Practice Parameter: Treatment of Postherpetic Neuralgia

© 2004 American Academy of Neurology February 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


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.


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


Methods of evidence reviewInclusion 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


Methods of evidence reviewInclusion criteria: • Detailed methodology and clear outcome

measure

• Demonstrate a decrease of pain related to postherpetic neuralgia

• Treatment was feasible for an outpatient setting


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


AAN Strength of evidenceClass I Prospective, randomized, controlled clinical trial

with masked outcome assessment, in arepresentative population. The following arerequired:•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


AAN Strength of evidenceClass 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


AAN Translation of evidence to level of recommendationLevel 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.


AAN Translation of evidence to level of recommendationLevel 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.


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


IntroductionPostherpetic 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


Introduction

Incidence– Postherpetic neuralgia is relatively common, affecting

10–15 % of those with herpes zoster

– Incidence increases with age


Clinical question

In patients with postherpetic neuralgia, which treatments provide benefit in terms of decreased pain and improved quality of life?


Tricyclic antidepressants


Class I and II EvidenceAuthor,

Year

Level of Evidence

Intervention Results

ARR* / NNT**

Watson, 1992

I • Amtriptyline vs. maprotiline

• Double blind, randomized, crossover

Benefit found for both treatment (AT > MT) compared to baseline

Watson, 1982

II • Amitriptyline• Double blind,

randomized, cross-over

Significant benefit for amitriptyline

ARR=62.5% NNT=1.6

*AAR=absolute risk reduction

** NNT=number needed to treat



Year

Level of Evidence


ARR / NNT

Max, 1988 II • Amitriptyline, lorazepam, and placebo


• 41 completed both arms

• Amitriptyline has improvement over lorazepam and placebo

Kishore-Kumar, 1990

II • Despiramine vs. benzotropine as active placebo

• Double blind randomized study

ARR=53%

NNT=1.9



Year

Level of Evidence


ARR / NNT

Watson, 1998

II • Amitriptyline vs. Nortriptyline


• 21 had similar benefit on AT and NT

• 5 on AT and 4 on NT had response to one, but not the other


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.


Antiepileptic Drugs



Year

Level of Evidence


ARR / NNT

Rowbotham, 1998

I • Gabapentin 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



Year

Level of Evidence


ARR / NNT

Max, 1988 (also TCA)

II • Amitriptyline, lorazepam, and placebo


• 41 completed both arms

• Amitriptyline had greater improvement over lorazepam and placebo


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.


Opioids



Year

Level of Evidence


ARR / NNT

Rowbotham,

1991

I MS 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

I • Oxycodone vs. placebo

• Double blind, randomized, two way cross over

• 38 completed study.• Benefit of oxycodone,

approximately 50% decrease in visual analog scale



Year

Level of Evidence


ARR / NNT

Max, 1988 II • Clonidine 0.2mg, codeine 120mg, ibuprofen 800mg, placebo

• Double blind, randomized

• Benefit only for clonidine over the rest.

• Significant adverse effects rate.


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.


Topical and Intradermal Agents

Anti-inflammatory agents Capsaicin

Topical anesthetics


Class I and II Evidence: Anti-inflammatory agentsAuthor,

Year

Level of Evidence


ARR / NNT

Tajti, 1999 I ASA 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

II • Benzydamine cream (a topical NSAI) vs. placebo

• Double blind

No benefit


Class I and II Evidence Capsaicin

Author,

Year

Level of Evidence


ARR / NNT

Watson,1993 I 0.075% 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


Class I and II Evidence Topical anesthetics

Author,

Year

Level of Evidence


ARR / NNT

Rowbotham,

1995

I • Lidocaine 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


Class I and II Evidence Topical anesthetics

Author,

Year

Level of Evidence


ARR / NNT

Rowbotham,

1996

I • Lidocaine 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


Class I and II EvidenceTopical anesthetics:

Author,

Year

Level of Evidence


ARR / NNT

Galer,

1999

I • Lidocaine 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


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.


NMDA antagonist


Class I and II Evidence NMDA

antagonist Author,

Year

Level of Evidence


ARR / NNT

Nelson,

1997

I dextromethorphan vs. placebo

• 5 reported benefit for DM

• 3 for placebo• (5 could not

complete study due to sedation)

ARR 15.4%

NNT = 65


Class I and II Evidence NMDA

antagonist Author,

Year

Level of Evidence


ARR / NNT

Eide,

1994

II Ketamine 0.15mg/kg

vs.

MS 0.075 mg/kg vs.

saline

• 6 improved with ketamine vs. 4 with MS


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.


Other modalities


Class I and II Evidence: Other ModalitiesAuthor,

Year

Level of Evidence


ARR / NNT

Kotani,

2000

I Intrathecal 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


Class I and II Evidence Other ModalitiesAuthor,

Year

Level of Evidence


ARR / NNT

Kikuchi,

1999

II • Intrathecal vs. epidural methylprednisolone

• 4 sessions at 1 week intervals

• At 24 weeks substantial benefit for intrathecal

• Not for epidural

NNT = 1.4


Class I and II Evidence

Author,

Year

Level of Evidence


ARR / NNT

Lewith,

1983

II • Acupuncture vs. mock transcutaneous electrical stimulation

• Single blind, randomized

• High drop out rate• No difference

between the groups


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.


Conclusion

• The minimal benefit reported for iontophoresis of vincristine is negated by side effects.


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


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.


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).


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


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


Recommendations

• There is insufficient evidence at this time to make any recommendations on the long-term effects of these treatments.


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.


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.


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.


To view the entire guideline and additional AAN

guidelines visit: www.aan.com/professionals/practice/index/cfm

Published in Neurology 2004;

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Practice Parameter: Treatment of Postherpetic Neuralgia