EFNS Guidelines on Neuropathic
Pain Assessment
Dr.ssa G Di Stefano Prof. G. Cruccu
Dipartimento di Neurologia e Psichiatria, Università “Sapienza” di Roma
Dolore neuropatico
Neuropathic pain is pain arising as a direct consequence of a lesion or
disease affecting the somatosensory system
Treede et al., Neurology 2008
Current therapeutic targets
Current therapeutic targets
Nerve excitability
Peripheral sensitization
-Topical lidocaine
-Capsaicin
-Sodium channel blockers
Current therapeutic targets
Nociceptive transmission
Central sensitization
-2δ ligands (Gabapentin,
Pregabalin)
Sensitizzazione centrale
Current therapeutic targets
Nociceptive transmission
Central sensitization
-2δ ligands (Gabapentin,
Pregabalin)
Current therapeutic targets
Descending control
Segmental inhibition
-Antidepressant (SNRI, TCA)
-Opioids (Tramadol, Oxycodone)
Future therapeutic targets
Nerve excitability
Peripheral sensitization
- Novel Sodium channel
blockers (Ralfinamide)
- Potassium channel blockers
(Retigabine)
Gene expression
-GDNF, Anti-NGF
Nociceptive transmission
Central sensitization
AMPA antagonists
(Terampanel)
Microglial activation
- Cytokine inhibitors
- MAPK inhibitors
EFNS guidelines
Condition
Level A rating for
efficacy
Level B rating for
efficacy
Recommendations
for first line
Recommendations
for second line
Diabetic NP
Duloxetine
Gabapentin-morphine
TCA
Gabapentin
Oxycodone
Pregabalin
TCA
Tramadol alone or with
Paracetamol
Venlafaxine ER
BTX-A**
Dextromethorphan
Gabapentin/
Venlafaxine**
Levodopa**
Duloxetine
Gabapentin
Pregabalin
TCA
Venlafaxine ER
Opioids
Tramadol
PHN
Capsaicin 8% patch*
Gabapentin
Gabapentin ER
Lidocaine plasters
Opioids
Pregabalin
TCAa
Capsaicin cream
Valproate**
Gabapentin
Pregabalin
TCA
Lidocaine plasters
Capsaicin
Opioids
Classic TN
Carbamazepine
Oxcarbazepine
Carbamazepine
Oxcarbazepine
Surgery
Central pain
Cannabinoids
(oro-mucosal* oral) (MS)
Pregabalin (SCI)
Lamotrigine (CPSP)
TCA (SCI, CPSP)
Tramadol (SCI)**
Opioids
Gabapentin
Pregabalin
TCA
Cannabinoids (MS)
Lamotrigine
Opioids
Tramadol (SCI)
Attal et al., Eur J Neurol 2010
Recommendations from EFNS guidelines
Condition
Level A rating for
efficacy
Level B rating for
efficacy
Recommendations
for first line
Recommendations
for second line
Diabetic NP
Duloxetine
Gabapentin-morphine
TCA
Gabapentin
Oxycodone
Pregabalin
TCA
Tramadol alone or with
Paracetamol
Venlafaxine ER
BTX-A**
Dextromethorphan
Gabapentin/
Venlafaxine**
Levodopa**
Duloxetine
Gabapentin
Pregabalin
TCA
Venlafaxine ER
Opioids
Tramadol
PHN
Capsaicin 8% patch*
Gabapentin
Gabapentin ER
Lidocaine plasters
Opioids
Pregabalin
TCAa
Capsaicin cream
Valproate**
Gabapentin
Pregabalin
TCA
Lidocaine plasters
Capsaicin
Opioids
Classic TN
Carbamazepine
Oxcarbazepine
Carbamazepine
Oxcarbazepine
Surgery
Central pain
Cannabinoids
(oro-mucosal* oral) (MS)
Pregabalin (SCI)
Lamotrigine (CPSP)
TCA (SCI, CPSP)
Tramadol (SCI)**
Opioids
Gabapentin
Pregabalin
TCA
Cannabinoids (MS)
Lamotrigine
Opioids
Tramadol (SCI)
Attal et al., Eur J Neurol. 2010
Opioid use
Italy
Breivik et al., Ann Oncol 2009
Safety concerns about opioids
• The lack of long-term studies of opioids in chronic noncancer patients pain was one of the main objections
raised in published guidelines and reccomendations1
• One study of slow-release oxycodone (average dose 52.5
mg) followed-up 233 patients for
36 months2
− 10% of patients required an increase in their average daily
dose from month 122
− 2.6% developed abuse/dependency2
• However, these are only the first results.
More controlled, long-term studies, and QoL assessments
are needed1
1. Attal et al., Eur J Neurol 2010; 2. Portenoy et al., Clin J Pain 2007
Opioid adverse events
Adverse events
Trials
Number/total (%)
Opioid
Placebo
Constipation
8
275/673 (41) 50/441 (11)
Nausea
8
215/673 (32) 52/441 (12)
Somnolence/sedation 7
178/627 (29) 37/395 (10)
Vomiting
7
91/602 (15)
Dizziness
8
132/673 (20) 33/441 (7)
Itching
6
83/556 (15)
23/324 (7)
Dry mouth
7
76/585 (13)
37/396 (9)
Headache
4
35/437 (8)
28/240 (12)
10/370 (3)
Relative risk
(95% CI)
3.6
(2.7–4.7)
2.7
(2.1–3.6)
3.3
(2.4–4.5)
6.1
(3.3–11)
2.8
(2.0–4.0)
2.2
(1.4–3.3)
1.5
(1.0–2.1)
0.8
(0.5–1.3)
NNH
(95% CI)
3.4
(2.9–4.0)
5.0
(4.0–6.4)
5.3
(4.3–7.0)
8.1
(6.4–11)
8.2
(6.3–12)
13
(8.4–27)
Not
calculated
Not
calculated
Kalso et al., Pain 2004
Oxycodone - Naloxone
Changes in bowel function index
Oxy-N vs Oxy
Changes in intensity of pain
Oxy-N vs Oxy
Clemens et al., Int J Clin Pract. 2011
Recommendations from EFNS guidelines
Condition
HIV Neuropathy
Level A rating for
efficacy
Capsaicin 8% patch
Smoked Cannabis
Post traumatic or post
surgical NP
Level B rating for
efficacy
Lamotrigine
Amitriptyline
Botulinum Toxin-A
Cancer NP
GBP
Phantom pain
Morphine
Tramadol
Multiaetiology NP
Bupropion
Cannabinoids
(oromucosal,
synthetic analogue)
Levorphanol
Amitriptyline
Tramadol
Methadone
TCA (nortriptyline,
clomipramine)
Attal et al., Eur J Neurol. 2010
RCT in central post-stroke pain
Drug
Study design
Number of
patients
Dose
Outcome
Reference
Amitriptyline
Cross-over
15
75 mg
Positive (NNT:
1.7)
Leijon and
Boivie, 1989
Carbamazepine
Cross-over
15
800 mg
Negative
Leijon and
Boivie, 1989
Lamotrigine
Randomized
cross over
30
400 mg
Positive
Vestergaard
et al., 2001
Pregabalin
Randomized
Parallel
19
300-600 Positive
Levorphanol
Randomized
parallel
10
0.15 mg Positive (23%
Rowbotham
0.75 mg mean decrease et al., 2003
in pain)
Duloxetine
Randomized
parallel
6
60-120
mg
Negative
Vranken
et al., 2008
Vranken et al.,
2011
RCT in Multiple Sclerosis-related pain
Drug
Study design
Pain condition
Number
Results
Reference
Cannabinoids
(THC - cannabidiol)
Randomized,
double-blind
Unspecified type of pain
630
Positive
Zajicek et al., 2003
Cannabinoids
(THC - cannabidiol)
Randomized,
double-blind,
cross-over study
Unspecified type of pain
18
Positive
Wade et al., 2003
Cannabinoids
(THC - cannabidiol)
Randomized,
double-blind
Unspecified type of pain
160
Negative
Wade et al., 2004
Cannabinoids
(THC - cannabidiol)
Randomized,
double-blind
Spontaneous or evoked
chronic neuropathic
pain
66
Positive
Rog et al., 2005
Cannabinoids
(Dronabinol)
Randomized,
double-blind,
cross-over
Central neuropathic
spontaneous pain
24
Positive
Svendsen et al., 2004
Lamotrigine
Randomized,
double-blind,
crossover study
Unspecified type of pain
12
Negative
Breuer et al., 2007
Levetiracetam
Randomized,
single-blind
20
Negative/Positive Rossi et al., 2009
Levorphanol
Doubleblind,dose–
response study
Constant or intermittent
sensory symptom with
unpleasant feelings or
pain
Unspecified type of pain
8
Negative/Positive Rowbotham et al., 2003
Truini et al., Expert Opin Pharmacother 2011
Guidelines on neuropathic pain treatment
EFNS
NeuPSIG
NICE
AAN
First line
treatment
Pregabalin
Gabapentin
TCA
SNRI
Pregabalin
Gabapentin
TCA
SNRI
TCA
Duloxetine
Pregabalin
Pregabalin
Second line
treatment
Tramadol
Oxycodone
Tramadol
Opioid agonists
(Morphine,
oxycodone,
methadone,
levorphanol)
Switch to or
combination of the
first line drugs
Gabapentin,
Sodium valproate,
SNRI
TCA
Dextromethorphan,
Morphine
Tramadol
Oxycodone
Bupropion,
SSRI,
Carbamazepine,
Lamotrigine,
Oxcarbazepine,
Topiramate,
Valproic acid
Tramadol
Third line
treatment
Guidelines on neuropathic pain treatment
EFNS
NeuPSIG
NICE
AAN
First line
treatment
Pregabalin
Gabapentin
TCA
SNRI
Pregabalin
Gabapentin
TCA
SNRI
TCA
Duloxetine
Pregabalin
Pregabalin,
Second line
treatment
Tramadol
Oxycodone
Tramadol
Opioid agonists
(Morphine,
oxycodone,
methadone,
levorphanol)
Switch to or
combination of the
first line drugs
Gabapentin,
Sodium valproate,
SNRI
TCA
Dextromethorphan,
Morphine
Tramadol
Oxycodone
Bupropion,
SSRI,
Carbamazepine,
Lamotrigine,
Oxcarbazepine,
Topiramate,
Valproic acid
Tramadol
Third line
treatment
1) 13% of patients suffering from PHN did not receive any treatment: low pain intensity
or underestimation of PHN in clinical practice?;
2) Nearly 25% of patients was treated with a 1st medication, alone or in combination
with other treatments: did clinicians neglect evidence-based recommendations?
3) More than 50% of patients started the treatment with 2nd or 3rd line medications;
4) Nearly 25% of patients was treated with a 3rd line medication, or a not-recommended
one: role of the clinical practice against evidence based recommendations.
THANK YOU!