European Federation of
Neurological Societies
EFNS Guidelines for medical treatment of
neuropathic pain. Revised 2009.
G. CRUCCU
EFNS Secretariat, Vienna
Dept. Neurological Sciences, Rome
EFNS guidelines on pharmacological
treatment of neuropathic pain
Attal et al. Eur J Neurol 2006
EFNS guidelines evidence/recommendations
Q-o-L and comorbidities
In all trials, pain relief is always the primary
endpoint. But in clinical practice our goal is to give
the patient a decent life.
Hence we do recommend to evaluate treatments for
they effect on global change, sleep, mood, functional
capacity, and quality-of-life (QoL).
Quality of life scales:
Nottingham Health Profile
and SF-36
Quality of Life, Mood, Sleep
8
GBP/Pregabalin
1
duloxetine
2
cannabis
1
4
opioids
lidocaine
Positive
Negative
1
0
10
20
30
40
50
60
70
80
90
100
Safety Concerns
TCA Antidepressant
Besides the typical contraindications regarding
glaucoma and prostatic hypertrophy, an
association between TCA treatment and sudden
cardiac death has raised concern; a recent
epidemiological study found a slight increase in
sudden cardiac death with high-dose TCA (Ray
et al. 2004). Therefore caution is recommended
for older patients, particularly those with
cardiovascular risk factors.
Safety Concerns
Opioids
Although in RCTs on neuropathic pain, the
side effect profile of opioids was good, less
than 20 % of patients continue with opioids
after one year, because of an unfavourable
balance between side effects and efficacy
(class I SR: Attal 2000). According to recent
European recommendations, opioids should
be considered for chronic non-cancer pain as
second line, if other reasonable therapies fail
to provide adequate analgesia (Kalso et al
2003).
How many patients do get a
decent pain relief in the
various pain conditions?
Pharmacological management of neuropathic pain remains
a challenge despite the availability of new treatments, while
no single treatment is appropriate for all neuropathic pain
conditions. Recent systematic reviews identified that only a
proportion of neuropathic pain patients obtain successful
pain relief (30-50%) with conventional medical
management.
Finnerup NB, Otto M, McQuay HJ, et al. Pain 2005;
Attal N, Cruccu G, Haanpää M, et al. Eur J Neurol 2006;
Diagrams of Reliability / Effective Gain
Diagram of Efficacy/Reliability
100
Effective Gain
75
Low Reliability
BEST
High efficacy
50
High Reliability
WORST
25
Low efficacy
0
0
25
50
Reliability
75
100
All Neuropathic Pains
40
TCA
SNRI
SSRI
PGB/GBP
NaCB
Lamotrigine
Topiramate
Valproate
Opioids
Mexiletine
NMDA
Cannabis
Capsaicin
Lidocaine
Net Gain
30
20
10
0
0
25
50
75
100
Reliability
Data from 91 double-blind RCTs across 7454 patients.
Cruccu & Taylor: Pain Pract 2007
EFNS guidelines evidence/recommendations
EFNS guidelines on pharmacological
treatment of neuropathic pain. Revised 2009.
N Attal, R Baron, G Cruccu, M Haanpää, P Hansson, TS Jensen, T Nurmikko
EFNS Panel Neuropathic Pain. Centre d'Evaluation et de Traitement de la Douleur,
Hôpital Ambroise Paré, Université Versailles-Saint-Quentin, France. Division of
Neurological
Pain
Research
and
Therapy,
Department
of
Neurology,
Universitatsklinikum Schleswig-Holstein, Kiel, Germany. Department of Neurological
Sciences, La Sapienza University, Rome, Italy. Departments of Anaesthesiology and
Neurosurgery, Pain Clinic, Helsinki University Hospital, Helsinki, Finland. Clinical Pain
Research and Pain Center, Department of Neurosurgery, Karolinska Institute,
University Hospital, Stockholm, Sweden. Dept. of Neurology and Danish Pain
Research Center, Aarhus University Hospital, Aarhus, Denmark. Pain Research
Institute, Division of Neurological Science, University of Liverpool, UK
Sample
size
(No. of
trials)
Total
Reliability
(mean ± SE)
Benefit
with active
(range)
Harm with
active
(range)
Benefit
with
control
(range)
Harm with
control
(range)
Net Gain
(95% CI)
Significance
TCA
672
(19)
155
(8.2 ± 1.3)
52.4%
(22–89)
10.5%
(0–24)
15.9%
(0–24)
3.0%
(0–14)
26.4 (21–32)
P<0.0001
SNRI
1079
(4)
80
(20 ± 3.5)
51.8%
(27–63)
11.2%
(9–20)
28.5%
(7–35)
4.0%
(4–5.3)
15 (8.6–21)
P<0.0001
SSRI
81
(3)
24
(8 ± 2.3)
43.2%
(20–50)
5.4%
(0–6)
28.4%
(15–41)
2.2%
(0–4)
11.1 (-3–25)
NS
2454
(12)
301
(25 ± 3.8)
47.8%
(21–61)
8.5%
(6.5–11)
18.8%
(1–31)
4.4%
(2.9–6.7)
19.6 (16–23)
P<0.0001
NaCB
300
(6)
52
(8.7 ± 1.6)
63.9%
(39–74)
13.7%
(0–28)
17.8%
(0–26)
3.1%
(0–8)
36.5 (28–45)
P<0.0001
Lamotrigine
422
(5)
59
(12 ± 2.7)
44.5%
(0–58)
6.7%
(0–10)
22.7%
(0–39)
8.0%
(0–10)
23.2 (15–32)
P<0.0001
Topiramate
323
(1)
25
45.7%
24.3%
23.0%
8.3%
0.4 (-8–9)
NS
Valproate
153
(4)
40
(10 ± 3.4)
51.5%
(26–83)
3.7%
(0–6)
14.0%
(9–20)
0.9%
(0–3)
34.5 (22–47)
P<0.0001
Opioids
480
(8)
130
(16 ± 1.9)
69.7%
(41–87)
12.1%
(9–16)
27.9%
(7–56)
3.8%
(0–9)
30 (22-38)
P<0.0001
Mexiletine
266
(4)
48
(12 ± 4.6)
64.9%
(46–75)
8.3%
(0–13)
49.0%
(9–70)
4.6%
(0–20)
11.7 (0–24)
NS
NMDA
194
(11)
50
(4.5 ± 0.2)
36.4%
(0–68)
10.4%
(0–29)
21.2%
(0–37)
1.8%
(0–13)
5.3 (-3–14)
NS
Cannabis
252
(4)
60
(15 ± 4.1)
13.9%
(1–46)
1.8%
(0–5)
6.7%
(0–17)
2.4%
(0-10)
7.2 (1–14)
P=0.0377
Capsaicin
738
(9)
85
(9.4 ± 2.5)
57.1%
(20–89)
13.3%
(0–24)
36.7%
(6–65)
3.4%
(0–8)
10.6 (3–18)
P=0.0045
Lidocaine
40
(1)
20
(20)
30.8%
0%
8.1%
1.7%
25.2
P=0.0068
Drugs
PGB/GBP
NP
condition
Level A rating for
efficacy
Level B rating for
efficacy
Level C rating for
efficacy
Level A/ B rating
for inefficacy or
discrepant results
Recommendations
for first line
Recommendations
for second line
Diabetic
PN 1
Duloxetine
Gapabentin
Dextrometorphan
Carbamazepine
Phenytoine
BTX-A*
Capsaicin cream
Lacosamide
Lamotrigine
Levodopa*
Memantine
Mexiletine
Mianserin
NK1 antagonist**
Oxcarbazepine
SSRI
Topical clonidine
Topiramate
Valproate
Zonisamide
Duloxetine
Gabapentin
Pregabalin
TCA
Venlafaxine
Opioids
Tramadol
Dextrometorphan
Memantine
Lorazepam
Mexiletine
COX-2 inhibitor**
Phenothiazine
Tramadol
Gapapentin
Pregabalin
TCA
Topical lidocaine3
Capsaicin
Opioids
Tramadol
Carbamazepine
Oxcarbazepine
Surgery
Gapabentin
Pregabalin
TCA
Lamotrigine (CPSP)
Opioids
SNRI
Cannabinoids (MS)
Gabapentinmorphine
Nitrate
derivatives**
Nicotine
agonist**
Gabapentinvenlafaxine
Oxycodone
Pregabalin
TCA
Tramadol
Venlafaxine
PHN
Capsaicin patch**
Gabapentin
Gabapentin ER**
Opioids
Pregabalin
TCA
Topical lidocaine
Capsaicin cream
Valproate
Classical
TN
Carbamazepine
Oxcarbazepine
Baclofen*
Lamotrigine*
Pimozide*
Tizanidine*
Central
pain
Cannabinoids
(oromucosal **,
THC) (MS)
Pregabalin (SCI)
TCA
Lamotrigine
(CPSP)
Opioids
Levetiracetam
Mexiletine
Valproate
Valproate
S-ketamine
iontophoresis
Treatments are presented in alphabetical order. Drugs marked with an asterix were found effective in single center
class II or III studies and are not recommended. Drugs marked with two asterixes are not (yet) available for use.
Aetiology of NP
Level A rating for efficacy
Level B rating for efficacy
Level A/ B rating for inefficacy/poor efficacy
or discrepant results
Post-traumatic or
postsurgical NP
Amitriptyline*
Botulinum toxin-A*
Cannabinoids
Capsaicin
Gabapentin
Levetiracetam
Propranolol
Venlafaxine ER
Chronic radiculo-pathy
Morphine*
Nortriptyline*
Nortriptyline-morphine *
Pregabalin (unpublished)
Topiramate
Amitriptyline*
Tramadol*
Valproate
HIV neuropathy
Cancer NP
Gabapentin
Phantom pain
Morphine
Tramadol
Multi-aetiology NP
Bupropion
Cannabinoids
(oromucosal, synthetic
analog)
Levorphanol
Amitriptyline
Gabapentin
Memantine
Mexiletine
Methadone
TCA (nortriptyline,
clomipramine)
Amitriptyline/ketamine topical
CCK2 antagonists
Dextrometorphan
Dihydrocodeine
Gabapentin1
Venlafaxine ER1
Lidocaine plasters
Lamotrigine
Lidocaine plasters
Mexiletine1
Nabilone
Riluzole
Treatments are presented in alphabetical order. Drugs marked with an asterix were found effective in single center
class II or III studies and are not recommended. Drugs marked with two asterixes are not (yet) available for use.
Important questions that the new
guidelines were expected to face
• Opioids: yes or not?
• Classic antiepileptics are really
effective?
• When and which polytherapy
Thank you for
your attention
Oppioidi: sì o no?
• L’obiezione principale (effetti a lungo termine)
è stata fino ad ora affrontata in modo
adeguato solo per l’ossicodone. Uno studio di
registrazione di 36 mesi in 233 pazienti ha
dimostrato che con ossicodone a rilascio
controllato (dose media 52 mg):
• la richiesta di incremento dose si stabilizzava
mediamente al 10% dopo un anno
• il 2.6% dei pazienti sviluppava
abuso/dipendenza nel corso dei 3 anni
Portenoy et al: Clin J Pain 2007
Antiepilettici nel dolore neuropatico
• Tranne per la comprovata efficacia di
carbamazepina e oxcarbazepina nella
nevralgia trigeminale,
• Topiramato, lamotrigina e oxcarbazepina sono
risultati insufficientemente efficaci nelle
polineuropatie dolorose
• Una esauriente revisione Cochrane conclude
che lamotrigina è inefficace nel dolore in
generale
Cruccu: Curr Opin Neurol 2007; Wiffen Rees: Cochrane Database Syst Rev
2007; Cruccu et al: Eur J Neurol 2008; Finnerup et al. MedGenMed 2008.
Politerapia
• Da un lato la maggior parte dei medici che si occupa
di dolore cronico ricorre alla politerapia molto spesso,
dall’altro gli studi controllati sono pochissimi
• Questi riguardavano solo gabapentin in associazione
con morfina o venlafaxina
• Fortunatamente siamo riusciti a sensibilizzare
l’industria e sono iniziati una serie di studi controllati
circa le principali associazioni.
• Per ora sono stati pubblicati due studi controllati
circa l’associazione tra ossicodone con pregabalin e
con gabapentin (che ne dimostrano i vantaggi), ma
altri importanti studi sono in corso (su Lancet è in
pubblicazione lo studio TCA + GBP e sta per partire
lo studio PGB + DUL)
Hanna et al. Eur J Pain 2008; Gatti et al, Eur Neurol 2009; Gilron et al,
Lancet, in press