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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
Treede et al., Neurology 2008
Neuropathic pain is pain arising as a direct consequence of a lesion ordisease affecting the somatosensory system
Current therapeutic targets
Nerve excitabilityPeripheral sensitization-Topical lidocaine -Capsaicin-Sodium channel blockers
Current therapeutic targets
Nociceptive transmissionCentral sensitization2δ ligands (Gabapentin, Pregabalin)
Current therapeutic targets
Sensitizzazione centrale
Nociceptive transmissionCentral sensitization2δ ligands (Gabapentin, Pregabalin)
Current therapeutic targets
Descending controlSegmental inhibition-Antidepressant (SNRI, TCA)-Opioids (Tramadol, Oxycodone)
Current therapeutic targets
Gene expression-GDNF, Anti-NGF
Microglial activation- Cytokine inhibitors- MAPK inhibitors
Future therapeutic targets
Nerve excitabilityPeripheral sensitization- Novel Sodium channel blockers (Ralfinamide)- Potassium channel blockers (Retigabine)
Nociceptive transmissionCentral sensitizationAMPA antagonists (Terampanel)
Condition Level A rating for efficacy
Level B rating for efficacy
Recommendations for first line
Recommendations for second line
Diabetic NP DuloxetineGabapentin-morphine
TCAGabapentinOxycodonePregabalin
TCATramadol alone or with
ParacetamolVenlafaxine ER
BTX-A**Dextromethorphan
Gabapentin/Venlafaxine**Levodopa**
DuloxetineGabapentinPregabalin
TCAVenlafaxine ER
OpioidsTramadol
PHN Capsaicin 8% patch*Gabapentin
Gabapentin ERLidocaine plasters
OpioidsPregabalin
TCAa
Capsaicin creamValproate**
GabapentinPregabalin
TCALidocaine plasters
CapsaicinOpioids
Classic TN Carbamazepine Oxcarbazepine CarbamazepineOxcarbazepine
Surgery
Central pain Cannabinoids (oro-mucosal* oral) (MS)
Pregabalin (SCI)
Lamotrigine (CPSP)TCA (SCI, CPSP)Tramadol (SCI)**
Opioids
GabapentinPregabalin
TCA
Cannabinoids (MS)Lamotrigine
OpioidsTramadol (SCI)
Attal et al., Eur J Neurol 2010
EFNS guidelines
Condition Level A rating for efficacy
Level B rating for efficacy
Recommendations for first line
Recommendations for second line
Diabetic NP DuloxetineGabapentin-morphine
TCAGabapentinOxycodonePregabalin
TCATramadol alone or with
ParacetamolVenlafaxine ER
BTX-A**Dextromethorphan
Gabapentin/Venlafaxine**Levodopa**
DuloxetineGabapentinPregabalin
TCAVenlafaxine ER
OpioidsTramadol
PHN Capsaicin 8% patch*Gabapentin
Gabapentin ERLidocaine plasters
OpioidsPregabalin
TCAa
Capsaicin creamValproate**
GabapentinPregabalin
TCALidocaine plasters
CapsaicinOpioids
Classic TN Carbamazepine Oxcarbazepine CarbamazepineOxcarbazepine
Surgery
Central pain Cannabinoids (oro-mucosal* oral) (MS)
Pregabalin (SCI)
Lamotrigine (CPSP)TCA (SCI, CPSP)Tramadol (SCI)**
Opioids
GabapentinPregabalin
TCA
Cannabinoids (MS)Lamotrigine
OpioidsTramadol (SCI)
Attal et al., Eur J Neurol. 2010
Recommendations from EFNS guidelines
Breivik et al., Ann Oncol 2009
Italy
Opioid use
• The lack of long-term studies of opioids in chronic non-cancer 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
Safety concerns about opioids
Adverse events TrialsNumber/total (%)
Relative risk (95% CI)
NNH (95% CI)Opioid Placebo
Constipation 8 275/673 (41) 50/441 (11)3.6 (2.7–4.7)
3.4 (2.9–4.0)
Nausea 8 215/673 (32) 52/441 (12)2.7 (2.1–3.6)
5.0 (4.0–6.4)
Somnolence/sedation 7 178/627 (29) 37/395 (10)3.3 (2.4–4.5)
5.3 (4.3–7.0)
Vomiting 7 91/602 (15) 10/370 (3)6.1 (3.3–11)
8.1 (6.4–11)
Dizziness 8 132/673 (20) 33/441 (7)2.8 (2.0–4.0)
8.2 (6.3–12)
Itching 6 83/556 (15) 23/324 (7)2.2 (1.4–3.3)
13 (8.4–27)
Dry mouth 7 76/585 (13) 37/396 (9)1.5 (1.0–2.1)
Not calculated
Headache 4 35/437 (8) 28/240 (12)0.8 (0.5–1.3)
Not calculated
Kalso et al., Pain 2004
Opioid adverse events
Oxycodone - Naloxone
Changes in intensity of painOxy-N vs Oxy
Changes in bowel function indexOxy-N vs Oxy
Clemens et al., Int J Clin Pract. 2011
Condition Level A rating for efficacy
Level B rating for efficacy
HIV Neuropathy Capsaicin 8% patch Smoked Cannabis
Lamotrigine
Post traumatic or post surgical NP
AmitriptylineBotulinum Toxin-A
Cancer NP GBP AmitriptylineTramadol
Phantom pain MorphineTramadol
Multiaetiology NP BupropionCannabinoids(oromucosal,
synthetic analogue)Levorphanol
MethadoneTCA (nortriptyline,
clomipramine)
Attal et al., Eur J Neurol. 2010
Recommendations from EFNS guidelines
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 Vranken
et al., 2008
Levorphanol Randomized
parallel
10 0.15 mg 0.75 mg
Positive (23% mean decrease
in pain)
Rowbotham
et al., 2003
Duloxetine Randomized
parallel
6 60-120 mg
Negative Vranken et al., 2011
RCT in central post-stroke 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 neuropathicpain
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
Constant or intermittent sensory symptom with unpleasant feelings or pain
20 Negative/Positive Rossi et al., 2009
Levorphanol Double-blind,dose–response study
Unspecified type of pain 8 Negative/Positive Rowbotham et al., 2003
Truini et al., Expert Opin Pharmacother 2011
RCT in Multiple Sclerosis-related pain
EFNS NeuPSIG NICE AAN
First line treatment
Pregabalin
Gabapentin
TCA
SNRI
Pregabalin
Gabapentin
TCA
SNRI
TCADuloxetinePregabalin
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
Third line treatment
Bupropion, SSRI, Carbamazepine, Lamotrigine,
Oxcarbazepine, Topiramate, Valproic acid
Tramadol
Guidelines on neuropathic pain treatment
EFNS NeuPSIG NICE AAN
First line treatment
Pregabalin
Gabapentin
TCA
SNRI
Pregabalin
Gabapentin
TCA
SNRI
TCADuloxetinePregabalin
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
Third line treatment
Bupropion, SSRI, Carbamazepine, Lamotrigine,
Oxcarbazepine, Topiramate, Valproic acid
Tramadol
Guidelines on neuropathic pain 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.
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