiovascular diseases
as the most common cause of death in the developed world.
Cancer is no longer a terminal disease; it is now considered
a chronic medical condition. In the United States, 64%
of cancer survivors live for more than 5 years, 15% live for
55
over 20 years, and 45% of all cancer survivors are over 70
years of age. Cancer patients and survivors will continue to
require the services of anesthesiology and perioperative
medicine, pain management and intensive care medicine
specialists well beyond their primary oncologic care needs.
Our understanding of the mechanisms of perioperative
tumor spread and control is rapidly evolving, and offers us
an opportunity to positively influence oncological outcomes
for our patients.
The perioperative period is associated with intense
emotional and physiological (surgical) stress, pain,
inflammation, immune suppression, metabolic
changes (rapid depletion of liver glycogen stores,
negative nitrogen balance, insulin resistance), and an
environment for pro-angiogenesis. While many of these
responses to surgical injury (incision) are important
for healing and recovery of function, uncontrolled –
they can have significant negative consequences on
perioperative outcomes. Despite significant advances
in our understanding of the mechanisms of acute postsurgical pain, patient surveys continue to show poor
satisfaction rates with pain control in the postoperative
period. Two consecutive postoperative patient surveys in
1993 and 2003 reported that over 80% of patients suffer
from postoperative pain and that over 85% of the patients
who suffer from postoperative pain report moderate to
extreme pain experience. Unfortunately, there seems to
be no improvement in the most recent reports either.
Therefore, this subject warrants a fresh review of our
current postoperative pain management strategies, and
demands a renewed focus on multimodal regimens that
offer better postoperative pain control.
Goal of perioperative management strategies in the
surgical patient is not only to attenuate the surgical stress
response and provide effective analgesia, but also to focus
on patient centered outcomes (enhanced and accelerated
functional recovery, attenuated symptom distress, and to
improve overall satisfaction with the care encounter). In the
cancer patient in particular, the strategy should be enhanced
functional recovery so that the patients can continue with their
individual journey. For the surgical patients with cancer, this
often involves adjuvant therapy. Multiple trials have identified
a survival benefit with the use of adjuvant chemotherapy after
a curative resection of solid tumors. Therefore, all strategies
(minimally invasive surgery where applicable, enhanced
recovery programs to reduce postoperative complications
and accelerate functional capability) to promote earlier
institution of adjuvant therapy after a successful surgical
resection are necessary to improve progression-free and
recurrence-free survival.
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While there are multiple laboratory and animal studies
outlining the influence of anesthetic techniques on the
inflammatory responses and cancer cell lines, in-vitro
and animal data cannot be correlated with or translated
to clinical experience. Published literature from in-vitro
models usually involves studying the effects of individual
cell lines in a controlled environment. Studies in animal
models are different from the clinical environment as: the
experiments are frequently conducted in an engineered
model (knock-out species), single cell lines are studied
for tumor retention and growth of the introduced cell
lines, and the effects of a particular drug (morphine for
example) tested are affected by dose of the drug, route
of administration, frequency of administration and the
metabolic pathway of the drug in the animal model (active
metabolite or not, as an example). The discrepancies in
the literature are also due to the differences in the models
used (syngeneic versus xenograft models). Furthermore,
studying the biology of introduced cancer cell lines in
an animal model is different from a model in which the
tumors develop de-novo, as the interaction with the native
immune function will influence the seeding, growth and
development of the tumors. The laboratory and animal
studies are however important to guide future research
models and appropriate clinical protocols.
Current understanding is that there is also phenotypic
and genotypic heterogeneity, and plasticity in each of the
tumors for a particular histological type, thereby pointing
to varied responses to therapy. In-addition, our growing
understanding of the concept of cancer stem cells offers
one possible explanation for the tenacity of some of the
tumors in escaping the innate immunity of the host with
resultant loco-regional and distant clinical metastases
years after the primary therapeutic interventions that
were deemed curative.
Currently there are no randomized controlled studies,
which offer clear benefits of one anesthetic technique (or
perioperative strategy) over others in terms of recurrencefree survival or overall survival after curative cancer surgery.
Published retrospective studies to date offer contradictory
results. Reasons for this discrepancy are multifactorial. Most
of the studies have not considered the oncological factors
(tumor stage and type, tumor burden, lympho-vascular
space invasion [LVSI], response to therapy, etc.), patient’s
nutritional state, preoperative inflammatory burden and
preoperative functional status (physical) into account in
the design of published studies or analysis of the results.
Furthermore, retrospective studies are prone to known
shortcomings (bias in treatment allocation to the study
groups) despite the strengths of the clinical endpoints.
Nonetheless, given the current understanding of the
potential role of anesthetic and perioperative strategies on
both immediate and long-term surgical and oncological
outcomes, a new approach to the perioperative care of the
cancer patient is warranted.
Future perioperative care strategies of the cancer
patient should focus on: controlling the surgical stress
response, providing optimal perioperative functional
analgesia (effective dynamic pain control), maintaining
metabolic homeostasis and hemodynamic stability,
modulating the inflammatory response to an antitumor response, and minimizing immune dysfunction.
The effectiveness of this strategy should be objectively
evaluated with laboratory parameters of inflammatory
markers and immunological function, clinical correlates
of surgical care (postoperative morbidity, length of stay,
patient centered QOL/symptom distress surveys, return
to intended oncological therapy, and progression-free
and overall survival) to better understand the mechanistic
principles and better delineate the clinical endpoints
with oncologic relevance.
19. I have a High Risk Patient. Now what?
Patricia Lavand’Homme
Department of Anesthesiology, St Luc Hospital University
Catholic of Louvain, Brussels, Belgium
Relieving postoperative pain remains a challenge for
some patients and the facts point out 30% of the patients
reporting severe pain during the first 24 hours after surgery.
Undermanaged postoperative pain causes a major health
care problem1 related to both immediate and potential
delayed morbidity. Postoperative acute pain severity remains
one of the major risk factors involved in the development of
persistent pain after surgery 2. As prevention is better than
cure, the first step is to detect as soon as possible the patients
who will be at risk for severe acute postoperative pain and
then those who will be at risk for persistent postsurgical
pain. Several studies have tried to determine the profile
of the aforementioned patients: presence of preoperative
pain either at the surgical site or elsewhere in the body,
presence of co-morbid stress symptoms like depression,
sleep disturbance, capacity overload are major risk factors.
Preoperative pain not only sensitizes the central nervous
system but is often associated to the intake of analgesics.
Chronic opioid use also sensitizes the central nervous
system and thereby contributes to enhanced postoperative
pain experience and will slower postoperative recovery3.
Now that high risk patients have been detected: what?
oral communications
Although we still need well designed studies to validate
the benefits expected of current ‘optimal’ perioperative
management, those patients certainly should receive
perioperative preventive (and protective) analgesic
treatments. In the past, the goal of preemptive analgesia
was to prevent nociceptive inputs from lesioned tissues to
reach and to sensitize the central nervous system, thereby
to reduce the expression of post-injury pain. Although
extremely attractive, the concept of preemptive analgesia
has only brought deceiving results in the perioperative
setting. Recent experimental models of incisional pain
clearly show that any analgesic treatment administered
before incision is not superior to the same treatment
provided after incision because, when the effects of the
analgesic treatment abate, the wound is able to reinitiate the
central sensitization. Consequently, preemptive analgesia
has evolved to the concept of preventive and protective
analgesia, a broader definition, which involves any
perioperative analgesic and antihyperalgesic treatments
aimed to control both peripheral and central nervous
system sensitization and in fine, to reduce the development
of persistent post-surgical pain. In preventive analgesia,
both the duration and the efficacy of the treatment are
more important than the timing of administration of the
drugs4. Recent clinical studies have highlighted the fact
that an optimal control of pre-operative, perioperative and
post-operative pain is mandatory to ensure the success
of preventive analgesia5. Modern analgesia relies on the
concept of balanced multimodal analgesia which allows the
reduction of perioperative opioids and thereby minimizes
well known side effects like nausea, vomiting, sedation… as
well as pro-nociceptive and hyperalgesic effects6. Systemic
drugs with anti-hyperalgesic properties i.e. ketamine,
gabapentinoids, nitrous oxide…7 and loco-regional analgesic
techniques8 are available. Recently, progresses made in the
assessment of endogenous mechanisms of pain processing
should allow to improve even more preventive analgesia
by an individualization of analgesic and antihyperalgesic
perioperative treatments9. As preoperative criteria do not
allow to detect all the patients, postoperative follow-up
remains extremely important to ensure early detection
of patients at risk of persistent postsurgical pain. The
development of pain trajectories10 may allow to detect
abnormal pain resolution after surgery. Different causes
account for such slower postoperative recovery that may
include mis-diagnosed and under-treated neuropathic
component of the pain11. The development of specific
‘transitional pain units’ by the anesthesiologists should
allow to detect and take care of the patients who will develop
persistent postsurgical pain12.
57
References
1. Breivik H, Stubhaug A. Management of acute postoperative
pain: still a long way to go! Pain. 2008;137(2):233-4.
2. Althaus A, Hinrichs-Rocker A, Chapman R, et al.
Development of a risk index for the prediction of chronic postsurgical pain. Eur J Pain. 2012;16(6):901-10
3. Steyaert A, Lavand’homme P. Postoperative opioids: let
us take responsibility for the possible consequences. Eur J
Anesthesiol. 2013;30(2):50-2
4. Scholz J, Yaksh TI. Preclinical research on persistent
postsurgical pain: what we don’t know, but should start studying.
5. Lavand’homme P. The progression from acute to chronic
pain. Curr Opin Anaesthesiol. 2011;24(5):545-50.
6. Martinez V, Fletcher D. Prevention of opioid-induced
hyperalgesia in surgical patients: does it really matter? Br J
Anaesth. 2012;109(3):302-4.
7. Chaparro LE, Smith SA, Moore RA, et al. Pharmacotherapy
for the prevention of chronic pain after surgery in adults. Cochrane
database 2013 Jul 24;7:CD008307.
8. Andreae MH, Andreae DA. Local anaesthetics and regional
anaesthesia for preventing chronic pain after surgery. Cochrane
database 2012 Oct 17;10:CD007105.
9. Yarnitsky D. Curr Opin Anesthesiol.
10. Chapman CR, Donaldson GW, Davis JJ, Bradshaw DH.
Improving individual measurement of postoperative pain: the pain
trajectory. J Pain. 2011;12(2):257-62.
11. Lavand’homme PM, Grosu I, France MN, Thienpont E. Pain
trajectories identify patients at risk of persistent pain after knee
arthroplasty: an observational study. Clin Orthop Relat Res 2013
Nov 21. [Epub ahead of print]
12. De Kock M. Expanding our horizons: transition of acute
postoperative pain to persistent pain and establishment of chronic
postsurgical pain services. Anesthesiology. 2009;111(3):461-3.
CHRONIC PAIN
20. Visceral Pain
Fernando Cervero
The Alan Edwards Centre for Research on Pain, McGill
University, Montreal, Canada
Visceral pain is an important component of the normal
sensory repertoire of all human beings and a prominent
symptom of many clinical conditions. Visceral pain is
also one of the most frequent reasons for patients to seek
medical attention. However, many practitioners regard
visceral pain as only a symptom of the underlying disease
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58
that will go away once the disease is cured. Also, much of
what we know about the basic mechanisms of pain derives
from experimental studies of somatic nociception. Even
chronic pain models are generally based on inflammatory
lesions of the skin, muscles or joints or on peripheral
nerve injuries and therefore pain of internal origin, or
visceral pain, is a subject of lesser interest.
The five main clinical features that make visceral
pain unique are that this form of pain: I) is not evoked
from all viscera, II) is not linked to visceral injury,
III) is referred to other locations, IV) is diffuse and
poorly localized, and V) is accompanied by motor and
autonomic reflexes. Properties I) and II) generated the
notion that some viscera lacked an afferent innervation.
We know that these features of visceral pain are due to
the functional properties of the peripheral receptors
that innervate different visceral organs and to the fact
that many viscera are innervated by receptors whose
activation does not evoke conscious perception and that
are not ‘sensory’ receptors in the strict sense. Properties
III), IV) and V) relate to the central organization of
visceral nociceptive mechanisms, particularly to the
lack of a separate visceral sensory pathway and to the
low proportion of visceral afferent fibers compared to
those of somatic origin.
It is now quite clear that different forms of pain are
mediated by different neurological mechanisms so that
it is no longer possible to maintain a view of the pain
system as a simple alarm device with a single, unique
organization. The study of visceral pain can offer insights
into the workings of the brain that may be complementary
to what we know from studies of somatic or neuropathic
pain. Also, the treatment of some forms of visceral pain is
now oriented more towards the neurological system that
mediates the pain than towards the underlying disease
of the visceral organ. This is particularly relevant in
conditions such as the irritable bowel syndrome where
treatment is often directed to the nervous system rather
than to the gastrointestinal tract.
Visceral nociception generates increases in pain
sensitivity in locations remote from a diseased organ.
Referred hyperalgesia is also present in functional pain
states without apparent damage of an internal organ.
These changes may be due to sensitization of peripheral
nociceptors, to excitability changes of spinal cord
neurons or to variations in descending control of spinal
transmission. Sensitization of visceral nociceptors
is influenced by the microenvironment where the
nociceptors are located and the function of non-neural
epithelial cells of the organ in question. The importance
of the GABAergic system in spinal nociceptive processing
has also been appreciated but we have only recently
begun to understand how this system is modulated by the
regulation of anion gradients. Also, hormonal dysfunction
can contribute to generate visceral hyperalgesic states as
shown in models of functional abdominal pain disorders
that are estrogen-dependent.
21. Pain Treatment Inequality: the International
Scenario
Gilberto Gerra
United Nations Office on Drugs and Crime, Vienna, Austria
The Commission on Narcotic Drugs requested the
UNODC to continue its efforts to ensure the adequate
availability of internationally controlled drugs and
psychotropic substances for medical and scientific
purposes, cooperating, as appropriate, through the
Access to Controlled Medications Programme of the
World Health Organization (WHO), while continuing its
activities to prevent diversion and abuse.
The tragedy of the inadequate availability of opioid
analgesics is well expressed by the International Narcotics
Control Board (INCB): ‘Although medical science has the
capacity to provide relief for most forms of moderate to
severe pain, over 80 per cent of the world population will
have insufficient analgesia, or no analgesia at all, if they
suffer from such pain’.
WHO estimates that each year 5.5 million terminal
cancer patients and 1 million end-stage HIV/AIDS patients
as well as many other people with chronic, non-malignant
pain suffer un- or under-treated moderate to severe pain,
including 800,000 patients with lethal injuries caused
by accidents and violence, patients with chronic illnesses,
patients recovering from surgery, women in labour (110
million births each year) and paediatric patients. Altogether,
WHO estimates that annually tens of millions of people are
not treated adequately for their moderate to severe pain.
Unrelieved pain affects the quality of life of individuals
and their families, friends and communities, and can
cause wider losses to society, such as through reduced
productivity of both patients and their caregivers.
Inadequate pain treatment may also lead to the seeking
of additional medical intervention.
Global inequalities in access to pain relief are stark,
with, for example, 90 per cent of the global consumption
of morphine, fentanyl and oxycodone registered in 2009
occurring in Australia, Canada, New Zealand, the United
States and several European countries.
oral communications
Both opioid and non-opioid analgesics should be
made available for appropriate pain management and
their rational use should follow an appropriate clinical
assessment, criteria for proportional interventions and
pharmacological rules for the integration in a complex
therapeutics approach. If appropriately used, opioid
medicines are safe and the patients rarely become
dependent on opioid analgesia. The management of
pain should be driven on a case-by-case basis, with
personalized therapeutic programmes, including
personalized dosage and frequency of administration.
The control provisions of the international
Conventions are designed to (a) ensure that controlled
medications are prescribed for legitimate medical
purposes and safely reach patients through a controlled
distribution chain and (b) combat illicit manufacture,
trade and distribution.
Measures which parties to the Conventions agree to
implement include:
• Government licensing of manufacture
• Government licensing of trade and distribution
• Government licensing of international trade
• Government import-export authorization
• Provision to the INCB annually estimates of medical
and scientific needs for narcotic drugs
• Record-keeping by governmental authorities and
persons engaged in manufacture, trade and distribution,
and conduct of inspections by government
• Requirement of medical prescriptions for supply or
dispensation to individuals
• Prohibition of advertising to the general public with
due regard to constitutional provisions
• Requirement of adequate labelling
• Requirements for commercial documents
• Suppression of use of the mails in accordance with
basic principles of domestic legal systems
• Prohibition of export to post office box
• Establishment of penal provisions for contraventions
of the above requirements.
While the availability of opioid analgesics for legitimate
treatment of pain in many countries is unacceptably low,
the major impediments to availability are widely known,
and progress is being made in some countries.
While States are not precluded from adopting
measures that are more restrictive than those required
by the Conventions if they deem them necessary or
desirable to protect public health or welfare, efforts
to limit the use of narcotic drugs and psychotropic
substances to medical and scientific purposes “must not
adversely affect their availability for such purposes”. A
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recent survey conducted by the INCB found that laws and
regulations that were unduly restrictive or burdensome
were commonly perceived as a significant limitation on
availability.
Examples of measures that may impede availability
and that are not required by the Conventions include:
• Limitations on the number of days’ supply that may
be provided in a single prescription (with too short a
period of time allowed);
• Limitations on doses that may be prescribed in a
single prescription (with allowed doses being too low);
• Excessive limitations on prescription authority, such
as only to some categories of medical doctors;
• Special prescription procedures for opioids, the use
of specific prescription forms, which may be difficult to
obtain, and/or a requirement that multiple copies of the
prescription be maintained;
• Requirements that patients receive special
permission or registration to render them eligible to
receive opioid prescriptions;
• Excessive penalties and prosecutions for
unintentional misprescription or mishandling of opioids;
• Arbitrary restrictions on the number of pharmacies
permitted to dispense opioid medications;
• Unreasonable requirements relating to the storage of
opioid medications.
These measures, not required by the Convention,
do not significantly improve control, but may interfere
significantly with accessibility to and availability of
essential medicines.
In many countries, healthcare professionals are
insufficiently trained in the recognition and management
of pain. Many do not know how to ask patients about
pain or how to understand patients’ descriptions of
pain, do not appreciate the need to ease pain, and
underestimate the extent to which pain can be relieved
through treatment that includes the use of opioid
analgesics. Many are overly concerned about the side
effects of opioid treatment.
In many countries, patients—often acting in the
context of family values and influence—do not report
pain or refuse to be treated with opioid analgesics. They
may have internalized social stigma relating to opioid
use, hold exaggerated fears of the side effects of opioid
use, or worry about the effects of opioid use on their
awareness.
As INCB notes, there may be deficiencies in drug
supply management due to lack of financial resources,
inadequate infrastructure, the low priority given to
health care, weak government authority, inadequate
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60
education and professional training, and outdated
knowledge. In some cases, medicines may be available
in large cities, but supply chains do not reach towns or
rural areas.
22. Mechanisms of Injury and Strategies to Avoid
Harm in Spine Interventional Procedures
Marc A. Huntoon
Department of Anesthesiology, Division of Pain Medicine,
Vanderbilt University, Nashville, TN, USA
Interventional procedures for spinal pathology
have exploded in popularity over the last decade1, but
with the increased numbers of procedures have come
unexpected and devastating complications. These
complications have largely been infectious, neurological
(ischemia, direct injury) and related to contained
bleeding (hematoma).
Infectious complications primarily have occurred
in the setting of immune compromise, from diabetes
mellitus, oncologic disease, autoimmune disease and the
concomitant use of therapeutic corticosteroids which
also impair immunity.2 In the modern era, the majority
of those infected were found to have a staphylococcus
species. 3 In the United States, a compounded form
of methylprednisolone, unfortunately unregulated by
the US Food and Drug Administration (FDA), from a
production facility known as New England Compounding
Center (NECC) was the source of an epidemic of fungal
meningitis in late 2012.4,5 This agent resulted in several
deaths due to stroke from effects of the fungal hyphae
on CNS blood vessels as well as other mortalities and
morbidities from meningitis and epidural abscesses.
Many of these deaths were in the states of Tennessee
and Michigan. The involvement of the national Centers
for Disease Control (CDC) and state medical boards
were instrumental in eventually solving the public health
disaster, shutting down and subsequently prosecuting
those involved in producing the tainted corticosteroid.
Those physicians that used the compounded products
largely did so for several reasons, including worries about
preservatives in the corticosteroid preparations being
unintended for neuraxial use, the lack of availability
of commercial FDA-regulated product through large
pharmaceutical companies (limited production leading to
rolling periods of unavailability), and lower costs associated
with procuring the compounded agent from NECC.
Another evolving complication is the occurrence
of major morbidity and several mortalities from the
performance of transforaminal epidural injections of
corticosteroid. Initial reports by Houten and Errico 6 in
the lumbar region and Brouwers and colleagues7 in the
cervical area, were followed by multiple other reports
of equally devastating injuries. Although, analysis of
closed legal claims suggested that direct needle trauma
to the spinal cord or nerve roots remains more prevalent
than these events. 8 Baker and colleagues 9 were the
first to discuss potential causes of these occurrences,
theorizing that embolic particles from the steroid
preparation might lead to occlusion of spinal cord/brain
stem blood flow via the vertebrobasilar arterial system.
They also considered the potential role of vasospasm
or other causes, and introduced the interventional
pain community to the idea that digital subtraction
angiography (DSA) use during real-time injection of
contrast dye might allow one to better see unintended
vascular injections. Anatomical studies led to a greater
understanding of the role of aberrant locations of the
vertebral arteries and arteries of Adamkiewicz, as well
as the role of other arterial systems and their positions
within the theoretical “safe-zones” for both lumbar and
cervical procedural recommendations.10,11 Subsequently,
surveys of the membership of the American Pain Society
(APS) by Scanlon and colleagues12 , demonstrated that
the complication was not rare, with a small sampling
of this group being aware of at least 13 deaths after
cervical transforaminal injections of particulate steroids.
Tiso and colleagues13, and Benzon and co-workers14
contributed greatly through confocal microscopy
studies of various formulations of steroid preparations,
as to their particulate appearance. Animal studies were
also important to understanding the pathophysiology.
Okubadejo and colleagues15 intentionally injected the
vertebral arteries of swine with either particulate or
non-particulate corticosteroids, showing that only those
animals receiving particulate steroids had brain injuries
and died, while all the animals that received nonparticulate dexamethasone were fine and suffered no
injuries. Dawley and colleagues 16, also studied a rodent
model where both methylprednisolone compounds and
their vehicle were separately tested and compared to non
particulate steroids (dexamethasone). Once again, only
the non-particulate agents resulted in no neural injuries,
but importantly the vehicle for the methylprednisolone
agents was also implicated as causing a chemical burn
of the arteries.
Recently, a group of topical experts and representatives
from several stakeholder societies (pain medicine,
radiological, orthopedic, and spine care) were convened
oral communications
as part of an FDA-sponsored safe-use initiative, to
develop guidelines for the use of various epidural
injections in order to limit the scope of these devastating
complications. The recommendations of this group are
currently submitted for potential publication.17
Hematoma formation causing paralysis or neurological
morbidity is a growing concern with proceduralists,
largely fueled by uncertainty with how to deal with a
plethora of new drugs, e.g. dabigatran, and larger scale
use of older drugs such as aspirin and warfarin.18 These
topics have led to the formulation of new guidelines
by the American Society of Regional Anesthesia and
Pain Medicine (ASRAPM) specific to the performance
of spinal injections in the chronic pain setting. These
guidelines will be submitted for publication at the time
of this lecture.
Overall, spinal complications, although catastrophic,
have likely been significantly curtailed by the prompt
and exhaustive study and research to date in these
specific areas. Efforts to study the potential unintended
side effects of neuraxially-administered agents in the
future will be necessary to prevent similar occurrences.
References
1. Martin B, Turner J, Mirza S, et al. Trends in health care
expenditures, utilization, and health status among US adults with
spine problems 1997-2006. Spine. 2009;34:2077-84.
2. Hooten WM, Kinney MO, Huntoon MA. Epidural abscess
and meningitis after epidural corticosteroid injection. Mayo Clin
Proc. 2004; 79(5):682-6.
3. Ptaszynski A, Huntoon M. Complications of spinal injections.
Techniques in Regional Anesthesia and Pain Management.
2007;11(3):122-32.
4. Pettit AC, Kropski JA, Castilho JL, et al. Brief report: the
index case for the fungal meningitis outbreak in the United States.
N Engl J Med. 2012;367:2119-25.
5. Kainer MA, Reagan DR, Nguyen DB, et al. Fungal infections
associated with contaminated methylprednisolone in Tennessee.
N Engl J Med. 2012;367: 2194-203.
6. Houten JK, Errico TJ. Paraplegia after lumbosacral nerve
root block: report of three cases. Spine J. 2002;2:70 –5.
7. Brouwers PJ, Kottink EJ, Simon MA, et al. A cervical anterior
spinal artery syndrome after diagnostic blockade of the right C6nerve root. Pain. 2001; 91:397-9.
8. Rathmell J, Michna E, Fitzgibbon D, et al. Injury and
liability associated with cervical procedures for chronic pain.
Anesthesiology. 2011;114:918-26.
9. Baker R, Dreyfuss P, Mercer S, et al. Cervical transforaminal
injection of corticosteroids into a radicular artery: a possible
mechanism for spinal cord injury. Pain. 2003;103:211-5.
61
10. Huntoon MA. Anatomy of the cervical intervertebral
foramina: vulnerable arteries and ischemic neurologic injuries after
transforaminal epidural injections. Pain. 2005;117(1-2):104-11.
11. Murthy NS, Maus TP, Behrns CL. Intraforaminal location
of the Great Anterior Radiculomedullary Artery (Artery of
Adamkiewicz): A retrospective review. Pain Med. 2010;11:1756-64.
12. Scanlon GC, Moeller-Bertram T, Romanowsky SM, et
al. Cervical transforaminal epidural steroid injections: more
dangerous than we think? Spine. 2007;32:1249 –56.
13. Tiso RL, Cutler T,Catania JA, et al. Adverse central nervous
system sequelae after selective transforaminal block: the role of
corticosteroids. Spine J. 2004;4:468-74.
14. Benzon HT, Chew TL, McCarthy RJ, et al. Comparison
of the particle sizes of different steroids and the effect of
dilution: a review of the relative neuro-toxicities of the steroids.
15. Okubadejo GO, Talcott MR, Schmidt RE, et al. Perils of
intravascular methylprednisolone injection into the vertebral
artery. An animal study. J Bone Joint Surg Am. 2008;90:1932-8.
16. Dawley JD, Moeller-Bertram T, Wallace MS, Patel PM.
Intrarterial injection in the rat brain: Evaluation of steroids used
for transforaminal epidurals. Spine. 2009;34:1638-43.
17. http://www.fda.gov/Drugs/DrugSafety/SafeUseInitiative/
ucm188762.htm#esi. Accessed January 4, 2014.
18. Benzon HT, Huntoon MA. Do we need new guidelines for
interventional pain procedures in patients on anticoagulants? Reg
Anesth Pain Med. 2014;39:1-3.
23. Safety of Epidural Steroid Injections: the FDA
Safe Use Initiative
Honorio T. Benzon
Northwestern University Feinberg School of Medicine,
Chicago, IL, USA
The latest American Society of Anesthesiologists
Closed Claims report noted that 22% of chronic pain
treatment claims were related to cervical interventions,
majority of which were spinal cord damage 1. The events
included direct needle trauma to a nerve or spinal cord
and cord infarction or stroke after intraarterial injection.
The spinal cord infarction or stroke presumably occurs
via intra-arterial injection of particulate steroid. Such
occurrences have been reported after transforaminal
(TF) injection in the cervical, lumbar and sacral levels 2 .
Animal studies supported embolism of the steroid as
the possible etiology. Methylprednisolone when injected
into the vertebral artery of pigs resulted in loss of
consciousness while the non-particulate dexamethasone
did not cause any neurologic injury 3. The injection
of methylprednisolone or the carrier into internal
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62
carotid artery of rats resulted in cerebral hemorrhage
while saline or dexamethasone did not 4. Clinically,
complications after particulate steroids were permanent
while those after non-particulate injectates such as
contrast and local anesthetic were temporary 2,5,6.
The Working Group, Food and Drug Administration
Safe Use Initiative, and endorsement by representatives of
national pain organizations
The United States Food and Drug Administration
(FDA) was made aware of these complications and helped
set up a Working Group of experts to discuss the reports
of central nervous system (CNS) injuries and make
recommendations to prevent or reduce such injuries.
The Working Group consisted of experts and
representatives from the FDA Safe Use Initiative.
The FDA Safe Use Initiative convened and facilitated
the teleconferences during which time the Working
Group identified reasonable recommendations.
These were presented to representatives of national
organizations which included the American Academy
of Orthopedic Surgeons, American Academy of Pain
Medicine, American Academy of Physical Medicine
and Rehabilitation, American Society of Interventional
Pain Physicians, American Society of Anesthesiologists,
American Society of Regional Anesthesia, International
Spine Intervention Society, North American Spine
Society, and Society for Interventional Radiology.
Representatives of the different organizations discussed
and voted on the recommendations.
Conclusions and recommendations of the Working Group,
FDA Safe Use Initiative, and representatives of national
organizations
The Working Group and the national organizations
concluded that the risk of spinal cord injury after
cervical interlaminar (IL) injections is increased when
the procedure is performed under heavy sedation, that
TF epidural steroid injections (ESIs) are associated
with a risk of catastrophic neurovascular complications,
and particulate steroids appear to be inordinately
represented in case reports of complications following
TF ESIs. The recommendations that were approved
by representatives of the national organizations are in
the Table.
The representatives disagreed with the recommendation that digital subtraction angiography (DSA)
should be used for cervical and lumbar transforaminal
injections, and that particulate steroids not be used in
lumbar TF steroid injections.
Table. Recommendations of the Working Group
that were Approved by the Representatives of the
National Organizations
1. Prior imaging studies is to be reviewed before any cervical
interlaminar injections
2. Cervical interlaminar therapeutic injections are
recommended over transforaminal injections
3. Cervical interlaminar injections at C6-7 or C7-T1 but not
above these levels
4. Particulate steroids may be used for interlaminar
injections
5. Use of image guidance and contrast medium for cervical
interlaminar injections
6. Injection of contrast medium under real-time fluoroscopy
and/or digital subtraction angiography for transforaminal
injections
7. Lumbar transforaminal injection is recommended when
the patient’s symptom involves a unilateral single nerve root
8. Lumbar interlaminar injection is recommended when
the symptoms involve several nerve roots unilaterally or
bilaterally
9. Dexamethasone should be used initially in lumbar
transforaminal injections
Discussion
Interlaminar ESIs at above C6-C7 have been advised
against because of the smaller epidural space and failure
of the ligamentum flavum to fuse in the midline in the
cervical levels 7. The routes of embolization, resulting
in infarction or stroke, in the cervical region include
the segmental radicular artery 8, ascending cervical and
deep cervical arteries which are close to the cervical
intervertebral foramina 9. In the lumbar and sacral regions,
the routes include a low-lying artery of Adamkiewicz, which
can originate from as low as L4, L5 or S1 10. The roots of the
cauda equina each receive a lower radiculomedullary artery
from the artery of Adamkiewicz 11.
The TF approach appears to be more efficacious than
the IL 12-15, caudal 16,17, or interspinous 18 approaches. Other
studies showed the TF to be equally effective in relieving
pain when compared with the IL 19-21, caudal 22 , or
interspinous 23 approaches. Studies on IL injections either
showed better efficacy of the particulate steroid 24, or a
non-significant trend favoring the particulate steroid 25.
The perception that particulate steroids give better results
and longer duration of pain relief after TF injections was
based on earlier studies 26,27. Recent studies however
showed equal efficacy and duration of TF ESIs with either
particulate or non-particulate steroids 28,29 although one
oral communications
study showed that more injections are required to achieve
the same efficacy 29.
The risk of intravascular injection is lower in lumbar
IL injections compared to caudal injections 30. The
incidence of intravascular injection is lower in lumbar
TF injections compared to cervical TF injections 30-32 .
A negative aspiration does not guarantee against
intravascular injection as intravenous placement of the
needle has been documented in the absence of blood on
aspiration 33. Aspiration also fails to produce a flashback
of blood in cases that turns out to be intravascular 30. The
presence of intravascular injections can be confirmed by
contrast injections and live fluoroscopy 32,34,35.
The use of DSA was not endorsed by the representatives
in spite of studies showing the increased ability of DSA
to detect intravascular injection 32,36. The use of DSA
however does not guarantee safety as paraplegia has been
reported in spite of negative DSA findings 37.
A Working Group of experts, representatives of
national organizations, and the FDA Safe Use Initiative
made recommendations to lower the incidence of
complications after ESIs. It is hoped that the occurrence
of such complications can be decreased by adherence of
the pain medicine clinician to the suggested measures.
References
1. Rathmell JP, Michna E, Fitzgibbon DR, et al. Injury and
liability associated with cervical procedures for chronic pain.
Anesthesiology 2011;114:918-26.
2. Benzon HT, Chew TL, McCarthy R, et al. Comparison
of the particle sizes of the different steroids and the effect of
dilution: A review of the relative neurotoxicities of the steroids.
3. Okubadejo GO, Talcott MR, Schmidt RE, et al. Perils of
intravascular methylprednisolone injection into the vertebral
artery. J Bone Joint Surg Am. 2008;90:1932-8.
4. Dawley JD, Moeller-Bertram T, Wallace MS, Patel PM.
Intra-arterial injection in the rat brain. Evaluation of steroids used
for transforaminal epidurals. Spine. 2009;34:1638-43.
5. McMillan MR, Crompton C. Cortical blindness and
neurological injury complicating cervical transforaminal injection
for cervical radiculopathy. Anesthesiology. 2003; 99:509-11.
6. Karasek M, Bogduk N. Temporary neurologic deficit after
cervical transforaminal injection of local anesthetic. Pain Med.
2004; 5:202-5.
7. Lirk P, Kolbitsch C, Putz G, et al. Cervical and high thoracic
ligamentum flavum frequently fails to fuse in the midline.
8. Rathmell JP, April C, Bogduk N. Cervical transforaminal
injection of steroids. Anesthesiology. 2004; 100:1595-600.
63
9. Huntoon M. Anatomy of the cervical intervertebral foramina:
vulnerable arteries and ischemic injuries after transforaminal
epidural injections. Pain. 2005;117:104-11.
10. Lo D, Vaslley JN, Spelle L, et al. Unusual origin of
the Adamkiewicz artery from the fourth lumbar artery.
Neuroradiology. 2002;44:153-7.
11. Thefenne L, Dubecq C, Zing E, et al. A rare case of
paraplegia complicating a lumbar epidural infiltration. Ann Phys
Rehabil Med. 2010;53:575-83.
12. Kraemer J, Ludwig J, Bickert U, et al. Lumbar epidural
perineural injection: a new technique. Eur Spine J. 1997;6:357-361.
13. Schaufele M, Hatch L, Jones W. Interlaminar versus
transforaminal epidural injections for the treatment of symptomatic
lumbar intervertebral disc herniations. Pain Physician. 2006;9:361-6.
14. Lee J, An J, Lee S. Comparison of the effectiveness
of interlaminar and bilateral transforaminal epidural steroid
injections in treatment of patients with lumbosacral disc
herniation and spinal stenosis. Clin J Pain. 2009;25:206-10.
15. Gharibo C, Varlotta G, Rhame E, et al. Interlaminar versus
transforaminal epidural steroids for the treatment of subacute
lumbar radicular pain: a randomized, blinded, prospective
outcome study. Pain Physician. 2011;14:499-511.
16. Ackerman 3rd W, Ahmad M. The efficacy of lumbar epidural
steroid injections in patients with lumbar disc herniations. Anesth
Analg. 2007;104:1217-22.
17. Lee J, Moon J, Lee S. Comparison of effectiveness according
to different approaches of epidural steroid injection in lumbosacral
herniated disk and spinal stenosis. J Back Musculoskelet Rehabil.
2009;34:83-9.
18. Thomas E, Cyteval C, Abiad L, et al. Efficacy of
transforaminal versus interspinous corticosteroid injection in
discal radiculalgia: a prospective, randomized, double-blind study.
Clin Rheumatol. 2003;22:299-304.
19. Candido K, Raghavendra M, Chinthagada M, et al.
A prospective evaluation of iodinated contrast flow patterns with
fluoroscopically guided lumbar epidural steroid injections: the lateral
parasagittal interlaminar epidural approach versus the transforaminal
epidural approach. Anesth Analg. 2008;106:638-44.
20. Rados I, Sakic K, Fingler M, Kapural L. Efficacy of
interlaminar vs. transforaminal epidural steroid injection for
the treatment of chronic unilateral radicular pain: prospective,
randomized study. Pain Med. 2011;12:1316-21.
21. Smith C, Booker T, Schaufele M, Weiss P. Interlaminar
versus transforaminal epidural steroid injections for the treatment
of symptomatic lumbar spinal stenosis. Pain Med. 2010;11:1511-5.
22. Mendoza-Lattes S, Weiss A, Found E, et al. Comparable
effectiveness of caudal vs. trans-foraminal epidural steroid
injections. Iowa Orthop J. 2009;29:91-6.
23. Kolsi I, Delecrin J, Berthelot J, et al. Efficacy of nerve root
versus interspinous injections of glucocorticoids in the treatment
oral communications
64
of disk-related sciatica. A pilot, prospective, randomized, doubleblind study. Joint Bone Spine. 2000;67:113-8.
24. Noe C, Haynsworth R Jr. Comparison of epidural DepoMedrol vs. aqueous betamethasone in patients with low back pain.
Pain Pract. 2003;3:222-5.
25. Kim D, Brown J. Efficacy and safety of lumbar epidural
dexamethasone versus methylprednisolone in the treatment of
lumbar radiculopathy: a comparison of soluble versus particulate
steroids. Clin J Pain. 2011;27:518-22.
26. Dreyfuss P, Baker R, Bogduk N. Comparative effectiveness
of cervical transforaminal injections with particulate and
nonparticulate corticosteroid preparations for cervical radicular
pain. Pain Med. 2006;7:237-42.
27. Lee JW, Park KW, Chung SK, et al. Cervical transforaminal
epidural steroid injection for the management of cervical
radiculopathy: a comparative study of particulate versus nonparticulate steroids. Skeletal Radiol. 2009;38:1077-82.
28. El-Yahchouchi C, Geske JR, Carter RE, et al. The
noninferiority of the nonparticulate steroid dexamethasone
and triamcinolone in lumbar transforaminal epidural steroid
injections. Pain Med. 2013;14:1650-7.
29. Kennedy DJ. Dexamethasone versus triamcinolone
for acute unilateral radicular pain due to a single level HNP: A
randomized, double-blind, multicenter trial. Pain Med (accepted
for publication).
30. Sullivan WJ, Willick SE, Chira-Adisai W, et al. Incidence of
intravascular uptake in lumbar spinal injection procedures. Spine.
2000;25:481-6.
31. Hong JH, Kim SY, Huh B, Shin HH. Analysis of
inadvertent intradiscal and intravascular injectrion during lumbar
transforaminal epidural injections. A prospective study. Reg
Anesth Pain Med. 2013;38:520-5.
32. Lee MH, Yang KS, Kim YH, et al. Accuracy of live fluoroscopy
to detect intravascular injection during lumbar transforaminal epidural
injections. Korean J Pain. 2010; 23:18-23.
33. Renfrew DL, Moore TE, Kathol MH, et al. Correct placement
of epidural steroid injections: Fluoroscopic guidance and contrast
administration. AJNR Am J Neuroradiol. 1991;12:1003-7.
34. Furman M, O’Brien E, Zglszewski T. Incidence of
intravascular penetration in transforaminal lumbosacral epidural
steroid injections. Spine. 2000;25:2628-32.
35. Furman MB, Giovanniello MT, O’Brien EM. Incidence
of intravascular penetration in transforaminal cervical epidural
steroid injections. Spine. 2003;28:2-5.
36. McLean JP, Sigler JD, Plastaras CT, et al. The rate of
detection of intravascular injection in cervical transforaminal
epidural steroid injections with and without digital subtraction
angiography. PM R. 2009; 1:636-42.
37. Chang Chien GC, Candido KD, Knezevic NN. Digital
subtraction angiography does not reliably prevent paraplegia
associated with lumbar transforaminal epidural steroid injection.
Pain Physician. 2012;15:515-23.
24. Central Neuropathic Pain: Mechanisms and
Treatment
Troels S. Jensen
Department of Neurology and Danish Pain Research Center,
Aarhus University, Aarhus, Denmark
Central pain (CP) represents different neuropathic pain
conditions, where lesions of somatosensory pathways in the
central nervous system (CNS) are assumed to be responsible
for the pain. CP are – as their peripheral counterparts –
characterised by pain in those body parts that correspond
to the brain or spinal cord area, whose function has been
disrupted by the CNS lesion. The distribution of pain
in CP represents only a fraction of the area with reduced
sensation, indicating that deafferentation is necessary
for the pain. The occurrence of evoked pain, summation
and aftersensations in the same body parts with reduced
sensory discrimination indicates that hyperexcitability
in addition to hyposensitivity also is manifestation of CP.
These findings have led to the proposal that partial or
complete loss of afferent input results in hyperexcitability
in certain neuronal pools and hence pain. The examination
of sensory threshold to thermal stimuli in patients with
post stroke pain permits a testing of the hypothesis that
specific loss of A-delta cooling fibers or cold perception
is related to the degree of pain. The etiology of central
neuropathic pain is multiple and includes pains caused by
stroke, by spinal cord injury, by immunological disorders
such as multiple sclerosis (MS) and transverse myelitis.
But also developmental disorders like syringomyelia or its
brainstem equivalent syringobulbia can give rise to a central
pain syndrome.
Treatment trials in patients with CP may contribute to
unravel mechanisms underlying these pain conditions.
Tricyclic antidepressants have a pain relieving effect
which may be related to a restoration of ascending
monoaminergic inputs to the thalamus.
Based on the observation that hyperexcitability in the
periphery can be reduced by sodium channel blockers,
the use of sodium channel blockers in CP appears to be
a rational approach. Lidocaine, an unspecific sodium
channel blocker, has in double-blind controlled trials
shown efficacy on pain and evoked abnormality in
patients with post stroke pain and in spinal cord injury
pain. Lamotrigine, a sodium channel blocker, has proven
to be efficacious in post stroke pain and in incomplete
oral communications
spinal cord injury. Gabapentin and pregabalin, both
antihyperalgesics, are likewise effective in relieving pain
in spinal cord injury pain. Cannabinoids have a proven
pain relieving effect in MS.
25. Human Spine and its Contents. Intervertebral
Foramen Region
Miguel Angel Reina1,2 , José De Andrés 3,4
1
Department of Anaesthesiology, Madrid-Montepríncipe
University Hospital, Madrid, Spain; 2 Department of Clinical
Medical Sciences and Applied Molecular Medicine Institute,
CEU San Pablo University School of Medicine, Madrid,
Spain; 3 Department of Surgical Specialties, Anesthesia
Division, Valencia University Medical School, Valencia,
Spain; 4 Anesthesia Department and Multidisciplinary Pain
Management Department, Valencia General University
Hospital, Valencia, Spain
The intervertebral foramen region has had interest
for anesthesiologists because it is the target of many
techniques used in pain treatment. In this place, we
can find nerve root cuffs, as other structures inside this
intervertebral canal.
Nerve root cuffs
Nerve root cuffs are lateral prolongations of dura mater
and arachnoid lamina, enclosing spinal nerve roots in their
way across the epidural space towards the intervertebral
foramen. Internal structure of nerve root cuffs is different at
preganglionar, ganglionar or postganglionar region.
Preganglionar region: Nerve root cuffs have internal
cellular and external fibrillar components, respectively.
Motor and sensory axons are separated into two cords.
In transversal and longitudinal section is possible to
identify independent and parallel cords where sensory
axons run to reach the dorsal root ganglia (DRG). Every
axon is surrounded by collagen fibers, as axons in
subarachnoid nerve roots. The structure is the same as
the endoneurium of peripheral nerves.
When successive transverse slides of tissue from
the preganglionar region of nerve root cuffs have been
analyzed, axons in small groups were found in motor and
sensitive areas. These small groups are evidence of the
passage of axons between sensitive and motor areas.
In the preganglionar region, between the dural
sac and DRG each cord is separated by sheets of cells,
stratified and joined together by tight junctions and
desmosome-type membrane connections. These cells
have cytoplasmic prolongations encroaching upon
neighboring cells, leaving very little extracellular space
65
that has rough appearance and few collagen fibers.
This structure functions as a barrier to any molecule
crossing the dural cuff to reach the axons. It is formed
by transition cells from pia mater cells and laminar and
trabecular arachnoid cells to perineural cells of more
distal peripheral nerves.
Outside the cellular component there is another fatty
and fibrillar layer. The fibrillar component is placed in
the outer portion of the root cuff; it is made up mostly
by collagen fibers arranged in concentric laminas with
scarce elastic fibers and a large number of adipocytes.
The dural laminas of nerve root cuffs keep continuity
with collagen fibers in dura mater of spinal cord.
The dural sac also works as a barrier to substances
administered in the epidural space from nerve roots
in the subarachnoid space. It has cellular and fibrillar
components. The cellular component is made up by an
inner arachnoid lamina, arachnoid cells that play the role
of barrier. There are also tight junctions and desmosome
type membrane connections between cells.
The fibrillar component in the dural sac contains
about 80 dural laminas, with collagen fibers oriented in
different directions and few elastic fibers; its thickness
varies between 270 and 350 microns at lumbar level.
However, differently from nerve root cuffs, adipocytes
are not found within the thickness of the dural sac. The
barrier effect of the dural sac is due to the arachnoid cells.
Differences in the thickness of the dura mater among
dural sac and the external fibrillar component do not
alter the barrier effect, because the arachnoid cells are
exclusively responsible for such an effect.
Dorsal root ganglia region: The location of DRG is
different depending on the spinal level. In the cervical
region it is located within the foraminal channel; in the
thoracic region it is closer to the medial aspect of the
foramen and in lumbar and sacral regions it is within
epidural space. The tissue in the dural cuff at ganglionar
region is different in comparison to the preganglionic
area. At ganglionar level there is also a cellular and a
fibrillar component, but the morphology of the cellular
component shows transitional changes between pre- and
postganglionic levels, although it resembles more to the
transitional changes at the postganglionic level, having
25-30 concentric cellular layers; these laminas are made
of single cell layers. Here, the cells have similar membrane
junctions. Specialized membrane junctions among
cells ensure the barrier effect, avoiding the passage of
substances from the epidural space to nerve axons.
Postganglionic region: At this level, the cellular
component has 9-14 single cell concentric layers. Their
oral communications
66
junctions are of the type desmosome. External fibrillar
components at ganglionar and postganglionar level are
similar to preganglionic area.
Plexus and peripheral nerves distal to DRG: there is a
transition zone of few millimeters before the beginning
of peripheral nerves. Here we can identify nerve fascicles:
axons that were grouped in motor and sensory cords at
proximal levels in this region that are mixing to result in
nerve fascicles.
Cerebrospinal fluid
The amount of cerebrospinal fluid (CSF) in spinal
subarachnoid space is another factor to consider. The
volume of CSF is different among patients.
When an epidural technique is performed, the
crossing of molecules to reach axons is limited by
arachnoid cells of dural sac and transition cells of nerve
root cuffs, responsible for the barrier effect. Dural sac
is made up of 80–90% of the external surface by dura
mater, a permeable structure that also brings mechanic
resistance to the dural sac. The rest, internal 10% is
the semipermeable arachnoid lamina that functions as
barrier to the free diffusion of molecules. This restriction
is due to several layers of arachnoid cells and intercellular
junctions that limit the loss of water and solutes of CSF.
The CSF volume close to motor and sensitive roots inside
nerve root cuffs is small. This place occupied by CSF is
renamed subarachnoid angle.
Epidural and foraminal fat
The distribution of epidural fat in the lumbar vertebral
canal is not constant, being greater in dorsal region and
lesser in anterior and lateral zones. Aspects such as amount,
distribution and direct relations of fat in the epidural space
along the vertebral canal, as well as within nerve root cuffs
and foraminal fat within intervertebral foramen, have an
effect on the diff usion of substances across them. Local
variations in the amount of fat and also in the distance
between fat and nerve root axons along the lumbar spinal
canal need further consideration. It is very likely that the
distance between fat and neighboring tissues affects the
redistribution of lipophilic drugs released from epidural
fat following epidural injection. The fat we found inside
root cuffs is in direct contact with nerve root axons; such
relationship may play a more defined role in the kinetics of
lipophilic substances injected near nerve roots.
Intervertebral foramen (IVF)
It is the space formed by two vertebrae (the vertebral
body, anterior and the pedicles in the superior and
inferior plane), disc and the zygapophyseal joint (Z joint),
posterior, with the spinal nerve and vessels running
through it.
At cervical level, they are almost oval in shape,
facing obliquely and anterolaterally. The foramina can
be considered as neural canals since they are 4-6 mm
in length. The vertical diameter of each foramen is
approximately 10 mm and the anteroposterior diameter
5 mm, although these dimensions change during spinal
movement. Structures that pass through the foramen
include the mixed spinal nerve with the nerve root cuffs,
lymphatic channels, and the vessels: the spinal branch of a
segmental artery and the communicating (intervertebral)
veins between the internal and external vertebral venous
plexuses. The spinal artery divides into three branches:
one to the posterior aspect of the vertebral body, one to
the posterior arch, and one to the mixed spinal nerve
(neural branch).
There is also adipose tissue surrounding all previous
structures and fibrous ligaments that bind the nerve root
cuff to the bone.
Recurrent meningeal nerves (also called sinuvertebral
nerve of von Luschka) originate from the most proximal
portion of the ventral ramus. This receives a branch
from the nearest gray communicating ramus of the
sympathetic chain before traversing the IVF. This nerve
provides sensory innervation (including nociception)
to the posterior aspect of the annulus fibrosus, the
posterior longitudinal ligament, anterior epidural veins,
periosteum of the posterior aspect of the vertebral bodies
and the anterior aspect of the spinal dura mater. There
are 2-4 recurrent meningeal nerves in each IVF.
The spinal nerve occupies only one fifth of the IVF
in the cervical region. Both, ventral and dorsal nerve
roots can be identified in the foramen’s lower portion at
or below the disk level. Dorsal nerve roots and ganglion
contact the superior facet. Ventral nerve roots contact
the uncinate process and bottom of the neural foramen.
Epidural fat and blood vessels are found in the superior
aspect of the IVF.
The IVFs in the thoracic and lumbar region face laterally
as a difference to the cervical (obliquely anterolaterally).
At lumbar level the vertical diameter of IVF is between 19
and 21 mm. The antero-posterior diameter varies from
9-11 mm at the upper part to 7.4-9.3 mm at the inferior
part. The size of nerve root canals varies from upper
to lower lumbar segments. They become progressively
longer from L1 to S1 as the dural root sleeves exit at a
more oblique inferior angle. Therefore, the nerve root
canals of L5 and S1 are the longest in the lumbar region.
oral communications
26. NSAIDs and Chronic Pain: What’s the Evidence?
Joseph Pergolizzi
Department of Medicine, Johns Hopkins University School
of Medicine, Baltimore, MD, USA; Temple University School
of Medicine, Philadelphia, PA, USA; Naples Anesthesia and
Pain Associates, Naples, FL, USA
The 2010 Patient Protection and Affordable Care Act
required the Department of Health and Human Services
(HHS) to enlist the Institute of Medicine (IOM) in
examining pain as a public health problem. Chronic pain
affects about 100 million American adults—more than
the total affected by heart disease, cancer, and diabetes
combined. Pain also costs the nation up to $635 billion
each year in medical treatment and lost productivity.
Pain is multidimensional and requires providers to
use a multimodal and multidisciplinary biopsychosocial
approach when treating patients. Still, analgesics are
considered the mainstay for the majority of the published
pain management guidelines 1. Two of the most common
pharmacotherapy treatments used for chronic pain
are opioids and nonsteroidal anti-inflammatory drugs
(NSAIDs), including acetaminophen. Americans consume
80% of the global supply of opioids and about 99% of the
world’s supply of hydrocodone, specifically 2 . As a result
of more aggressive treatment of pain in the United States
(US), the medical use of opioids has increased at least 10fold over the last twenty years. Because of their euphoric
value, opioids have also been associated with misuse and
abuse. To help mitigate issues of misuse and abuse of
opioid analgesics and other controlled substances, the
State of Florida recently incorporated a tracking system,
a system that 34 other states already have in place. Many
of the 34 states plan to share prescription tracking
information via the Prescription Monitoring Program
Information Exchange to track inter-state prescription
drug dispensing activity.
The CDC estimates the societal cost of prescription
drug abuse in 2001 at about $8.6 billion. In 2007,
deaths involving opioids were almost twice that of deaths
involving cocaine and more than five times those involving
heroin. In 2008, the Drug Abuse Warning Network
estimated that of the 1 million emergency department
visits involving prescription or over-the-counter drugs
used non-medically in 2008, about 306,000 involved
opioid pain medication 3. Non-medical use included
taking more than prescribed, taking drugs prescribed to
someone else or substance abuse. Those patients taking
more than the prescribed amount of medication may
not understand well the ramifications of such actions or
67
may not have been advised well by either the prescribing
physician or dispensing pharmacist. A recent FDAcommissioned evaluation found that only 75% of written
consumer medication information provided to patients
at the time a new prescription is filled meets minimal
criteria for usefulness 4.
NSAIDs are one of most commonly used pain relievers.
There is a wide variety of over-the-counter (OTC) NSAIDs
available, allowing patients to self-medicate. Prescription
NSAIDs are normally reserved for more intense pain and
are available in many different delivery routes. The major
problem with use of NSAIDs is the occurrence of adverse
events (AEs). AEs occur in various organ systems.
Gastropathy associated with use of nonspecific NSAIDs is
the most frequent AE in the United States. In patients with
RA and OA, nonspecific NSAID-associated gastropathy
is associated with approximately 107,000 hospitalizations
annually in the United States 5. It is estimated that 16,500
nonspecific NSAID-related deaths occur among patients
with RA and OA in the United States as well 5. In the United
Kingdom, an estimated 12,000 upper GI admissions and
2230 deaths appear to be attributable annually to the use of
nonspecific NSAIDs 6.
Renal: by inhibiting renal prostaglandins, use of
nonspecific NSAIDs may result in acute renal failure,
fluid and electrolyte imbalances, exacerbation of chronic
renal insufficiency, interstitial nephritis, and nephrotic
syndrome 7. Patients at risk for reduced renal function
with nonspecific NSAID use include those with renal
disease, congestive heart failure (CHF), cirrhosis with
ascites, volume depletion, and diuretic use 8.
Cardiovascular (CV): nonspecific NSAIDs can increase
blood pressure and interfere with the blood pressure–
lowering effects of certain antihypertensive agents,
especially angiotensin-converting enzyme (ACE) inhibitors,
β-blockers, and diuretics 9. In addition, nonspecific NSAIDs
can cause fluid retention, which can exacerbate congestive
heart failure (CHF) 8.
Hematologic reactions associated with nonspecific
NSAIDs include inhibition of platelet aggregation and
function, which can lead to an increased risk of bleeding
and bruising 9.
From the US 10 to Europe, regulatory agencies recommend
that NSAIDs be prescribed at the lowest effective dose and
for the shortest possible duration. Medical societies are also
aligned with the recommendation that NSAIDs should be
prescribed at the lowest effective dose 11. Recent findings
highlight the fact that both duration of exposure and dose
contribute to potential NSAID-related AEs but that higher
doses might play an even larger role. Properties of lower
oral communications
68
dose NSAIDs using SoluMatrix Fine Particle Technology™
may address these recommendations through increases
in surface area and enhanced dissolution. This allows for
enhanced absorption kinetics (potentially shortens time after
administration when the maximum plasma concentration
is reached [Tmax]) and reduced systemic exposure while
providing effective pain relief.
References
1.
http://www.americanpainsociety.org/resources/content/
clinical-practical-guidelines.html accessed Dec. 2013.
2. Manchikanti S, Fellows B, Ailinani H, Pampati V. Therapeutic
use, abuse, and nonmedical use of opioids: a ten-year perspective.
Pain Physician. 2010;13:401-35.
3. US Centers for Disease Control (CDC). Unintentional Drug
Poisoning in the United States. July 2010.
4. Kimberlin CL, Winterstein AG. Expert and Consumer
Evaluation of Consumer Medication Information – 2008,
Final Report to the U.S. Department of Health and Human
Services and the Food and Drug Administration, November 4,
2008. (http://www.fda.gov/AboutFDA/CentersOffices/CDER/
ReportsBudgets/ucm163777.htm.
5. Singh G. Recent considerations in nonsteroidal antiinflammatory drug gastropathy. Am J Med. 1998;105 (suppl
1B):31S-8S.
6. Blower AL, Brooks A, Fenn GC, et al. Emergency admissions
for upper gastrointestinal disease and their relation to NSAID use.
Aliment Pharmacol Ther. 1997;11:283-91.
7. Brooks P. Use and benefits of nonsteroidal anti-inflammatory
drugs. Am J Med. 1998;104(suppl 3A):9S-13S.
8. Girgis L, Brooks P. Nonsteroidal anti-inflammatory drugs:
differential use in older patients. Drugs Aging. 1994;4:101-12.
9. Verburg KM, Maziasz TJ, Weiner E, et al. COX-2-specific
inhibitors: definition of a new therapeutic concept. Am J Ther.
2001;8:49-64.
10. FDA. www.FDA.gov.
11. AGS Panel on the Pharmacological Management of Persistent
Pain in Older Persons. Pharmacological management of persistent
pain in older persons. J Am Geriatr Soc. 2009;57(8):1331-46.
27. Ultrasound and Chronic Pain: Is it Useful to
Reduce Complications?
Philip Peng
Department of Anesthesiology and Pain Management,
Toronto Western Hospital, University Health Network,
University of Toronto, Toronto, Canada
Ultrasound provides an affordable, radiation-free, and
portable imaging modality, allowing excellent imaging of
soft tissue, and real-time appreciation of needle placement
and medication spread at the target. The limitation
of ultrasound is related to the physical properties. It
provides limited view of bony structures, and the image
resolution degrades with depth of the tissue.
In the context of “is it useful to reduce complications”,
two issues need to be considered. Based on the target
structures, ultrasound-guided pain intervention (UGPI)
can be divided into three categories: peripheral, axial and
musculoskeletal. The other issue is the broader definition
of complication. Putting a needle in the wrong place can
result in failure of block and inadvertent damage of tissue.
These are the complications of inaccurate block.
With this information in context, the literature
supporting that UGPI in peripheral and musculoskeletal
tissues reduces complications is strong. The literature,
however, is mixed in the context of UGPI in axial
structures.
Ultrasound-guided pain intervention in peripheral
tissue
Ultrasound provides excellent visualization of the
soft tissue. It allows the practitioner to avoid inadvertent
damage of structures such as vessels and organs. A
notable example is cervical sympathetic chain injection.
This is commonly performed by inserting needle at C6 or
C7 level between the cricoid/trachea and carotid artery
using bone as a landmark. In the needle path, volume of
literature suggests the presence of different important
structures such as esophagus and vessels. The latter can
be arteries such as vertebral artery (10% not covered by
bone at C6), inferior thyroid artery, deep cervical artery.
The prevalence of the presence of artery ranges from 2329% at C6 and 43% at C7. As a matter of fact, one study
showed that the ‘blind approach’ results in hematoma
formation in 25% of individuals. Fluoroscopy can identify
vascular puncture only after the vessel is punctured.
Hematoma formation in the retropharyngeal space can
be very disastrous.
In term of accuracy, ultrasound improves accuracy
and in a lot of situations, the study showed the accuracy
of landmark-guided injection was very low. Examples
are: lateral femoral cutaneous nerve (5% vs. 95%), and
ilioinguinal nerve (30% vs. 95%).
Ultrasound-guided pain intervention in musculoskeletal structures
The literature in supporting superior accuracy of
UGPI in musculoskeletal structures is robust in various
regions: shoulder, hip, knee and ankle; irrespective of the
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experience of practitioner. Furthermore, UGPI reduces
complications and patient discomfort. One example is in
the hip injection in which landmark-based injection with
anterior approach resulted in inadvertent puncture of
femoral nerve in 27% of individuals.
Ultrasound-guided pain intervention in axial structures
Two areas have been well examined: lumbar and
cervical spine facet medial branch block.
Lumbar region
In contrast to the peripheral and musculoskeletal
structures, the literature did not support any superiority
of facet injection (medial branch and facet joint) in
the lumbar region. This reflects the limitation of the
ultrasound in the imaging of bone and deep structures.
The accuracy of facet medial branch and facet joint
injection is in the range of 90-95%. However, the accuracy
plummets to an average of 62% when the technique was
applied to a population of body mass index >35. Needless
to say, there is no advantage of ultrasound-guided
technique in reducing complications.
Cervical region
In the cervical region, the influence of obesity is less
important. Two approaches to the cervical medial branch
block had been examined and validated. One is the long
axis view approach by the Swiss group. In an exploratory
study performed in 50 chronic neck pain patients, the
ultrasound visibility of the relevant structures in the
cervical facet joint region (i.e. medial branches, bony
target of medial branch blocks) was classified as excellent
for the levels C2-C6, with exception of the C7 medial
branch, most likely due to the difficulty to scan the distal
cervical vertebra in the presence of the ipsilateral clavicle.
In a recent study the accuracy of ultrasound guided
cervical facet joint nerve blocks was determined in 60
healthy volunteers. The needles were placed out-of-plane
using ultrasound imaging and the needle tip position and
contrast dye distribution were assessed with fluoroscopy,
which served as a ‘gold standard’. The accuracy was very
high for the levels C2-C6 (88-94%) with exception of the
medial branch C7, where accuracy was low, probably due
to the above mentioned difficulties of ultrasound imaging
of the lower cervical region.
Another approach was examined by the McGill
group in Canada. They used a transverse view and the
needle is inserted in plane and continuously visualized
as it is directed towards the articular pillar (AP). A
recent study evaluating this technique in 209 blocks
involving 53 patients found that injection on the AP
was achieved in all cases, and level specific accuracy
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was 100% for C2-C3 and C3, 98% for C4, 91% for
C5 and 85% for C6. The C7 medial branch was not
studied. The presence of a blood vessel overlying the
AP was noted in 7.9% of blocks and was successfully
avoided during needle insertion.
In both approaches, the visualization and accuracy is
excellent for upper cervical spine. A recent randomized trial
was conducted in which the third occipital nerve block was
either performed with ultrasound-guided or fluoroscopyguided approach. While there were no differences in
accuracy, block-produced hypoesthesia and post-block
pain score, the ultrasound-guided approach was associated
with a significantly shorter performance time (212.8 vs.
396.5 seconds; P=0.000) and fewer needle passes (2 vs. 6;
P=0.000). Increase in procedure time and needle attempts
may be translated to increases in patient’s discomfort. In
addition, C2-C3 intra-articular spread of radiographic
contrast and vascular breach were noted in 15% and 10%
of patients in the fluoroscopy group respectively while they
were both 0% in the ultrasound group.
In conclusion, UGPI improves the accuracy and
reduces complications in peripheral and musculoskeletal
targets but not in lumbar facet block. For cervical medial
branch block, it provides a safe and reliable alternative to
fluoroscopy.
28. Rational Opioid Pharmacotherapy
Christopher Gharibo
Department of Anesthesiology, Pain Management, New York
University Langone Medical Center, New York, NY, USA
Pain is a universal experience and the main reason for
which patients seek medical care. Virtually all clinicians
encounter and regularly treat pain in patients, yet chronic
pain control remains a global problem.
Chronic non-cancer pain in adults, with an average
global prevalence of about 20%, diminishes quality of life,
disrupts productivity, interferes with work and activities
of daily living, may result in complete or partial disability,
and can adversely affect the patient’s family and personal
life. The recognition of chronic non-cancer pain as a
clinically important pain syndrome has led to a variety
of pharmacological treatment options. Long-term opioid
therapy for chronic non-cancer pain syndromes has
increased steadily year over year in the United States over
the past decade but continues to be an unmet medical
need in major parts of the globe.
Chronic non-malignant pain requires long-term
therapy and there is currently no ideal analgesic agent
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for chronic use in all patients. While most clinicians are
comfortable prescribing any number of analgesic agents
for acute pain syndromes and understand the benefit of
opioid agents to treat cancer pain, chronic non-cancer
pain remains a ‘blind spot’. In this session we will discuss
pros and cons of pharmacotherapy including responsible
opioid prescribing in 2014.
29. Opioid Induced Hyperalgesia (OIH) and
its Management in Acute and Chronic Pain
Christopher Gharibo
Department of Anesthesiology, Pain Management, New York
University Langone Medical Center, New York, NY, USA
Multidisciplinary treatment of degenerative diseases
may include pharmacological, rehabilitative, psychological,
interventional and surgical approaches. Goals include
improvement of function, self-sufficiency, skills training,
maladaptive habit reversal, maintenance, and relapse
prevention. There is strong evidence that combination
interventional and non-interventional treatment breaks the
cycle of pain, improves function and reduces pain relative to
non-multidisciplinary treatment.
In this session, we will focus on benefits and risks of pain
interventions, including sorting out the mechanisms efficacy
and injury in an effort to improve the safety of interventions
to the same degree that these interventions are effective.
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Posters
BEST POSTER AWARD REGIONAL ANESTHESIA
01. Adrenocorticotrophic hormone level and postoperative patient controlled analgesia in orthopedic
patients: epidural versus intravenous
Saeid Reza Entezary – Mahmoud-Reza Alebouyeh – Seyed Hamid-Reza Faiz – Poupak Rahimzadeh – Mahsa Motavaf – Saeid Safari
Iran University of Medical Sciences, Department of Anesthesiology and Pain Medicine, Rasoul Akram Medical Center, Tehran, Iran
BACKGROUND AND AIMS: The aim of this randomized study was to compare the adrenocorticotrophic hormone
(ACTH) levels in patient-controlled intravenous analgesia (PCIA) versus patient-controlled epidural analgesia (PCEA) in patients
undergoing lower extremities orthopedic surgery. METHODS: After obtaining approval from university ethics committee,
60 ASA class I-II patients between 19-85 years scheduled for lower extremities orthopedic operation were randomly allocated
to receive either postoperative analgesia with PCEA or PCIA (30 patients/group). ACTH levels, visual analogue scale (VAS)
and Ramsay Sedation Score (RSS) were assessed upon arrival to the operating room and at 1, 12, and 24 hours after surgery.
RESULTS: Compared to the PCIA group, ACTH levels in the PCEA group were down-regulated markedly 12 and 24 hours
after surgery (P<0.001). The VAS scores at 1, 12, and 24 hours after surgery were significantly lower in the PCEA group (P=0.029,
P=0.010, P=0.001) respectively. The RSS scores at 12 and 24 hours after surgery were significantly higher in the PCIA group
(P=0.001). PCEA compared to PCIA had lower incidence of nausea (n=8 vs. n=16; P=0.023) and vomiting (n=3 vs. n=11; P=0.021).
CONCLUSION: Assessment of ACTH, as a potential biomarker for stress, and RSS and VAS for assessment of behavioral
responses, indicated that PCEA provide lower stress responses with improved analgesia compared with PCIA.
BEST POSTER AWARD CHRONIC PAIN
02. Genome-wide expression profiling of complex regional pain syndrome
Won Hyung Lee
Department of Anesthesia and Pain medicine, Chungnam National University Hospital, Daejeon, Korea
BACKGROUND: Complex regional pain syndrome (CRPS) is a chronic, progressive, and devastating pain syndrome
characterized by spontaneous pain, hyperalgesia, allodynia, altered skin temperature, and motor dysfunction. The aim of this
study was to identify certain pain-related genes through genome-wide expression profiling in the blood from CRPS patients.
METHODS: We analyzed 4 CRPS patients (2 CRPS I and 2 CRPS II) and 5 controls with Illumina Human HT-12 v4 Expression
BeadChip (Illumina, Inc., San Diego, USA). We validated genes from microarray using quantitative reverse transcriptionpolymerase chain reaction (qRT-PCR) in 24 CRPS patients and 18 controls. The experimental procedures were performed in
accordance with the animal care guideline of the Korean Academy of Medical Science. RESULTS: We found that 80 genes
were differentially expressed between 4 CRPS patients (2 CRPS I and 2 CRPS II) and 5 controls (cut-off value:1.5-fold change
and p<0.05). Most of those genes were associated with signal transduction, developmental processes, cell structure and motility,
and immunity and defense. The expression levels of major histocompatibility complex class I A subtype (HLA-A29.1), matrix
metalloproteinase 9 (MMP9), alanine aminopeptidase N (ANPEP), L-histidine decarboxylase (HDC), granulocyte colonystimulating factor 3 receptor (G-CSF3R), and signal transducer and activator of transcription 3 (STAT3) genes selected from
the microarray were confirmed in 24 CRPS patients and 18 controls by qRT-PCR. The MMP9 gene, by qRT-PCR, showed a
statistically significant difference in expression in CRPS patients compared to controls with the highest relative fold change
(4.0±1.23 times and p=1.4ⅹ10-4). CONCLUSION: Our findings, which offer a valuable contribution to the understanding of the
differential gene expression in CRPS, may help in the understanding of the pathophysiology of CRPS pain progression.
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BEST POSTER AWARD PAIN AND BASIC SCIENCE
BEST YOUNG RESEARCHER AWARD
03. GPCR heterodimerization leads to opioid-induced hyperalgesia
Marino Convertino(1) – Alexander Samoshkin(2) – William Maixner(2) – Luda Diatchenko(3) – Nikolay V. Dokholyan(1)
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, United States(1) – Center
of Neurosensory Disorders, University of North Carolina at Chapel Hill, Chapel Hill, United States(2) – Alan Edwards Centre for
Research on Pain, McGill University, Montreal, Canada(3)
BACKGROUND AND AIMS: Opioids are the most prescribed and effective drugs for treatment of moderate and severe pain.
They act as agonists towards μ-opioid receptor (mOR), a G Protein-Coupled Receptor (GPCR) that mediates the perception of noxious
stimuli at the level of the central nervous system.1 Despite their pharmacological efficacy, the use of opioids in therapy is compromised
by the onset of severe side effects, the most important one being the opioid-induced hyperalgesia (OIH).1 A recently discovered six
trans-membrane-helices variant of mOR (6TM-mOR) is directly involved in the generation of an excitatory cellular response, leading
to the onset of OIH.2,3 Moreover, evidence of the involvement of β2 adrenergic receptor (b2AR) in mediating opioid-dependent side
effects has been reported in literature.4,5 Our main aim is to understand and describe, at the molecular level, the role and function of
6TM-mOR and b2AR in the development of OIH. METHODS: We have performed protein-protein docking calculations,6 as well
as classical7 and discrete molecular dynamics8 simulations to investigate structural and dynamical features of mOR isoforms, upon
binding of morphine. We have used MedusaDock,9 our in-house developed docking algorithm simultaneously accounting for ligand
and receptor flexibility, to generate structural models of the morphine-bound GPCRs. Biochemical assay, immunofluorescence
microscopy and site-directed mutagenesis experiments have been adopted to validate our computational findings. RESULTS AND
CONCLUSIONS: We have collected solid evidence demonstrating that 6TM-mOR is able to heterodimerize with β2 adrenergic
receptor (b2AR), upon chronic exposure to membrane-permeable opioids. We have further observed that the newly formed 6TMmOR/b2AR heterodimer migrates to the cell surface and, in response to binding of b2AR to agonist, undergoes agonist–induced
internalization. Finally, we have demonstrated that morphine-dependent 6TM-mOR/b2AR activation leads to stimulation of
intracellular signaling pathways and activates an excitatory cellular response, ultimately leading to the development of OIH.
References
1. Reisine T, Pasternak G. The Pharmacological Basis of Therapeutics. (1996) Goodman & Gilman (ed. McGraw-Hill, NY), 528-532
2. Shabalina SA et al. (2009) Hum. Mol. Genet. 18:1037-1051
3. Gris P et al. (2010) Mol. Pain. 2:6-33
4. Liang DY et al. (2006) Anesthesiology 104:1054-1062
5. Liang DY et al. (2007) Behav. Brain Res. 181(1):118-126
6. Minteseris J et al. (2007) Proteins, 69:511-520
7. Van der Spoel D. et al. (2005) J. Comput. Chem., 26:1701-1718
(8. a) Dokholyan NV et al. (1998) Fold. Des., 3:577-587; (b) Shirvanyants D et al. (2012) J. Phys. Chem. B, 116:8357-8382
9. (a) Ding F et al. (2010) J. Chem. Inf. Model., 50:1623-1632; (b) Yin S et al. (2008) J. Chem. Inf. Model. 48:1656-1662
BEST POSTER AWARD PERIOPERATIVE CARE
04. Severe hypoglycemia in laparoscopic colectomy without glucose infusion
Nobutada Morioka – Mirei Nagai – Rie Kanamori – Makoto Ozaki
Tokyo Women’s Medical University, Tokyo, Japan
BACKGROUND: A preoperative carbohydrate load has been shown in some studies to be effective in suppressing
postoperative insulin resistance. However, not much is known about the effects of no-loading carbohydrate
administration on glucose, lipid, and protein metabolism during surgery. Therefore, we studied the effects of
preoperative intravenous carbohydrate administration on intraoperative glucose, lipid, and protein metabolism.
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METHODS: Forty patients who were scheduled for elective laparoscopic colectomy were randomly assigned to 2
groups: a glucose group that received 1500 mL of a maintenance solution with 10% glucose (glucose 150 g) and a
control group that received the same amount of an extracellular solution without glucose. Glucose metabolism during
and after surgery (blood glucose levels, insulin, C-peptide), lipid metabolism (ketone body fractions, free fatty acids),
and protein metabolism (urinary 3-methylhistidine) were also evaluated. RESULTS: Blood glucose levels during
surgery remained significantly lower (P=0.003) in the control group than in the glucose group. One patient had a blood
glucose level below 40 mg/dL, and 6 patients had blood glucose levels below 60 mg/dL. Lipid catabolism increased
before the induction of aneshesia. CONCLUSION: In elective laparoscopic colectomy, perioperative administration
of carbohydrates should be considered to prevent hypoglycemia and to suppress catabolism.
05. Stem cell as advanced therapy for experimental neuropathic pain
Silvia Franchi(1) – Anna Teresa Brini(2) – Alberto Emilio Panerai1 – Paola Sacerdote(1)
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy(1) – Department of Biomedical,
Surgical and Dental Sciences, University of Milan, Milan, Italy(2)
BACKGROUND: Neuropathic pain (NP) is a highly invalidating and incurable disease that commonly derives from a
damage of the peripheral nervous system. In previous studies, in a murine model of NP, we obtained pain remission with
the intravenous injection of adult neural stem cells. We now use mesenchimal stem cells from human adipose tissue (hASC).
These cells are characterized by strong immunomodulatory properties, are able to differentiate into cells of the mesodermal
and ectodermal lineage and their use could be relevant in future clinical applications allowing autologous transplantation.
METHODS: Painful neuropathy was induced in mice using chronic constriction injury model (CCI). hASC were obtained
from lipoaspirates of aesthetic surgery and were injected into the caudal vein of mice 7 days after surgery. Thermal hyperalgesia
and mechanical allodynia were monitored overtime to assess the effect of the cells on pain. The ipsilateral sciatic nerves were
used for IL-1 and IL-10 measurements while the lumbar dorsal spinal cord (L4-L6 level) for iNOS evaluation. RESULTS:
hASCs are able to induce a significant, rapid and long lasting antihyperalgesic and antiallodynic effect: the effect starts 1 day
after cell injection with a complete reverse of thermal hyperalgesia, lasts 21 days and can be restored by a second injection.
hASCs can restore physiological levels of sciatic nerve IL-1 , increased by the lesion, while the anti-inflammatory cytokine
IL-10, decreased by CCI, was gradually augmented until its level became higher than in controls. Moreover a dose response
effect is evident both on pain and cytokines. Cells can induce changes also at spinal cord level reducing the iNOS levels.
CONCLUSION: In conclusion we suggest that stem cells can start a bidirectional interaction with the lesioned-inflammed
nerve which is at the basis of the positive modulation of pain and neuroinflammation.
06. Role of a new family of chemokines, the prokineticins, in experimental neuropathic pain
Mara Castelli(1) – Sarah Moretti(1) – Silvia Franchi(1) – Gianfranco Balboni(2) – Roberta Lattanzi(3) – Lucia Negri(3) – Alberto
Emilio Panerai1 – Paola Sacerdote(1)
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Milan, Italy(1) – Dipartimento
di Tossicologia, Università di Cagliari, Cagliari, Italy(2) – Dipartimento di Fisiologia Umana e Farmacologia “V. Erspamer”,
Università “La Sapienza” di Roma, Rome, Italy(3)
BACKGROUND: It is known that the development of neuropathic pain (NP) is due to a pathological interaction between
neuronal and immune cells and the recently discovered chemokines, prokineticins, might have a role in this crosstalk. Since
PK2 and its receptors (PKR1 and PKR2) are involved in nociception and immunomodulation we investigated the role in NP
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evaluating the effect of a PKRs antagonist, PC1, in different models of NP, the chronic constriction injury of sciatic nerve (CCI)
and the diabetic neuropathy (STZ). METHODS: Three days after surgery CCI animals developed allodynia and hyperalgesia
and a group of them was injected with PC1 (s.c. 150 μg/kg twice-daily) for one week. Diabetic neuropathy was induced in mice
using streptozotocin (STZ, i.p. 200 mg/kg). Two weeks after STZ, when allodynia was fully developed, mice were treated
with PC1 for two weeks. As controls, neuropathic and normal mice treated with either PC1 or saline were used. PK2 and
PKRs levels in spinal cords and sciatic nerves were measured by RT-PCR. We also analyzed IL-1 and IL-10 production in
the same tissues from different groups by RT-PCR and ELISA. RESULTS: Ten days after CCI and 28 days after STZ, PK2
and PKRs levels increased in CCI and STZ spinal cords and sciatic nerves. At these times in spinal cord and sciatic nerve of
neuropathic mice an imbalance between pro- and anti-inflammatory cytokines was present with an increase of IL-1 levels and
a reduction of IL-10. PC1 induced a significant relief of painful symptoms both in CCI and STZ treated mice and restored the
physiological balance between pro- and anti-inflammatory cytokines in the spinal cord and sciatic nerve. CONCLUSION:
Our data suggest that PKs system may act as a pivotal mediator for the neuro-inflammatory components of NP and could be
an interesting target for its treatment.
07. Telephone survey of patient experience and satisfaction with regional anaesthesia for hand surgery
Reshma Bhosale – Nafeesa Akhtar – Tim Moll
Northern General Hospital, Sheffield Teaching Hospitals, Sheffield, United Kingdom
BACKGROUND AND AIM: Regional anaesthesia is a safe and well-established technique for upper limb day case
surgeries. We routinely use this technique for our upper limb surgeries. We undertook a review of our clinical practice to
analyse patient experience and satisfaction. METHODS: We interviewed 45 consecutive patients who received brachial
plexus blocks under Ultrasound guidance with or without nerve stimulator. The standard drugs used were Prilocaine 1%,
Lignocaine 2% and Bupivacaine 0.255%, 0.375% or 0.5% either solely or in combination. All patients were discharged
by six hours post surgery and contacted by telephone 48 hours later. Questions related to regional block duration and
experience, information given, pain scores (VAS) during block procedure and at home were asked. RESULTS: We
identified 42 out of 45 (93.3%) patients who reported that the amount of information given to them was about right. We
found that 42/45 (93.3%) would have regional anaesthesia again. Majority (44/45, 97.8%) would recommend this technique
to others. The overall action of the block lasted for five hours in 20/45 (44.4%), 6-11 hours in 10/45 (22.2%), 12-24 hours in
10/45 (22.2%) and more than 24 hours in 4/45 (8.9%) cases. 41/45 (92%) patients had pain score less than six. Pain score
of six or more was reported by 19/45 (42%) when the block wore off. In total 35/45 (77.8%) patients thought the duration of
block was just about adequate, while 6/45 (13.3 %) felt it as too long and 3/45 (6.7%) felt it as too short. In our group none
of the patients reported any adverse events related to blocks. CONCLUSION: We found high level of patient satisfaction
and no technique related adverse events. So we conclude that regional anaesthesia is a desirable option for day case hand
surgeries and patients can be reliably discharged within six hours of anaesthetic.
08. Acute pain antagonizes the anti-inflammatory effects of opioids
Peggy Compton(1) – Charles Griffis(2) – Breen Elizabeth(3) – Matthew Torrington(4) – Eshetu Tefera(5) – Michael Irwin(3)
School of Nursing and Health Studies, Georgetown University, Washington DC, United States(1) – Department of Anesthesiology, UCLA,
Los Angeles, United States(2) – Semel Institute for Neurosciences, UCLA, Los Angeles, United States(3) – Dept of Family Medicine, UCLA,
Los Angeles, United States(4) – Dept of Biostatistics and Epidemiology, MedStar Health Research Institute, Washington DC, United States(5)
BACKGROUND: Accumulating evidence suggests that pain and opioids separately induce changes to the activity of
innate immune system. What has not been explored is the degree to which acute pain and opioid analgesics act together
to influence markers of inflammation. The purpose of this study was to characterize pro-inflammatory responses to acute
pain and opioid analgesia, separately and together, in healthy control subjects. METHODS: The study was designed to
compare molecular inflammatory signaling (unstimulated nuclear factor (NF)-kB expression) and cellular cytokine markers
of inflammation (interleukin-6, IL-6; soluble tumor necrosis factor receptor II, TNFRII; interleukin-1 receptor antagonist,
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IL-1ra;) in healthy individuals (n=23, 11 female) following randomly ordered experimental sessions of: opioid-only (IV
fentanyl 1 μg/kg), pain-only (cold-pressor), pain+opioid, or a control (resting) condition. Blood samples were obtained
before, during and three hours after experimental sessions. The study received full and continuous approval from the
UCLA Institutional Review Board. RESULTS: Expected physiological effects of pain and opioids on sympathetic and
nociceptive systems were observed. Opioid alone trended toward decreases in the levels of the majority of inflammatory
markers examined, and significantly so in the case of the cytokine receptor TNFRII (p=0.005). However, neither short-term
responses in the pain-only nor pain+opioid conditions differed from control responses. CONCLUSIONS: Inconsistent
with previous investigations, experimental pain did not result in significant changes in immune markers, with patterns of
response to pain similar to those of controls. However, acute opioids had consistent depressant effects on inflammatory
systems, depressing markers with pro-inflammatory effects. Interestingly, across subjective and immune measures, opioid
effects were reversed or antagonized by the presence of experimental pain. That pain may protect the patient from the
immune consequences of opioid administration is a novel and intriguing finding.
09. The novel combination of pregabalin, oxycodone/naloxone and Tiobec® for relief of neuropathic
cancer-related pain: a preliminary study
Stefano De Santis
Palliative Care and Oncological Pain Service, San Camillo-Forlanini, High Specialization Hospitals, Rome, Italy
BACKGROUND: The prevalence of neuropathic pain in patients with cancer has been estimated at 19–39%. Targin®
(oxycodone/naloxone controlled-release tablets) have been shown to be effective and potentially have fewer side effects
in treating moderate–severe cancer-related pain. The CR oxycodone plus pregabalin represent a valuable addition to the
existing pharmacotherapy for cancer-related neuropathic pain (Gatti, Eur Neurol 2009; Garassino, PLoS ONE 2013).
The Cochrane Review demonstrated efficacy of gabapentin with alpha-lipoic acid for the treatment of neuropathic pain
(Chaparro, Cochrane Database of Systematic Reviews 2012). We set out to investigate the effectiveness and safety of Targin®
combined with pregabalin and alpha-lipoic acid (Tiobec®, Laborest, Italy) for the management of neuropathic cancer pain.
METHODS: We conducted an observational study on lung cancer patients in advanced stage, with moderate to severe
neuropathic pain treated with Targin® plus pregabalin and Tiobec® 800 mg bid for 28 days. Patients were started on
dosages of Targin® and pregabalin included in the recommended ranges, as required by their pain condition. The initial
mean daily dose of Targin® was 28.04 mg, pregabalin was 96.73 mg. Daily doses were titrated at scheduled visits on days
7, 14, 21 to achieve optimal efficacy and tolerability, based on patient response and adverse events. Concomitant fentanyl
sublingual tablets were used for the management of breakthrough pain. RESULTS: From January 2013 to July 2013
were enrolled 23 patients with advanced non-small lung cancer which showed moderate-severe intensity neuropathic
pain with 20 patients (87%) demonstrating BTcP. The combination therapy was effective for alleviating neuropathic pain
(reduction in NRS value: 32%). Improvements from baseline in quality of life and HADS score were reported. At the end of
treatment, the majority (92.3%) of patients found that the treatment had been ‘effective’. Combination therapy also allowed
neuropathic pain free in 62.5%, a 60% reduction of BTcP occurrence as median number of daily episodes. Combination
treatment was effective at low mean doses of Targin® plus pregabalin probably due to Tiobec® adjuvant therapy, and had
a favorable safety profile. CONCLUSION: This study found pioneering correlation between neuropathic cancer pain and
emerging BTcP in a model of combination therapy that integrates Targin® plus pregabalin and Tiobec® into cancer pain
management and allows an effective control of cancer pain and BTcP.
10. High-frequency spinal cord stimulation for the treatment of FBSS: preliminary results
Giuliano De Carolis – Mery Paroli – Lara Tollapi – Franca Bondi – Paolo Poli
Pain Therapy Unit, Santa Chiara University Hospital, Pisa, Italy
INTRODUCTION: Spinal cord stimulation (SCS) has gained wide acceptance for the management of chronic pain
secondary to failed surgery (failed back surgery syndrome, FBSS). Despite advances in SCS technology, lower limb pain can
be alleviated easily with SCS but it is more difficult to achieve sufficient pain relief in the low back region. The novel SenzaTM
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(Nevro Corp., Menlo Park, CA, USA) allows high frequency (up to 10 kHz) to be delivered to the spinal cord stimulation
without inducing paresthesia. The aim of our work was to quantify the efficacy and safety of a SCS system that utilizes highfrequency waveforms, which do not produce paresthesia for the treatment of chronic FBSS. METHODS: Five patients
(mean age 53.2 yrs) with diagnosis of FBSS and indication for SCS were recruited for a trial of high frequency stimulation
with a percutaneous eight-contact epidural lead. We evaluated psychiatric disorders according to DSM IV criteria, intensity
of pain (VAS) and disability (Oswestry Disability Index-ODI). Outcome measure scores were assessed after 3 and 6 months
from the implant. RESULTS: After a trial period 100% of patients reported a significant improvement in VAS scores and
underwent permanent implantation of the high frequency SCS system. Mean back pain was reduced from 7 to 2.2 after
six months. Mean leg pain VAS of 5.8 was reduced to 1.8 at six months. There were significant improvements both in
ODI score and quality of sleep. Percentage of disability decreased from 51% to 25% after six months. All patients reduced
pain medication use. No adverse events were observed. CONCLUSION: In patients with intractable chronic FBSS, high
frequency SCS provided significant low back and leg pain relief, improvement in disability and sleep. Notably this was
achieved without paresthesia and with a reduction in the surgical procedure time.
11. Paravertebral block versus IV lidocaine in unilateral total mastectomy: comparison of perioperative
opioid requirements
Katy French – Elizabeth Rebello – Alicia Kowalski – Jeff Cerny – Farzin Goravanchi – Spencer Kee
MD Anderson Cancer Center, University of Texas, Houston, United States
BACKGROUND: Paravertebral block (PVB) use for breast surgery has been well documented. Most providers have
used either Bupivacaine or Ropivacaine with or without Clonidine. With this preparation in a single injection technique
8-24 hours of analgesia have been reported. At MD Anderson Cancer Center a combination of Ropivacaine, Epinephrine,
Clonidine, and Dexamethasone has been used with stronger and longer lasting analgesia. METHODS: An institutional
IRB approved prospective study was conducted. Patients having total mastectomy with or without immediate tissue
expander, and segmental mastectomy with sentinel lymph node biopsy were selected. Six injections at the level of T1-T6
PVB space were done under IV sedation. The surgery was also performed under general anesthesia with LMA. Propofol
induction with volatile vapor maintenance with additional fentanyl as required was used for anesthesia. After recovery
in PACU, patients spent the night at the observation unit and were discharged home the following morning. All patients
received the same oral analgesia for pain management. Opioid consumption, post-operative nausea, and patient satisfaction
were measured. RESULTS: All patients were very satisfied with their anesthetic management as well as post-operative
analgesic care. No incidence of nausea was reported and a low number of pain pills were taken (Table). CONCLUSIONS:
In 7 patients the combination of Clonidine, Dexamethasone and Epinephrine in Ropivacaine solution provided analgesia
5 days postoperatively for major breast surgery.
PATIENT
TOTAL NUMBER PAIN SATISFACTION
PILLS TAKEN THE FIRST
6 DAYS
NAUSEA
**NUMBER PAIN PILLS TAKEN POST-OPERATIVE DAYS 0-5
st
POD # 0
POD # 1
POD # 2
POD # 3
POD # 4
POD # 5
1
12
Very Satisfied
None after 1 day
2
3
1
1
3
2
2
7
Very Satisfied
None
1
2
2
2
0
0
3
8
Very Satisfied
None
1
3
1
1
1
1
4
8
Very Satisfied
None
2
2
2
1
1
0
5
3
Very Satisfied
None
2
1
0
0
0
0
6
3
Very Satisfied
None
1
1
1
0
0
0
7
6
Very Satisfied
None
2
2
2
0
0
0
** Pills Taken: Hydrocodone 5 mg / Acetaminophen 500 mg
#
POD: Post Operative Day
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References
Aufforth, R et al. Paravertebral blocks in breast cancer surgery: is there a difference in postoperative pain, nausea, and vomiting? Ann Surg
Oncol. 2012 Feb;19(2):548-52.
Beyaz, S et al. Thoracal paravertebral block for breast surgery. Dicle Medical Journal. 2012;39(4): 594-603.
Bhuvaneswari, V et al. Post-operative pain and analgesia requirements after paravertebral block for mastectomy: A randomized controlled
trial of different concentrations of bupivacaine and fentanyl. Indian J Anesth. 2012 Jan-Feb; 56(1):34-39.
Coveney, E et al. Use of paravertebral block anaesthesia in the surgical management of breast cancer: experience in 156 cases. Ann Surg.
1998 April; 227(4):496-501.
Das, S et al. Multiple-injection thoracic paravertebral block as an alternative to general anesthesia for elective breast surgeries: a randomized
controlled trial. Indian J Anesth. 2012 Jan- Feb; 56(1):27-33.
Schnabel, A et al. Efficacy and safety of paravertebral blocks in breast surgery: a meta analysis of randomized controlled trials. Br J Anaesth
2010;105:842-52.
Tahiri, Y et al. General anaesthesia versus thoracic paravertebral block surgery: a meta analysis. J Plast Reconstr Aesthet Surg 2011;
64:1261-9.
12. Comparison of postoperative analgesic effect of dexamethasone and fentanyl added to lidocaine through
axillary block in forearm fracture
Siamak Yaqubi
Department of Anesthesiology, Rajaii Hospital/Qazvin University of Medical Science, Qazvin, Iran
AIM: Regional analgesia has been introduced as better analgesic technique compared to using systemic analgesic
agents, and it may decrease the adverse effects and provide a higher degree of satisfaction. Several additives have
been suggested to enhance analgesic effect of local anesthetic agents such as opioids and steroids. We designed
this randomized double-blind controlled study to compare the analgesic efficacy of dexamethasone and fentanyl
added to lidocaine using axillary block in patients undergoing forearm fracture surgery. MATERIALS AND
METHODS: Seventy eight patients 20-60 years old were recruited in a prospective, double-blinded, randomized
way. Axillary block was performed in the three groups by using lidocaine 40 ml and distilled water 2 ml (L Group),
lidocaine 40 ml and dexamethasone 2 ml (LD group), and lidocaine 40 ml and fentanyl 2 ml (LF group).The
onset time of sensory and motor block, duration of sensory and motor block, the total analgesic dose administered
during 6 hours after the surgery and hemodynamic variables were recorded. RESULTS: The duration of sensory
and motor block were significantly longer in LD group compared to other groups (P<0.001). Similarly the total
analgesic consumption in LD groups was smaller compared to other groups (P<0.001). Comparison of hemodynamic
consequences of axillary block and surgery failed to reveal any statistically significant differences between all
groups. CONCLUSION: Addition of dexamethasone to lidocaine significantly prolonged the duration of analgesia
compared with fentanyl/lidocaine mixture or lidocaine alone using axillary block in patients undergoing forearm
fracture surgery.
13. Rapydan®: patient satisfaction vs. physician satisfaction
Lynn Puissant – Julie Lauweryns
UZ Leuven – Department of Anesthesiology, University Hospitals Leuven, Leuven, Belgium
BACKGROUND AND AIMS: Anesthesia induction in children can be done intravenously or by inhalation.
Because intravenous access offers additional safety during induction, methods for painless intravenous puncture
have been investigated. The present study was designed to evaluate satisfaction with Rapydan®, a medicinal patch
containing 70 mg of lidocaine and tetracaine, as a tool for painless venous puncture. METHODS: After approval
by the ethical committee, 20 children, starting from the age of 5, were included. By asking: “Who would use
Rapydan® again for a future anesthetic induction?˝ we evaluated satisfaction of the children and their doctors. We
scored the answers using a 5-point Likert scale (0=definitely disagree; 1=rather disagree; 2=agree; 3=rather agree;
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4=definitely agree). An anesthesiologist administered the Rapydan® patch and placed the intravenous catheter.
RESULTS: 8 out of 20 children definitely agreed to use Rapydan® again for a future anesthetic induction, 6
agreed and 3 tended to agree, only 3 children tended to disagree. No patient would definitely not use Rapydan®
again. In 6 cases, the anesthesiologist definitely agreed, in 7 cases he agreed and in 7 other cases he tended to
agree. No anesthetist tended to disagree or definitely disagreed to use the patch again (Figure). Limitation in our
study is a low number of patients. CONCLUSION: This study shows good satisfaction for venous puncture in
children and anesthesiologists.
Who would use Rapydan® again in the future?
8
7
Number of patients
6
5
4
Physician
Patient/Parents
3
2
1
0
0
1
2
3
4
Likert Scale
14. New safety meta-analysis of ketoprofen vs. ibuprofen and diclofenac: risk and benefit of non steroidal antiinflammatory drugs beyond efficacy meta-analysis
Piercarlo Sarzi-Puttini(1) – Fabiola Atzeni(1) – Luigi Lanata(2) – Alessandra Monguzzi(2) – Michela Bagnasco(2)
Rheumatology Unit, L. Sacco University Hospital, Milan, Italy(1)– Medical Department, Dompé S.p.A, Milan, Italy(2)
BACKGROUND AND AIMS: Ketoprofen, ibuprofen and diclofenac have been widely used in the last 30 years
for the management of mild-to-moderate pain. In light of greater efficacy of oral ketoprofen vs. ibuprofen and/
or diclofenac demonstrated in our recent previous meta-analysis, we decided to perform a new meta-analysis of
randomised controlled trials (RCTs) in order to compare the safety of oral ketoprofen vs. ibuprofen and diclofenac and,
as a consequence, to define complete risk/benefit profiles of these well-known molecules. METHODS: A systematic
literature search was performed on main scientific databases until July 2013 to identify RCTs comparing directly
therapeutic doses of oral ketoprofen (50-200 mg/day) vs. ibuprofen (600-1800 mg/day) or diclofenac (75-150 mg/
day). Two rheumatologists, in accordance with the Cochrane Collaboration guideline, carried out independently study
selection. Trials included in this meta-analysis were the same evaluated in the efficacy meta-analysis. RESULTS:
All the included studies (13 RCTs, involving 898 patients) showed a good safety profile for ketoprofen; in particular,
treatments based on ketoprofen showed a 4% lower risk (RR) of developing an adverse event (AE) vs. treatments based
on diclofenac or ibuprofen, even though there was no statistical significance in this result (P=0.7593, 95% CI 26%25%). The difference between rates of AEs (Risk Difference) with the three molecules was equal to 0 (P=0.9323, 95%
CI –5%-4.5%), and no serious AE was observed. No difference across the studies in the heterogeneity test for the
safety outcome, demonstrating the reliability of meta-analysis results. CONCLUSIONS: Ketoprofen is well tolerated
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and its safety profile is comparable to ibuprofen and diclofenac, with no AE observed. Therefore, on the basis of
the superior efficacy previously demonstrated, these safety features suggest that ketoprofen has the best risk/benefit
profile vs. ibuprofen and diclofenac and support its strong recommendation in clinical practice.
15. Different electrical neuromodulation treatments in chronic knee osteoarthritis pain: preliminary results
of a multi-centric study
Massimo Allegri(1) – Massimo Barbieri(2) – Giuliano De Carolis(3) – Fabio Intelligente(4) – Alessia Violini(5) – Mery Paroli(3)
Terapia del Dolore, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy(1) – Centro Osp. Terapia del Dolore, Clinica S. Carlo,
Paderno Dugnano (MI), Italy(2) – UO Terapia del Dolore, Azienda Ospedaliero-Universitaria Pisana – Ospedale Santa Chiara, Pisa,
Italy(3) – UO Anestesia Generale, Istituto Humanitas, Milan, Italy(4) – UO Anestesia e Terapia Intensiva, Azienda Provinciale
per i Servizi Sanitari, Trento, Italy(5)
BACKGROUND: Chronic osteoarthritis (OA) pain of the knee is often not effectively managed with conservative
treatment models and some of them have serious adverse effects. Intra-articular Pulsed Radiofrequency (PRF),
Neurostimulation with PENS therapy device and Genicular Neurotomy Procedure are therapeutic alternatives for
the treatment of chronic pain. We investigated short- and mid-term effectiveness of these different techniques in
patients with chronic knee pain due to OA. METHODS: This study was carried out in five Italian Pain Therapy
units between January 2013 and June 2013. Eleven patients who received intra-articular PRF, six patients who
received PENS therapy and seven patients who received Genicular Neurotomy were retrospectively reviewed.
Intensity of pain and activity were evaluated by a VAS (0=no pain/activity; 10=worst possible pain/activity). Patients
were evaluated at baseline and after 1, 3, 6 mths from the procedures. Changes in pain medications were noted.
RESULTS: Mean sample age was 76.2 yrs. Before procedure mean intensity of pain was 8.6. During a 3 mths
follow-up period all patients showed a significant reduction of pain during activity. Pain intensity was 3.8 after
one mth; 4.2 after two mths and 5 after three mths. Pain was absent at rest that resulted in an improvement in
quality of sleep. Activity improved but not in significant way probably due to the high average age. All patients
decreased drugs rescue dose. No significant differences among the procedures were found due to the small sample.
CONCLUSION: Electrical neuromodulation treatments for chronic knee OA appears to be effective both in pain
reduction and functional improvement in a cohort of elderly patients. A larger sample is needed to confirm this
data and to compare the outcomes of the procedures considered.
16. Sacro-iliac arthrodesis: our experience and preliminary results
Viola Marta Custodi(1) – Vittorio Silvani(1) – Raffaelino Pugliese(1) – Francesco Lombardi(1) – Antonio Fratto(1) – Mariarosaria
Verlotta(1) – Andrea Cattalani(1) – Danilo Miotti(2) – Massimo Allegri(1) – Paolo Gaetani(1)
IRCCS Policlinico San Matteo, Pavia, Italy(1) – Fondazione Salvatore Maugeri, Pavia, Italy(2)
BACKGROUND AND AIMS: Between 15-30% of patients presenting with low back pain have some SI joint
involvement. The diagnosis of instability of SI joint is quite difficult and depends on a detailed combination of
clinical maneuvers and injection tests. In 5% of patients with SI joint pain, the joint is physically unstable resulting
in ineffectiveness of the medical-conservative approach. In this preliminary study we present the results of the first
15 cases of SI joint instability treated using a minimally invasive SI joint arthrodesis system (iFuse Implant System)
in order to evaluate the safety and the efficacy of this system. METHODS: Medical charts at a single center were
reviewed for demographics, perioperative metrics, patient reported outcomes for pain, function and quality of life
(assessed through NRS, ODI and RDQ respectively), as well as satisfaction with surgery and results of postoperative
CT scan. RESULTS: Mean age was 53 years and all patients were female. Patient reported outcomes at followup (range 8-24 months) improved clinically as well as statistically as evidenced by a mean improvement in pain on
NRS of 4 points, back related function on ODI by 19.4 points, and in quality of life measured using RDQ of 13.6
points (all P=0.01). The only complication occurred had been local hematoma that required drainage in two patients.
Patient satisfaction was 100%. All 3 month CT scans showed initial fusion. CONCLUSION: The results of this study,
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although follow-up is short, confirm that minimally invasive SI joint fusion using the iFuse Implant System is a safe
and effective method of treating patients with sacro iliac joint instability.
17. RNA-seq of the DRG nociceptome
Gian Luigi Gonnella(1) – Samridhi Goswami(2) – Santosh Mishra(3) – Hal Kominski(2) – Jason M. Keller (2)– Bruno A.
Zanfini(1) – Stefano Catarci(1) – Gaetano Draisci(1) – Mark Hoon(3) – Michael J. Iadarola(2)
Department of Anesthesiology and Intensive Care Medicine, Catholic University School of Medicine, Rome, Italy(1) –
Anesthesia Section, Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda MD,
United States(2) – Molecular Genetics Unit, LSB, NIDCR, National Institutes of Health, Bethesda MD, United States(3)
BACKGROUND AND AIMS: Our understanding of nociceptive molecular biology is rudimentary at best and has
never been dissected with a strategy that combines genetic labeling with comprehensive transcriptome sequencing.
This report investigates the pain transcriptome of the nociceptive circuit. We present a preliminary study investigating
gene expression in TRPV1-enriched vs. TRPV1-depleted cell populations of the dorsal root ganglion and modulation
of their expression patterns by peripheral nerve damage. METHODS: Total RNA extraction has been applied to
harvested dorsal root ganglia (DRG) from mice and rats after sciatic nerve transection. DRG cell populations were
analyzed from transgenic mice expressing Cre recombinase under control of the TRPV1 promoter to label or delete
TRPV1-lineage neurons. RNA-seq was performed on an Illumina Hi-Seq 2000 device to quantify gene expression.
RESULTS: Reads mapping back to ~ 25,000 genes revealed ~20,500 well expressed genes in the DRG of which 45
exhibited a ten-fold or greater expression in TRPV1-enriched compared to 62 in TRPV1-depleted neuronal populations.
Analyzing the differentially expressed genes after axotomy, according to their basal expression and TRPV1 lineage
helped to identify functional groups involved in neuropathic pain and nerve regeneration. CONCLUSIONS: Using
such an approach we have elucidated the complete transcriptome of an important and clinically relevant population of
nociceptors: those that express TRPV1. RNA-seq provides a comprehensive determination of expressed genes that, in
combination with physiological manipulations, allows new in-depth investigations of nociceptive and non-nociceptive
neurons molecular alterations developed in chronic pain. Altered gene expression occurred in ion channels, protein
kinases, transcription factors, consistent with excitability and regeneration processes.
18. Validation of the analgesia nociception index in patients undergoing major abdominal surgery
during sevoflurane-based general anaesthesia
Christian Compagnone – Eleonora Schiappa – Greta Migliavacca – Adriana Angeletta – Giovanna Goldaniga –
Alessandra Markidis – Matteo Dall’Aglio – Alessandro Marchignoli – Fernanda Tagliaferri – Marco Berti – Guido
Fanelli – Nazarena Vignali
Department of Anesthesiology, Critical Care and Pain Medicine, University Hospital of Parma, Parma, Italy
BACKGROUND AND AIMS: The Analgesia Nociception Index, based on heart rate variability analysis, constitutes a
measure of parasympathetic tone and has been described to reflect different levels of intraoperative nociceptive stimulation
during total intravenous anaesthesia. Currently in general anesthesia anesthetic vapors are mostly used. In this study,
we hypothesized that the reliability of the index does not change under sevoflurane-based anaesthesia. METHODS: To
test this hypothesis, we analyzed ANI’s response to painful stimulus (tetanic stimulation of the ulnar nerve) in patients
undergoing major abdominal surgery. ANI and haemodynamic data were recorded before and after the painful stimulus
in two different anesthetic moments: after induction with intravenous anesthetic and during maintenance with gas. The
depth of hypnosis was monitored by the Bispectral Index (BIS) in order to reduce variables. RESULTS: Five patients
were enrolled, including 4 males (80%) and 1 female (20%) with a median ASA of 3 (IQR 1). The median age was 67 (IQR
26.5). The median of the ANI variation after tetanic stimulation during induction with intravenous anesthetic (propofol)
was 17 (IQR 23) and with sevoflurane was 16 (IQR 38). The difference was not statistically significant. CONCLUSIONS:
Several studies have analyzed the difference of the effects of intravenous anesthetics and anesthetic vapors on HRV. The
induction of anesthesia with propofol decreases blood pressure, entropy, and HF in a BIS-dependent manner, indicating
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that propofol reduces cardiac parasympathetic tone depending on the depth of hypnosis. Conversely, sevoflurane does not
show the BIS-dependent decreases in heart rate, blood pressure, HF, and entropy, indicating that sevoflurane has little or
no effect on cardiac parasympathetic tone.This preliminary study sought to lay the groundwork for a possible use of the
index under general anesthesia with anesthetic vapors. The Analgesia Nociception Index appears to be realizable also
during sevoflurane-based general anaesthesia.
19. Long term outcome in children treated with intrathecal baclofen
Giovanna Goldaniga – Christian Compagnone – Maurizio Leccabue – Guido Fanelli
Department of Anesthesiology, Critical Care and Pain Medicine, University Hospital of Parma, Parma, Italy
INTRODUCTION: Intrathecal baclofen (ITB) is used in therapy of severe spasticity. The most common cause of
severe spasticity in children is cerebral palsy. The incidence of cerebral palsy is 2-3/1000 newborns but increases to 4080/1000 if newborns weigh less than 1500 grams. There aren’t studies that describe long term outcome in children
treated with intrathecal baclofen. AIM: This is a retrospective study to evaluate the outcome in cerebral palsy underage
after almost 5 years in therapy with continuous ITB and to evaluate if the outcome varies depending on the age when the
sample started the therapy. METHODS: Retrospective evalutation of 48 cerebral palsy underage with severe spasticity
in therapy with ITB for at least 5 years. Of 48 underage: 23 patients started therapy with ITB between 6-12 years old, 25
between 13-18 years old. We evaluated all visits and made a telephone interview to evaluate: efficacy, satisfaction on the part
of the family, advantages, disadvantages and side effects (pharmacological and complication of system). RESULTS: 79%
of the sample evaluated as good the efficacy and they were satisfied with the ITB. The most common advantages were ease
of nursing care and physiotherapy, pain, sleep; only some patients had advantages about posture and functionality. There
weren’t many disadvantages but 77% of patients had side effects. The outcomes did nor differ depending on the age when
the children started the therapy. CONCLUSIONS: Despite the high incidence of complications, that require a continuous
monitoring of these patients, the satisfaction of the family was very high and there were several advantages. There are no
statistically significant differences in the long-term outcome of patients starting the therapy after 6 years of age.
20. The optimal dose of Targin® administered in association with continuous peripheral nerve block
for total knee arthroplasty: a preliminary study
Laura Camici(1) – Valeria Cedrati(2)– Gianluca Cappelleri (2)
Scuola di Specializzazione Anestesia e Rianimazione, Università degli Studi dell’Insubria, Varese, Italy(1) – Istituto
Ortopedico G. Pini, Azienda Ospedaliera, Milan, Italy(2)
BACKGROUND: Targin® (oxycodone + naloxone) is a common drug used either in chronic and postoperative acute
pain. Several dosages included between 5 up to 40 mg/die have been proposed, but no study demonstrated the ‘optimal
dose’ in case of concomitant use of continuous peripheral nerve block. The aim of this observational, prospective study,
was to compare three conventional doses (10, 20, 30 mg/die) routinely used after total knee arthroplasty. METHODS:
Forty-eight patients who had undergone primary total knee arthroplasty (TKA) were observed between March 15, 2013
and June 30, 2013. All patients received continuous femoral nerve block or lumbar plexus block + a single-shot sciatic nerve
block. Targin® was started 12h postoperatively and continued at least for 48h. Patients received 3 different doses (5x2,
10x2, 15x2) depending on the anaesthesiologist's choice. Postoperative analgesia also included ketorolac 30 mg x 3/die,
and Perfalgan® 1 g as rescue dose. A P<0.05 was considered significant. RESULTS: All 48 patients received a perfusion
of local anesthetic through nerve catheter at least for 48h. Eleven patients (23%) received Targin® 5x2, 20 patients (41%)
received 10x2, and 17 patients (35%) received 15x2. No differences in nausea, vomiting and pruritus were observed between
the 5x2, and 10x2 postoperative administration, while statistical difference was seen between the 5x2 and 15x2 dosages
(P<0.05). CONCLUSION: Preliminary data of this observational study demonstrated that Targin® 5x2 mg/die did not
provide adequate pain relief compared with higher doses (10x2, 15x2) after TKA when a continuous femoral/lumbar plexus
block was administered. The dosage of 30 mg/die did not add any benefit in terms of analgesia compared with 10x2 mg/
die, increasing the risk of complications.
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VAS SCORE
10
9
*
8
*
7
6
5
4
5x2
10x2
15x2
3
2
1
0
6h
12h
24h
48h
21. How personal post-operative pain experience affects nurses’ attitudes towards the assessment and
management of patients’ pain: a phenomenological study
Panagiota Gardeli – Clifford Richardson – Penelope Stanford
University of Manchester, Manchester, United Kingdom
BACKGROUND AND AIMS: Barriers to pain assessment are numerous and often not clearly identified. These barriers
challenge practice and are resistant to effective efforts to change. The aim of this study was to explore Greek nurses’ personal
experiences of post-operative pain in order to understand how this may influence their attitudes, beliefs and ability to assess and
manage post-operative pain. This research was part of a larger PhD study. METHODS: A qualitative research method with a
phenomenological approach, based on participants’ semi-structured interviews, was used to explore how the lived experience of
personal pain experiences informed nurses pain management practice. Data were collected in a large teaching Greek hospital from
May to September 2013. A purposive sample of fifteen registered nurses, with a minimum of two-year post qualification surgical
experience, and who had experienced postoperative pain, was recruited. The analysis was based on Colaizzi’s approach. RESULTS:
Participants described how fear and anxiety due to the lack of preoperative information, postoperative pain and discomfort, led to
significant mood changes alongside reduced sleep and lack of appetite. This affected their personal and professional attitude, beliefs
and behaviour. Participants became more sensitive, sympathetic, attentive and understanding towards patient’s pain. Additionally, after
this painful post-operative experience, participants felt they could assess patient’s post-operative pain effectively without the use of pain
assessment tools. CONCLUSIONS: Assuming that knowledge is based on both reality and experience, personal painful experiences
acquired by the nurses demonstrate that they can enhance nurses’ empirical knowledge relating to the assessment of patient’s pain.
Nurses’ own lived experiences contribute to a deeper understanding and therefore to a more systematic approach to their patient’s care.
22. The meaning of the pain experience in the family context: allowance for a nursing therapeutic intervention
Anabela Mendes
Escola Superior de Enfermagem de Lisboa, Lisbon, Portugal
BACKGROUND AND AIMS: The pain experience assumes a remarkable record in a context of malignant disease
with successive admissions for hemodynamic instability. The severe but not always effective drug regimen conditions
the sick person daily life as well as the family where he belongs. The aim of this study was to understand: the meaning
of the pain experience for the family; the reported nursing interventions as facilitators in the process of experiencing
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pain; the family strategies used to ensure support to the most vulnerable members of the family. METHODS: Using
the methodology of the case study, according to Yin (2009), data collection has been based on the open structured
interviews supported by Kvale (2009). To ensure detailed and faithful data, was used the Nvivo support. RESULTS: It
was verified that in the transition health-disease process (2000) the pain experience meant suffering and reduced life
quality not only for the sick person but also for families. Nursing interventions mentioned as facilitators are: the opportunity
to express their doubts and find relevant and assiduous information; drug and non-drug therapeutics as open visits who
allow comfort and pain relief to the sick person. As support strategies to the more vulnerable family members are listed
the tracking and monitoring of the situation understanding. CONCLUSIONS: Pain is responsible for the emergence of
major pathophysiological changes which contribute to the appearing of organic and psychological comorbidities (2008) in
the people who experience it. In situations of great vulnerability as the pain experience, the sick person and family are the
nursing attention focus, being the most important to ensure symptoms relief and support life quality.
23. Occipital nerve stimulation (ONS) for treatmeant of intractable chronic migraine: our fi rst experience
Annamaria Vilardo
School of Anesthesia and Intensive Care, University of Pavia, Pavia, Italy; Department of Anesthesia and Intensive Care I and
Pain Service, Foundation IRCCS Policlinico San Matteo, Pavia, Italy
BACKGROUND AND AIMS: WHO recognizes migraine as a public health problem, ranking it at 7th place among
worldwide diseases leading to disability. Migrainous people are physically, emotionally and psychologically disabled by
attacks, with inferior quality of life and greater health resource utilization. Numerous acute and prophylactic medications
are used for treatment, however a subset of chronic migrainous remains medically intractable. Neuromodulation offer an
opportunity to these patients: Occipital Nerve Stimulation (ONS) is employed off-label for medically refractory headache.
Aim of this case report is to prove safety and efficacy of this emerging technique reporting our experience. METHODS:
Our patient was a female 45 years old, suffering of chronic migraine, with a story of daily attacks unresponsive to prescribed
medical therapy, complaining of drugs overuse, depression and disability disrupting work, family and social life. With
patient consent we have implanted ONS: the procedure was performed in local anaesthesia, an incision was made close
to the occiput, under radiologic control a lead was positioned over the emergency of bilateral occipital nerves. Trial
stimulation was performed intraoperatively to confirm correct lead placement and paresthesia coverage. After a successful
trial period of 1 month a pocket was created under the right pectoral muscle for implantable pulse generator. Stimulating
parameters were optimized till patient experienced mild paresthesia in the stimulated area. No procedure complications
were registered. RESULTS: At 1 month and at long-term follow-up a significant decrease in all pain parameters was noted
(reduction of VAS score from 8 to 2), and a significant reduction in analgesic use, now used ‘on demand’ with effectiveness.
Quality of sleep and life improved. Patient satisfaction is presently very high and with a hand-held personal programmer
she can adjust stimulation. CONCLUSIONS: ONS involves a minimally invasive surgical procedure and, while body of
evidence is still emerging, appears to show great promise in managing pain and disability of intractable migraine.
24. Stress affects COMT haplotype dependent pain in a gender specific manner: a gene-sex-environment
interaction
Carolina Meloto(1) – Eric Bair(2) – Gary Slade(2) – William Maixner(2) – Luda Diatchenko(1)
McGill University, The Alan Edwards Centre for Research on Pain, Montreal, Canada(1) – University of North Carolina at
Chapel Hill, Regional Center for Neurosensory Disorders, Chapel Hill, United States(2)
BACKGROUND AND AIMS: Catechol-O-methyltransferase (COMT) is an enzyme that controls level of
catecholamines and is involved in several biological functions, including pain perception and stress response. COMT
genetic variants have been associated with these phenotypes, however, a growing body of evidence suggests that
genetic effects are often greatly modified by gender and environment. COMT activity has been shown to affect pain
via β-adrenergic receptors in a haplotype dependent manner; exposure to stress leads to an increase in release of
catecholamines, suggesting that COMT-haplotype dependent pain might be masked by the overload of stress-sensitive
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catecholamines. Moreover, stress and pain are known to be gender-related, also suggesting that there might be an
interaction between COMT haplotypes, stress, and gender affecting response to pain. METHODS: We investigated the
effect of this three-way interaction on different experimental pain phenotypes from the OPPERA cohort, and replicated
these findings on a clinical pain cohort (CRASH). Both studies were approved by their respective institutional review
boards. RESULTS: OPPERA cohort results showed that COMT haplotypes are associated with rating of noxious
stimuli in both genders in such way that only in low stress situations COMT haplotypes show robust contribution to
pain ratings. COMT haplotypes by stress and COMT haplotypes by gender interactions were significant with major
contribution of stress. The clinical pain cohort proved the three-way interaction to be significant (p=0.03), and that
COMT haplotype dependent pain is only true for males in low stress situation (p=0.003). CONCLUSIONS: Our
findings highlight the capital importance of sex-gene-environment interactions and provide the first example of such
interactions for the COMT gene in humans by demonstrating that COMT-haplotype dependent pain is evidenced if
one controls for gender and stress level. This is particularly important for future studies that will aim to investigate the
effect of COMT haplotypes on different pain phenotypes.
25. Five days of postoperative analgesia with unique solution
Farzin Goravanchi – Spencer Kee – Alicia Kowalski – Joel Berger – Katy French
University of Texas MD Anderson Cancer Center, Houston, United States
BACKGROUND: Paravertebral block (PVB) use for breast surgery has been well documented. Most providers
have used either Bupivacaine or Ropivacaine with or without Clonidine. With this preparation in a single
injection technique 8-24 hours of analgesia have been reported. At MD Anderson Cancer Center a combination
of Ropivacaine, Epinephrine, Clonidine, and Dexamethasone has been used with stronger and longer lasting
analgesia. METHODS: An institutional IRB approved prospective study was conducted. Patients having total
mastectomy with or without immediate tissue expander, and segmental mastectomy with sentinel lymph node
biopsy were selected. Six injections at the level of T1-T6 PVB space were done under IV sedation. The surgery
was also performed under general anesthesia with LMA. Propofol induction with volatile vapor maintenance with
additional fentanyl as required was used for anesthesia. After recovery in PACU, patients spent the night at the
observation unit and discharged home the following morning. All patients received the same oral analgesia for pain
management. Opioid consumption, post-operative nausea, and patient satisfaction were measured. RESULTS: All
patients were very satisfied with their anesthetic management as well as post-operative analgesic care. No incidence
of nausea was reported and a low number of pain pills were taken (Table). CONCLUSIONS: In 7 patients the
combination of Clonidine, Dexamethasone and Epinephrine in Ropivacaine solution provided analgesia 5 days
postoperatively for major breast surgery.
PATIENT
TOTAL NUMBER PAIN SATISFACTION
PILLS TAKEN THE FIRST
6 DAYS
NAUSEA
**NUMBER PAIN PILLS TAKEN POST-OPERATIVE DAYS 0-5
POD # 0
st
POD # 1
POD # 2
POD # 3
POD # 4
POD # 5
1
12
Very Satisfied
None after 1 day
2
3
1
1
3
2
2
7
Very Satisfied
None
1
2
2
2
0
0
3
8
Very Satisfied
None
1
3
1
1
1
1
4
8
Very Satisfied
None
2
2
2
1
1
0
5
3
Very Satisfied
None
2
1
0
0
0
0
6
3
Very Satisfied
None
1
1
1
0
0
0
7
6
Very Satisfied
None
2
2
2
0
0
0
** Pills Taken: Hydrocodone 5 mg / Acetaminophen 500 mg
#
POD: Post Operative Day
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26. Pain sensitivity during pregnancy and labor
Stefano Catarci – Bruno Antonio Zanfini – Gonnella Gian Luigi – Luciano Frassanito – Marco Scorzoni – Gaetano Draisci
Institute of Anesthesiology and Intensive Care, Catholic University School of Medicine, Rome, Italy
BACKGROUND AND AIMS: Animal studies suggest that pain perception is modified during pregnancy: aim of this study
is to investigate if pain sensitivity is modified in pregnant women. METHODS: Sixty pregnant women have been investigated
for cold detection, warm detection, cold pain and heat pain threshold (by quantitative sensory testing) and mechanical detection
threshold (by Von Frey hair) in two body areas (C6-C7 right forearm and T10 dermatome) according to these groups: 33-35
gestational weeks (group A), 38-40 gestational weeks (group B), early stage of active labor (group C); group C was also investigated
24 hours after the delivery (group C1). A group of 20 non-pregnant subjects has been used as control. RESULTS: Heat pain
threshold was significantly increased both at forearm in group A (median±IQR: 39.6±0.7 °C), group B (40.6±1.1 °C) and group
C (40.8±1.5 °C) (p<0.001) and at T10 level in group A (41.0±1.6 °C), group B (42.1±1.8 °C), and group C (42.3±1.3 °C) (p<0.001);
a significant difference was found also between groups C and C1 (p<0.001) (Table). Cold detection, warm detection, cold pain
and mechanical detection thresholds were not significantly different between pregnants and controls. CONCLUSIONS: In
pregnant women there is a progressive increase of heat pain threshold as compared to non pregnant subjects; moreover these
modifications involved body parts not directly affected by labor and delivery nociceptive stimuli.
Table – Differences in heat pain threshold between pregnant and non-pregnant women.
C6-C7 forearm
Median (±IQR)
33-35 GW (group A)
39.6 (0.7)
38-40 GW (group B)
40.6 (1.1)
Labour (group C)
40.8 (1.5)
Control group
39.0 (1.1)
T10 dermatome
p
Median (±IQR)
P
41.0 (1.62)
<0.001
42.1 (1.81)
42.3 (1.32)
<0.001
40.1 (1.73)
Differences in heat pain threshold before and after delivery
Labour (group C)
40.8 (1.5)
24 hs after delivery
(group C1)
39.6 (1.4)
42.3 (1.32)
<0.001
40.4 (1.42)
<0.001
27. Ultrasound training life-like manikin for pain therapy invasive procedure
Giuliano De Carolis (1) – Vincenzo Ferrari (2) – Marina Carbone (2) – Sara Sereni (2)
UO Terapia del Dolore, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy (1) – ENDOCAS, Università degli Studi di Pisa,
Pisa, Italy (2)
BACKGROUND: Invasive procedures for chronic pain control could be a good therapy in pharmacologically nonresponsive patients. However, the spread of these methods requires a specific training of the medical staff done by
experienced specialists in invasive procedures. In our Pain Therapy Unit, together with Pisa ENDOCAS bioengineering
centre, we produced a special ultrasound training life-like manikin for pain therapy invasive procedures. METHODS:
The phantom is designed to permit training for ultrasound guided pain therapy. The design takes into account that this
procedure is destructive and a way to verify the reaching of the nerves, which during a real procedure is verified reading
the impedance on a monitor. The simulation system is based on a commercially available spine phantom fi xed in a box.
For each trial the box is filled with a cheap gelatine that allow ultrasound examination and that can be easily replaced. Thin
electric terminations, invisible under ultrasound, are fi xed on the spine surface, in the real anatomic positions. An acoustic
signal informs the trainee that he/she reached the goal with the needle. RESULTS AND CONCLUSIONS: After first
trials it seems that the realism of this simulator is enough for training of ultrasound guided pain therapy. Further studies
are required to validate this simulator.
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28. Efficacy and safety of ropivacaine and methylprednisolone wound infusion after major abdominal
surgery: preliminary data of a phase III RCT
Stefano Cattaneo
Pain Therapy Service, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
BACKGROUND: Continuous wound infusion (CWI) of local anaesthetics is a simple intuitive approach to post-operative pain (POP)
treatment (Lavandhomme 2011). Results of trials about its use in abdominal surgery are controversial (Liu 2006, Gupta 2011). CWI with
steroids seems a rational approach to reduce even more local inflammation with higher effect on primary hyperalgesia (Romundstad
2007), but so far no trials have investigated its efficacy/safety and effects on POP. MATERIALS AND METHODS: After written
informed consent, a wound catheter was placed between peritoneum and trasversus in patients undergoing major abdominal
procedures. Following an initial bolus of 10 ml (Ropivacaine 0.2%) a 10 ml/h infusion (Ropivacaine 0.2% + Methylprednisolone 1 mg/
kg) was maintained in the first 24 hs together with morphine PCA. Pain scores at rest and movement were registered at 0, 6, 12 and 24
hs. RESULTS: In the Table we present preliminary data of our PHASE III RCT regarding morphine requirement and pain values in
the first 24 hs for 9 patients (Group A). An observational comparison, without any inferential intent, was made with the latest patients
(15/4/2013-19/07/2013) of trial NCT01233752 about postoperative analgesia after major abdominal procedures with IV morphine-PCA
(Group B). No side effect has been registered, neither related to drugs used nor related to catheter. CONCLUSIONS: No statistically
significant conclusion can be drawn from our results in consideration of the small dimension of our population; nevertheless some
considerations are cues to the trial continuation. Patients treated by CWI demonstrated an halve in morphine consumption (≈ 15 mg) in
the first 24 hs, which is one of the most important aims in perioperative pain therapy. This supports even more the placement of CWI
as an effective alternative in POP treatment. Noteworthy, administration of Methylprednisolone did not bring any side effects or delay in
wound healing, and suggests its potential role in POP treatment. Further data are needed to confirm our results.
Table
GROUP A
GROUP B
Morphine Consumption
15 mg (IQR 7.5-27.5)
30 mg (IQR 1-47.5)
NRS (24hs)
1.50 (± 1.31)
1.78 (± 2.64)
NRSm (24hs)
3.75 (± 1.91)
3.22 (± 2.86)
Acknowledgements
Supported by a grant from Italian Health Ministry and IRCCS Foundation Policlinico S. Matteo
References
Gumpta A. A meta-analysis of the efficacy of wound catheters for post-operative pain management. Acta Anaesthesiol Scand 2011 Aug;55(7):785-96.
Lavandhomme P. Improving postoperative pain management: Continuous wound infusion and postoperative pain. Eur J Pain Suppl 2011;5(2):357-63.
Liu SS, Richman JM, Thirlby RC, Wu CL. Efficacy of continuous wound catheters delivering local anesthetic for postoperative analgesia: a
quantitative and qualitative systematic review of randomized controlled trials. J Am Coll Surg 2006;203(6):914–32.
Romundstad L, Stubhaug A. Glucocorticoids for acute and persistent postoperative neuropathic pain: what is the evidence? Anesthesiology.
2007 Sep;107(3):371-3.
29. Acute pain service at the “Tor Vergata" Polyclinic in Rome: protocol management of postoperative pain
through the use of PCA
Bruno De Meo – Elisa Palombo – Simona Finocchi – Clarissa Caldarulo – Riccardo Ranaldi – Simone Parrino – Generoso
Storti – Daniele Munalli – Silvia Natoli – Mario Dauri
Emergency Care, Critical Care Medicine, Pain Medicine and Anesthesiology Department, Policlinico Tor Vergata, Rome, Italy
INTRODUCTION: Pain is an important symptom that can affect patients in the post-operative management,
often costly. In our retrospective observational study, we evaluated the effectiveness of the introduction of devices PCA
posters
CADD® – Solis in the APS protocol. METHODS: We enrolled 246 patients (130 males and 116 females) undergoing
surgery with predictable moderate-to-severe intensity pain that received a PCA device, with a reservoir containing 50
ml of morphine at 1 mg/ml concentration. At the end of surgical intervention morphine was titrated by 2 mg boluses up
to the achievement of NRS≤4. At this time the PCA has been set as follows: bolus 1 mg, lock-out 10 minutes, maximum
16 mg in 4 hours. The pain intensity was evaluated at rest (RIP) by NRS before surgery (T0), on awakening (T1) and at
regular time intervals : T2 (2 h), T3 (6 h),T4 (12h), T5 (18 h), T6 (24h), T7 (36h), T8 (48h). RESULTS: NRS evaluated
in controls was as follows: T0 (1.5), T1 (5.3), T2 (3.0), T3 (1.6), T4 (1.0), T5 (0), T6 (0), T7 (0,) T8 (0). Morphine
administered in titration was on average 13 mg, then 10 mg by 1 mg bolus. Thirty three patients (13.41%) reported side
effects: nausea 60%, vomiting 45%, sleepiness 15%. CONCLUSIONS: The self-administration of opiates as needed
by PCA allows the patient to quickly reach the minimum effective analgesic concentration (MEAC), ensuring optimal
control of postoperative pain with a low incidence of side effects and shorter hospitalization time.
30. Fentanyl pectin nasal spray for the treatment of breakthrough cancer pain (BTcP): our experience on
448 patients
Fausto Turriziani – Simona Finocchi – Elisa Palombo – Clarissa Caldarulo – Riccardo Ranaldi – Domenico Garreffa –
Marco Barbuto – Silvi Natoli – Mario Dauri
INTRODUCTION: BTcP affects 20-95% of patients with cancer pain and it negatively impacts on quality of
life. In this setting, opioids delivered by non-invasive routes, such as fentanyl pectin nasal spray (FPNS) may provide
rapid onset of analgesia and adequate pain relief. Aim of this study was to evaluate the efficacy of FPNS in the
treatment of BTcP. METHODS: Patients with cancer pain and BTcP were enrolled. Inclusion criteria included a
baseline pain of mild intensity on prolonged release (PR) opioid treatment. Before inclusion BTcP was treated by
paracetamol, tramadol or NSAIDs with poor effects. Once included, FPNS was given for the treatment of BTcP and
titrated to achieve pain relief. Over the 4-week follow-up, patients were asked to fill a daily questionnaire assessing
pain intensity, ease of use, FPNS effects on BTcP relief and its impact on the quality of sleep. Questionnaires were
evaluated weekly. RESULTS: 448 (241 males and 207 females; mean age 63.3 years) patients with BTcP were
enrolled. At inclusion mean NRS for baseline pain was 2.6 and mean NRS for BTcP episodes was 8.4. PR opioids
were oxycodone, hydromorphone, fentanyl-transdermal and tapentadol. Overall, 68% of patients complained a poor
quality of sleep. FPNS was titrated over the first week in all patients. To achieve BTcP relief, 100, 200, 400 and
800 μg of FPNS were needed in 35.5%, 41.3%, 15.7% and 7.5% of patients, respectively. Mean NRS score for BTcP
treated by FPNS was 2.58-2.44-2.63 after two, three and four weeks, respectively, while the onset of pain relief was
on average 5.12-5.82-5.77 minutes at the same study times. At the end of the study the quality of sleep improved in
80.31% of patients. CONCLUSIONS: FPNS provided fast and significant analgesia of BTcP episodes and improved
quality of life by means of rapid onset and ease of use.
31. Efficacy and safety of long lasting intrawound infusion in patients affected by breast cancer undergoing
mastectomy with immediate breast reconstruction: randomized, double blind study
Federico Romagnoli
Pain Therapy Service, IRCCS Policlinico San Matteo, Pavia, Italy
BACKGROUND AND AIMS: In patients undergoing mastectomy for breast cancer, immediate reconstruction provides
great psychological relief, but is often followed by acute and chronic pain and functional impairment1,2. Continuous wound infusion
(CWI) with local anaesthetics (LA) was shown to be an effective analgesic technique3,4, even if studies concerning its prolonged
use and long-term outcome are still lacking. METHODS: Patients were treated with CWI (levobupivacaine 0.25% 5 ml/h) for
the first 24 hs, together with IV morphine PCA, and then randomized to group A (levobupivacaine) or B (saline) through Patient
Controlled Intrawound Analgesia (PCIA) for 13 days. Rescue analgesia was provided by an oral fix combination of Acetaminophen
and Tramadol (325+27.5 mg: Patrol®). NRS/mNRS values, morphine consumption, rescue doses and side effects were registered.
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88
Catheters were removed after 48 hs of non-use. RESULTS: Preliminary data of our randomized controlled trial are presented.
After IRB approval, 14 patients were enrolled. In the first 24 hs, considering both groups, average morphine consumption was 7.9
mg ( 5.86 SD), mean NRS scores were lower than 4, while mean NRSm scores at any evaluation were higher than 4. Four patients
experimented PONV. Three patients in group A and 1 in group B kept the catheter all over the 14 days, while other patients kept
it for a mean of 5.5 days. Three catheters obstruction/dislocation occurred, while 6 catheters were removed because not used for
more than 48 hs. CONCLUSIONS: CWI with LA provided good pain relief and low morphine consumption in the first 24 hs
after mastectomy with immediate reconstruction, with the only exception of dynamic pain. Rescue dose request after 24 hs was
greater in group B, as shown in Table 1; this group had also a greater use of PCIA during the second postoperative day, with this
trend tending to invert by the third day. Prolonged catheter permanence was well tolerated without side effects, even if 14 days
could be unnecessary (considering the few patients keeping it all over the study period). Further data are needed to confirm this
observation and understand the effect on persistent pain.
Table 1 – Average NRS values from the second postoperative day, mean bolus administered through the catheter,
average oral rescue doses required
GROUP A n=9
GROUP B n=5
RESCUE DOSE/ DAY
0.83
1.23
PCIA N° BOLUS 2 POP
4
5.8
3.4
2.6
2.7
1.4
NRS max- mean- min 2 POP
3.5 – 1.7 – 0.5
4.8 – 2.8 – 1
NRS max- mean- min 5 POP
3.4 – 1.4 – 0.57
2.5 – 1.75 – 1
NRS max- mean- min 1 month
3.5 – 2.25 – 0.875
2 – 0.7 – 0.25
NRS max- mean- min 3 months
1.8 – 0.8 – 0
1.6 – 0.6 – 0
PCIA, Patient Controlled Intrawound Analgesia.
References
1. Brummett CM. Chronic pain following breast surgery. Tech Reg Anesth Pain Manag. 2011;15:124-32
2. Andersen KG, Kehlet H. Persistent Pain After Breast Cancer Treatment: A Critical Review of Risk Factors and Strategies for Prevention.
J Pain 2011;12:725-46
3. Pacik PT. Pain management in augmentation mammoplasty: a randomized, comparative study of the use of a continuous infusion versus
self administration intermittent bolus of local anesthetic. Aesthetic Surg J 2004;24:523-30
4. Rawal N, Gupta A, Helsing M. Pain relief following breast augmentation surgery: a comparison between incisional patient-controlled
regional analgesia and traditional oral analgesia. Eur J Anaesthesiol 2006;23:1010-7.
32. The older people and the experience of pain: impact on self-care, self-esteem and quality of life
Anabela Mendes
Escola Superior de Enfermagem de Lisboa, Lisbon, Portugal
BACKGROUND AND AIMS: In a significant number of cases older people live with more than one chronic disease
and pain is mentioned as one of the most frequent symptoms and one of the major factors in older people commitment
to self-care, quality of life and self-esteem. In this study it is intended to know: how the experience of pain impacts on
everyday lives of elderly people and the strategies found by the elderly person and his family in order to enable comfort
and well-being in an everyday of illness and pain; nursing interventions mentioned as facilitators in the pain experience
process. METHODS: This study fits into a qualitative paradigm. The data collection had as resource a semi-structured
interview. Ethics committee approval. Data analysis was performed according to the method for generating a grounded
theory. The Nvivo support analysis of the data. RESULTS: It was found in the transition health-disease process that the
posters
experience of pain leads to deep changes in elderly patient daily life, including: refusal or inability for self-care exercise,
the isolation of the sick person due to their inability to solve the painful factor and to the risk of widening the symptoms;
significant change in self-esteem by the inability to undertake activities previously assumed without limitations. In the
strategies found to allow comfort and well-being in the disease process the constant monitoring and presence of family
members is a reference. Nursing interventions mentioned as facilitators are: the opportunity to express their doubts and
find relevant and assiduous information, the medication therapeutic actions taken in due course, the professional calm and
serene discourse and the establishment of a trustful relationship. CONCLUSIONS: Pain resulting from pathophysiologic
processes that stem from organic and psychological comorbidities translates into significant changes in the everyday life of
the people that experience it. In situations of great vulnerability as the experience of pain, the sick person, family and nurses
seek to develop strategies to ensure the relief of symptoms and the desired welfare.
33. Neutrophil/lymphocyte ratio as a predictive factor of postoperative pain after major abdominal surgery
Christian Compagnone
Anestesia, Rianimazione e Terapia Antalgica, Università di Parma, Italy
INTRODUCTION: Despite progress in pain treatment, a high number of patients continue to suffer from moderatesevere post-operative pain. Several authors have correlated the post-operative increase in pro-inflammatory cytokines
with the intensity of post-operative pain. At the moment, there is no a simple and cost-effective method that predicts
or measures this response. The Neutrophil/Lymphocyte ratio (N/L) has been used in differents circumstances in the
evaluation of the pro-inflammatory state. The purpose of our investigation is to evaluate the association between the
N/L ratio and acute, subacute and chronic post-operative pain in a population of patients undergoing major abdominal
surgery. MATERIALS AND METHODS: We extracted from the Acute Pain Service database a sample of 70 patients
undergoing elective surgery between January 2010 and December 2010. We considered, for each patient, the N/L
ratio, and information related to the acute post-operative pain 15, 30, 90 and 130 days after surgery. RESULTS:
Epidemiological data: 40 males (57.1%) who underwent abdominal surgery. Median ASA status was 2 (IQR 1), mean age
66 ± 12.2 years. Seven percent of patients presented NRS>8 in the immediate post-operative stage, an incidence of
persistent pain of 27%, with the mean N/L ratio of 4.98 ± 6.07. We found a statistically significant difference between
patients with severe acute post-operative pain (NRS>8) and pain present at 7th, 15th, and 30th postoperative day
(p = 0004). The ROC curve had an AUC of 0.67, with a sensitivity of 75% and a specificity of 65% (cut-off N/L=1.98).
DISCUSSION: This new index has a statistically significant association with acute and subacute pain. Despite the
limited sample, the N/L index has sufficient sensitivity and specificity. Further investigations involving other variables
could improve this association. In this study, N/L ratio had no association with the development of persistent pain.
34. “Non analgesic” effects of opioids
Alessandra Rocco – Annunziata Ferrari – Piera Clemenzi – Consalvo Mattia
ICOT- Polo Pontino Latina, “La Sapienza”, Università di Roma, Latina, Italy
Opioids, as all the "agonist-drugs”, mimic the action of a naturally occurring substance, targeting on whole the
body. Hence, beyond the main therapeutic effect (analgesia) and the well- known adverse effects (respiratory
depression, nausea and vomiting, constipation and cognitive impairment), there are other “non-analgesic” actions of
opioids. IMMUNOLOGICAL AND ANTI-INFLAMMATORY EFFECTS: Experimental evidence indicates
the involvement of the endogenous opioid system in epidermal homeostasis, cell differentiation, proliferation and
migration, underlying the immunomodulatory action of opioids. In periphery opioids have also anti-inflammatory effects
and, during inflammation, there is a sprouting of opioid receptors on sensory nerve terminals. ENDOCRINOUS
DISORDERS AND ALTERATION OF BONE METABOLISM: Endocrinous disorders due to the recurring use
of opioids involve hypothalamic-pituitary-gonadal or hypothalamic-pituitary-adrenal axis. Opioid-induced androgen
deficiency (OPIAD) and other disorders, as hypogonadism, are already well-known in clinical practice. Moreover longutilization of opioids might reduce bone mass density, increasing the risk of fracture. So the utilization of these drugs
89
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90
can be crucial in the treatment of patients with chronic pain, particularly if they are suffering from osteoporosis too.
HEART DISORDERS: Cardiovascular opioid responses (decreases in HR, BP, inotropism, cardiac output) are highly
dependent on the autonomic balance between sympathetic and parasympathetic systems when the opioidergic stimulus
is applied. New opioid peptide receptor-based cardiovascular therapies modulate the electrophysiological function, HR,
inotropism, vascular function and cellular stress resistance. Moreover opioids also protect cardiac tissue from ischemiareperfusion injury, contribute to protective conditioning responses and may trigger beneficial cardiac adaptations to
exercise. OCULAR EFFECTS: Opioids may have a protecting action for ocular tissues, with special emphasis on
the molecular mechanisms of neuroprotection against ischemic/hypoxic injury. The increasing prevalence of opioids
prescription is closely paralleled by the increasing emphasis on the ‘non-analgesic effects’, hence a ‘dark side of the
moon’ ready to be studied.
35. Suboptimal health: a potential translational instrument for chronic pain control and management
Wei Wang
Global Health and Genomics, Edith Cowan University, WA, Australia
Chronic pain is known to affect general health, psychological health, and social and economic wellbeing. Also it is one of the
most common personally compelling reasons for seeking medical advice 1-6. The random population-based studies in China
indicated that the prevalence of pain in China is over 40%. And more than half of the patients suffered from chronic pain 8-10.
Therefore, chronic pain management is a growing challenge for both primary care physicians and specialists. Traditional
Chinese Medicine (TCM), including Chinese herbal medicine, moxibustion and acupuncture, has been playing an important
role in pain control and management 7-10. Patients with chronic pain are more likely to use TCM than patients with other types
of pain 8. The advantages of TCM, such as fewer side-effects, low complication, low-addictive and cheap price, may partially
account for this phenomenon. But chronic pain has been identified empirically by traditional Chinese medicine practitioners;
a uniform convenient measurement or diagnostic instrument, therefore, is urgently needed 7-10. Suboptimal health status (SHS)
is characterized by ambiguous health complaints, general weakness, chronic pain and lack of vitality, and it has become a
new public health challenge in China. SHS is believed to be a subclinical, reversible stage of chronic disease. As studies of
intervention and prognosis for SHS are expected to become increasingly important, a reliable and valid instrument for its
assessment is essential. A questionnaire for measuring SHS in urban Chinese was developed based on focus group discussions
and a literature review. Questionnaire validity and reliability were evaluated in a small pilot study and then in a cross-sectional
study of 3000 individuals. The analyses included tests for reliability and internal consistency, exploratory and confirmatory
factor analysis, and tests for discriminative ability and convergent validity. The final questionnaire incorporated 25 items
on SHS (SHSQ-25), and encompassed 5 subscales: fatigue, cardiovascular system, digestive tract, immune system, and mental
status. The SHSQ-25 has proved to be a reliable and valid instrument for measuring sub-health status in urban Chinese 11, 12.
A new domain of SHS for chronic pain is being developed for chronic pain management. The progress of a combined genomics
and glycomics study 13-14 for screening biomarkers and exploring SHS as a preventive tool for non-communicable disease such
as chronic pain control and management will be presented.
Acknowledgements
This study was fi nancially supported by the National ‘‘12th Five-Year’’ Plan for Science and Technology Support, China (2012BAI37B03),
the Grant of Commonwealth of Australia (ACSRF06444) and the EU-fp7 Pain-Omics Grant (602736).
References
1. Becker N, et al. Pain epidemiology and health related quality of life in chronic nonmalignant pain patients referred to a Danish multidisciplinary pain center. Pain. 1997;73:393–400.
2. Magni G, et al. Chronic musculoskeletal pain and depressive symptoms in the National Health and Nutrition Examination—I:
epidemiological follow-up study. Pain. 1993;53:163–8.
3. Gureje O, et al. Persistent pain and well-being: a WHO study in primary care. JAMA. 1998;280:147–51.
4. Turk DC, et al. Toward an empirically derived taxonomy of chronic pain patients: integration of psychological assessment data. J Consult
Clin Psychol. 1988;56:233–8.
posters
5. Latham J, et al. The socioeconomic impact of chronic pain. Disabil Rehabil. 1994; 16:39–44.
6. Locker D. Disability and disadvantage. London: Tavistock Publications. 1983.
7. Zhang L, et al. Status of the pain treatment use traditional Chinese medicine. China Journal of Traditional Chinese Medicine and
Pharmacy. 2009;S1:142-4.
8. Todd J, et al. Prevalence and correlates of chronic pain in a random population study of adults in Chongqing, China. Clin J Pain. 2013;
PMID: 23887340.
9. Kwok Fu Jacobus Ng, et al. Prevalence of common chronic pain in Hong Kong adults. The Clin J Pain. 2002;18:275-81.
10. Joanne WY Chung, et al. Prevalence of pain in a community population. Pain Medicine. 2007;8(3):235-42.
11. Yan YX, et al. Development and evaluation of a questionnaire for measuring suboptimal health status in urban Chinese. J Epidemiol.
2009; doi: 10.2188/jea.JE20080086
12. Yan YX, et al. Association of suboptimal health status and cardiovascular risk factors in urban Chinese workers. J Urban Health. 2012;
doi10.1007/s11524-011-9636-8
13. Lu JP, et al. Screening novel biomarkers for metabolic syndrome by profi ling human plasma N-glycans in Chinese Han and Croatian
populations. J Proteome Res. 2011;10(11):4959-69.
14. Lauc G, et al. Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and
haematological cancers. PLoS Genetics. 2013; 9(1): e1003225. doi:10.1371/journal.pgen.1003225
36. The development of sensorimotor reflexes in albino mice; albino rats and black-hooded rats
Ahmed A. Allam (1) - Rasha E. Abo-Eleneen (2)
King Saud University, College of Science, Zoology Department, Riyadh, Saudi Arabia (1) - Beni-Suef University, Faculty of Science,
Zoology Department, Beni-Suef, Egypt (2)
The present investigation aimed to show the differences in the development of sensorimotor reflexes and their
relationship to the structural changes in spinal cord, cerebellum and cerebral cortex in three rodent species. The
three species are albino rats (A-Rats), black-hooded rats (B-Rats) and albino mice. The development of selected
reflexes was examined from day 1 (D1) to D21. The structural changes were investigated at D7, D14, and D21. The
following reflexes were analyzed: fore-limb/hind-limb grasp, surface body righting, fore-limb hopping, chin tactile
placing, visual placing and body righting in the air. The developmental pattern of the reflexes was different in the three
rodent species. Although the black-hooded rats and albino rats belong to the same species, they are different in their
appearance and developmental pattern. The development of external features and sensorimotor reflexes appeared
earlier in mice than in A-Rats and B-Rats. At D7, differentiation of neurons was observed in the spinal cord while in
cerebellum and cerebrum the neurons were found to be undifferentiated. At D14 and D21, the differentiated neurons
were observed in spinal cord, cerebellum and cerebrum. Our data indicate that the developmental pattern of the
reflexes in rodents may not be species-specific but may be related to the animal strain.
37. Analysis of the influence of locoregional anesthesia on respiratory mechanics in short-duration
pediatric surgery, using spontaneous ventilation and spontaneous ventilation with pressure support
Tania Avilez Padilla – Eva Blázquez – Mª Ángeles Ariza – José Luis Casielles – José Luis Laguillo – Aurora Cruz –
Antonio Ontanilla
Department of Anesthesiology, Universitary Hospital Virgin Macarena, Seville, Spain
INTRODUCTION: Regional anesthesia has become a widely accepted tool in pediatric anesthesia practice, rarely
used as isolation technique, commonly used in combination with general anesthesia. OBJECTIVES: Establish the
influence of locoregional techniques on the use of opiates and ventilatory mechanics in children undergoing surgical
procedures of short duration, with spontaneous ventilation and spontaneous ventilation with pressure support.
MATERIAL AND METHODS: 123 children undergoing pediatric surgery of short duration were analyzed over
12 months. We included low-risk patients, ASA I – II, interventions with maximum duration of 90 minutes, excluding
patients under 6 months of age and predictors of difficult airway in anesthetic study. We analyzed anthropometric
91
posters
92
variables, tidal volume, RF, pulse oximetry and ETCO2 at the beginning and end of the intervention, use of opioids and
locoregional anesthesia. Four groups were considered: VE0 (spontaneous ventilation without locoregional anesthesia);
VP0 (pressure support ventilation without locoregional anesthesia); VE1 (locoregional anesthesia with spontaneous
ventilation), and VP1 (pressure support ventilation with locoregional anesthesia). Statistical analysis used a comparison
test ANOVA and a Student-Newman-Keuls (SN K) post-hoc analysis for intergroup differences was performed.
RESULTS: Of the study population, 77.2% (95 cases) received some type of regional anesthesia during surgery (Table).
CONCLUSIONS: We cannot clearly define the influence of regional anesthesia on ventilatory parameters, since
receiving pressure support ventilation were the best performing of these showed (VP0 and VP1), there appears to be a
trend that assertion. It is necessary to establish a more stringent to ensure our scenario analysis.
Table
WITHOUT LOCOREGIONAL ANESTHESIA
WITH LOCOREGIONAL ANESTHESIA
VE0 (N=10)
VP0 (N=18)
VE1 (N=49)
VP1 (N=46)
TOTAL (N=123)
p
Age (ys)
7.30
6.83
5.45
5.39
5.78
0.01
Body weight (kg)
27.3
28.6
20.5
19.9
22.1
0.0001
Opiates (%)
100
100
92
41
75
0.0001
Opiates dose
46
55.6
29.7
8.7
26.1
0.0001
SatO2, initial
97.1
98.8
97.4
99
98.2
0.0001
SatO2, end
98.7
99.3
98.9
99.8
99.3
0.0001
CO2, initial
50.2
44.3
47.6
45.2
46.1
0.016
CO2, end
54.1
40.9
49.5
43.1
46.4
0.0001
Tidal vol, initial
123
258
138
186
172
0.0001
Tidal vol, end
176
254
165
196
189
0.0001
RF, initial
18
17.4
19.2
18.3
18.5
ns
RF, end
20.2
16.1
19.1
19.9
19.1
0.0001
38. Prolonged-release oxycodone/naloxone is effective and well tolerated in patients with cancer pain
Rossella Bellino – Simona Finocchi – Clarissa Caldarulo – Elisa Palombo – Francesca Riccobelli – Maria Rosciano –
Maria Clelia Bucarelli – Marzia Lazzari – Mario Dauri
INTRODUCTION: Opioids are the elective treatment for cancer pain but are associated with bowel dysfunction,
often requiring opioid dose reduction or interruption. The fixed-dose combination of prolonged-release (PR)
Oxycodone and Naloxone (OXN) has been developed to address the problem of opioid-induced bowel dysfunction. This
retrospective, observational, single-center study investigated OXNPR efficacy and tolerability in a real-life setting of
210 consecutive patients with chronic moderate-to-severe malignant pain (NRS score ≥4; mean age 64.6±13, subjects
>65 years 53.8%; female 44.8%; opiod-experienced 68.5%). METHODS: Patients received OXNPR (up to 40 mg
oxycodone/20 mg naloxone) twice daily for 2 months with visits at baseline (T0) and 14 (T1), 30 (T2) and 60 days (T3).
The neuropathic DN4 score, sleep disturbances (assessed using the Chronic Pain Sleep Inventory, CPSI), Quality of life
(measured using the Short Form 12 [SF-12]), and bowel function (assessed using the validated Bowel Function Index
[BFI], score ranging from 0 to 100 [most severe symptoms]) were also evaluated. Treatment-related adverse events
(AEs) were recorded at each visit. RESULTS: OXN resulted in a considerable reduction in pain intensity throughout
the observation (mean NRS scores 6.9±1.3 at baseline vs. 4.0±1.8 at T3, p<0.001); pain reduction was significant as
early as T1 (NRS = 5.8±1.5). DN4 (baseline 5.9±1.4 vs. 4.1±1.5 at T3), CPSI (68.1±13.5 vs. 40.5±17.1) and SF-12 (26.4±6.4
vs. 37.1±6.0) also markedly improved during the observation (p<0.001 for all); BFI score decreased from 42.8±33.2 at
T0 to 15.8±19.4 at T3 (p<0.0001). Subgroup results in opiod-pretreated patients or ≥65 years were consistent with the
overall population. During the study, 12 (5.7%) patients withdrew from treatment due to AEs (expected AE profile of
posters
opioids in 9, diarrhea in 3 other patients). CONCLUSIONS: Prolonged-release Oxycodone/Naloxone was found to be
an effective and well tolerated treatment in patients with cancer pain.
39. Comparison of single opioid versus opioid+anticonvulsant therapy for the treatment of pancreatic
cancer pain: our experience
Rossella Bellino – Clarissa Caldarulo – Simona Finocchi – Elisa Palombo – Francesca Riccobelli (1) – Anna Maria Rutilo –
Cristina Caputo – Marzia Lazzari – Mario Dauri
INTRODUCTION: 75-90% of patients with pancreatic cancer experience mixed nociceptive/neuropathic pain of
severe intensity. Typically, outbreak of pain indicates splanchnic nerve plexus invasion by the tumor. The efficacy of
opioid and invasive therapy is well documented in this setting. The aim of this study was to evaluate the effectiveness
and safety of opioid therapy versus “combination therapy” (opioid+anticonvulsant) for the treatment of pancreatic
cancer pain. METHODS: This study was a 8-week retrospective observational analysis of data from 60 patients
treated for pancreatic cancer pain at the Pain Unit of Tor Vergata Polyclinic in Rome. Patients were treated either
with opioid therapy (Group A) or “combination therapy” (Group B). We evaluated effectiveness [pain intensity using
Numerical Rating Scale (NRS), Patient’s Global Impression of Change (PGIC) and Chronic Pain Sleep Inventory
(CPSI)], daily drug doses, use of rescue medication and safety of both pharmacological treatments. RESULTS: All
patients were treatment naïve before inclusion. At the first medical examination (T0), mean NRS was 7.28±1.48.
We included 30 patients in Group A and 30 in Group B. During the observation the drug dose was determined and
modified according to patients’ needs. Patients were re-evaluated 15, 30 and 60 days (T3) after the first medical
examination. At T3 the combination therapy was associated with a significant decrease in pain intensity (NRS: 3.8
versus 5.06, p<0.05) and less need for rescue medication compared to the opioid therapy alone. PGCI and CPSI
were better in Group B. Moreover the mean opioid dose was lower in Group B; the adverse events similar in both
groups. CONCLUSIONS: The combination therapy was well tolerated and more effective than the single opioid
therapy in the treatment of severe pancreatic cancer pain, providing valuable short-term pain relief and a significant
improvement of sleep and quality of life.
40. Symptomatic treatment of trigger point due to a neuro-muscular damage after electrocution
Mosè De Iaco (1) – Sabrina Baltieri (1) – Marta Dall’Aglio (2) – Ciro Russolillo (1) – Federico Mondin (1) – Alberto Corona (1) –
Anna Spazzolini (1)
Azienda Ospedaliera Luigi Sacco, Polo Universitario Milano, Milan, Italy (1) – Azienda Ospedaliera Niguarda, Milan, Italy (2)
BACKGROUND: Patients experiencing electrical shock (ES) may sustain a wide spectrum of injuries, requiring
special management. The current amount flowing through the body is the primary determinant of electrocution
damage, together with voltage, resistance, type and pathway of current, and duration of contact with the electrical
source. We report the case of an electrocution damage in an industrial injury. METHODS: Case report. REPORT:
OT, 55 years old, male, experienced an ES touching a livewire. He immediately referred tremors at the right upper
limb, chest pain, shortness of breath and an important burning thirst. After few hours he experienced paresthesia and
hypomobility of the same limb and lockjaw. MRI showed disc protrusion at C 3 C 4 level, with a mark on the dural sac. He
participated in a program of physiotherapy, with partial improvement of clinical findings. Six months after ES he came
to the Chronic Pain Centre with worsening symptoms. The symptomatic therapy was optimized by implementation of
paracetamol and pregabalin and infiltration of trigger points with lignocaine 2%. After the second month of treatment,
pain therapy was implemented by the introduction of a centrally acting muscle relaxant and infiltrations with local
anaesthetic and betamethasone. After eight months the clinical findings improved with significant results in terms of
reduction of pain (VAS currently 2-3) and weakness, with an almost complete recovery of strength in the right arm,
allowing the patient to go back to work and social life. CONCLUSIONS: The best treatment of trigger point seems to
be symptomatic. This treatment permitted motor recovery as well as psychological adjustment.
93
94
posters
41. An odd case of general anaesthesia after lumbar plexus block
Mosè De Iaco – Federico Mondin – Sabrina Baltieri – Marta Dall’Aglio – Loredana Metelli – Alberto Corona – Anna Spazzolini
Azienda Ospedaliera Luigi Sacco, Polo Universitario Milano, Milan, Italy
BACKGROUND: Lumbar plexus block (LPB) is generally used for hip thigh and knee surgery. Complications may occur due to
the highly vascular nature of the area and possible intravascular injection. The most frequent are: systemic toxicity, epidural spread,
neuropathy, minor bleeding. However, major complications – seizure, death, cardiac arrest and respiratory failure – are reported
too, albeit very rarely. We report a case of general anaesthesia (GA) after LPB. METHODS: Case report. REPORT: A 85 years
old woman was given both a L5-S1 subarachnoid block (10 mg of isobaric levo-bupivacaine) and a right LPB [25 ml/187.5 mg of
ropivacaine (R)] for femoral plate osteosynthesis. After 5 minutes, coma, severe bradycardia and hypotension occurred. After 1.5 mg
atropine plus 10 mg of etilefrine boluses, cardiac rhythm shifted to a pulseless ventricular tachycardia. ROSC was got after 5 minutes
by external cardiac massage associated with a synchronic 100 joules electrical shock. The patient was admitted to ICU with coma
and total ponto-medullary and peripheral neurological areflexia. CT scan was negative, EEG and somato-sensitive evoked potentials
documented hypo voltage and absence of central and peripheral response of the median nerve, respectively. After 4 hours the patient
commenced to move the head and to reactivate all central and ponto-medullary reflexes and autonomous breath trigger. After 7
hours the patient, as she awoke and responded to simple orders, was extubated. CONCLUSION: The most likely etiopathogenetic
hypothesis of GA may be systemic toxicity due to direct R spreading or injection into the intravascular fluid compartment.
42. A comparison of prolonged-release oxycodone vs. oxycodone + naloxone in pre-emptive and postoperative pain management
Mosè De Iaco (1) – Sabrina Baltieri (1) – Federico Mondin (1) – Marta Dall’Aglio (2) – Ciro Russolillo (1) – Roberto Rech (1) –
Alberto Corona (1) – Anna Spazzolini (1)
Azienda Ospedaliera Luigi Sacco, Polo Universitario Milano, Milan, Italy (1) – Azienda Ospedaliera Niguarda, Milan, Italy (2)
BACKGROUND: Recent reports revealed that numerous patients still experience pain after surgery. The main objective of this
prospective audit was to evaluate the effectiveness of different pre-emptive analgesia (PEA) provided by our acute pain service (APS).
METHODS: All patients undergoing abdominal surgery from January 2010 through May 2013 and needing the APS intervention,
were recruited. Patients were given either diazepam (D) or oxycodone (O) or oxycodone-naloxone (O-N) for PEA. Intra- and postoperative analgesias (POAs) were standardised (epidural analgesia [EA], patient controlled epidural analgesia [PCEA], i.v. patient
controlled analgesia [PCA], i.v. opiates). The verbal numeric scale (VNS) was used to assess pain by 24 hrs after surgery. Itch and
nausea/vomiting (PONV) were reported too. RESULTS: We enrolled 897 patients (51.1% males, median [IQR] age: 59 [44-71]).
PEA was based on D in 284 pts (31.3%), O in 417 (46.5%) and O-N in 196 (21.9%). Pts were divided into 4 groups according to POA
based on (i) PCEA (289, 32.2%); (ii) EA (206, 23%); (iii) PCA (140, 15.6%); (iv) i.v. opiates (262, 29.2%). We found that the use of O-N
was correlated with lower mean VNS values (Spearman rho: –0.92, p=0.005) than those recorded with O or D. The use of O-N
is correlated with a higher percentage (78.9% vs. 66.5%, p=0.036; OR [95%CI] = 0.533 [0.290-0.963]) of pts with a VNS< 5.
Moreover, after stratifying data according to the groups, mean VNS values were lower in pts that were given O-N (group (i)=1.84[1.4],
p=0.532, group (ii)=not treated with O-N, group (iii) 2.35[1.6], p=0.857, group (iv)= 2.58[2.1], p=0.418) albeit the difference was not
statistically significant. Adverse effects occurred less frequently with O-N than with N (PONV: 0.35 vs.0.5, p=0.035; itching 15.3 vs.
16.4, p=0.734). CONCLUSION: O-N seems to be correlated with a better pain control and fewer adverse effects.
43. Intravenous analgesic requirements in paediatric hydronephrosis surgery
Eva Blazquez-Gomez (1) – Luis Garcia-Aparicio (2) – Tania Sandina Avilez (1) – Antonio Ontanilla Lopez (1)
Department of Anaesthesiology, Critical Care and Pain Medicine, Hospital Universitario Virgen Macarena, Seville, Spain (1) –
Pediatric Urology Division, Pediatric Surgery Department, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain (2)
OBJECTIVE: To compare postoperative intravenous (IV) analgesic requirements in patients who underwent
Anderson-Hynes pyeloplasty according to the type of approach used. METHODS: Retrospective study in which we
reviewed the guidelines of postoperative IV analgesia in patients undergoing Anderson-Hynes pyeloplasty from 2007
posters
to 2012. Patients were divided into two groups: those who underwent open surgery (group OS) and those undergoing
laparoscopy (LS group). We excluded patients who suffered complications in the immediate postoperative period and
those without data for postoperative analgesia. The following data were collected: type of analgesia and days requiring
IV analgesia. Statistical analysis was performed using a Student t-test for quantitative variables and the Fisher test
for qualitative variables. The statistical package was SPSS 18.0. RESULTS: We analyzed 93 of the 99 patients who
underwent pyeloplasty. We excluded 6 patients because data were not available, so we analyzed a total of 87 patients (CA:
38, CL: 49). The used pattern of analgesia was: metamizole + acetaminophen (M +A) in 73 patients, metamizole alone
in 3, paracetamol alone in 8, tramadol in 1 and meperidine in 2. No significant differences between groups OS and LS
were observed. The mean days of IV treatment were: M + A: 4.1 (± 2.04); metamizole: 3 (± 1); paracetamol: 3.88 (± 1.72);
tramadol: 2 (± 2.8) and meperidine: 1.67 (± 1.5). No significant differences between groups OS and LS were observed.
CONCLUSION: In our hospital, the approach in pyeloplasty did not modify the pattern of analgesia and its duration;
that could be due to inadequate pain assessment in the postoperative period.
44. Does age change the antialgesic response due to inflammation in rats?
Francisco Pellicer – Karina Simón-Arceo – Bernardo Contreras – Ulises Coffeen – Martha León-Olea
Instituto Nacional de Psiquiatría “Ramón de la Fuente Muñiz”, Mexico City, Mexico
INTRODUCTION: Considering that the growing elderly population has inconsistencies in pain perception,
new strategies against pain are needed. Using a controlled animal model, the present study explored changes in
antinociception between the young and the elderly as well as the response to inflammatory pain along a lifetime.
METHODS: In Wistar rats, inflammation was induced by the intraplantar injection of carrageenan (50 μl) and
tested at 3 and 24 h post infiltration by thermal (plantar test) and mechanociception tests (von Fray). Groups: Young
rats control group (12 weeks); old rats group (56 weeks); rats in which the initial inflammation test was carried out at
28 weeks of age and subsequently at 44 and 56 weeks, and rats initially tested at 56 weeks of age and subsequently
at 72 weeks of age. RESULTS: Animals tested for the first time at 12 and 56 weeks of age presented hyperalgesia
secondary to carrageenan infiltration after 3 and 24 h, indicating that in old rats the antialgesic response to
inflammation is not modified. However, the repeated inflammatory response of rats tested at 44, 56, and 72 weeks
showed a gradual increase in the latency of the thermal and mechanociceptive responses at 3 h when compared
to rats exposed for the first time to the same stimuli. A histological study was carried out on anatomical elements
of the inflammed paws of 12- and 56 week-old rats. The inflammatory process in the subdermic connective tissue
exhibited no significant changes; therefore, the algesic response cannot be attributed to cytoarchitectonic alterations.
CONCLUSIONS: The response to thermal or mechanical nociception in old rats is the same as in young animals
as long as they are not repeatedly exposed to the same stimulus. The repetition of the stimulus induces changes
compatible with desensitization of the response.
This study was approved by the Institutional Research and Bioethics Committees of INPRF, project NC093230.0 to FP.
45. Opioid tolerance vs. opioid-induced hyperalgesia: the general practitioner’s perspective
Michael Sein (1) – Lucy Chen (2)
Center for Pain Medicine, University of California, San Diego, CA, United States (1) – Massachusetts General Hospital,
Harvard Medical School, Boston, MA, United States (2)
BACKGROUND: Opioid tolerance is a physiologic phenomenon that develops through repeated use of opioids, and
necessitates dose escalation in order to maintain equipotent analgesia. In contrast, opioid-induced hyperalgesia (OIH)
is a state of paradoxical nociceptive sensitization caused by prolonged exposure to opioids. Despite the accumulation
of compelling evidence in preclinical studies demonstrating this phenomenon, the clinical impact of these findings
remains uncertain. OIH may explain reduced opioid efficacy in some patients; however, it can be difficult to distinguish
from other entities including opioid tolerance and underlying disease progression. The purpose of this project was to
survey prescribers in order to review their awareness of diagnostic approach to and treatment practices for patients
95
96
posters
suspected of having opioid tolerance versus OIH. METHODS: General practitioners (GPs) practicing in Boston,
Massachusetts were invited to participate. Physicians were contacted via e-mail and provided a link to complete the
web-based survey. The two-page survey was based on reports previously conducted to survey physicians about chronic
opioid therapy. RESULTS: The survey was completed by 100 physicians; 74% of whom practiced at a university/
teaching hospital and 26% were in a group practice. Ninety-one percent of respondents reported caring for a patient
with opioid tolerance. Thirty-eight percent of GPs reported that the duration of patients’ usage of opioid therapy before
development of tolerance was greater than 6 months, followed by 3 to 6 months (33%), then 1 to 3 months (26%) and
lastly, less than 1 month (3%). The most common signs used to identify individuals with opioid tolerance were decreased
opioid effectiveness (88%), increased pain despite dose escalation (74%), and frequent medication dose escalation (72%).
For management of opioid tolerance, only 28% of respondents used an opioid rotation. Fifty-five percent reported
they had treated a patient with OIH. The most common signs used to identify individuals with OIH were increased
sensitivity to non-painful stimuli (75%), increased pain despite increased opioid dosage (62%) and decreased opioid
effectiveness (42%). For management, 33 respondents employed an opioid rotation. Of those who used a rotation,
13 (39.4%) used methadone, 11 (33.3%) used another long-acting oral opioid, 6 (18.2%) used a fentanyl patch and 3
(9.1%) used an immediate-release opiate. Adjunct medication was employed by 38% of physicians. Overwhelmingly,
patients with suspected opioid tolerance or OIH were referred to a pain medicine specialist (84% and 90%, respectively).
CONCLUSIONS: This is the first study, to our knowledge, exploring the awareness and practice habits of GPs regarding
both opioid tolerance and OIH. The results of this survey underscore the prevalence of these conditions among patients
receiving opioid therapy. They also highlight the important role pain management specialists play in the care of these
patients: the vast majority of GPs employ consultation as a means of managing these conditions.
46. Efficacy of sacroiliac joint corticosteroid injection based on arthrographic contrast patterns
Jaspal Singh (1) – Paul Scholten (1) – Schonuck Patel (2)
Weill Cornell Medical College, New York Presbytarian, New York, United States (1) – Kessler, UMDNJ, New Brunswick, United States (2)
OBJECTIVE: To determine the relationship between sacroiliac joint (SIJ) contrast dispersal patterns during
therapeutic SIJ corticosteroid injection and pain relief at 2 weeks and 2 months post-procedure. The association between
the number of positive provocative SIJ physical examination maneuvers and patient response to the intervention was also
assessed. DESIGN: Retrospective chart review. SETTING: Academic outpatient musculoskeletal office. PATIENTS:
30 subjects who underwent therapeutic SIJ corticosteroid injection. METHODS: A retrospective review of electronic
medical records identified patients who underwent therapeutic SIJ corticosteroid injection. Fluoroscopic contrast
flow patterns were categorized as Type I (cephalad extension within SIJ) or Type II (minimal cephalad extension with
inferior extravasation). Self-reported Numeric Pain Rating Scale (NPRS) values at the time of injection and 2 and 8
weeks post-procedure were recorded. The number of positive provocative SIJ physical examination maneuvers at the
time of initial evaluation was also recorded. MAIN OUTCOME MEASURES: The primary outcome measure was
the effect of type of contrast pattern on change in NPRS values at 2 weeks and 2 months post-injection. The secondary
outcome measure was the association between number of positive provocative SIJ physical examination maneuvers and
decrease in level of pain following the procedure. RESULTS: All subjects had decreased NPRS values at 2 and 8 weeks
compared to baseline. Subjects with Type I flow had greater reductions in pain at 2 and 8 weeks compared to those
with Type II flow. CONCLUSIONS: Fluoroscopically guided corticosteroid injections into the SIJ joint are effective in
decreasing NPRS values in patients with SIJ-mediated pain. Intra-articular delivery of corticosteroid to the SIJ leads to
more favorable clinical outcomes. Furthermore, those patients with as few as one positive provocative maneuver for SIJ
pain may benefit from the procedure.

fighting pain

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