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BMJ Clin Evid. 2007; 2007: 0905.
Published online 2007 July 3.
PMCID: PMC2943822

Postherpetic neuralgia

Dr David William Wareham, MB BS MSc MRCP DGM DTM&H DipRCPath, Senior Clinical Lecturer (Honorary Consultant) in Microbiology

Abstract

Introduction

The main risk factor for postherpetic neuralgia is increasing age; it is uncommon in people under 50 years, but develops in 20% of people aged 60-65 years who have had acute herpes zoster, and in more than 30% of those people aged over 80 years. Up to 2% of people with acute herpes zoster may continue to have postherpetic pain for 5 years or more.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of interventions, during an acute attack of herpes zoster, aimed at preventing postherpetic neuralgia? What are the effects of interventions to relieve established postherpetic neuralgia after the rash has healed? We searched: Medline, Embase, The Cochrane Library and other important databases up to December 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 28 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: corticosteroids, dextromethorphan, dressings, gabapentin, oral antiviral agents, oral opioid analgesics, topical anaesthesia (lidocaine), topical antiviral agents (idoxuridine), topical counterirritants (capsaicin), tricyclic antidepressants.

Key Points

Pain that occurs after resolution of acute herpes zoster infection can be severe. It may be accompanied by itching and follows the distribution of the original infection.

  • The main risk factor for postherpetic neuralgia is increasing age; it is uncommon in people under 50 years, but develops in 20% of people aged 60-65 years who have had acute herpes zoster, and in more than 30% of those people aged over 80 years.
  • Up to 2% of people with acute herpes zoster may continue to have postherpetic pain for 5 years or more.

Oral antiviral agents (aciclovir, famciclovir, valaciclovir, and netivudine), taken during acute herpes zoster infection, may reduce the duration of postherpetic neuralgia compared with placebo.

  • We don't know whether topical antiviral drugs, tricyclic antidepressants, or corticosteroids taken during an acute attack reduce the risks of postherpetic neuralgia, as few good-quality studies have been found.
  • Corticosteroids may cause dissemination of herpes zoster infection.
  • We don't know whether the use of dressings during an acute attack reduces the risk of postherpetic neuralgia, as we found no studies.

Gabapentin and tricyclic antidepressants may reduce pain at up to 8 weeks in people with established postherpetic neuralgia compared with placebo.

  • Adverse effects of tricyclic antidepressants are dose related and may be less frequent in postherpetic neuralgia compared with depression, as lower doses are generally used.
  • Opioid analgesic drugs are likely to be effective in reducing pain associated with postherpetic neuralgia, but they can cause sedation and other well known adverse effects.
  • We don't know whether dextromethorphan is effective at reducing postherpetic neuralgia.
  • We don't know whether topical anaesthesia or topical counterirritants such as capsaicin reduce postherpetic neuralgia.

About this condition

Definition

Postherpetic neuralgia is pain that sometimes follows resolution of acute herpes zoster and healing of the zoster rash. It can be severe, accompanied by itching, and follows the distribution of the original infection. Herpes zoster is caused by activation of latent varicella zoster virus (human herpes virus 3) in people who have been rendered partially immune by a previous attack of chickenpox. Herpes zoster infects the sensory ganglia and their areas of innervation. It is characterised by pain in the distribution of the affected nerve, and crops of clustered vesicles over the area.

Incidence/ Prevalence

In a UK general practice survey of 3600-3800 people, the annual incidence of herpes zoster was 3.4/1000. Incidence varied with age. Herpes zoster was relatively uncommon in people under the age of 50 years (< 2/1000 a year), but rose to 5-7/1000 a year in people aged 50-79 years, and 11/1000 in people aged 80 years or older. A population-based study in the Netherlands reported a similar incidence (3.4/1000 a year) and a similar increase of incidence with age (3-10/1000 a year in people over 50 years). Prevalence of postherpetic neuralgia depends on when it is measured after acute infection. There is no agreed time point for diagnosis.

Aetiology/ Risk factors

The main risk factor for postherpetic neuralgia is increasing age. In a UK general practice study (involving 3600-3800 people, 321 cases of acute herpes zoster) there was little risk in those under the age of 50 years, but postherpetic neuralgia developed in over 20% of people who had had acute herpes zoster aged 60-65 years, and in 34% of those aged over 80 years. No other risk factor has been found to predict consistently which people with herpes zoster will experience continued pain. In a general practice study in Iceland (421 people followed for up to 7 years after an initial episode of herpes zoster), the risk of postherpetic neuralgia was 1.8% (95% CI 0.6% to 4.2%) for people under 60 years of age, and the pain was mild in all cases. The risk of severe pain after 3 months in people aged over 60 years was 1.7% (95% CI 0% to 6.2%).

Prognosis

About 2% of people with acute herpes zoster in the UK general practice survey had pain for more than 5 years. Prevalence of pain falls as time elapses after the initial episode. Among 183 people aged over 60 years in the placebo arm of a UK trial, the prevalence of pain was 61% at 1 month, 24% at 3 months, and 13% at 6 months after acute infection. In a more recent RCT, the prevalence of postherpetic pain in the placebo arm at 6 months was 35% in 72 people over 60 years.

Aims of intervention

To prevent or reduce postherpetic neuralgia by intervention during acute attack; to reduce the severity and duration of established postherpetic neuralgia, with minimal adverse effects of treatment.

Outcomes

Prevalence of persistent pain 6 months after resolution of acute infection and healing of rash. We did not consider short-term outcomes such as rash healing or pain reduction during the acute episode. In established postherpetic neuralgia, it is difficult to assess the clinical significance of reported changes in "average pain"; therefore, we present data as dichotomous outcomes where possible (pain absent or greatly reduced, or pain persistent).

Methods

BMJ Clinical Evidence search and appraisal December 2006. The following databases were used to identify studies for this systematic review: Medline 1966 to December 2006, Embase 1980 to December 2006, and The Cochrane Library and Cochrane Central Register of Controlled Clinical Trials Issue 4, 2006. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE). Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using predetermined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language. RCTs had to be at least single blinded if possible to blind; we excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. RCTs had to contain 20 or more individuals, of whom 80% or more were followed up. There was no minimum length of follow-up required to include studies. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. Where reliable meta-analyses from systematic reviews were available, they were taken to be the most accurate estimates of treatment effectiveness. In trials, the most common time point chosen for assessing the prevalence of persistent pain was 6 months, which we use in this review unless otherwise specified. Crossover RCTs are included in this topic and results before crossover are reported where available. Results after crossover should be treated with caution owing to the possibility of carry-over effects. We did not include articles available in any language other than English. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table ).

Table
GRADE evaluation of interventions for postherpetic neuralgia

Glossary

High-quality evidence
Further research is very unlikely to change our confidence in the estimate of effect.
Low-quality evidence
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidence
Any estimate of effect is very uncertain.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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2007; 2007: 0905.
Published online 2007 July 3.

Antiviral agents (oral aciclovir, famciclovir, valaciclovir, netivudine)

Summary

PERSISTENT PAIN Aciclovir compared with placebo: The effects of aciclovir on persistent pain after 3 months compared with placebo are unclear, but aciclovir may be no better than placebo at reducing pain after 4–6 months ( low-quality evidence ). Famciclovir compared with placebo: Famciclovir reduces the duration of postherpetic pain compared with placebo in immunocompetent adults ( high-quality evidence ). Aciclovir compared with valaciclovir: Valaciclovir reduces the proportion of people with persistent pain after 6 months compared with aciclovir (high-quality evidence). Aciclovir compared with netivudine: Aciclovir may be more effective at eradicating postherpetic pain after 6 months compared with netivudine (low-quality evidence). Aciclovir compared with topical idoxuridine: Oral aciclovir may be as effective as topical idoxuridine at reducing the prevalence of postherpetic pain after 1 month (low-quality evidence). Valaciclovir compared with famciclovir: Valaciclovir is as effective as famciclovir at reducing postherpetic neuralgia after 7 days' treatment (high-quality evidence). Combined corticosteroids plus aciclovir compared with aciclovir alone: Combined corticosteroids plus aciclovir may be no more effective than aciclovir alone at reducing persistent pain after 6 months ( low-quality evidence ). NOTE We found no clinically important results about the effects of adding amitriptyline to oral antiviral drugs.

Benefits

Oral aciclovir versus placebo:

We found one systematic review (search date 1998). It included results from five RCTs comparing aciclovir alone versus placebo. It found important heterogeneity among studies, making it difficult to summarise results. Meta-analysis was not conducted. The first RCT (376 people, mean age 71 years) compared aciclovir (4 g/day for 7 days) versus placebo. It found no significant difference between aciclovir and placebo for pain at 3 or 6 months (at 3 months: AR for pain 24% in both groups; at 6 months: AR: 14% with aciclovir v 13% with placebo; difference reported as not significant; figures not reported). The second RCT (187 people, mean age 49 years, aciclovir 4 g/day for 10 days) found that aciclovir significantly reduced pain compared with placebo at 1–3 months (AR for pain: 4% with aciclovir v 17% with placebo; P = 0.012). However, it found no significant difference at 4–6 months (4% with aciclovir v 6% with placebo; CI not reported in the review). The third RCT (83 people, mean age 52 years, aciclovir 4 g/day for 7 days) found that aciclovir significantly reduced pain at 3 months (AR: 10% with aciclovir v 40% with placebo; P = 0.0082). The fourth RCT (46 people, mean age 66 years, aciclovir 4 g/day for 10 days) found that aciclovir significantly reduced pain at 3 months (7% with aciclovir v 38% with placebo; P = 0.05), but the difference was not significant at 6 months (5% with aciclovir v 26% with placebo; P = 0.07). The fifth RCT (65 people, aged > 50 years, aciclovir 2 g/day for 10 days) found no significant difference in pain between aciclovir and placebo (time to outcome and AR not reported in the review).

Oral famciclovir versus placebo:

We found one systematic review (search date 1998, 1 RCT, 419 people, mean age 50 years). The multicentre RCT in the review compared two different doses of famciclovir in immunocompetent adults (aged > 18 years) and defined duration of postherpetic neuralgia as time to pain resolution. It found that both doses of famciclovir significantly reduced the duration of pain after acute herpes zoster compared with placebo (median duration of pain with 500 mg [138 people] 63 days, with 750 mg [135 people] 61 days, with placebo [146 people] 119 days; lower dose v placebo P = 0.02, higher dose v placebo P = 0.005).

Oral aciclovir versus oral valaciclovir:

We found one systematic review (search date 1998, 1 RCT, 1141 people) The RCT in the review compared 7 days of aciclovir versus oral valaciclovir (a precursor of aciclovir) given three times daily for 7 or 14 days. When the results from the 7 and 14 day valaciclovir regimens were combined, those treated with valaciclovir had a lower prevalence of pain at 6 months (AR: 19% with valaciclovir for 7 or 14 days v 26% with aciclovir for 7 days; P = 0.02).

Oral aciclovir versus oral valaciclovir:

We found one double blind RCT (511 people) comparing aciclovir versus netivudine, and found no significant difference between groups in time to the first pain free period. However, it found a significantly shorter time to complete resolution of postherpetic neuralgia with aciclovir compared with netivudine (P = 0.007). It found that the proportion of people with persistent pain at 6 months was lower in people treated with aciclovir compared with netivudine (10% with aciclovir v 15% with netivudine; P value not reported).

Oral valaciclovir versus oral famciclovir:

We found one systematic review (search date 2003, 1 RCT, 597 immunocompetent people aged 50 years and over). The RCT compared valaciclovir (1 g 3 times/day) versus famciclovir (500 mg 3 times/day) started within 72 hours of appearance of the rash and given for 7 days. It found no significant difference between groups in resolution of postherpetic neuralgia (HR 1.01, 95% CI 0.82 to 1.24).

Oral aciclovir versus topical idoxuridine:

See benefits of topical antiviral agents (idoxuridine).

Addition of corticosteroids to oral antiviral agents:

See benefits of corticosteroids.

Addition of amitriptyline to oral antiviral agents:

We found no systematic review or RCTs that evaluated the effects of amitriptyline in addition to oral antiviral drugs compared with oral antiviral drugs alone.

Harms

One previous systematic review (search date 1993) found that the most common adverse events reported with aciclovir were headache and nausea. In placebo controlled trials, these effects occurred with similar frequency with treatment and placebo (headache: 37% with aciclovir v 43% with placebo; nausea: 13% with aciclovir v 14% with placebo). There were no major adverse events reported in the RCTs included in the systematic review. In the RCTs, famciclovir, valaciclovir, and netivudine had similar safety profiles to aciclovir. In the RCT comparing valaciclovir versus famciclovir the two drugs had similar safety profiles.

Comment

Clinical guide:

We found no evidence on adherence to treatment, but it has been suggested that adherence to treatment may be better with the newer antiviral drugs because they are given one to three times daily compared with five times daily for aciclovir.

Substantive changes

No new evidence

2007; 2007: 0905.
Published online 2007 July 3.

Dressings

Summary

We found no clinically important results about the effects of dressings during an acute attack of herpes zoster for the prevention of postherpetic neuralgia.

Benefits

We found no systematic review or RCTs examining the effects of dressings during an acute attack of herpes zoster for the prevention of postherpetic neuralgia.

Harms

We found no RCTs.

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0905.
Published online 2007 July 3.

Antiviral agents (topical idoxuridine)

Summary

PERSISTENT PAIN Compared with placebo: Topical idoxuridine may be no more effective than placebo at reducing postherpetic pain after 6 months ( very low-quality evidence ). Compared with oral aciclovir: Topical idoxuridine may be as effective as oral aciclovir at reducing the prevalence of postherpetic pain ( low-quality evidence ).

Benefits

We found one systematic review (search date 1993, 4 RCTs, 431 people).

Topical idoxuridine versus placebo:

Three included RCTs (242 people, mean age not reported) compared topical idoxuridine versus placebo. Pooled results were not reported because of heterogeneity, and the poor quality of the trials. The review reported that two of the three studies found “beneficial effects” on pain reduction at 1 month (statistical analysis and P value not reported), but none of the three RCTs found any significant difference at 6 months.

Topical idoxuridine versus oral aciclovir:

The review included one RCT (189 people, mean age not reported) that compared topical idoxuridine versus oral aciclovir. The RCT found a non-significant trend towards fewer cases of postherpetic neuralgia in the idoxuridine group compared with aciclovir (pain 1 month after rash healing: 5% with topical idoxuridine v 13% with oral aciclovir; reported as not significant; figures not reported).

Harms

We found no reports of important adverse effects from idoxuridine. Application beneath dressings may be cumbersome.

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0905.
Published online 2007 July 3.

Tricyclic antidepressants (amitriptyline) to prevent postherpetic neuralgia

Summary

PERSISTENT PAIN Compared with placebo: Amitriptyline may reduce the prevalence of postherpetic neuralgia compared with placebo after 6 months ( very low-quality evidence ).

Benefits

We found one systematic review (search date 2002, 1 RCT, 80 people aged > 60 years). The RCT found that amitriptyline 25 mg taken within 48 hours of rash onset (prescribed with or without antiviral agents, at the practitioner's discretion) and continued for 90 days reduced the prevalence of postherpetic neuralgia at 6 months compared with placebo (pain free: 32/38 [84%] with amitriptyline with or without antiviral v 22/34 [65%] with placebo with or without antiviral; P < 0.05; see comment below).

Harms

The RCT did not report adverse effects. In another RCT reported by a systematic review, amitriptyline was associated with adverse anticholinergic effects such as dry mouth, sedation, and urinary difficulties.

Comment

Interpretation of the RCT is complicated because practitioners were allowed to decide whether an antiviral agent was prescribed as well as amitriptyline. Blinding may also have been inadequate. The result was of borderline significance, and six people who had started treatment but had not completed a full course of amitriptyline or placebo were excluded from the analysis.

Substantive changes

No new evidence

2007; 2007: 0905.
Published online 2007 July 3.

Corticosteroids

Summary

PERSISTENT PAIN Compared with placebo: Corticosteroids may not reduce the prevalence of postherpetic neuralgia compared with placebo after 6 months ( low-quality evidence ). Corticosteroids plus aciclovir compared with aciclovir alone: Combined corticosteroids plus aciclovir may be no more effective than aciclovir alone at reducing persistent pain after 6 months ( low-quality evidence ). ADVERSE EFFECTS There is concern that corticosteroids may cause dissemination of herpes zoster.

Benefits

Corticosteroids alone:

We found two systematic reviews (search dates 1993 and 1998). The earlier review included RCTs of corticosteroids with conflicting results and concluded that it was not possible to assess the effect of corticosteroids on postherpetic neuralgia. The more recent review found similar results but identified one RCT subsequent to the earlier review. This RCT is reported below.

Corticosteroids plus aciclovir:

We found one systematic review (search date 1998, 2 RCTs, 608 people). The first identified RCT (400 people, mean age not reported) randomised people into four active treatment groups: 7 days of aciclovir (101 people, mean age 58 years); 7 days of aciclovir plus 21 days of prednisolone (99 people, mean age 59 years); 21 days of aciclovir (101 people, mean age 60 years); or 21 days of aciclovir plus prednisolone (99 people mean age 59 years). It found no significant differences in relief of postherpetic neuralgia (reported as not significant; figures not reported). The second RCT (208 people, median age 61 years) had a factorial design, randomising people to 21 days of aciclovir plus prednisolone (60 mg initially, tapered over 3 weeks), prednisolone plus placebo, aciclovir plus placebo, or two placebos. Although there was evidence of short-term benefit from prednisolone, there was no significant difference between groups in pain prevalence at 6 months after disease onset (reported as not significant; figures not reported).

Harms

Corticosteroids alone:

It is feared that corticosteroids might cause dissemination of herpes zoster. This effect was not reported in an RCT of prednisolone in the earlier systematic review.

Corticosteroids plus aciclovir:

In the RCT of aciclovir plus prednisolone, two people receiving prednisolone plus aciclovir placebo and one receiving aciclovir plus prednisolone placebo developed cutaneous dissemination of lesions (see harms of corticosteroids in review on rheumatoid arthritis).

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0905.
Published online 2007 July 3.

Gabapentin

Summary

PAIN Compared with placebo: Gabapentin increases the likelihood of improvement in pain compared with placebo after 7–8 weeks ( high-quality evidence ). Compared with nortriptyline: Gabapentin may be as effective as nortriptyline at reducing pain ( moderate-quality evidence ).

Benefits

We found one systematic review comparing gabapentin versus placebo. It found that gabapentin reduced pain compared with placebo at 7–8 weeks (search date 2004, 2 RCTs, 428 people; AR for improvement in pain: 89/207 [43%] with gabapentin v 38/221 [17%] with placebo; RR 2.5, 95% CI 1.8 to 3.3; NNT 3.9, 95% CI 3.0 to 5.7). Two subsequent systematic reviews (search dates 2004 and 2005) identified the same RCTs and reported similar findings (NNT 4, 95% CI 3 to 6). One RCT found no significant difference between gabapentin titrated to the maximum tolerated dose compared with nortriptyline in reducing pain scores, but gabapentin was associated with fewer adverse effects.

Harms

The review did not report on the adverse effects of gabapentin specifically in people with postherpetic neuralgia. The first RCT included in the review found that gabapentin increased adverse effects compared with placebo (somnolence: 27% with gabapentin v 5% with placebo; dizziness: 24% with gabapentin v 5% with placebo; ataxia: 7% with gabapentin v 0% with placebo; peripheral oedema: 10% with gabapentin v 3% with placebo; infection: 8% with gabapentin v 3% with placebo; P values not reported). It found similar withdrawal rates caused by adverse effects between gabapentin and placebo (13% with gabapentin v 9% with placebo; P value not reported). The second RCT included in the review also found that gabapentin increased adverse effects compared with placebo (somnolence: 17% with gabapentin 1800 mg v 20% with gabapentin 2400 mg v 6% with placebo; dizziness: 31% with gabapentin 1800 mg v 33% with gabapentin 2400 mg v 10% with placebo; peripheral oedema: 5% with gabapentin 1800 mg v 11% with gabapentin 2400 mg v 0% with placebo; P values not reported). This RCT found that more people taking gabapentin than placebo withdrew because of adverse effects (13% with gabapentin 1800 mg v 18% with gabapentin 2400 mg v 6% with placebo; P value not reported).

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0905.
Published online 2007 July 3.

Tricyclic antidepressants to treat postherpetic neuralgia

Summary

PAIN Compared with placebo: Tricyclic antidepressants may increase pain relief in postherpetic neuralgia after 3–8 weeks compared with placebo ( low-quality evidence ). Compared with each other and with fluoxetine: Desipramine seems to be as effective as either amitriptyline or fluoxetine at reducing pain in postherpetic neuralgia ( moderate-quality evidence ). Compared with tricyclic antidepressants: Tricyclic antidepressants may be less effective at reducing pain compared with morphine and methadone(low-quality evidence).

Benefits

We found two systematic reviews (search date 2004, 4 RCTs and search date 2005, 4 RCTs) comparing tricyclic antidepressants with placebo.

Tricyclic antidepressants versus placebo:

The first review found that tricyclic antidepressants significantly reduced pain relief compared with placebo at 3–6 weeks (3 RCTs, 145 people with postherpetic neuralgia; AR for at least moderate pain relief: 44/77 [57%] with tricyclic antidepressants v 8/68 [112%] with placebo; RR 4.83, 95% CI 2.47 to 9.45; NNT 2.20, 95% CI 1.70 to 3.13). One RCT (49 people, mean age 73 years) identified by this first review compared four treatments: amitriptyline alone; amitriptyline plus fluphenazine (an SSRI); fluphenazine alone; and placebo. Data from this RCT were not included in the review's meta-analysis of dichotomous outcomes, as only continuous data were reported. The RCT found that amitriptyline reduced visual analogue scale (VAS) pain scores compared with placebo at 8 weeks (VAS scale 0–100: VAS reduced from 55.9 to 26.6 with amitriptyline v from 53.92 to 48.53 with placebo; significance not reported). The second systematic review pooled the data from the four RCTs identified in the first review (248 patient episodes). It found that tricyclic antidepressant drugs significantly improved pain compared with placebo (NNT 3, 95% CI 2 to 4).

Tricyclic antidepressants compared with opioids:

See benefits of opioids.

Harms

Tricyclic antidepressants are associated with anticholinergic adverse effects. The first review did not report specifically on adverse events in people with postherpetic neuralgia. One of the RCTs included in the review reported syncope and heart block in one person taking desipramine. Another RCT included in the review found that amitriptyline significantly increased dry mouth compared with placebo. A further RCT included in the review found that more people taking amitriptyline than placebo experienced adverse effects (dry mouth, AR: 62% with amitriptyline v 40% with placebo; sedation, AR: 62% with amitriptyline v 40% with placebo; urinary difficulties, AR: 12% with amitriptyline v < 5% with placebo).

Comment

The meta-analysis is based on results after crossover.

Clinical guide:

The adverse effects of tricyclic antidepressants are dose related. Adverse effects may be less pronounced when treating postherpetic neuralgia rather than depression because lower doses are used. Treatments were not assessed for more than 8 weeks.

Substantive changes

No new evidence

2007; 2007: 0905.
Published online 2007 July 3.

Opioid analgesic drugs (oral)

Summary

PAIN Tramadol compared with placebo: Tramadol may reduce pain compared with placebo after 6 weeks ( low-quality evidence ). Tramadol compared with clomipramine: Tramadol may be as effective as clomipramine, either alone or with levomepromazine, at reducing pain ( very low-quality evidence ). Other opioids compared with placebo: Oxycodone, morphine, and methadone reduce pain associated with postherpetic neuralgia compared with placebo ( high-quality evidence ). Opioids compared with tricyclic antidepressants: Morphine and methadone may be more effective at reducing pain compared with tricyclic antidepressants (low-quality evidence).

Benefits

Tramadol:

We found one systematic review (search date 2005, 2 RCTs, 149 people, meta-analysis not performed) of tramadol for postherpetic neuralgia. The first included RCT (127 people, mean age 67 years) found that tramadol 100–400 mg significantly reduced mean pain intensity compared with placebo after 6 weeks (measured on a visual analogue pain score: 19.9 with tramadol v 28.5 with placebo; P = 0.0499; RR 1.37, 95% CI 1.04 to 1.81). However, it found no significant difference between groups in mean pain assessed on a verbal rating scale after 6 weeks (P = 0.068). The second included RCT (open label, 21 people, 40% withdrawal) compared tramadol 250–290 mg versus clomipramine 50–100 mg with or without levomepromazine. It found no significant difference in efficacy between groups (measured on a verbal rating scale, data not presented). However, it is difficult to draw reliable conclusions because of the small number of people, poor methods, and because the results may have been biased by the co-intervention levomepromazine.

Oxycodone, morphine, and methadone:

We found one systematic review (search date 2004, 2 RCTs, 211 person episodes) of the opioids: oxycodone, morphine, and methadone. A meta-analysis of both RCTs found that opioids significantly increased the proportion of people reporting benefits for postherpetic neuralgia compared with placebo (number of people reporting benefit, opioids: 54/110 [49%] with opioids v 12/101 [12%] with placebo; RR 3.89, 95% CI 2.23 to 6.77, P < 0.0001; NNT 3, 95% CI 2 to 4, P < 0.0001).

Opioids compared with tricyclic antidepressants:

The review reported a further RCT, which compared morphine and methadone versus tricyclic antidepressants. It found that morphine and methadone significantly improved pain relief compared with tricyclic antidepressants (NNT for tricyclic antidepressant: 4, 95% CI 2 to 8; NNT for morphine and methadone: 3, 95% CI 2 to 5; no further data reported).

Harms

Tramadol:

In the RCT comparing tramadol versus placebo, the proportion of people reporting at least one adverse event was similar between groups (30% with tramadol v 32% with placebo). The total number of adverse events reported were also similar (31% with tramadol v 28% with placebo). In the RCT comparing tramadol versus clomipramine, the number of people withdrawing because of adverse events was 41% for the tramadol group versus 39% for the clomipramine group.

Oxycodone:

One review found that oxycodone significantly increased adverse effects such as constipation, nausea, and sedation compared with placebo (76% with oxycodone v 49% with placebo; P = 0.0074).

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0905.
Published online 2007 July 3.

Dextromethorphan

Summary

We found no clinically important results about the effects of dextromethorphan for pain relief in postherpetic neuralgia.

Benefits

We found no systematic review or RCT that fitted the inclusion criteria for this review.

Harms

We found no RCTs.

Comment

None.

Substantive changes

No new evidence

2007; 2007: 0905.
Published online 2007 July 3.

Lidocaine (topical)

Summary

PAIN Compared with placebo: Topical lidocaine may reduce pain in people with postherpetic neuralgia compared with placebo ( very low-quality evidence ).

Benefits

We found three systematic reviews and one additional RCT. The first review (search date 2005, 4 RCTs, all short duration up to 3 weeks) reported improvement in allodynia in people with postherpetic neuralgia compared with placebo (absolute data not reported, statistical meta-analysis not performed). The second review (search date 2004, 3 RCTs, 123 people) evaluated topical lidocaine for the treatment of postherpetic neuralgia. The first RCT included in the review found that lidocaine patches significantly improved pain compared with placebo (improvement: 29/32 [91%] with lidocaine v 13/32 [40%] with placebo; RR 2.23, 95% CI 1.45 to 3.44; NNT 2, 95% CI 1 to 3). The second RCT included in the review found that lidocaine patches improved pain relief compared with placebo (data not reported). The third RCT included in the review found no significant difference with lidocaine gel applied for either 24 hours under an occlusive dressing or for 8 hours with no dressing compared with placebo (data not reported). The third review (search date 2000, 2 RCTs with evaluation period > 24 hours, 204 people, mean age not reported, meta-analysis not performed) evaluated topical lidocaine for the treatment of postherpetic neuralgia. The first RCT included in the review (unpublished, 171 people) found no significant difference in pain rated on a visual analogue scale between lidocaine patches and placebo after 3–4 weeks (reported as not significant, P value not reported). The second RCT (33 people, mean age 77 years) only recruited people who had responded to lidocaine patches (see comment below). The additional RCT (35 people with pain present more than 1 month after healing of rash, and well defined area of painfully sensitive skin on torso or limbs; mean age 75 years) found that lidocaine patches significantly reduced average pain scores on a visual analogue scale over 12 hours compared with placebo. However, it did not measure outcomes beyond 12 hours.

Harms

All three reviews reported that lidocaine patches were well tolerated, with only mild local skin reactions and no systemic adverse effects. Systemic absorption as determined by blood concentrations was minimal.

Comment

One RCT included in the review only recruited people who had responded to lidocaine. Results are therefore likely to be biased in favour of lidocaine. It found that lidocaine patches were more effective for pain relief than placebo.

Substantive changes

No new evidence

2007; 2007: 0905.
Published online 2007 July 3.

Capsaicin (topical)

Summary

PAIN Compared with placebo: Topical capsaicin may reduce the pain of postherpetic neuralgia compared with placebo ( low-quality evidence ). ADVERSE EFFECTS Capsaicin may cause painful skin reactions (including burning, stinging, and erythema).

Benefits

We found three systematic reviews (search dates 1993, 2004, 2005) and one additional RCT. The reviews found that topical capsaicin significantly improved pain relief compared with placebo (2 RCTs, 175 people, mean age not reported; OR for complete or greatly reduced pain 0.29, 95% CI 0.16 to 0.54; see comment below). A further meta-analysis of the two RCTs in the most recent review also found that topical capsaicin significantly improved pain relief compared with placebo (improvement: 50/90 [56%] with capsaicin v 22/85 [26%] with placebo; RR 1.98, 95% CI 1.33 to 2.95, P < 0.008; NNT 3, 95% CI 2 to 6, P < 0.0001). The additional RCT (31 people, mean age not reported) found no significant difference in pain between capsaicin and placebo during 6 months (measured on visual analogue scale and by McGill's test; P > 0.05; see comment below).

Harms

Reported local skin reactions included burning, stinging, and erythema. These effects tended to subside with time and frequency of use. In the subsequent RCT, six people had skin burning with capsaicin compared with none with placebo (P value not reported).

Comment

The first review noted that the difficulty in blinding studies with capsaicin because of skin burning could have caused overestimation of benefit. The first review also included one unpublished RCT (30 people) that found no significant difference in pain between capsaicin and placebo. It was excluded from the meta-analysis as its inclusion resulted in significant statistical and clinical heterogeneity between the RCTs. Clinical heterogeneity occurred because the RCT had used a weaker preparation of capsaicin, shorter treatment period, and different emollient vehicle. In the subsequent RCT, eight people did not complete the study (5 with capsaicin v 3 with placebo).

Substantive changes

No new evidence


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