The Efficacy of topical Capsaicin in the management of painful diabetic peripheral neuropathy: A unicenter double-blind, randomized clinical trial

Painful Neurotropic drugs, which are the drugs of choice, have moderate efficacy due to high first pass metabolism. Topical Capsaicin, derived from the capsicum plant, is effective in relieving the pain of diabetic peripheral neuropathy in Caucasians. Due to an intercultural bias in pain treatment response, we evaluated the efficacy of Capsaicin on painful diabetic neuropathy in sub-Saharan subjects Methods: 22 subjects with type 2 diabetes having painful diabetic polyneuropathy were randomly assigned using a 1:1 blocking pattern, with parallel design, to an intervention group of capsaicin cream, or to a control group of Miconazole cream. Participants and investigators were blinded to the randomization. Both groups applied the supplied drug topically three times daily for 08 weeks. Pain intensity was noted in both groups, using a visual analogue scale, at intervals of 2 weeks. The trial took place at the national obesity center in Cameroon. The primary analysis was intention-to-treat, and compared the reduction in the mean pain score from baseline, per 2 week period. 2


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Peripheral neuropathy in people living with diabetes mellitus is frequent, affecting about 50% of the population, ensuring it is the most common diabetic microvascular complication [1]. This peripheral neuropathy can clinically be motor, sensory, mixed or autonomic in nature. Pain, or painful paresthesias when present, can interfere with daily activities, work, and sleep, greatly reducing the quality of life of its sufferers.
The treatment of painful diabetic neuropathy, according to the Ad Hoc Panel on Endpoints for Diabetic Neuropathy Trials management is first to assure optimal glucose control, symptomatically treat the pain, and thirdly with the use of ancillary therapies directly interfering with the pathophysiologic cycle of diabetic neuropathy [2]. Symptomatic therapies for painful diabetic neuropathy include Tricyclic antidepressants, anticonvulsants, Gamma Amino Butyric Acid analogs, Selective Serotonin reuptake inhibitors, and rarely opioids. Despite this seemingly rich availability of options to treat painful diabetic neuropathy, effective treatment of diabetic neuropathic pain remains a challenge for both physicians and patients [3]. Most of these drugs are orally administered, and thus present with a high risk of systemic side effects and decreased drug bioavailability due to first-pass mechanism [4].
Capsaicin (Trans-8-methyl-N-vanillyl-6-nonenamide) is the active ingredient found in various species of chili peppers, and exhibits pharmacologic effects on type C nociception nerve fibers, which are necessary for conduction of slow neuropathic pain. Its application is topical and repeated applications result in functional injury to peripheral nerves, resulting in desensitization to painful stimuli [5]. This peculiar characteristic of capsaicin is the basis for its usage in relieving the pain of HIV neuropathy, post-herpetic neuralgia and surgical post-op pain [6]. Topical Capsaicin has been proven to have moderate efficacy in diabetic peripheral neuropathy in Caucasians. Pain perception threshold shows ethnic and racial differences with treatment response in Africans different from Caucasians [7]. In this population milieu, there is a lack of data indicating the efficacy of capsaicin in painful diabetic neuropathy. We therefore hypothesized that an 8-week treatment course using Capsaicin 0.075% would significantly improve pain sensation associated to diabetic distal peripheral neuropathy and overall quality of life of sub-saharan patients with type 2 diabetes involved in the study. We also investigated the possibility of occurrence of side effects with Capsaicin treatment.

Trial design
This was a unicenter, balanced 1:1 randomized double-blind, placebo-controlled clinical trial, with a parallel design, conducted at the National obesity center, Cameroon.

Participants
Twenty-two participants with painful symmetrical diabetic neuropathy were recruited for this study, and were randomized to receive either capsaicin or the placebo cream. All were patients with type 2 diabetes who had daily pain or painful paresthesias in a neuropathic or radiculopathic distribution, intensity between 4 and 7 on a visual analogic scale, interfering with daily activities, work or sleep for at least 3 months duration.
Excluded, were patients with; History of allergies to any capsaicin product Diabetic patients with other diagnosed etiology responsible for peripheral neuropathy such as hepatitis, AIDS, Nutritional deficiencies (folate, vitamin B12) there was development of any serious harm as a result of the trial. At the end of the 8 th week, the study was stopped. Equipoise was assured by making sure all investigators, participants and data analysts were blinded to the allocation. Only members of the data and safety monitoring board were aware of the subjects per allocated arm. The data and safety monitoring board was accessible by telephone to all participants throughout the study.

Statistical analysis
The student t test was used to compare means for continuous variables between both groups.
Categorical variables were compared using the chi square test. The primary analysis was intention-totreat and involved all patients who were randomly assigned. The efficacy endpoint was the change in mean bi-weekly pain score on the Visual analogic scale. Values were expressed as means with ranges, and numbers and percentages. Statistical significance was set for p ≤ 0.05

Results
The flowchart below shows the numbers of participants who were randomly assigned, received intended treatment, and analyzed for the primary outcome.

Baseline characteristics of the patients
The study was conducted between January and April 2018. Patients' baseline characteristics were comparable between the two groups of treatments (Table 2) Outcomes and estimation Table 3 shows the results of the effect of our intervention on the pain intensity values for each group per time period.
There is strong evidence that participants who applied capsaicin cream attested to a more favorable change, as shown by the primary efficacy parameter, than subjects who applied the placebo cream.
There was a decrease in mean pain intensity value in the capsaicin group within 2 weeks of drug administration, maintained as such till the sixth week. At the eighth week however, there was a rebound in pain intensity in the capsaicin-treated group, greater than baseline values (figure 2) Quality of life analysis was done using data from the fourth and eighth week of the study. Comparison for both groups revealed no statistically significant improvement as shown in Table 4.

Harms:
Of the 11 participants allocated to receive the drug, 8 complained of a burning, stinging sensation at site of application only. 2 participants, in addition to this burning sensation, complained of sneezing and tearing eyes upon administration, and another 1, complained of diffuse redness on site of application, in addition to the burning. These side effects were noticed upon first administration and were significantly reduced or absent two weeks later.
The eleven participants assigned to the placebo group had no side effects throughout the duration of study (Table 5).

Discussion
Limitations: The limitations of our study were the short duration of study and the lack of nerve conduction studies, which are the best methods in diagnosing and determining the type of neuropathy.

Interpretation
The results of our double-blind placebo controlled randomized study in sub-Saharan participants with diabetic painful neuropathy show that 0.075% capsaicin cream significantly reduces neuropathic pain for 6 weeks of use. In this study, burning or heat sensations at site of administration was the most frequent adverse effect, which was tolerable, and decreased with repeated continuous administration.
This shows that topical capsaicin may be of some value in the symptomatic management of painful diabetic neuropathy in cases where conventional agents fail to elicit a favorable response.
Ten out of eleven of the participants taking the topical capsaicin achieved a drop in their pain levels from baseline within 14 days from the start of therapy [9]. Our study demonstrated a pain reduction between weeks 2 to 6 which was statistically significant for Capsaicin versus placebo (3.08 units drop vs. 1.46, p= 0.02).
At the end of the 8 th week, there was no statistically significant reduction in mean pain value in the capsaicin group, (-0.3 vs. 0.44, p= 0.55) but rather an increase in mean pain intensity compared to pre-treatment values. Capsaicin mediates its effect by defunctionalizing c fiber nociceptors (neurolysis). It is a TRPV1 agonist and its prolonged activation of TRPV1 results in loss of receptor functionality, causing impaired local nociception for extended periods. [10] Also defunctionalization of peripheral nerve fibers is partially as a result of capsaicin-induced substance p depletion, along with other sensory mediators in the spinal dorsal root ganglia. Regeneration or reinnervation of these nerve fibers after a functional insult is completed after about 6-8 weeks, explaining this increased pain intensity.
There was an improvement in the Quality of life at Week 4 analysis of the capsaicin participants, manifested by better sleep and less interference in physical activities and emotion. 9 out of 11 of these experienced a positive change to Quality of life. However, comparison to the placebo group yielded no significant difference (p=0.28) despite a significant mean pain level difference. Our findings can be explained by the fact that we limited our patient recruitment to those with a maximum pain level of 7. Thus, their baseline Quality of life was likely to be acceptable, and as such a large change unlikely. Quality of life comparisms at the 8 th week were not significant either and comparatively impaired in the capsaicin group. This was most likely due to the worsening pain intensity due to nerve reinnervation.
Our study also sought to identify the safety profile of topical Capsaicin. All the 11 participants undergoing treatment complained of a Burning or stinging sensation at site of application of drug.
This side effect gradually decreased with continuous application of drug, and was greatly reduced or tolerable by the second week of treatment. This finding corresponds to capsaicin-induced initial hyperalgesia of nociceptors followed by desensitization [11]. 1 participant out of the 11 complained of an on-site burning pain associated with erythema. This redness is due to the release of histamine from mast cells. [5] Conclusion 11 The above findings show that topical capsaicin has a transitory superb short term effect on neuropathic pain, but without any modification to clinical neuropathy severity grading, indicating it can be used as a symptomatic add-on option in periods of exacerbation of neuropathic pain. It also appears less likely to cause major side effects and improves quality of life modestly. The initial burning that capsaicin induces, may negatively impact compliance, and hence the drug's efficacy. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare no competing interest.

Funding
The funding for this study was supplied by the primary investigator. BBA was involved in the conception, design of the study, interpretation of data and drafting of the manuscript.
AsacPharma laboratories Cameroon provided the capsaicin drug, as a free sample.
Authors' contributions BBA was involved in the conception, design of the study, interpretation of data and drafting of themanuscript. DM, MCE and YF were involved in the study conception, design, protocol writing, critical review and revision of the manuscript. DDA and YFW were involved in data analysis and interpretation. NE, JCK, NA and AOB were involved in the training of workers for subject follow up and data collection, and critical review of this manuscript. SE and MJC were involved in the conception of the study, its design and general supervision. All the authors have read and agreed to the final manuscript.  Tables.docx