1. EFNS Guidelines on Neuropathic Pain Assessment Dr.ssa G Di Stefano Prof. G. Cruccu Dipartimento di Neurologia e Psichiatria, Università “Sapienza” di Roma

2. Dolore neuropatico Treede et al., Neurology 2008 Neuropathic pain is pain arising as a direct consequence of a lesion or disease affecting the somatosensory system

3. Current therapeutic targets

4. Nerve excitability Peripheral sensitization -Topical lidocaine -Capsaicin -Sodium channel blockers Current therapeutic targets

5. Nociceptive transmission Central sensitization -  2δ ligands (Gabapentin, Pregabalin) Current therapeutic targets

6. Sensitizzazione centrale

7. Nociceptive transmission Central sensitization -  2δ ligands (Gabapentin, Pregabalin) Current therapeutic targets

8. Descending control Segmental inhibition -Antidepressant (SNRI, TCA) -Opioids (Tramadol, Oxycodone) Current therapeutic targets

9. Gene expression -GDNF, Anti-NGF Microglial activation - Cytokine inhibitors - MAPK inhibitors Future therapeutic targets Nerve excitability Peripheral sensitization - Novel Sodium channel blockers (Ralfinamide) - Potassium channel blockers (Retigabine) Nociceptive transmission Central sensitization AMPA antagonists (Terampanel)

10. ConditionLevel A rating for efficacy Level B rating for efficacy Recommendations for first line Recommendations for second line Diabetic NPDuloxetine 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 PHNCapsaicin 8% patch* Gabapentin Gabapentin ER Lidocaine plasters Opioids Pregabalin TCA a Capsaicin cream Valproate** Gabapentin Pregabalin TCA Lidocaine plasters Capsaicin Opioids Classic TNCarbamazepineOxcarbazepineCarbamazepine Oxcarbazepine Surgery Central painCannabinoids (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 EFNS guidelines

11. ConditionLevel A rating for efficacy Level B rating for efficacy Recommendations for first line Recommendations for second line Diabetic NPDuloxetine 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 PHNCapsaicin 8% patch* Gabapentin Gabapentin ER Lidocaine plasters Opioids Pregabalin TCA a Capsaicin cream Valproate** Gabapentin Pregabalin TCA Lidocaine plasters Capsaicin Opioids Classic TNCarbamazepineOxcarbazepineCarbamazepine Oxcarbazepine Surgery Central painCannabinoids (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

12. Breivik et al., Ann Oncol 2009 Italy Opioid use

13. 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 reccomendations 1 One study of slow-release oxycodone (average dose 52.5 mg) followed-up 233 patients for 36 months 2 − 10% of patients required an increase in their average daily dose from month 12 2 − 2.6% developed abuse/dependency 2 However, these are only the first results. More controlled, long-term studies, and QoL assessments are needed 1 1. Attal et al., Eur J Neurol 2010; 2. Portenoy et al., Clin J Pain 2007 Safety concerns about opioids

14. Adverse eventsTrials Number/total (%) Relative risk (95% CI) NNH (95% CI) OpioidPlacebo Constipation8275/673 (41)50/441 (11) 3.6 (2.7–4.7) 3.4 (2.9–4.0) Nausea8215/673 (32)52/441 (12) 2.7 (2.1–3.6) 5.0 (4.0–6.4) Somnolence/sedation7178/627 (29)37/395 (10) 3.3 (2.4–4.5) 5.3 (4.3–7.0) Vomiting791/602 (15)10/370 (3) 6.1 (3.3–11) 8.1 (6.4–11) Dizziness8132/673 (20)33/441 (7) 2.8 (2.0–4.0) 8.2 (6.3–12) Itching683/556 (15)23/324 (7) 2.2 (1.4–3.3) 13 (8.4–27) Dry mouth776/585 (13)37/396 (9) 1.5 (1.0–2.1) Not calculated Headache435/437 (8)28/240 (12) 0.8 (0.5–1.3) Not calculated Kalso et al., Pain 2004 Opioid adverse events

15. Oxycodone - Naloxone Changes in intensity of pain Oxy-N vs Oxy Changes in bowel function index Oxy-N vs Oxy Clemens et al., Int J Clin Pract. 2011

16. ConditionLevel A rating for efficacy Level B rating for efficacy HIV Neuropathy Capsaicin 8% patch Smoked Cannabis Lamotrigine Post traumatic or post surgical NP Amitriptyline Botulinum Toxin-A Cancer NPGBPAmitriptyline Tramadol Phantom painMorphine Tramadol Multiaetiology NPBupropion Cannabinoids (oromucosal, synthetic analogue) Levorphanol Methadone TCA (nortriptyline, clomipramine) Attal et al., Eur J Neurol. 2010 Recommendations from EFNS guidelines

17. DrugStudy designNumber of patients DoseOutcomeReference AmitriptylineCross-over1575 mgPositive (NNT: 1.7) Leijon and Boivie, 1989 CarbamazepineCross-over15800 mgNegativeLeijon and Boivie, 1989 LamotrigineRandomized cross over 30400 mgPositiveVestergaard et al., 2001 PregabalinRandomized Parallel 19300-600PositiveVranken et al., 2008 LevorphanolRandomized parallel 100.15 mg 0.75 mg Positive (23% mean decrease in pain) Rowbotham et al., 2003 DuloxetineRandomized parallel 660-120 mg NegativeVranken et al., 2011 RCT in central post-stroke pain

18. DrugStudy designPain conditionNumberResultsReference Cannabinoids (THC - cannabidiol) Randomized, double-blind Unspecified type of pain630PositiveZajicek et al., 2003 Cannabinoids (THC - cannabidiol) Randomized, double-blind, cross-over study Unspecified type of pain18PositiveWade et al., 2003 Cannabinoids (THC - cannabidiol) Randomized, double-blind Unspecified type of pain160NegativeWade et al., 2004 Cannabinoids (THC - cannabidiol) Randomized, double-blind Spontaneous or evoked chronic neuropathic pain 66PositiveRog et al., 2005 Cannabinoids (Dronabinol) Randomized, double-blind, cross-over Central neuropathic spontaneous pain 24PositiveSvendsen et al., 2004 LamotrigineRandomized, double-blind, crossover study Unspecified type of pain12NegativeBreuer et al., 2007 LevetiracetamRandomized, single-blind Constant or intermittent sensory symptom with unpleasant feelings or pain 20Negative/PositiveRossi et al., 2009 LevorphanolDouble- blind,dose– response study Unspecified type of pain8Negative/PositiveRowbotham et al., 2003 Truini et al., Expert Opin Pharmacother 2011 RCT in Multiple Sclerosis-related pain

19. EFNSNeuPSIGNICEAAN First line treatment Pregabalin Gabapentin TCA SNRI Pregabalin Gabapentin TCA SNRI TCA Duloxetine 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

20. EFNSNeuPSIGNICEAAN 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 Third line treatment Bupropion, SSRI, Carbamazepine, Lamotrigine, Oxcarbazepine, Topiramate, Valproic acid Tramadol Guidelines on neuropathic pain treatment

21. 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 1 st medication, alone or in combination with other treatments: did clinicians neglect evidence-based recommendations? 3)More than 50% of patients started the treatment with 2 nd or 3 rd line medications; 4)Nearly 25% of patients was treated with a 3 rd line medication, or a not-recommended one: role of the clinical practice against evidence based recommendations.

22. THANK YOU!