Keywords

Capsaicin is a naturally occurring trans-8-methyl-N-vanillyl-6-noneamide, extracted from the hot pepper plant and other peppers from the genus Capsicum (no relation with black pepper) [1, 2]. Capsaicin is the component of chili peppers which makes them taste hot. It is found in the ‘placenta’, the white fibrous material that holds the seeds [3]. Its use in dermatology is dedicated to abnormal sensations: pain (post-zoster, neuralgias, vulvodynia, HIV neuropathy, osteoarthritis, etc.…), paresthesias (diabetes) and pruritus. Capsaicin is traded in some countries (Zostrix® or Axsain®) but it has to be prepared by pharmacists in many countries (example: Capsicum tincture 12.5 g with a cosmetic base 37.5 g). A new patch containing 8 % capsaicin (Qutenza®) is also available [4].

Mechanisms of Action

Transient receptor channels (TRP) are a family of sensory receptors that can be activated by both chemical and physical factors [5, 6]. Growing arguments are in favour of a role for TRP in the pathogenesis of itch and its treatment [7–9]. Temperature-sensitive TRP channels establish a basic syntax and molecular substrate of pruriception. Among them, TRPV1 is very important.

TRPV1 is transient receptor potential vanilloid 1. The capsaicin receptor was previously named vanilloid receptor 1 or VR1 but it has been demonstrated that it belongs to the TRP family [10] and is now named TRPV1. TRPV1 is activated by physical (temperature >42 °C, osmotic pression) or chemical factors (capsaicin, protons, endocannabinoids, diphenyl compounds and some some endogenous lipid-derived molecules) [11]. TRPV1 is broadly expressed in the skin: on nerve fibers, mast cells, epithelial cells, Langerhans cells, sebocytes, endothelial cells and smooth muscle cells but not melanocytes [12, 13]. Its expression is upregulated by capsaicin and protons, allowing the induction of its expression on fibroblasts [14]. TRPV1 is not expressed by all neurons but defines a subset of peripheral sensory neurons involved in pain sensation and also at a number of other neuronal and non-neuronal sites in the mammalian body [6].

Structurally, TRPV1 subunits have six transmembrane (TM) domains with intracellular N- (containing 6 ankyrin-like repeats) and C-termini and a pore region between TM5 and TM6 containing sites that are important for channel activation and ion selectivity [6]. The N- and C- termini have residues and regions that are sites for phosphorylation/dephosphorylation and PI(4,5)P2 binding, which regulate TRPV1 sensitivity and membrane insertion. The channel has several interacting proteins, some of which are important for TRPV1 phosphorylation. Four TRPV1 subunits form a non-selective, outwardly rectifying ion channel permeable to monovalent and divalent cations with a single-channel conductance of 50–100 pS. TRPV1 channel kinetics reveal multiple open and closed states, and several models for channel activation by voltage, ligand binding and temperature have been proposed.

Studies with TRPV1 agonists and antagonists and Trpv1 (−/−) mice have suggested a role for TRPV1 in itch, pain, thermoregulation and osmoregulation, as well as in cough and overactive bladder [6, 15]. Topically administrated capsaicin to normal human skin produces itch prior to burning sensation [7], suggesting that the superficial itch-mediating fibers express functional TRPV1. Furthermore, specific ablation of TRPV1-expressing neurons abolished both thermal pain and itch [16]. Although there is evidence suggesting that itch may be induced by activation of TRPV1 alone [17], TRP channels generally act as downstream effectors in pruriceptors for itch signaling transduction [15].

Because itch is induced by capsaicin, it might be surprising that itch could be a treatment of itch. The local application of capsaicin excites C nerve fibers and causes the release of substance P (responsible for side effects) but prolonged repeat applications deplete sensory nerve endings in substance P and other neurotransmitters [18]. Hence, chronic or high-dose use induces nerve ending degeneration (that can be eventually permanent) and allows the alleviation of itch.

Clinical Data

Effects on Pruritus

Capsaicin is used as an anti-pruritic agent in various diseases. Because of the central role of TRPV1, capsaicin can be used against pruritus of different mechanisms. Capsaicin prevents histamine-induced itch [19] and can be also effective in histamine-independent itch [15].

The topical application of capsaicin can effectively interrupt the vicious itch circle in 70 % of patients with nostalgia paresthetica [20], 12/15 patients with brachioradial pruritus [21], aquagenic pruritus [22], psoriasis [23], pruritus ani [24], prurigo nodularis [25] or hydroxyethyl-starch-induced pruritus [26]. Its effects are disappointing in uremic pruritus [27], aquadynia [28], atopic dermatitis [29].

Finally, a systematic review was performed in 2010 [2] and the authors concluded that there was no convincing evidence, in any medical condition, that topically applied capsaicin was effective in the treatment of pruritus but was sufficiently promising to merit further study once the methodological obstacles have been overcome. No more clinical trial using creams containing capsaicin was published since this review. In our own experience, capsaicin is a valuable treatment for localized neuropathic itch.

The effects 8 % capsaicin patch (Qutenza®) on neuropathic pain have been demonstrated in numerous clinical trials [4, 30], especially in postherpetic neuralgia and HIV-neuropathy, but none of these studies have included data on pruritus. Because neuropathic itch is frequently associated with neuropathic pain and because they appear as two manifestations of the same disorders [9], it is probable that this high-concentration capsaicin is also effective in the treatment of localized neuropathic itch. Indeed, series of patients with localized neuropathic itch show very interesting results [31, 32].

Side Effects

The nerve desensitization is preceded by some adverse events which are secondary to the neurogenic inflammation induced by neuropeptide release: pain, burning, heat hyperalgesia, erythema. Few patients discontinue treatment because of these side effects, which are present only for 1 week, even in the case of high-concentration capsaicin [2, 4, 19–32]. These effects can be prevented by pre-treatment with topical anesthesic EMLA 1 h before application of capsaicin [33].

Practical Use

Consequently, it is necessary to inform patients on side effects and to advise them to use EMLA or to be confident with the spontaneous disappearance of these side effects. The usual concentrations for topical applications of capsaicin are 0.025 and 0.075 %. The number of applications varies from two to five a day. The treatment has to performed for 4 weeks or more. Pharmaceutic preparations need to be preserved at 4 °C. The 8 % capsaicin patch is applied for 1 h by specialized centres.

Other Vanilloids

Considering that capsaicin can be badly tolerated, a therapeutic challenge is to find TRPV1 antagonists which cause only minor receptor excitation but still possess a significant desensitization power [7]. The most promising product might be resiniferatoxin (RTX), a vanilloid extracted from cactus-lie plant Euphorbia resinifera [34] but there are few clinical trials with RTX. It might be because RTX is expensive to isolate from natural sources and difficult to synthesize. Therefore, the synthesis of simplified and orally active vanilloids is an ongoing objective. Unsaturated 1,4-dialdehydes and triprenyl phenols might provide new clues for vanilloid drug development. But we lack of clinical trials. The DA-5018 vanilloid has shown some antipruritic effects in mice [35]. The effects of SB-705498 on allergic rhinitis were disappointing, including on nasal itch [36]. SB-705498 did not show any significant with placebo in histamine- or cowhage-induced pruritus [37]. Other clinical trials are ongoing [38].