1. © 2004 American Academy of NeurologyFebruary 25, 2004 Practice Parameter: Treatment of Postherpetic Neuralgia An Evidence Based Report of the QSS of the American Academy of Neurology Richard M. Dubinsky, MD; Haidar Kabbani, MD; Ziad El- Chami, MD; Christine Boutwell, MD; and Hassim Ali, M.D. Published in Neurology 2004;63:959-965

2. © 2004 American Academy of NeurologyFebruary 25, 2004 Objective of the guideline To determine which treatments provide benefit in terms of decreased pain and improved quality of life in patients with postherpetic neuralgia.

3. © 2004 American Academy of NeurologyFebruary 25, 2004 Methods of evidence review Searched Medline database and the Cochrane database for: –peer reviewed articles –published between 1960 and August, 2003, updating in January, 2004 –using MESH terms herpes zoster/*complications and neuralgia/*treatment Reviewed titles and abstracts of these articles, for interventions that decrease the pain of postherpetic neuralgia

4. © 2004 American Academy of NeurologyFebruary 25, 2004 Methods of evidence review Inclusion criteria: Alleviation of pain in postherpetic neuralgia, of at least 8 weeks after healing of the herpetic rash Prospective, retrospective, or case series studies with clinical information on the subjects who received treatment

5. © 2004 American Academy of NeurologyFebruary 25, 2004 Methods of evidence review Inclusion criteria: Detailed methodology and clear outcome measure Demonstrate a decrease of pain related to postherpetic neuralgia Treatment was feasible for an outpatient setting

6. © 2004 American Academy of NeurologyFebruary 25, 2004 Methods of evidence review 206 articles met original Medline search criteria: –111 articles regarding the treatment of postherpetic neuralgia were reviewed in their entirety –42 met the predefined inclusion criteria –9 additional articles were found by searching bibliographies of review articles and by searching Medline using names of primary authors in the original search

7. © 2004 American Academy of NeurologyFebruary 25, 2004 AAN Strength of evidence Class IProspective, randomized, controlled clinical trial with masked outcome assessment, in a representative population. The following are required: primary outcome(s) is/are clearly defined exclusion/inclusion criteria are clearly defined adequate accounting for drop-outs and cross-overs with numbers sufficiently low to have minimal potential for bias relevant baseline characteristics are presented and substantially equivalent among treatment groups or there is appropriate statistical adjustment for differences

8. © 2004 American Academy of NeurologyFebruary 25, 2004 AAN Strength of evidence Class II Prospective matched group cohort study in a representative population with masked outcome assessment that meets a-d above OR a RCT in a representative population that lacks one criteria a-d. Class III All other controlled trials (including well-defined natural history controls or patients serving as own controls) in a representative population, where outcome assessment is independent of patient treatment. Class IV Evidence from uncontrolled studies, case series, case reports, or expert opinion

9. © 2004 American Academy of NeurologyFebruary 25, 2004 AAN Translation of evidence to level of recommendation Level A Level A rating requires at least one convincing class I study or at least two consistent, convincing class II studies. Established as effective, ineffective, or harmful for the given condition in the specified population. Level B Level B rating requires at least one convincing class II study or at least three consistent class III studies. Probably effective, ineffective, or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population.

10. © 2004 American Academy of NeurologyFebruary 25, 2004 AAN Translation of evidence to level of recommendation Level C Level C rating requires at least two convincing and consistent class III studies. Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. Level U Data inadequate or conflicting. Given current knowledge, treatment is unproven.

11. © 2004 American Academy of NeurologyFebruary 25, 2004 Introduction Acute herpetic neuralgia –Associated with the outbreak of a herpes zoster rash –Characterized by: Burning Aching Electric shock like pain Unbearable itching –Pain may precede the onset of the herpetic rash –Often herpetic neuralgia occurs with the development of a rash

12. © 2004 American Academy of NeurologyFebruary 25, 2004 Introduction Postherpetic neuralgia –Persistence of the pain of herpes zoster more than three months after resolution of the rash –Clinical case definition of Postherpetic neuralgia varies from one to six months after resolution of the rash –Zoster-associated pain describes the range of pain from acute herpes zoster to the development of postherpetic neuralgia –Duration of postherpetic neuralgia is highly variable

13. © 2004 American Academy of NeurologyFebruary 25, 2004 Introduction Incidence –Postherpetic neuralgia is relatively common, affecting 10–15 % of those with herpes zoster –Incidence increases with age

14. © 2004 American Academy of NeurologyFebruary 25, 2004 Clinical question In patients with postherpetic neuralgia, which treatments provide benefit in terms of decreased pain and improved quality of life?

15. © 2004 American Academy of NeurologyFebruary 25, 2004 Tricyclic antidepressants

16. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Author, Year Level of Evidence InterventionResults ARR* / NNT** Watson, 1992 IAmtriptyline vs. maprotiline Double blind, randomized, crossover Benefit found for both treatment (AT > MT) compared to baseline Watson, 1982 IIAmitriptyline Double blind, randomized, cross- over Significant benefit for amitriptyline ARR=62.5% NNT=1.6 *AAR=absolute risk reduction ** NNT=number needed to treat

17. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Author, Year Level of Evidence InterventionResults ARR / NNT Max, 1988IIAmitriptyline, lorazepam, and placebo Double blind, randomized, crossover 41 completed both arms Amitriptyline has improvement over lorazepam and placebo Kishore- Kumar, 1990 IIDespiramine vs. benzotropine as active placebo Double blind randomized study ARR=53% NNT=1.9

18. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Author, Year Level of Evidence InterventionResults ARR / NNT Watson, 1998 IIAmitriptyline vs. Nortriptyline Double blind, randomized, crossover 21 had similar benefit on AT and NT 5 on AT and 4 on NT had response to one, but not the other

19. © 2004 American Academy of NeurologyFebruary 25, 2004 Conclusion Based upon class I and class II evidence, the tricyclic antidepressants, amitriptyline, nortriptyline, maprotiline and desipramine are effective in lessening the pain of postherpetic neuralgia.

20. © 2004 American Academy of NeurologyFebruary 25, 2004 Antiepileptic Drugs

21. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Author, Year Level of Evidence InterventionResults ARR / NNT Rowbotham, 1998 IGabapentin up to 3600 mg/d vs. placebo Double blind, randomized Decrease of 2.1 on Gabapentin, 0.5 placebo. Based on global perception of change 66/94 improved on gabapentin, 25/79 on placebo ARR=46.2% NNT=2

22. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Author, Year Level of Evidence InterventionResults ARR / NNT Max, 1988 (also TCA) IIAmitriptyline, lorazepam, and placebo Double blind, randomized, crossover 41 completed both arms Amitriptyline had greater improvement over lorazepam and placebo

23. © 2004 American Academy of NeurologyFebruary 25, 2004 Conclusion Based upon two class I studies of gabapentin and a single class I study of pregabalin these antiepileptic drugs are of benefit in the reduction of pain from postherpetic neuralgia. Data are insufficient to reach a conclusion on the use of carbamazepine.

24. © 2004 American Academy of NeurologyFebruary 25, 2004 Opioids

25. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Author, Year Level of Evidence InterventionResults ARR / NNT Rowbotham, 1991 IMS 0.3mg/kg vs. lidocaine 5mg/kg vs. placebo 11 chose MS as providing the most relief 4 lidocaine 1 saline 3 reported no benefit Watson, 1998 IOxycodone vs. placebo Double blind, randomized, two way cross over 38 completed study. Benefit of oxycodone, approximately 50% decrease in visual analog scale

26. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Author, Year Level of Evidence InterventionResults ARR / NNT Max, 1988IIClonidine 0.2mg, codeine 120mg, ibuprofen 800mg, placebo Double blind, randomized Benefit only for clonidine over the rest. Significant adverse effects rate.

27. © 2004 American Academy of NeurologyFebruary 25, 2004 Conclusion There is class I evidence that long acting oral opioid preparations and class II evidence that tramadol provide relief in treatment of postherpetic neuralgia.

28. © 2004 American Academy of NeurologyFebruary 25, 2004 Topical and Intradermal Agents Anti-inflammatory agents Capsaicin Topical anesthetics

29. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence: Anti-inflammatory agents Author, Year Level of Evidence InterventionResults ARR / NNT Tajti, 1999IASA in ointment vs. lidocaine in ointment Benefit for both compared to baseline (20 vs. 2 for ASA and 15 vs. 3 for lidocaine) McQuay, 1990 IIBenzydamine cream (a topical NSAI) vs. placebo Double blind No benefit

30. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Capsaicin Author, Year Level of Evidence InterventionResults ARR / NNT Watson,1993I0.075% capsaicin vs. placebo Benefit for capsaicin vs. placebo during 6 week study. Benefit maintained for 77 subjects in 2 year follow-up ARR=31.5% NNT=3.2

31. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Topical anesthetics Author, Year Level of Evidence InterventionResults ARR / NNT Rowbotham, 1995 ILidocaine base 5% in gel vehicle, covered with occlusive dressing vs. placebo Double blind, randomized, cross over No significant relief for cranial PHN, Significant decrease in VAS by 14mm at 8 hours for torso – limb PHN

32. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Topical anesthetics Author, Year Level of Evidence InterventionResults ARR / NNT Rowbotham, 1996 ILidocaine 5% in non-woven polyethylene patch Double blind randomized, cross over Pain relief by 12.3mm on visual analog scale 24 had from slight to complete relief

33. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II EvidenceTopical anesthetics: Author, Year Level of Evidence InterventionResults ARR / NNT Galer, 1999 ILidocaine patches vs. placebo Enriched population, double blind, randomized >14 D for lidocaine 3.8 D for placebo 91% reported benefit on lidocaine vs. 41 on placebo NNT = 2

34. © 2004 American Academy of NeurologyFebruary 25, 2004 Conclusion Based upon class I evidence topical lidocaine is effective in reducing the pain of postherpetic neuralgia. Based on class II and class III evidence aspirin in ointment or cream, is probably effective in reducing the pain of postherpetic neuralgia. The magnitude of benefit for topical capsaicin and for aspirin in cream is below the level that is considered clinically important in treatment of chronic pain.

35. © 2004 American Academy of NeurologyFebruary 25, 2004 NMDA antagonist

36. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence NMDA antagonist Author, Year Level of Evidence InterventionResults ARR / NNT Nelson, 1997 Idextromethorphan vs. placebo 5 reported benefit for DM 3 for placebo (5 could not complete study due to sedation) ARR 15.4% NNT = 65

37. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence NMDA antagonist Author, Year Level of Evidence InterventionResults ARR / NNT Eide, 1994 IIKetamine 0.15mg/kg vs. MS 0.075 mg/kg vs. saline 6 improved with ketamine vs. 4 with MS

38. © 2004 American Academy of NeurologyFebruary 25, 2004 Conclusion There are single class II studies with evidence for the lack of efficacy of the NMDA antagonists dextromethorphan and memantine in treatment of postherpetic neuralgia.

39. © 2004 American Academy of NeurologyFebruary 25, 2004 Other modalities

40. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence: Other Modalities Author, Year Level of Evidence InterventionResults ARR / NNT Kotani, 2000 IIntrathecal methylprednisolone plus lidocaine vs. intrathecal lidocaine vs. no treatment Long lasting benefit for methylprednisolone and lidocaine, compared to lidocaine ARR of 75.6% NNT = 1.3

41. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Other Modalities Author, Year Level of Evidence InterventionResults ARR / NNT Kikuchi, 1999 IIIntrathecal vs. epidural methylprednisolone 4 sessions at 1 week intervals At 24 weeks substantial benefit for intrathecal Not for epidural NNT = 1.4

42. © 2004 American Academy of NeurologyFebruary 25, 2004 Class I and II Evidence Author, Year Level of Evidence InterventionResults ARR / NNT Lewith, 1983 IIAcupuncture vs. mock transcutaneous electrical stimulation Single blind, randomized High drop out rate No difference between the groups

43. © 2004 American Academy of NeurologyFebruary 25, 2004 Conclusion Based on single class I and II studies intrathecal methylprednisolone was effective in reducing the pain of postherpetic neuralgia. Due to invasive nature of this treatment, potential for arachnoiditis, and difficulty in obtaining preservative free methylprednisolone, it should be considered only after agents noted above have been tried and failed.

44. © 2004 American Academy of NeurologyFebruary 25, 2004 Conclusion The minimal benefit reported for iontophoresis of vincristine is negated by side effects.

45. © 2004 American Academy of NeurologyFebruary 25, 2004 Recommendations The following are effective and should be used in the treatment of postherpetic neuralgia (Level A, Class I and II): –Tricyclic antidepressants (amitriptyline, nortriptyline, desipramine and maprotiline) –Gabapentin –Pregabalin –Opioids –Topical lidocaine patches

46. © 2004 American Academy of NeurologyFebruary 25, 2004 Recommendations There is limited evidence to support nortriptyline over amitriptyline, (Level B, single Class II study) and the data are insufficient to recommend one opioid over another. Amitriptyline has significant cardiac effects in the elderly when compared to notriptyline and desipramine.

47. © 2004 American Academy of NeurologyFebruary 25, 2004 Recommendations Aspirin in cream is possibly effective in the relief of pain in patients with postherpetic neuralgia, (Level C, Class II and III) but the magnitude of benefit is low, as is seen with capsaicin (Level A, Class I and II). In countries where preservative-free intrathecal methylprednisolone is available, it may be considered in the treatment of post herpetic neuralgia (Level A, Class I and II).

48. © 2004 American Academy of NeurologyFebruary 25, 2004 Recommendations The following treatments are not of benefit (Level B, Class II): –Acupuncture –Benzydamine cream –Dextromethorphan –Indomethacin –Epidural methylprednisolone –Epidural morphine sulfate –Lontophoresis of vincristine –Lorazepam –Vitamin E –Zimelidine

49. © 2004 American Academy of NeurologyFebruary 25, 2004 Recommendations The effectiveness of the following treatments for postherpetic neuralgia are unproven: (Level U, single Class II study and Class IV studies) –Carbamazepine –Nicardepine –Biperiden –Chlorprothixene –Ketamine –He: Ne laser irradiation –Intralesional triamcinolone –Cryocautery –Topical piroxicam –Extract of Ganoderma lucidum –Dorsal root entry zone lesions –Stellate ganglion block

50. © 2004 American Academy of NeurologyFebruary 25, 2004 Recommendations There is insufficient evidence at this time to make any recommendations on the long-term effects of these treatments.

51. © 2004 American Academy of NeurologyFebruary 25, 2004 Future Research Further areas for research in treatment of postherpetic neuralgia should expand upon: –Variety of treatments –Natural history of postherpetic neuralgia –Response of the various components of the pain of postherpetic neuralgia (dysesthesias, paresthesias, hyperalgesia, hyperesthesia, and allodynia) to treatment Contribution of evoked pain in the outcomes assessment of treatment of postherpetic neuralgia.

52. © 2004 American Academy of NeurologyFebruary 25, 2004 Future Research The case definition of postherpetic neuralgia has changed, with a trend towards a longer duration of symptoms required to distinguish postherpetic neuralgia from acute herpetic neuralgia. This is a major confounder in any attempt to generalize the results of many studies.

53. © 2004 American Academy of NeurologyFebruary 25, 2004 Future Research Direct comparison studies of topical and oral agents are needed. Research into use of combinations of therapies, and therapies aimed at disease modification needs to be addressed. Long-term efficacy of treatments of postherpetic neuralgia must be compared to the natural history for resolution of postherpetic neuralgia.

54. © 2004 American Academy of NeurologyFebruary 25, 2004 To view the entire guideline and additional AAN guidelines visit: www.aan.com/professionals/practice/index/cfm Published in Neurology 2004;