By Concepta Merry, MB, BCh, BAO, BA

Associate Professor, Global Health, School of Medicine, Trinity College, Dublin

Dr. Merry reports no financial relationships relevant to this field of study.

SUMMARY POINTS

  • A 12-week study showed that an 8% capsaicin patch treatment provided modest pain relief and sleep quality improvements compared to a placebo patch in patients with painful diabetic peripheral neuropathy.
  • This was a single 30-minute treatment.
  • The topical therapy was well-tolerated and did not compromise peripheral sensation.

SYNOPSIS: An 8% capsaicin patch relieves pain and improves sleep in patients with painful diabetic peripheral neuropathy.

SOURCE: Simpson DM, Robinson-Papp J, Van J, et al. Capsaicin 8% patch in painful diabetic peripheral neuropathy: A randomized, double-blind, placebo-controlled study. J Pain 2017;18:42-53.

One-quarter of patients with type 2 diabetes mellitus experiences painful diabetic peripheral neuropathy.1 The current standard of care for painful diabetic peripheral neuropathy focuses on centrally acting agents, such as antidepressants, anticonvulsants, and opioid analgesics.2 These oral treatments may not be well-tolerated and offer modest clinical benefit.3 Capsaicin is derived from chile peppers (Capsicum spp.). An 8% capsaicin patch has been suggested as a second-line agent for management of peripheral diabetic neuropathy pain.3

Capsaicin is a vanilloid receptor (subtype one) agonist that provides rapid, sustained pain relief by depolarizing hyperactive nociceptors.4 Since capsaicin is delivered topically, the risk of drug-drug interactions and systemic side effects are minimized.5 Studies have shown that the 8% capsaicin patch was beneficial in post-herpetic neuralgia, HIV-associated peripheral polyneuropathy, and painful neuropathic pain in non-diabetic patients.6,7,8

Simpson et al assessed the safety and efficacy of the 8% capsaicin patch vs. placebo in patients with painful diabetic peripheral neuropathy. There are several important factors to consider when analyzing the study results.

First, Astellas Pharma Europe funded the study and provided the study drug. The first author of the paper consults for Astellas Pharma, and the senior author was a paid consultant to support the study design. Four other study authors are employees of Astellas Pharmaceutical Company, and only three of the authors disclosed no conflicts of interest. Second, an unspecified amount of the manuscript was outsourced. The article stated that the authors were “fully responsible for the content and editorial decision for the report.” Of note, the paper did not follow the standard referencing guidelines and began with reference number 8, followed by reference number 22. Reference 22 in the text relates to consensus guidelines, while the paper listed in the reference section as number 22 is a randomized, controlled trial. Reference 21 in the reference section is a paper on consensus guidelines.

This was a four-week, Phase III, randomized, double-blind, placebo-controlled trial conducted at multiple sites across the United States. Eligible patients were 18 years of age and had a diagnosis of painful diabetic peripheral neuropathy due to type 1 or type 2 diabetes mellitus for 1 year; HbA1C 11 and < 1% difference in the HbA1C level between the screening and prescreening values; stable doses of pain medication for four weeks prior to the screening visit; and an average numeric pain rating scale 4 (scale 0 to 10).9

Exclusion criteria included significant foot deformity, body mass index 40 kg/m2, impaired glucose tolerance not meeting the criteria for diabetes, amputation, current or previous foot ulcer, use of topical pain medication within the previous seven days, or history of hypersensitivity to capsaicin.

The primary endpoint of the study was the percentage change in the daily numeric pain rating scale according to question 5 of the Brief Pain Inventory-Diabetic Neuropathy (BPI-DN) from baseline to the mean daily score over the two- to eight-week follow-up period.

There were nine secondary study endpoints, including time to treatment response and change in sleep interference (question 9F of the BPI-DN). Seven safety and tolerability assessments were listed independently of the primary and secondary endpoints.

The researchers screened 761 patients at 29 participating U.S. sites; 369 of the 761 patients fulfilled the inclusion and exclusion criteria and participated in the study. Failure to meet the glycemic control criteria was the main reason for the high number of patients who were screened but not enrolled in the study.

Most participants were Caucasian (71.3%), and baseline demographics were similar between the treatment and control arms.

Use of pain medication was similar among the treatment and placebo arms, with 76.3% of patients in the capsaicin group taking pain medications compared to 71.6% in the placebo group. Patients were randomized 1:1 to receive a single treatment with an 8% capsaicin patch or an identical placebo patch to painful areas on the feet for a period of 30 minutes. The treatment area was mapped at screening and application visits. A local anesthetic cream was applied prior to the application of the treatment/placebo patch. Patients were required to call daily and report their average pain over the previous 24 hours. Patients also visited the clinic at weeks 2, 4, 8, and 12 for review.

Application of a capsaicin patch can cause local pain and erythema. This raised the possibility of functional unblinding in the treatment arm of the study. Extra steps were taken to try to minimize this risk. The staff assigned to apply patches (capsaicin or placebo) were different from the staff who assessed the safety and efficacy of these patches.

Seventeen screened and enrolled patients did not complete the study. Nine patients discontinued in the capsaicin arm — seven patients withdrew from the study and two patients were lost to follow-up. Eight patients discontinued in the placebo arm — six patients withdrew from the study, one patient was lost to follow-up, and one patient discontinued because of a treatment emergent adverse event. The treatment emergent adverse event was hypertension, which was not thought to be related to the study.

An intention-to-treat analysis showed a reduction in the average daily pain from baseline to weeks 2 to 8 in the capsaicin vs. placebo group (mean [SD] = -27.4% [26.79%] vs. -20.9% [28.92%], respectively; P = 0.025). The authors interpreted this as “modest but within the boundary of statistical significance” for a reduction in average daily pain. The authors recommended that clinicians decide for themselves as to the clinical relevance of these findings.

Secondary endpoints included time to treatment response and sleep interference. The median time to treatment response was shorter with the 8% capsaicin patch than the placebo patch, with 50% of patients achieving a 30% reduction in average daily pain after 19 days (95% confidence interval [CI], 12-37) in the 8% capsaicin patch group vs. 72 days (95% CI, 190 to noncalculable) in the placebo group.

A greater mean percent of reduction in the BPI-DN sleep interference score was seen in the 8% capsaicin group vs. the placebo group from baseline to between weeks 2 to 8 (P = 0.030 for weeks 2 to 8; P = 0.020 for weeks 2 to 12). Clinically, this means that people in the treatment arm enjoyed better sleep than those in the placebo arm of the study.

About 46.8% of patients in the capsaicin group reported treatment adverse events as opposed to 33.9% in the placebo group. Most were mild to moderate in severity, with three patients in the capsaicin group reporting severe treatment-associated adverse events, burning sensation (n = 2), and application site pain (n = 1). There were no drug-related treatment adverse events, and no drug-related study discontinuations were necessitated in either group.

The change in sensory perception was measured at the end of the study, showing that most patients had no change in sensation or slightly improved sensation in both capsaicin and placebo groups. Specifically, 52.5% to 83.8% of patients across tests had no change, and 12% to 30% across tests had improved sensation in both groups.

Overall, the study authors concluded that a single 8% capsaicin patch provided modest improvements in pain relief compared with a placebo patch over 12 weeks for patients with painful diabetic peripheral neuropathy. They acknowledged that the treatment delta observed was narrow but stated that it was within the boundary of statistical significance as laid out in the intention-to-treat analysis.

COMMENTARY

Painful diabetic peripheral neuropathy can be very debilitating. Consultations can be frustrating for both physician and patient when the diabetes is well-
controlled metabolically but the patient is unable to sleep despite trying usual treatments. This study found that the 8% capsaicin patch provided modest pain relief and sleep quality improvements in patients with painful diabetic peripheral neuropathy.

The onset of pain relief in the capsaicin arm occurred (on average) one week later than studies of capsaicin in other groups (e.g., HIV, post-herpetic neuralgia).10 The authors proposed a number of possible explanations for this, including thickened skin, dehydration, or a reduction in the number of vanilloid receptors.

This study has a number of significant limitations. As noted above, many of the study team members had conflicts of interest. Additionally, the paper referencing was both unconventional and inaccurate. The study excluded patients with foot deformities, such as Charcot’s foot, amputation, or foot ulcers. The study results were at best “within the boundary of statistical significance.” However, the treatment was well-tolerated. Given the favorable safety profile of the patch, the lack of alternative effective options, and the negative effect of the combination of chronic pain plus lack of sleep on quality of life, this patch is worth considering for patients with painful diabetic peripheral neuropathy who fail to respond to other interventions.

REFERENCES

  1. Davies M, Brophy S, Williams R, Taylor A. The prevalence, severity, and impact of painful diabetic peripheral neuropathy in type 2 diabetes. Diabetes Care 2006;29:1518-1522.
  2. Tesfaye S, Vileikyte L, Rayman G, et al. Painful diabetic peripheral neuropathy: Consensus recommendations on diagnosis, assessment and management. Diabetes Metab Res Rev 2011;27:629-638.
  3. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis. Lancet Neurol 2015;14:162-173.
  4. Anand P, Bley K. Topical capsaicin for pain management: Therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth 2011;107:490-502.
  5. Astellas Pharma Ltd. Qutenza 179mg cutaneous patch. Available at: https://www.medicines.org.uk/emc/medicine/23156. Accessed Sept. 21, 2015.
  6. Backonja M, Wallace MS, Blonsky ER, et al. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomised, double-blind study. Lancet Neurol 2008;7:1106-1112.
  7. Clifford D, Simpson DM, Brown S, et al. A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy. J Acquir Immune Defic Syndr 2012;59:126-133.
  8. Haanpaa M, Cruccu G, Nurmikko T, et al. Capsaicin 8% patch vs. oral pregabalin in patients with peripheral neuropathic pain. Eur J Pain 2016;20:316-328.
  9. Zelman DC, Gore M, Dukes E, et al. Validation of a modified version of the brief pain inventory for painful diabetic peripheral neuropathy. J Pain Symptom Manage 2005;29:401-410.
  10. Simpson DM, Brown S, Tobias J; for the NGX-4010 C107 Study Group. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology 2008;70:2305-2313.