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.

THANK YOU!THANK YOU!