Capsaicin and substance P

Capsaicin and Substance I, JOEL E. BERNSTEIN, MD

F or centuries people have known that the seeds and membranes of certain species of plants of the nightshade family, notably capsicum, possess a principle that produces intense erythema, pain,

and inflammation when applied to skin or mucous mem- brane. Capsicum was first referred to in 1494 by Chauca, a physician who accompanied Columbus on his second voyage to the West Indies. The active principle for this reaction and what makes hot pepper hot is known as capsaicin.

Until recently, capsaicin itself was never used on the skin. Capsicum oleoresin, which contains very small amounts of capsaicin, has been used topically for decades as a counterirritant for arthralgias and arthritis.’ Smith et al demonstrated that the capsaicin in capsicum produces erythema and burning without vesiculation when applied to human skin. 2 These effects apparently are not related to labilization of epidermal lysosomes, as is the case with some other epidermal irritants. In the 1960s Jansco and co-workers demonstrated that local administration of capsaicin leaves skin insensitive to various types of pain stimuli.3 Their results suggested that capsai- tin renders a subpopulation of cutaneous nerves insensitive to chemical pain stimuli. Bernstein and co-workers subsequently demonstrated that topically applied capsai- tin blocks axon reflex vasodilation in the skin induced by a variety of erythematogenic chemicals.4*5

Capsaicin effects generally have been attributed to its ability to deplete substance P from local sensory terminals.6 Substance P (SP) is an undecapeptide widely distributed in afferent sensory fibers that functions as a neurotransmitter for the communication of pain and some itch sensations from the periphery to the central nervous system. Substance P is also an important mediator of inflammation in a variety of tissues including the skin6

_ From the GenDerm Corporation, Lincolnshire, Illinois.

Address correspondence to: Joel E. Bernstein, MD, Chairman, GenDerm Corporation, 600 Knightsbridge Parkzoay, Lincolnshire, IL 60069.

0 1992 by Elsevier Science Publishing Co., Inc. l 0738-081x/92/$5.00

The implication of SP in the pathophysiology of several inflammatory dermatologic processes has led to capsai- tin’s development and use as the first neuropeptide-active topical agent in dermatology.

Pharmacology and Chemistry

Neurons transmit their impulses across most synapses and neuroeffector junctions by means of specific cherni- cal agents known as neurohumoral transmitters. The neurohumoral agents mediating transmission from sensory fibers have not been established unequivocally; however, SP, an undecapeptide widely distributed in afferent sensory fibers, in dorsal root ganglia, and in dorsal horn of the spinal cord, is considered the principal candidate for the neurotransmitter that functions in the passage of painful stimuli from the periphery to the spinal cord and higher structures. 7-9 Numerous experiments have demonstrated SP release in response to noxious stimuli with resulting hyperalgesia, and the inhibition of certain types of pain sensation with agents locally depleting SP.lo~ll SP is also a powerful vasodilator, and experiments suggest that SP is likely to be the exclusive vasoactive neurohumor responsible for axon reflex vasodilation (flare).6

Capsaicin is a naturally occurring alkaloid with the structure shown in Fig 1. Chemically, capsaicin is trans-8- methyl-N-vanillyl-6-nonenamide. Capsaicinhasamolec- ular weight of 305.40 and forms white translucent crys- tals that melt at 64.5”C.

Systemic pretreatment of adult rats with capsaicin rendered them temporarily insensitive to painful chemical sensory irritants, but neonatal systemic capsaicin treatment resulted in completely irreversible impairment of the function of chemosensitive neurones.12 It was also demonstrated that the erythema produced by the antidromic stimulation of sensory nerves can be inhibited by capsaicin. l3 These effects of capsaicin led to the sugges- tion that capsaicin interferes with the production, storage, or release of one or more vasoactive neurohumors re-

497

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e CH2NH-C-(CH,),CH=CH-CH,), / (3 \ OCH,

bH

Figure 1. Structure of capsaicin.

leased under the influence of chemical stimulation of chemosensitive primary sensory neurons or antidromic stimulation of chemosensitive primary neurons.

Within the last 10 years it has been demonstrated that the neurohumor principally responsible for the effects of capsaicin is the neuropeptide !?JP.‘~-‘~ The effects of capsaicin on SE’ appear to be exerted principally on the type C sensory neuron. 16-18 It is these unmyelinated slow-conducting fibers of the type C group that have been implicated in mediating cutaneous pain and “pathologic” itch sensations.19 Capsaicin does not appear to act directly on central cells in the spinal cord and brain.16

Local application of capsaicin to the peripheral axon results in depletion of SP from the whole neuron, both peripherally and centrally. l6 Initially axonal transport is blocked, and subsequently the synthesis of SF’ is reduced.20 The effect may be similar to cutting a nerve or ligating it, which also depletes the ‘3’ content of the neuron. z Capsaicin also appears able to act on the terminals of type C fibers without affecting the rest of the neuron.16-22 For instance, local application to the eye results in chemical insensitivity and SP depletion from the cornea.22 Chemical sensitivity recovers in a few days, suggesting that the effect is limited to the terminal and has not spread to the dorsal root ganglion. Direct effects of capsaicin on dorsal root ganglia have not been tested.

Aside from these important functions in conducting sensory impulses from the periphery to the central nervous system, SE’ also is intimately involved in the inflammatory response in tissues as diverse as the skin, lung, gastrointestinal tract, and synovium. In such tissues, SP can cause the release and/or recruitment of a variety of inflammatory medications including histamine, kinins, and prostaglandins. 23 It is therefore not surprising that a selective SP antagonist such as capsaicin has been found to have potential useful anti-inflammatory actions.

Capsaicin and Skin Disease

On the basis of its effects on SP in cutaneous sensory neurons, topical capsaicin has been evaluated in a variety of cutaneous disorders. In such studies capsaicin has been

demonstrated to have salutory effects on conditions such as psoriasis, apocrine chromhidrosis, and contact allergy, as well as cutaneous sensory disorders, that is, pain and pruritus.

Capsaicin Treatment of Cutaneous Pain

Although capsaicin cream is currently being investigated in a variety of superficial pain syndromes including post- surgical neuromas,24 reflex sympathetic dystrophy syndrome,25 and vulvar vestibulitus,26 it receives its most extensive use today in painful neuropathy.

Postherpetic Neuralgia

Herpes zoster is frequently followed by a segmental neuralgia characterized by severe unrelenting pain or intractable itch in affected dermatomes.27~28 Although the incidence of this postherpetic neuralgia following acute zoster is about 20% in all age groups, the incidence in- creases to over 50% in patients 60 years or older.29 De- pression often accompanies the pain along with vegeta- tive signs such as insomnia, anorexia, constipation, and decreased libido.30 In some individuals, particularly those over 60 years of age, pain may be so severe, intractable, and demoralizing that it may lead to suicide.

Treatment of postherpetic neuralgia has usually been unsatisfactory and essentially symptomatic, requiring potent analgesics and psychoactive drugs. The pain is sufficiently severe and persistent so that neurosurgical procedures may be required in an effort to relieve patients’ discomfort. A variety of experimental approaches have been used, including tricyclic antidepressants, anti- convulsants, L-dopa, phenothiazine tranquilizers, trans- cutaneous nerve stimulation, acupuncture, iontophore- sis, ultrasound, and biofeedback.31 Most of these therapeutic modalities are without benefit and may be associated with serious side effects. These approaches, as well as the limitations of current therapy for postherpetic neuralgia, have been thoroughly discussed elsewhere.31

Older patients, the principal sufferers from postzoster neuralgia, generally have other diseases, and frequently take one or more systemic medications. As potent analgesics, narcotics, antidepressants, tranquilizers, and anti- convulsants cause drug interactions or undesirable systemic side effects, a topically applied product is desirable for treatment of this condition. Because chemically induced pain in the skin is thought to be mediated by SP, and such pain closely resembles the pain of postherpetic neuralgia, capsaicin cream has been used to abolish or ameliorate this pain.

An open-design pilot study first suggested that topical application of capsaicin in a cream base could relieve

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CAPSAICIN AND SUBSTANCE P

postherpetic neuralgia. 32 Seventy-five percent of 12 patients applying capsaicin cream four times daily for 4 weeks reported partial or complete relief of severe chronic pain. The only adverse effect noted was a mild to moderate burning sensation at the site of application on one patient.

In a second larger open-design study,33 topical capsai- tin cream was used to treat 33 patients with postherpetic neuralgia, having moderate or severe pain on a daily basis, unrelieved or poorly controlled on prior medications. The duration of postherpetic neuralgia in these patients ranged from 3 months to 14 years (median 2 years), and patients applied capsaicin cream four times daily to the painful area of skin for 4 weeks. Seventy-eight percent of the patients completing this study had some improvement in pain, and in 56% treatment results were categorized as good or excellent. Burning on initial applications of capsaicin was common in this study, and when very severe could be ameliorated by pretreatment with 5% xylocaine ointment.

More recently two large double-blind vehicle-controlled studies have been reported.34,35 The first double- blind study involved 32 patients with severe intractable postherpetic neuralgia of 12 or more months’ duration who applied either capsaicin cream or an identical-ap- pearing vehicle three to four times daily for 6 weeks.34 Patients participating in this study had postherpetic neuralgia for a median of 3 years, with six having experienced continuous pain for over 5 years. Such patient selection is important, as postherpetic neuralgia has a well-established tendency to improve spontaneously during the first year after the acute episode of zoster. Patients in this study were evaluated by categorical and visual analog scales of pain and pain relief, as well as a physician’s global rating of response to therapy. After 6 weeks of treatment, the capsaicin-treated group showed significantly greater improvement than the vehicle-treated group for all efficacy parameters measured. Seventy-se- ven percent of capsaicin-treated patients experienced a reduction in pain, as compared with 31% of the vehicle- treated patients. Thirty-one percent of patients treated with capsaicin and 12.5% of patients treated with the vehicle experienced burning or stinging at sites of application. These sensations decreased or disappeared with time and frequency of application, and persisted throughout the 6-week treatment period in only one patient treated with capsaicin.

The second double-blind study was a 143-patient vehicle-controlled study with a 2-year long-term phase.35 In this study all patients had to have postherpetic neuralgia for at least 6 months. Efficacy parameters (physician’s global, categoric pain severity, and visual analog scales of pain) demonstrated significant improvement in the cap-

saicin-treated patients versus those treated with vehicle. In a long-term continuation of this study, which contin- ued to 2 years, physicians’ global evaluations were used to ascertain the value of continuing topical capsaicin for longer than a 6-week treatment period, using the status of postherpetic neuralgia after 6 weeks of capsaicin treatment as the baseline. At the end of the long-term follow- up, 50% of the patients remained improved, 36% showed further improvement, and only 14% were worse than at the end of the first 6-week treatment period. No new or serious side effects were noted with long-term capsaicin treatment.

Diabetic Neuropathy

Although dermatologists are familiar with the character- istics and course of postherpetic neuralgia, they more rarely recognize painful diabetic neuropathy. This is un- fortunate as painful diabetic neuropathy is much more common than postherpetic neuralgia (up to 40% of all diabetics) and it is just as readily treated with topical capsaicin. 36,37 The pain that results from the small-fiber polyneuropathy of diabetes is usually symmetric in dis- tribution and initially affects the distal extremities (sock and glove pattern), with gradual encroachment into more proximal regions of the extremities. Diabetes is in fact by far the most common cause of the “burning foot syndrome.” In some patients, allodynia (exquisite sensitivity to light touch) further interferes with sleep because the bed covers trigger additional foot pain.

An B-week, double-blind vehicle-controlled study was recently reported that involved treatment of 277 diabetic patients with moderate to severe pain from radiculopathy and/or peripheral neuropathy.36 Physician’s global evaluations demonstrated that capsaicin-treated patients were significantly improved (P = 0.042) versus vehicle after just 2 weeks of therapy. The improvement of the capsaicin-treated patients was even more dramatic by the end of the study (P = 0.007).

Visual analog scales for pain relief and pain intensity also demonstrated that capsaicin was far superior to vehicle. The degree of pain relief provided by capsaicin cream was significantly greater than that provided by vehicle at weeks 4 (P = 0.031), 6 (P = 0.004), and 8 (P = 0.005). The decrease in pain intensity was significantly greater with capsaicin at week 8 (P = 0.014). Capsaicin cream therefore provided noticeable relief of painful diabetic neuropathy within 2 weeks, and after 8 weeks of treatment all efficacy parameters measured significantly favored capsaicin.

The 277-patient multicenter trial also assessed the effect of topical capsaicin on patient quality-of-life.38 By the end of the study, patients treated with capsaicin reported

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significantly greater improvement in working, sleeping, walking, and recreational activities than those in the vehicle group. 38 As painful diabetic neuropathy is so common, it behooves the dermatologist to solicit any such painful symptoms from diabetic patients. The dermatologist can then successfully treat such symptoms with capsaicin cream.

Capsaicin Treatment of Pruritus

Although pruritus is the most common symptom of cutaneous disease and also accompanies a variety of systemic disorders, its underlying pathophysiologic mechanisms remain poorly understood. Attempts to elucidate the me- diators of itch have implicated a number of chemicals that have the ability to trigger itching, including serotonin, bradykinin, SP, the endopeptidases, and histamine. Of these, histamine is considered to be the most important mediator of itch, and most therapeutic approaches to itching have used compounds that antagonize histamine’s effects.39,40 The classic Hi-binding antihistamines have therefore assumed a significant role in the treatment of pruritus, especially in conditions such as urticaria or mastocytosis, in which itching is clearly medicated pri- marily by histamine; however, in a number of other pruritic conditions, such as cutaneous T-cell lymphomas, hemodialysis, and cholestasis, antihistamines at moderate dosages provide very little, if any, relief, which suggests important nonhistaminic mechanisms may produce this itching.

A close association between itch and pain was noted many years ago. 41 Although itch and pain share common neuroanatomic pathways, they are nonetheless distinct sensory modalities. 42 Illustrative of this difference is the alleviation of pain, but the aggravation of itch, by morphine and other opiate alkaloids. This provocation of itch by morphine is a well-described clinical phenomenon. Feldberg and Paton’s demonstration of morphine-induced histamine release from mast cells suggested a peripheral histaminic mechanism for this itching;43 however, the frequent inability of systemic antihistamines to provide significant relief from such opiate-induced itching, as well as the ability to stimulate an apparent itch and scratch response in animals by intracisternal or intramed- ullary injection of morphine, suggested other nonhistaminic mechanisms for opiate-induced itch.44 Numerous studies have provided evidence for a central or peripheral opine@ itch pathway. 45-49 It is of interest in this regard that capsaicin has been demonstrated to impair opiate- mediated nociceptive responses in animals50

The similarities between pain and itch pathways, the known relationship of SP and histamine, the impairment of opiate mechanisms by capsaicin, and the ability of

capsaicin to block sensory transmission along peripheral nerves have stimulated recent trials of capsaicin in pruritus. Although data from such studies are limited thus far, it appears that capsaicin cream may have beneficial anti- pruritic effects in lichen simplex chronicus (including pru- rigo nodularis), psoriasis, notalgia peristhetica,51 post- burn pruritus, and hemodialysis-associated pruritus.52 In a large multicenter evaluation of topical capsaicin in postherpetic neuralgia, capsaicin was as effective in relieving intractable itching in areas so affected as it is in relieving intractable pain in this condition.35

Psoriasis

Psoriasis is a cutaneous inflammatory disorder common in patients genetically predisposed to the disorder and of highly controversial etiology. Although much has been made pathophysiologically and therapeutically of the epidermal hyperplasia characteristic of psoriasis, it appears clear that profound alterations in the neurovascular system usually precede these epidermal changes and may indeed be the initiating factors in psoriasis.53-60 The vascular changes observed in the early psoriatic lesion in- clude vasodilation,53*54 elongation and convolution of papillary vessels,55,56 and leakiness in these vessels, resulting in an exudate of serum and inflammatory cells in the papilla. 53,57 Histologically, these vascular changes are evident long before epidermal hyperplasia can be observed. Another early morphologic change in the psoriatic lesion is an accumulation of degranulating mast cells.61 Not uncommonly, sensory nerve terminals are observed in direct proximity to the mast cell membranes, and these sensory nerve terminals are intimately associated with the dilated dermal microvasculature.62 It has further been demonstrated that there is an increase in substance P (SP)-containing nerve fibers associated with the microvasculature in psoriatic lesions.61 It has also been demonstrated that the SP content of active psoriatic lesions is very high and that these levels decrease significantly with resolution of the lesion.63 SP has been demonstrated to be a principal neurotransmitter of pain, itch, and inflammation that can act directly on the microvasculature to cause dilation in the skin. These observations therefore suggest an intimate but complex relationship between the vascular and peripheral nervous systems, which when disturbed in the genetically predisposed can result in the pathologic alterations called the psoriatic plaque. Substance P is the likely chemomediater for this disturbance in cutaneous neurovascular homeostasis.”

Several clinical trials have been conducted that demon- strate capsaicin’s effects on psoriasis. In one study, 44 patients with symmetrically distributed psoriatic lesions applied topical capsaicin four times daily to one side of

Clinics in Dermatology 1992;9:497-503

their body and vehicle to the other side for 6 weeks under a double-blind paradigm. 65 Over the course of the study significantly greater overall improvement was observed on sides treated with capsaicin compared with sides treated with vehicle. Similarly, significantly greater re- ductions in scaling and erythema accompanied capsaicin application.

In another much larger study, 197 patients with pruritic psoriasis were treated with capsaicin or vehicle using a double-blind parallel design.66 Patients applied either capsaicin cream or vehicle to psoriatic lesions four times daily for 6 weeks. Psoriasis was cleared or markedly improved in 82% of capsaicin-treated patients versus 33% of vehicle-treated patients (P < 0.01). Itching was also significantly reduced in the capsaicin-treated patients versus those treated with vehicle.

These two studies, along with the continually expand- ing evidence for SP’s important role in the pathogenesis of psoriasis, suggest that topical capsaicin is a valuable addition to the psoriasis therapy armamentarium.

Dosage, Administration, and Adverse Effects

As capsaicin has a very short duration of action, it is necessary to apply capsaicin cream at least three to four times daily. Less frequent application prevents the total deletion and inhibition of synthesis and transport of SP, thus decreasing efficacy while increasing local discomfort. Patients using capsaicin cream may experience burning, stinging, or redness of the skin in areas of application. The incidence and severity of this local adverse experience vary widely in reported studies and are at least partially related to the condition being treated. These reactions are thought to result from the release of SP stores from peripheral sensory neurons into the skin, and are thus related to the pharmacologic actions of the drug. With repeated applications of capsaicin, these reactions usually diminish with time and often disappear within 72 to 96 hours of regular use. In cases in which capsaicin-induced burning is especially severe or intolerable, pretreatment with xylocaine 5% ointment may prevent or reduce the severity of this burning.33

Pain or itch relief is usually noted within 14 to 28 days, but in occasional cases of postherpetic neuropathy or painful diabetic neuropathy relief may not be noted until 42 days of therapy. The duration of treatment will vary with the age of the patient as well as with the nature, severity, and chronicity of the condition being treated.

Until more extensive long-term data are accumulated and analyzed, deciding how long a patient should stay on capsaicin is essentially a question of clinical judgment. Most younger patients (< 55 years), with short durations of pain from neuropathies before capsaicin therapy, can

BERNSTEIN 501 CAPSAICIN AND SUBSTANCE P

stop receiving the agent after 3 to 5 months of pain relief. If pain recurs, capsaicin therapy may be promptly reinsti- tuted. Alternatively, if a patient is 85 years old and had intractable pain for several years before capsaicin provided relief, the patient would best be left on capsaicin for life. In such cases, ceasing the regimen not only could cause pain, but may lead to serious psychologic problems.

Conclusions

The growing awareness of the role of SP in a variety of cutaneous pharmacologic and pathologic processes has led to the evaluation of the effects of topically applied capsaicin, a potent SP depletor, in a variety of cutaneous disorders. Although capsaicin cream appears to be a promising treatment for a variety of principally dermatologic conditions including psoriasis, pruritus, and chromhidrosis, it has thus far received its greatest use in the treatment of superficial sensory disorders, especially postherpetic neuralgia and painful diabetic neuropathy. In postherpetic neuralgia, capsaicin cream appears to be equally effective at relieving painful and pruritic dysesth- esias, and has proved to be safer and more effective than previously employed systemic remedies. Recent clinical studies in certain types of psoriasis and itching have demonstrated impressive clinical effects and indicate that topical capsaicin may assume a growing role in the treatment of these disorders.

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Capsaicin and substance P