Abbreviations
- DPN
diabetic peripheral neuropathy
- ICER
incremental cost-effectiveness ratio
- NP
neuropathic pain
- NPRS
numeric pain rating scale
- OA
osteoarthritis
- PHN
post-herpetic neuralgia
- PNI
post-traumatic nerve injury
- PNP
peripheral neuropathic pain
- POMWP
pain on movement for worst procedure
- QALY
quality adjusted life year
- TCA
tricyclic antidepressant
- TRPV1
transient receptor potential vanilloid 1 receptor
- VAS
visual analog scale
Context and Policy Issues
Pain is a common experience. Generally, acute pain is defined as lasting less than three months, and chronic pain is defined as pain lasting three months or longer.1 Acute pain includes pain from sprains, strains, and tendonitis; and muscle aches. Chronic pain includes pain associated with osteoarthritis (OA), neuropathic pain (NP), and back pain.1 According to the Canadian Community Health Survey of individuals during the period 2007 to 2008, the prevalence of chronic pain in adults over the age of 18 years was 18.9% in Canada, and ranged between 16% and 22% for the different provinces.2 Pain is associated with reduced quality of life, absenteeism from work, and substantial healthcare costs.1
There are several treatment options for managing pain; both pharmacological and non-pharmacological options. A variety of pharmacological options such as non-steroidal anti-inflammatory drugs (NSAIDs), local anesthetics, tricyclic antidepressants, and capsaicin have been used for pain management.1,3 Capsaicin, which is found in chili peppers, has been used as a topical agent to relieve pain.4 It is a transient receptor potential vanilloid 1 receptor (TRPV1) agonist; it binds to nociceptors (sensory receptors responsible for sending signals that cause the perception of pain) in the skin, specifically to the TRVP1 receptor. This binding initially results in depolarization, initiation of action potential, and pain signal transmission to the spinal cord, and subsequently causes desensitization of the sensory axons and inhibition of pain transmission.4–6 There are various formulations for capsaicin: cream, gel, lotion and patch.5 It is available as low concentration (e.g., 0.025%, 0.075%, and 0.25%) and high concentration (e.g., 8%) product.4–6 Several capsaicin products are available over-the-counter in Canada. According to a report dated 2018, capsaicin is available in Canada as a cream (0.025%, 0.05%, and 0.075%), gel (0.025%), and patch (0.025%), as well as in creams, gels, or lotions (0.025% or 0.035%) in combination with other active ingredients.7 There appears to be some uncertainty regarding the therapeutic efficacy of capsaicin for the management of pain.8
A recent CADTH rapid response report,9 presented a summary and critical appraisal of evidence-based guidelines regarding capsaicin products for the treatment of acute and chronic non-cancer pain. There was variability in the recommendations for use of capsaicin for the management of pain due to OA. Two guidelines recommended the use of capsaicin (8%) patch as second line therapy for NP. The purpose of this report is to review the clinical effectiveness, safety and cost-effectiveness of capsaicin products for the treatment of acute and chronic non-cancer pain.
Research Questions
What is the clinical effectiveness of over-the-counter capsaicin products for the treatment of acute and chronic non-cancer pain?
What is the safety of over-the-counter capsaicin products for the treatment of acute and chronic non-cancer pain?
What is the cost-effectiveness of over-the-counter capsaicin products for the treatment of acute and chronic non-cancer pain?
Key Findings
The eight relevant publications identified comprised two systematic reviews with network meta-analysis (NMA), four randomized controlled trials (RCTs) and two economic evaluations.
Six publications reported on clinical efficacy (related to pain relief) of capsaicin compared to other drugs. Four publications reported on neuropathic pain (peripheral neuropathic pain [PNP] or painful diabetic neuropathy [DPN]); these comprised one systematic review with network analysis (NMA) (with comparators: pregabalin, gabapentin, and duloxetine) and three non-inferiority randomized controlled trials (with comparators: pregabalin, amitriptyline, or clonidine; one each). For neuropathic pain, similar or non-inferior efficacy was reported for capsaicin (8%) patch compared to oral drugs (pregabalin, gabapentin, and duloxetine), and capsaicin (0.75%) cream compared to topical drugs (amitriptyline and clonidine). One systematic review with NMA involving patients with pain due to osteoarthritis, reported similar efficacy with capsaicin (0.0125% or 0.025%) compared to topical non-steroidal anti-inflammatory drugs. One randomized controlled trial involving patients with acute back and neck pain suggested greater efficacy with capsaicin (0.075%) compared with diclofenac, statistical significance was not reported.
Four publications reported on safety outcomes (related to adverse events). These comprised one systematic review with NMA and three RCTs (two being non-inferiority trials). Capsaicin was associated with dermatological complications (application site pain, erythema, itching, and burning sensation) whereas pregabalin, gabapentin, and duloxetine were associated with somnolence, dizziness, and nausea. There was no statistically significant difference in headache events with capsaicin compared to pregabalin, gabapentin, or duloxetine. Itching was greater with capsaicin compared to amitriptyline or clonidine; statistical significance was not reported.
One cost utility analysis showed that for patients with PNP, the probability of capsaicin (8%) patch being cost-effective versus optimized dose pregabalin was 97%, at a willingness to pay threshold of £20,000 per QALY. Another cost utility analysis showed that for patients with post-herpetic neuropathy (PHN), treatment with capsaicin (8%) patch versus oral agents (tricyclic antidepressant [TCA], gabapentin, pregabalin, or duloxetine) was cost-effective at a willingness to pay threshold of US$50,000 to US$100,000.
Findings need to be interpreted with caution considering the limitations, such as limited quantity of evidence, variable quality of evidence, limited number of head-to-head trials comparing capsaicin with other agents, concerns related to reliability of findings from indirect comparisons, unclear long term effects, and potential biases; and for economic evaluations, findings are dependent on the assumptions on which the evaluations were based.
Methods
Literature Search Methods
A limited literature search was conducted by an information specialist on key resources including PubMed, the Cochrane Library, the University of York Centre for Reviews and Dissemination (CRD) databases, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search was used for both this report and a previous related report9. The search strategy was comprised of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were capsaicin or capsaicin and safety. Search filters were applied to limit retrieval by publication type as follows: Question 1 - health technology assessments, systematic reviews, meta-analyses, or network meta-analyses; Question 2 - randomized controlled trials, controlled clinical trials, any other type of clinical trial or safety data; Question 3 - economic studies. Where possible, retrieval was limited to the human population. The search was limited to English language documents published between January 1, 2015 and May 19, 2020 for Questions 1 and 2. For Question 3 the search was limited to English language documents published between January 1, 2010 and May 19, 2020.
Selection Criteria and Methods
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in .
Exclusion Criteria
Articles were excluded if they did not meet the selection criteria outlined in , they were duplicate publications, or were published prior to 2015 for Q1 and Q2, or prior to 2010 for Q3. Systematic reviews, which lacked details of the included primary studies, were excluded, if the primary study reports were identified by the literature search and could be used instead.
Critical Appraisal of Individual Studies
The included publications were critically appraised by one reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)10 for systematic reviews, the “Questionnaire to assess the relevance and credibility of a network meta-analysis”11 for network meta-analyses, the Downs and Black checklist12 for randomized and non-randomized studies, and the Drummond checklist13 for economic evaluations. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
Summary of Evidence
Quantity of Research Available
A total of 445 citations were identified in the literature search. Following screening of titles and abstracts, 416 citations were excluded and 29 potentially relevant reports from the electronic search were retrieved for full-text review. No potentially relevant publications were retrieved from the grey literature search for full-text review. Of these 29 potentially relevant articles, 21 publications were excluded for various reasons, and eight publications met the inclusion criteria and were included in this report. These comprised two systematic reviews,14,15 four randomized controlled trials (RCTs),16–19 and two economic evaluations.20,21
Appendix 1 presents the PRISMA22 flowchart of the study selection.
Summary of Study Characteristics
The study characteristics are summarized below. Additional details regarding the characteristics of included publications are provided in Appendix 2, (systematic reviews), (RCTs), and (economic evaluations).
Study Design
The two included systematic reviews14,15 included network meta-analysis (NMA). One systematic review14 included 28 RCTs published between 1991 and 2017, and another systematic review included 25 RCTs published between 1987 and 2017. In both systematic reviews14,15 the network structure was presented; in one NMA14 both frequentist and Bayesian approaches were used and in the second NMA15 a Bayesian approach was used.
The four included primary studies16–19 were RCTs. One RCT16 was a double-blind trial, two RCTs18,19 were double-blind non-inferiority trials, and one RCT17 was an open-label non-inferiority trial.
Two relevant economic evaluations20,21 were identified. One economic evaluation20 was a cost utility analysis using a decision tree model, and the second economic evaluation21 used was a cost utility analysis using a Markov model. For one economic evaluation20 the perspective was that of the National Health Services and Personal and Social Services of Scotland, UK; and the time horizon was two years; and data sources included clinical data from published literature and the files of the Industry, and cost data from the British National Formulary and Scottish Medicines Consortium. In this economic evaluation, it was assumed that patients with initial response continued to respond, all patients who responded to capsaicin were retreated, and no additional costs were incurred to manage adverse events. For the second economic evaluation21 the perspective was that of the payer (managed care organization); and the time horizon was one year; and data sources included clinical data from published literature, and cost data from drug store data or the industry. In this economic evaluation it was assumed that nortriptyline represented the TCA class, for capsaicin the next administration was linear and divided equally over the monthly cycle, and 30% change in pain was taken as the efficacy endpoint. Sensitivity analyses were conducted in both economic evaluations.20,21
Country of Origin
The two systematic reviews14,15 were from the UK 14 and the Netherlands.15
The first author of one RCT16 was from Germany, and the study was conducted in Germany and Russia. The first author of the second RCT17 was from Finland and the study was conducted in several European countries and the UK. The first author of remaining two RCTs18,19 were from Iran and the studies were conducted in Iran.
The two economic evaluations,20,21 were from the UK,20 and the USA.21
Patient Population
One systematic review14 included 28 RCTs with a total of 6,957 patients with pain due to OA; in the included RCTs, the mean age ranged between 49 years and 69 years; proportion of females ranged between 45% and 100%; duration of OA was not reported. The second systematic review15 included 25 RCTs with a total of 999 patients with painful diabetic peripheral neuropathy (DPN); in the included RCTs the mean age varied between 53 years and 71 years, the proportion of females were not reported, and the mean duration of painful DPN, when reported, ranged between 0.8 to 5.7 years across 14 RCTs and was not reported in 11 RCTs.
One RCT16 involved 446 patients with acute back and neck pain, mean age was 43.7 years, proportion of females was 59.2%, and time of onset of pain was 10 days. The second RCT17 involved 559 patients with peripheral neuropathic pain (PNP) (includes postherpetic neuralgia [PHN], post-traumatic nerve injury [PNI], non-diabetic painful peripheral polyneuropathy), mean age was 55.9 years, proportion of females was 59.2%, and duration of pain was 2 years. The third RCT18 involved 102 patients with DPN, mean age was 56.7 years, proportion of females was 67.7%, and duration of pain was 19 years. The fourth RCT19 involved 139 patients with DPN, mean age was 57 years, proportion of females was 72.6%, and 17.3 years.
One economic20 evaluation involved patients with peripheral neuropathic pain (PNP). The second economic evaluation21 involved patients with postherpetic neuropathy (PHN).
Interventions and Comparators
One systematic review14 compared capsaicin (0.025% or 0.0125%) cream with topical non-steroidal anti-inflammatory drugs (NSAIDs) using NMA involving RCTs comparing NSAIDs with placebo, and five RCTs comparing capsaicin cream (0.0125% or 0.025%) with placebo. The second systematic review15 compared capsaicin (8%) patch with oral neuropathic pain medication (duloxetine, gabapentin, pregabalin, and amitriptyline), using NMA involving RCTs comparing duloxetine, gabapentin, pregabalin, and amitriptyline, with placebo or amongst each other, and one RCT comparing capsaicin (8%) with placebo.
One RCT16 compared capsaicin (0.075%) gel with diclofenac (2%) gel. The second RCT17 compared capsaicin (8%) patch with optimized dose pregabalin. The third RCT18 compared capsaicin (0.75%) cream with amitriptyline (2%) cream. The fourth RCT19 compared capsaicin (0.75%) cream with clonidine (0.1%) gel.
One economic evaluation20 compared capsaicin (8%) patch with optimized dose pregabalin. The second economic evaluation21 compared capsaicin (8%) patch with tricylic antidepressants (TCAs), pregabalin, gabapentin, duloxetine, and lidocaine.
Outcomes
Outcomes reported included change in pain,14–19 and adverse events.15–19 In one systematic review14 change in pain was measured using various scales and was expressed as effect size. The second systematic review15 reported on proportion of responders (≥ 30% reduction in pain scores and ≥ 50% reduction in pain scores, assessed using the 11-point numeric rating scale; scale details were not presented). One RCT reported on change in pain in terms of pain on movement for worst procedure (POMWP); measured with a visual analogue scale (VAS) ranging from 0 to 10 centimeters, and decrease in POMWP indicates less pain.16 The second RCT reported on the proportion of responders (≥ 30% reduction in pain scores, assessed using the numeric pain rating scale; scale details were not presented).17 The third and fourth RCTs reported on proportion of responders (≥ 50% reduction in pain, assessed using a VAS with scores from 0 to 10; higher scores indicating greater pain).18,19 In the two systematic reviews14,15 the study duration of the included studies varied between one week and 12 weeks in one systematic eview14 and between four weeks and 14 weeks in another systematic review.15 In the included RCTs16–19 the treatment duration varied between 5 days and 12 weeks.
The two included economic evaluations,20,21 reported on incremental cost-effectiveness ratio (ICER) expressed as cost per quality of life year gained (QALY).
Summary of Critical Appraisal
An overview of the critical appraisal of the included publications is summarized below. Additional details regarding the strengths and limitations of included publications are provided in Appendix 3, (systematic reviews), (RCTs), and (economic evaluations).
In the two included systematic reviews,14,15 the objective was stated, a comprehensive literature search was conducted, and the article selection was described (i.e., number of articles selected and flow chart of selection provided) but it was unclear if article selection was done in duplicate. In one systematic review14 the data extraction and quality assessment were done in duplicate, and studies were judged by the systematic review authors to have considerable risk of bias. In another systematic review15 data extraction was done by one reviewer and checked by another reviewer, and quality assessment was done by one reviewer and the studies were judged to be of variable quality. One systematic review14 did not appear to have investigated publication bias, and in one systematic review15 investigation of publication had been planned, but could not be done due to few studies. In both systematic reviews conflicts of interest were declared and one or more authors were associated with industry, hence the potential for bias cannot be ruled out.
Both systematic reviews14,15 conducted NMA. In one systematic review,14 both frequentist and Bayesian approaches were used; a random effects model was used; and effect size and uncertainty (associated confidence intervals and credible intervals) of the estimate were reported. There was difference in the populations with respect to the type of OA among the studies included in the NMA. The majority of NSAID studies involved patients with knee OA, whereas the capsaicin studies involved patients with hand, elbow, wrist, shoulder, hip, knee, and ankle OA. This difference in population could impact results of the indirect comparison in the NMA. The direction of impact is unclear. In the second systematic review15 a Bayesian approach was used; effect size and uncertainty (credible intervals) of the estimate was reported. The fixed effects models were used, as goodness-of-fit was similar or better for fixed effects models compared to random effects models. The authors mentioned that impact of effect modifiers was assessed. In case of heterogeneity identified in terms of factors such as drug dose, efficacy definitions, and treatment duration, analyses were conducted excluding heterogeneous studies or conducting scenario analyses. However, these results were not presented. The authors also mentioned that it was not possible to control for many other factors such as patient inclusion criteria, and concomitant medications used. Reliability of the NMA findings is unclear.
In the four included RCTs16–19 the objective, and inclusion and exclusion criteria were stated, patient characteristics, interventions and outcomes were described. In three RCTs, randomization method was described and appeared to be appropriate. Three RCTs16,18,19 were mentioned to be double-blinded, and in one RCT17 there was no blinding, hence possibility of detection bias and performance bias cannot be ruled out. In one RCT16 the withdrawals were few, but in three RCTs17–19 withdrawals were high and varied between capsaicin and the comparator groups. In one RCT17 withdrawals (reasons not reported) were 2.1% with capsaicin and 14.8% with pregabalin. In the second RCT18 withdrawals due to adverse events were 43.4% with capsaicin and 37.3% with amitriptyline. In the third RCT,19 withdrawals due to adverse events were 42.9% with capsaicin and 23.1% with clonidine, hence there is potential for attrition bias. In two RCTs 18,19 conflicts of interest were not declared, and in two RCTs,16,17 the authors had association with industry, hence the potential for bias cannot be ruled out.
In the two included economic evaluations20,21, the objective, strategies compared, perspective taken, time horizon, sources for clinical and cost data were stated. Time horizons were between one and two years, hence outcome in the long term would not be captured. The sources of clinical and cost data used seemed appropriate. The models used were described, and assumptions were reported and appeared to be reasonable. Sensitivity analyses were conducted by varying different model parameters to ensure the validity of the model. Incremental analyses were reported. Conclusions were consistent with the results reported. Conflicts of interest of the authors were declared and some of the authors had association with or were employed by the industry hence potential for bias cannot be ruled out.
Summary of Findings
The main findings are summarized below. Details of the main study findings and authors’ conclusions are presented in Appendix 4, (systematic reviews) (RCTs), and (economic evaluations).
Clinical effectiveness of capsaicin for treating various pain conditions
Peripheral neuropathic pain (PNP)
One RCT17 involving patients with PNP (includes PHN, PNI, non-diabetic painful peripheral polyneuropathy) reported that capsaicin (8%) patch was non-inferior to optimized dose pregabalin with respect to the proportion of treatment responders (assessed using a non-inferiority margin of a change of −8.5% for the proportion of responders). Treatment duration was eight weeks.
Diabetic peripheral neuropathy (DPN)
One systematic review15 with NMA, reported odds ratios and 95% credible intervals and reported on pain relief (in terms of proportions of patients having ≥ 30% reduction in pain and ≥ 50% reduction in pain, assessed using a 11-point numerical rating scale, with higher values indicating greater pain). This systematic review showed (based on indirect comparison) that for patients with painful DPN, treatments with capsaicin (8%) and oral agents (duloxetine, gabapentin, or pregabalin) were similar in terms of pain relief (i.e., in terms of proportions of patients having ≥ 30% reduction in pain), as demonstrated by the 95% credible interval (0.91 to 3.34) for capsaicin compared to pregabalin; (0.74 to 3.23) for capsaicin compared to gabapentin, and (0.50 to 1.79) for capsaicin compared to duloxetine. Also, this systematic review showed (based on indirect comparison) that for patients with painful DPN, treatments with capsaicin (8%) and oral agents (duloxetine, gabapentin, or pregabalin) were similar in terms of pain relief (i.e., in terms of proportion of patients having ≥ 50% reduction in pain) as demonstrated by the 95% credible interval (0.55 to 2.40) for capsaicin compared to pregabalin; (0.39 to 2.00) for capsaicin compared to gabapentin; and (0.40 to 1.71) for capsaicin compared to duloxetine. Treatment duration varied between four to 13 weeks.
One RCT18 reported that for patients with painful DPN, there was no statistically significant difference between capsaicin (0.75%) cream and amitriptyline (2%) cream (P = 0.545) in terms of proportion of treatment responders (having ≥ 50% reduction in pain, using VAS scores). Treatment duration was 12 weeks
One RCT19 reported that for patients with painful DPN, the proportion of treatment responders (having ≥ 50% reduction in pain, using VAS scores) was 40.6% with capsaicin (0.75%) cream and 57.1% with clonidine (0.1%) gel, P = 0.051. The authors reported a non-inferiority limit of 25%, i.e., “the upper limit of a 95% two-sided confidence interval would exclude a difference in favor of the standard group of more than 25%. [p. 3 of 11]”19). The graphical representation of VAS scores over the treatment duration of 12 weeks were presented and it was reported that that there was no statistically significant difference between the capsaicin and clonidine treatments (P = 0.931); the slopes of VAS decline were not statistically significantly different between the two treatments, P = 0.189.
Osteoarthritis (OA)
One systematic review14 with NMA, showed (based on indirect comparison) that for patients with pain due to OA, treatments with topical capsaicin (0.25% or 0.125%) and topical NSAIDs were similar in terms of pain relief, as demonstrated by the credible interval (−0.28 to 0.35) for the difference in effect. Treatment duration varied between one to 12 weeks.
Back and neck pain
One RCT16 involving patients with acute back and neck pain showed that numerically, decrease in POMWP from baseline was greater for capsaicin than for diclofenac, statistical significance was not reported. Treatment duration was five days.
Safety of capsaicin for treating various pain conditions
Peripheral neuropathic pain (PNP)
One RCT17 involving patients with PNP (includes PHN, PNI, non-diabetic painful peripheral polyneuropathy) reported that capsaicin (8%) patch was associated with treatment emergent adverse events (TEAEs) such as application site pain, erythema, and burning sensation, whereas optimized dose pregabalin was associated with TEAEs such as nausea, dizziness, and somnolence.
Diabetic peripheral neuropathy (DPN)
One systematic review15 with NMA, involving patients with painful DPN, reported odds ratios and 95% credible intervals for tolerance of treatment (in terms of adverse event: headache) for patients with painful DPN. It reported credible intervals 0.01 to 1.33 for pregabalin compared to capsaicin (8%) patch, 0.01 to 1.96 for gabapentin compared with capsaicin (8%) patch, and 0.01 to 3.05 for duloxetine compared with capsaicin (8%) patch, indicating similar tolerability of capsaicin (8%) patch compared with pregabalin, gabapentin and duloxetine.
One RCT18 involving patients with painful DPN showed that the proportion of patients with adverse events was greater with capsaicin (0.75%) cream compared with amitriptyline (2%); 56.9% in the capsaicin group, 29.9% in the amitriptyline group, P = 0.001. In the capsaicin group, proportions of patients with itching, blister formation, and erythema were 20%, 8.5%, and 5.7% respectively. In the amitriptyline group, proportion of patients with dryness and itching were 8.8% and 4.4% respectively.
One RCT19 involving patients with painful DPN, showed that the proportions of patients with dermatological complications were 58% with capsaicin, and 5.7% with clonidine, P = 0.001.
Back and neck pain
One RCT16 involving patients with acute back and neck pain reported that the proportion of patients experiencing adverse events such as application site pain, infection and infestation, and skin and subcutaneous tissue disorder were numerically higher with capsaicin (0.075%) gel than with diclofenac (2%) gel. Also, the proportion of patients experiencing nervous system disorders were numerically higher with diclofenac compared with capsaicin.
Cost-Effectiveness of capsaicin for treating various pain conditions
Peripheral neuropathic pain (PNP)
One economic evaluation20 investigated cost-effectiveness of capsaicin (8%) patch versus dose optimized pregabalin in non-diabetic patients with PNP from the perspective of the National Health Service and Personal and Social Services in Scotland, UK. The ICER (incremental cost per incremental QALY gained) indicated that capsaicin dominated pregabalin, i.e., capsaicin was more effective with lower cost. One-way sensitivity analysis showed on varying different parameters (such as time to retreatment with capsaicin, grade 6 nurse time, and number of capsaicin patches per treatment) capsaicin either dominated or was cost-effective (i.e., ICER was less than the willingness to pay threshold of £20,000 per QALY). The ICER was most sensitive to variations in the time to retreatment with the capsaicin patch; at the low value (117 days), the ICER increased to £7,951 per QALY, whereas at the high value (241 days), the capsaicin patch was the dominant treatment strategy. The cost-effectiveness acceptability curve showed that the probability of capsaicin being cost-effective versus pregabalin was 97%, at a willingness to pay threshold of £20,000 per QALY.
One economic evaluation21 investigated cost-effectiveness of capsaicin (8%) patch versus lidocaine (5%) patch, or oral agents (TCA, gabapentin, pregabalin, or duloxetine) for treating patients with PHN, from a payer perspective. ICER for capsaicin compared to TCAs was approximately US$60,000; and compared to duloxetine, gabapentin, or pregabalin was less than US$40,000. Capsaicin was considered cost-effective compared to TCAs, duloxetine, gabapentin and pregabalin at a willingness to pay threshold of US$50,000 per QALY gained to US$100,000 per QALY gained. Sensitivity analysis showed that the ICER (incremental cost per incremental QALY gained) was most sensitive to the retreatment time. If the capsaicin patch retreatment interval was increased to 14.5 weeks, the ICER for capsaicin compared to the oral agents (TCAs, duloxetine, gabapentin, and pregabalin) was less than US$51,000 per QALY gained. If the capsaicin patch retreatment interval was increased to 17.7 weeks, the ICER for capsaicin compared to the oral agents (TCAs, duloxetine, gabapentin, and pregabalin) was less than US$44,000 per QALY gained.
Limitations
The evidence is limited in quantity. In the systematic reviews, the studies included in the NMA were of low quality or variable quality, furthermore in one systematic review, for capsaicin only one study of limited size was included, hence reliability of the findings is uncertain. Head-to-head studies comparing capsaicin with other pharmacological medications were lacking Comparison across studies was difficult as populations, types of capsaicin used, and comparator treatments varied. The studies in the systematic reviews, as well as the selected RCTs were of short duration (5 days to 14 weeks), hence long-term effects are not known. In one non-inferiority RCT, the non-inferiority margin was not reported and in one non-inferiority RCT, the non-inferiority margin was substantial and furthermore the rationale for choosing such a margin was not presented.
Most of the studies were funded by industry, and many of the study authors were associated with or employed by the industry; potential for bias cannot be ruled out.
Generalizability of the findings to the Canadian context is unclear as the studies were conducted in various countries. Furthermore, according to a 2018 report,7 topical capsaicin is not approved by Health Canada for indications such as OA, PHN, DPN, and pruritic disorders. Also, one systematic review,15 one primary study,17 and the two economic evaluations were on capsaicin (8%) patch, a product that is not available in Canada.7
Findings need to be interpreted with caution considering the limitations, such as evidence of limited quantity, lack of head-to-head trials, potential biases; and for economic evaluations, findings are dependent on the assumptions on which the evaluations were based.
Conclusions and Implications for Decision or Policy Making
The eight relevant publications identified comprised two systematic reviews,14,15 with NMA, four RCTs,16–19 and two economic evaluations.20,21 The majority of these studies were on neuropathic pain.
Six publications14–19 reported on clinical effectiveness outcomes. One RCT17 showed that for patients with PNP, treatment with capsaicin (8%) patch was non-inferior to pregabalin, in terms of the proportion of treatment responders. Three publications15,18,19 reported on painful DPN. One systematic review15 with NMA, suggested that for patients with painful DPN and based on indirect evidence, treatment with capsaicin (8%) patch was similar to oral agents: pregabalin, gabapentin and duloxetine, in terms of pain relief. One RCT18 showed that for patients with painful DPN, there was no statistically significant difference between treatment with capsaicin (0.75%) cream and amitriptyline (2%) cream, in terms of the proportion of treatment responders. One RCT19 showed that for patients with painful DPN, there was no statistically significant difference between capsaicin (0.75%) and clonidine (0.1%) gel, in terms of proportion of treatment responders. One systematic review14 with NMA, suggested that for patients with pain due to OA and based on indirect evidence, treatments with topical capsaicin (0.025% or 0.0125%) and topical NSAIDs were similar in terms of pain relief. One RCT16 involving patients with acute back and neck pain showed that capsaicin (0.075%) produced a greater decrease in the pain outcome (POMWP) from baseline value compared with diclofenac (2%), statistical significance was not reported.
Four publications15,17–19 reported on safety outcomes. One RCT17 involving patients with PNP (includes PHN, PNI, non-diabetic painful peripheral polyneuropathy) reported that capsaicin (8%) patch was associated with adverse events such as application site pain, erythema, and burning sensation, whereas optimized dose pregabalin was associated with adverse events such as nausea, dizziness, and somnolence. One systematic review with NMA, suggested that for patients with painful DPN, tolerance was similar for capsaicin (8%) patch, pregabalin, gabapentin and duloxetine. One RCT18 involving patients with painful DPN showed that the proportion of patients with adverse events was greater with capsaicin (0.75%) cream than with amitriptyline (2%) cream. One RCT19 involving patients with painful DPN, showed that the proportion of patients with dermatological complications were statistically significantly higher with capsaicin (0.75%) compared with clonidine (0.1%) gel. One RCT16 involving patients with acute back and neck pain, reported that the proportion of patients experiencing dermatological adverse events was numerically higher with capsaicin (0.075%) gel compared with diclofenac (2%) gel.
One cost utility analysis20 showed that for patients with PNP, the probability of capsaicin (8%) patch being cost-effective versus optimized dose pregabalin was 97%, at a willingness to pay threshold of £20,000 per QALY. Another cost utility analysis21 showed that for patients with PHN, treatment with capsaicin (8%) patch versus oral agents (TCA, gabapentin, pregabalin, or duloxetine) was cost-effective at a willingness to pay threshold of US$50,000 to US$100,000. Similar cost-effectiveness ratios for the capsaicin (8%) patch and lidocaine (5%) patch were reported.
One economic evaluation23 did not meet are inclusion criteria as the comparison did not meet inclusion criteria for this current report. It may provide some useful insights, so is discussed here. It was a cost-effectiveness analysis conducted in Germany and investigating prior and post capsaicin use, in patients with brachioradial pruritis and notalgia paraesthetica. It found that after introduction of capsaicin (8%) patch, there was reduced pruritis and improved quality of life, and the overall cost (cost to the health insurer and cost to the patient) was similar. Study authors mentioned that investigating cost-effectiveness over the long term is necessary.
Findings need to be interpreted with caution considering the limitations, such as evidence of limited quantity and variable quality, lack of head-to-head trials, reliability concerns regarding the findings from indirect comparisons, unclear long-term effects, and potential biases.
Further studies are needed to investigate long term effects, various pain conditions, and direct evidence of capsaicin versus alternative pharmacological treatment options for pain, to have a better understanding of the role of capsaicin for management of pain.
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Appendix 1. Selection of Included Studies
About the Series
CADTH Rapid Response Report: Summary with Critical Appraisal
Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.
Suggested citation:
Capsaicin for Acute or Chronic Non-Cancer Pain: A Review of Clinical Effectiveness, Safety, and Cost-Effectiveness. Ottawa: CADTH; 2020 Jul. (CADTH rapid response report: summary with critical appraisal).
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