BMJ  2004;328:991 (24 April), doi:10.1136/bmj.38042.506748.EE (published 19 March 2004)

Primary care

Systematic review of topical capsaicin for the treatment of chronic pain

¹ Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe Hospital, Headington, Oxford OX3 7LJ

Abstract

Objective To determine the efficacy and safety of topically applied capsaicin for chronic pain from neuropathic or musculoskeletal disorders.

Data sources Cochrane Library, Medline, Embase, PubMed, an in-house database, and contact with manufacturers of topical capsaicin.

Study selection Randomised controlled trials comparing topically applied capsaicin with placebo or another treatment in adults with chronic pain.

Data extraction Primary outcome was dichotomous information for the number of patients with around at least 50% pain reduction. Outcomes were extracted at four weeks for musculoskeletal conditions and eight weeks for neuropathic conditions. Secondary outcomes were adverse events and withdrawals due to adverse events.

Data synthesis Six double blind placebo controlled trials (656 patients) were pooled for analysis of neuropathic conditions. The relative benefit from topical capsaicin 0.075% compared with placebo was 1.4 (95% confidence interval 1.2 to 1.7) and the number needed to treat was 5.7 (4.0 to 10.0). Three double blind placebo controlled trials (368 patients) were pooled for analysis of musculoskeletal conditions. The relative benefit from topical capsaicin 0.025% or plaster compared with placebo was 1.5 (1.1 to 2.0) and the number needed to treat was 8.1 (4.6 to 34). Around one third of patients experienced local adverse events with capsaicin, which would not have been the case with placebo.

Conclusions Although topically applied capsaicin has moderate to poor efficacy in the treatment of chronic musculoskeletal or neuropathic pain, it may be useful as an adjunct or sole therapy for a small number of patients who are unresponsive to, or intolerant of, other treatments.

Introduction

Capsaicin, from chilli peppers, binds to nociceptors in the skin, causing excitation of the neurones and a period of enhanced sensitivity perceived as itching, pricking, or burning, with cutaneous vasodilation. This is followed by a refractory period with reduced sensitivity and, after repeated applications, persistent desensitisation.¹

Topical creams with capsaicin are used to treat pain from postherpetic neuralgia and diabetic neuropathy, osteoarthritis, and rheumatoid arthritis.^{2 3} Capsaicin is available in the United Kingdom on prescription only, but may be present in small quantities in topical rubefacients sold through pharmacies.

Adverse events from capsaicin are mainly burning, stinging, and erythema at the application site; systemic events are rare.² Respiratory irritation has also been reported from inhalation of dried cream.⁴

We performed a meta-analysis of randomised controlled trials to determine the efficacy of topical capsaicin in the treatment of chronic pain from neuropathic and musculoskeletal disorders and adverse events and withdrawals.

Methods

Relevant studies were sought through the Cochrane Library, Medline, PreMedline, Embase, and PubMed up to April 2003. We also searched an in-house database of 13 000 randomised clinical trials in pain research from 1950 identified through a refined Medline search strategy together with handsearching of 40 biomedical journals.⁵ Reference lists of retrieved articles and reviews were also examined.

We identified randomised, active or placebo controlled trials in which treatments were in adults with chronic pain from either neuropathic conditions or musculoskeletal disorders. Treatment had to be applied 3-4 times daily, with at least 10 patients in each group. Outcomes closest to four weeks (minimum three weeks) were extracted in musculoskeletal conditions and outcomes closest to eight weeks (minimum six weeks) were extracted in neuropathic conditions.

Quality and validity assessment and data abstraction
Each trial was assessed for quality using a validated scale with a maximum score of five.⁶ Studies had to score at least two points (randomised, double blind) to be included for efficacy analysis. Trial validity was assessed on a 16 point scale.⁷

Outcomes were extracted by one reviewer and verified by another. Assessments of quality and validity were made independently by at least two reviewers. Disputes were settled by consensus.

Outcomes
We defined clinical success as about a 50% reduction in pain.⁷ This was the number of patients with either a "good" or "excellent" global assessment of treatment or "none" or "slight" pain on rest or movement. We also included patients showing undefined "improvement." We performed a separate sensitivity analysis on these trials. Secondary outcomes were the numbers of patients reporting one or more local adverse event, cough, and withdrawal due to adverse events.

Quantitative data synthesis
Analysis was based on an intention to treat. We calculated the numbers needed to treat and relative benefits along with 95% confidence intervals.^{8 9} Numbers needed to harm and relative risks were similarly calculated for adverse effects and withdrawals.

Provided there was sufficient information, we aimed to perform sensitivity analyses on pooled outcomes using the z test (P < 0.01 for a significant difference) in neuropathic compared with musculoskeletal pain and in any given pain condition.¹⁰ Homogeneity of trials was assessed visually.¹¹

Results

Overall, 38 potential papers were identified and 22 excluded (see table A on bmj.com). A large review included 14 trials and 991 patients.¹² We excluded nine of those trials for various reasons. In addition to the five remaining papers from the review,^13-17 we found seven with information on efficacy and four with information only for adverse events or withdrawals.^18-28 We included 16 papers in this review, totalling 1556 patients aged 20 to 95 years.

Only two trials scored fewer than three points for quality (see tables B and C on bmj.com).^{24 25} One, the only single blind trial, was an active controlled trial comparing different doses of capsaicin.²⁴ Validity scores ranged from nine to 14. In 11 trials baseline pain was moderate to severe, and in five trials patients were only included if they were unresponsive or intolerant to conventional therapies. In neuropathic pain, seven trials^{13 16 17 20 22 23 28} allowed concomitant oral drugs for pain without change in dose or frequency, and three trials made no mention of concomitant therapy.^{14 21 27} In musculoskeletal pain, two trials allowed concomitant oral drugs for pain without change in dose or frequency,^{15 25} three trials prohibited concomitant therapy,^{18 19 24} and one trial made no statement.²⁶

Efficacy and sensitivity analyses
Capsaicin was significantly better than placebo for the treatment of both neuropathic and musculoskeletal pain (table and figure; also see bmj.com). In neuropathic conditions, the mean treatment response rate (percentage of patients with at least 50% pain relief) at four weeks for capsaicin 0.075% was 57% (range 53% to 75% in individual trials), and the mean placebo response rate was 42% (range 31% to 55%). The number needed to treat was 6.4 (95% confidence interval 3.8 to 21). The mean treatment response rate at eight weeks for capsaicin 0.075% was 60% (range 20% to 75%), and the mean placebo response rate was 42% (range 10% to 65%; figure). The number needed to treat was 5.7 (4.0 to 10).

View this table: [in this window] [in a new window]   Estimates of efficacy and harm from meta-analysis of randomised controlled trials of capsaicin for treatment of chronic pain associated with neuropathic or musculoskeletal conditions

 

View larger version (42K): [in this window] [in a new window]   L'Abbé plot showing response to capsaicin and placebo in individual randomised controlled trials

 

In musculoskeletal conditions, the mean treatment response rate at four weeks for capsaicin 0.025% or plaster was 38% (range 34% to 42%; figure), and the mean placebo response rate was 25% (range 17% to 37%). The number needed to treat was 8.1 (4.6 to 34). Only one of the three trials with efficacy data allowed concomitant oral therapy.

Data were insufficient from which to draw any conclusions concerning relative efficacy for alternative drugs or doses. Sensitivity analyses of pooled information showed no significant difference between numbers needed to treat for trial size, type of pain, or outcome (table). Insufficient information prevented other sensitivity analyses.

Adverse events and withdrawals
Significantly more patients had local adverse events and adverse event related withdrawals with capsaicin than with placebo.

The number needed to harm for one patient to have a local adverse event with capsaicin who would not have done so with placebo was 2.5 (2.1 to 3.1). Adverse event related withdrawals occurred in 13% of capsaicin treated patients and 3% of patients receiving placebo. The number needed to harm was 9.8 (7.3 to 15.0).

Discussion

Topical capsaicin is better than placebo in the treatment of chronic pain from neuropathic and musculoskeletal disorders. This finding agrees with the results of a review published in 1994, but there are also major differences.¹² Firstly, we have given numbers needed to treat rather than odds ratios, because they are easier to understand and interpret and give an absolute rather than relative measure of treatment effect.^{29 30}

Secondly, more trials have become available since the 1994 review, and our findings are based on more studies and more patients. We excluded nine of 14 studies in the previous review because they were duplicate publications, concerned dermatological conditions, used outcomes that were not direct measurements of pain, or provided insufficient information on relevant outcomes. We used intention to treat analysis and a more structured hierarchy of outcomes from which to extract information. The net effect of these differences should be a more accurate, but more conservative, estimate of efficacy.

Our review gives lower estimates of efficacy for capsaicin. In neuropathic conditions the number needed to treat at eight weeks was 5.7. This means that for around every six patients using topical capsaicin 0.075%, one would achieve at least a 50% reduction in pain who would not have done so if given placebo. At four weeks, the number needed to treat was slightly worse (6.4). In musculoskeletal conditions, the number needed to treat at four weeks was 8.1 for at least 50% pain relief with topical capsaicin 0.025% or plaster compared with placebo.

Even this may be an overestimate, due to the difficulty in creating double blind conditions; some patients will recognise a stinging or burning sensation with treatment. Both active and placebo treatments were rubbed on, precluding any effect of rubbing. Average placebo responses in topical capsaicin trials of 42% for neuropathic pain and 25% for musculoskeletal conditions are comparable with placebo responses for oral analgesics or topical NSAIDs (12%-40%) for a variety of conditions and end points.³¹

Although capsaicin has lower efficacy in musculoskeletal conditions, the difference was not statistically significant. Too few trials were available to be certain if the difference in efficacy resulted from the lower dose of capsaicin. Patients with neuropathic pain received three times the dose used in musculoskeletal pain. In addition, efficacy estimates for musculoskeletal pain were based on information from fewer trials and fewer patients than for neuropathic pain and are therefore less robust.

We only had sufficient information to pool results from placebo controlled trials, making it impossible to judge relative efficacy with other analgesics. Indirect comparisons between treatments are still valid, however.³² A substantial meta-analysis of topical NSAIDs and a review of rubefacients from limited data have been performed.^{7 33} In chronic musculoskeletal conditions, capsaicin 0.025% or plaster was not as effective as topical NSAIDs (number needed to treat 3.1, 95% confidence interval 2.7 to 3.8) or rubefacients (5.3, 3.6 to 10.2), giving a rank order of efficacy of topical NSAIDs (most effective), followed by rubefacients then capsaicin. The efficacy of topical NSAIDs and rubefacients in neuropathic pain is unknown.

Local adverse events were common when reported. The number needed to harm for local adverse events for capsaicin in musculoskeletal and neuropathic pain were similar, despite dose. Around one in three patients treated with capsaicin will experience a local adverse event who would not have done so if given placebo. Combined outcomes in neuropathic and musculoskeletal pain give a number needed to harm for adverse event related withdrawals of 9.8; for every 10 patients treated with capsaicin, one will withdraw due to an adverse event who would not have done so if given placebo.

A study in healthy volunteers showed that epidermal nerve fibres significantly degenerate within a few days of capsaicin 0.075% treatment.¹ Once capsaicin is discontinued, reinnervation occurs, with almost full return of sensation (over six weeks after three weeks of treatment).

What is already known on this topic A large review found that capsaicin was effective in reducing pain associated with diabetic neuropathy, osteoarthritis and psoriasis, but was less effective for postherpetic neuralgia What this study adds Compared with placebo, treatment of neuropathic pain with 0.075% capsaicin for eight weeks would benefit one additional patient for every six treated Compared with placebo, treatment of musculoskeletal pain with 0.025% capsaicin for four weeks would benefit one additional patient for every eight treated One in three patients experienced local adverse events with capsaicin, and one in 10 withdraw from treatment, who would not have done so with placebo

Most of the trials stated that patients had moderate or severe chronic pain, and some recruited patients only if they were unresponsive to other treatments. For patients with chronic moderate or severe pain, even a small reduction in pain can be beneficial.

---

See also p 995

Details of search terms and studies are on bmj.com

This is the abridged version of an article that was posted on bmj.com on 19 March 2004: http://bmj.com/cgi/doi/10.1136/bmj.38042.506748.EE

Contributors: See bmj.com

Funding: This study was supported by funds from the Oxford Pain Relief Trust.

Competing interests: RAM and HJM have consulted for various pharmaceutical companies, but no company manufacturing capsaicin. RAM, HJM, and JE have received lecture fees from pharmaceutical companies related to analgesics and other healthcare interventions. All authors have received research support from charities, government, and industry sources at various times, but no such support was received for this work. No author has any direct stock holding in any pharmaceutical company.

Ethical approval: Not required.

References

1. Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, Hazen E, Kennedy WR. Topical capsaicin in humans: parallel loss of epidermal nerve fibres and pain sensation. Pain 1999;81: 135-45.[CrossRef][ISI][Medline]
2. Reynolds JEF, ed. Martindale: the extra pharmacopoeia. 32nd edn. London: Royal Pharmaceutical Society, 1999.
3. British Medical Association. Royal Pharmaceutical Society of Great Britain. British national formulary. London: BMA, RPS, 2003. (No 45.)
4. Rains C, Bryson HM. Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging 1995;7: 317-28.[ISI][Medline]
5. Jadad AR, Carroll D, Moore A, McQuay H. Developing a database of published reports of randomised clinical trials in pain research. Pain 1996;66: 239-46.[CrossRef][ISI][Medline]
6. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17: 1-12.[CrossRef][ISI][Medline]
7. Moore RA, Tramer MR, Carroll D, Wiffen PJ, McQuay HJ. Quantitative systematic review of topically applied non-steroidal anti-inflammatory drugs. BMJ 1998;316: 333-8.[Abstract/Free Full Text]
8. Cook D, Sackett DL. On the clinically important difference. Ann Intern Med 1992;117: A16-7.
9. Morris JA, Gardner MJ. Calculating confidence intervals for relative risk, odds ratios and standardised ratios and rates. In: Gardner MJ, Altman DG, eds. Statistics with confidence—confidence intervals and statistical guidelines. London: British Medical Journal, 1995: 50-63.
10. Tramer MR, Reynolds DJ, Moore RA, McQuay HJ. Impact of covert duplicate publication on meta-analysis: a case study. BMJ 1997;315: 635-40.[Abstract/Free Full Text]
11. L'Abbe KA, Detsky AS, O'Rourke K. Meta-analysis in clinical research. Ann Intern Med 1987;107: 224-33.
12. Zhang WY, Li Wan Po A. The effectiveness of topically applied capsaicin. A meta-analysis. Eur J Clin Pharmacol 1994;46: 517-22.[ISI][Medline]
13. The Capsaicin Study Group. Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. Arch Intern Med 1991;151: 2225-9.[Abstract]
14. Chad DA, Aronin N, Lundstrom R, McKeon P, Ross D, Molitch M, et al. Does capsaicin relieve the pain of diabetic neuropathy? Pain 1990;42: 387-8.[CrossRef][ISI][Medline]
15. Deal CL, Schnitzer TJ, Lipstein E, Seibold JR, Stevens RM, Levy MD, et al. Treatment of arthritis with topical capsaicin: a double-blind trial. Clin Ther 1991;13: 383-95.[ISI][Medline]
16. Bernstein JE, Korman NJ, Bickers DR, Dahl MV, Millikan LE. Topical capsaicin treatment of chronic postherpetic neuralgia. J Am Acad Dermatol 1989;21: 265-70.[ISI][Medline]
17. Watson CP, Evans RJ. The postmastectomy pain syndrome and topical capsaicin: a randomized trial. Pain 1992;51: 375-9.[CrossRef][ISI][Medline]
18. Altman RD, Aven A, Holmburg CE, Pfeifer LM, Sack M, Young GT. Capsaicin cream 0.025% as monotherapy for osteoarthritis: a double-blind study. Semin Arthritis Rheum 1994;23: 25-33.
19. Keitel W, Frerick H, Kuhn U, Schmidt U, Kuhlmann M, Bredehorst A. Capsicum pain plaster in chronic non-specific low back pain. Arzneimittelforschung 2001;51: 896-903.[Medline]
20. Ellison N, Loprinzi CL, Kugler J, Hatfield AK, Miser A, Sloan JA, et al. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol 1997;15: 2974-80.[Abstract]
21. Low PA, Opfer-Gehrking TL, Dyck PJ, Litchy WJ, O'Brien PC. Double-blind, placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy. Pain 1995;62: 163-8.[CrossRef][ISI][Medline]
22. Watson CP, Tyler KL, Bickers DR, Millikan LE, Smith S, Coleman E. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther 1993;15: 510-26.[ISI][Medline]
23. Biesbroeck R, Bril V, Hollander P, Kabadi U, Schwartz S, Singh SP, et al. A double-blind comparison of topical capsaicin and oral amitriptyline in painful diabetic neuropathy. Adv Ther 1995;12: 111-20.[ISI][Medline]
24. Schnitzer TJ, Posner M, Lawrence ID. High strength capsaicin cream for osteoarthritis pain: rapid onset of action and improved efficacy with twice daily dosing. J Clin Rheumatol 1995;1: 268-73.
25. Schnitzer T, Morton C, Coker S. Topical capsaicin therapy for osteoarthritis pain: achieving a maintenance regimen. Semin Arthritis Rheum 1994;23: 34-40.
26. Winocur E, Gavish A, Halachmi M, Eli I, Gazit E. Topical application of capsaicin for the treatment of localized pain in the temporomandibular joint area. J Orofac Pain 2000;14: 31-6.[ISI][Medline]
27. McCleane G. Topical application of doxepin hydrochloride, capsaicin and a combination of both produces analgesia in chronic human neuropathic pain: a randomized, double-blind, placebo-controlled study. Br J Clin Pharmacol 2000;49: 574-9.[CrossRef][ISI][Medline]
28. Paice JA, Ferrans CE, Lashley FR, Shott S, Vizgirda V, Pitrak D. Topical capsaicin in the management of HIV-associated peripheral neuropathy. J Pain Symptom Manage 2000;19: 45-52.[CrossRef][ISI][Medline]
29. Naylor CD, Chen E, Strauss B. Measured enthusiasm: does the method of reporting trial results alter perceptions of therapeutic effectiveness? Ann Intern Med 1992;117: 916-21.
30. Moore R, Edwards J, Barden J, McQuay H. Bandolier's little book of pain. Oxford: Oxford University Press, 2003: 238-40.
31. Kalso E, Moore RA. Five easy pieces on evidence-based medicine (2). Eur J Pain 2000;4: 321-4.[CrossRef][ISI][Medline]
32. Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ 2003;326: 472.[Abstract/Free Full Text]
33. Mason L, Moore RA, Edwards JE, McQuay HJ, Wiffen PJ. Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. BMJ 2004: doi:10.1136/bmj.38040.607141.EE

(Accepted 20 February 2004)

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