Capsaicin

Capsaicin, or 6-nonenamide, N-[(4-hydroxy-3-methoxyphenyl) methyl]-8-methyl, (6E), is a highly selective agonist for the transient receptor potential vanilloid 1 receptor (TRPV1). The initial effect of capsaicin is the activation of TRPV1-expressing cutaneous nociceptors, which results in pungency and erythema due to the release of vasoactive neuropeptides.

Pharmacodynamic effects

Following capsaicin exposure, cutaneous nociceptors become less sensitive to a variety of stimuli. These later-stage effects of capsaicin are frequently referred to as “desensitization” and are thought to underlie the pain relief. Sensations from non TRPV1-expressing cutaneous nerves are expected to remain unaltered, including the ability to detect mechanical and vibratory stimuli. Capsaicin-induced alterations in cutaneous nociceptors are reversible and it has been reported and observed that normal function (the detection of noxious sensations) returns within weeks in healthy volunteers.

Clinical efficacy and safety

Efficacy of a single 30-minute application of capsaicin to the feet has been shown in controlled clinical trials conducted in patients with painful Human Imunodeficiency Virus–Associated Neuropathy (HIV-AN) and painful diabetic peripheral neuropathy. Efficacy of a single 60-minute application of capsaicin to locations other than the feet has been shown in controlled clinical trials conducted in patients with postherpetic neuralgia (PHN). Pain reduction was observed at week 1 in PHN, week 2 in HIV-AN and week 3 in painful diabetic peripheral neuropathy. For all three aetiologies efficacy was maintained throughout the 12-week study period. For painful diabetic peripheral neuropathy consistent and reproducible efficacy has been demonstrated with repeated treatments during a 52-week period.

The safety profile of capsaicin in diabetic patients was consistent with that seen in the non-diabetic population.

Capsaicin has been shown to be effective when used alone or when used in combination with systemic medicinal products for neuropathic pain.

The capsaicin is intended for delivery into the skin.

In vitro data (active substance dissolution and skin permeation assays) demonstrate that the rate of release of capsaicin from capsaicin patch is linear during the application time. Based on in vitro studies, approximately 1% of capsaicin is estimated to be absorbed into the epidermal and dermal layers of skin during one-hour applications. As the amount of capsaicin released from the patch per hour is proportional to the surface area of application, this amounts to an estimated total maximum possible dose for a 1000 cm² area of application of approximately 7 mg. Assuming 1000 cm² of patch area delivers approximately 1% of capsaicin from the patch to a 60 kg person, the maximum potential exposure to capsaicin is approximately 0.12 mg/kg, once every 3 months.

According to the EC Scientific Committee on Food, the average European oral intake of capsaicin is 1.5 mg/day (0.025 mg/kg/day for a 60 kg person) and the highest dietary exposure is 25 to 200 mg/day (up to 3.3 mg/kg/day for a 60 kg person).

Pharmacokinetic data in humans showed transient, low (< 5 ng/ml) systemic exposure to capsaicin in about one third of PHN patients, in 3% of patients with painful diabetic peripheral neuropathyand in no HIV-AN patients following 60-minute applications of capsaicin patch. No data are available following 30-minute treatments. In general, the proportions of PHN patients with systemic exposure to capsaicin increased with larger treatment areas and with longer treatment durations. The highest concentration of capsaicin detected in patients treated for 60 minutes was 4.6 ng/mL, which occurred immediately after patch removal. Most quantifiable levels were observed at the time of patch removal, with a clear trend towards disappearance by 3 to 6 hours after removal. No detectable levels of metabolites were observed in any subject.

A population pharmacokinetic analysis of patients treated for 60 and 90 minutes indicated that capsaicin levels in plasma peaked around 20 minutes after capsaicin patch removal and declined very rapidly, with a mean elimination half-life of about 130 minutes.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, single-dose toxicity, and repeated-dose toxicity.

Genotoxicity studies performed with capsaicin show a weak mutagenic response in the mouse lymphoma assay and negative responses in the Ames, mouse micronucleus and chromosomal aberrationin human peripheral blood lymphocytes assays.

A carcinogenicity study performed in mice indicates that capsaicin is not carcinogenic.

A reproductive toxicology study conducted in rats showed a statistically significant reduction in the number and percent of motile sperms in rats treated 3 hours/day beginning 28 days before cohabitation, through cohabitation and continuing through the day before sacrifice. Although neither statistically significant nor dose dependent, the Fertility Index and the number of pregnancies per number of rats in cohabitation were reduced in all capsaicin-treated groups.

A teratology study conducted in rabbits did not show any potential for embryofetal toxicity. Delays in skeletal ossification (reductions in ossified metatarsals) were observed in a rat teratology study at dose levels higher than human therapeutic levels; the significance of this finding for humans is unknown. Peri- and post-natal toxicology studies, conducted in rats do not show potential for reproductive toxicity. Lactating rats exposed to capsaicin daily for 3 hours showed measurable levels of capsaicin in the mothers' milk.

A mild sensitization was seen in a cutaneous sensitization study with guinea pigs.