Capsicum

Common Names: Cayenne Pepper, Chili Pepper, Red Pepper

Clinical Names: Capsicum annuum, Capsicum frutescens

Summary

botanical names: Capsicum anuum, Capsicum anuum var frutescens.

common names: Cayenne.

overview of interactions:
• herb/nutrient affecting drug toxicity: Acetylsalicylic Acid

• herb/nutrient possibly affecting drug performance and toxicity: Warfarin

• herb/nutrient possibly affecting drug class performance and toxicity: ACE Inhibitors

• herbal constituent affecting drug performance and toxicity: Major Anesthetics

• herb/nutrient with potential pharmacokinetic activity: Absorption modifier

See Herb Groups: Pharmacokinetic: GI Modifiers: Irritants

AHPA Botanical Safety Rating:
• internal: 1
• external : 2d




Clinical

botanical name: Capsicum frutescens, Capsicum annuum

common name: Cayenne pepper, Red pepper, Chili pepper.

part used: Fruit.

qualities: Very pungent, hot, with secondary cooling effect, dry.

affinities: Arterial circulation, heart, stomach, intestines, lungs, kidneys.

dosage:
• Fruit powder: 30 - 120 mg
• Tincture (1:10:) 0.3 - 1 ml.
• Strong tincture: (1 : 3) 0.05 - 0.15 ml.
• Semi solid preparations (topical): up to 50mg capsaicin in 100g neutral base.
(Manufacturer's preparations vary, typically from 0.025-0.075% capsaicin)

therapy:
• internal: Stimulant to heart and circulation; peripheral circulatory insufficiency, Raynaud's, intermittent claudication. Low vitality, cold, weak, debility syndromes. Stimulant and tonic to the gastro-intestinal tract; warms digestion, poor appetite, atonic conditions; membranes pale, relaxed, or flabby; impaired secretion; chronic gastric catarrh in absence of inflammation; atonic dyspepsia; gastric flatulence; migraines and cluster headaches.
• external: Topical stimulant, rubefacient, and counter-irritant; used for local pain, bursitis, diabetic neuropathies, Herpes zoster (shingles), intercostal neuralgia, pleurodynia, postherpetic neuralgia, osteoarthritis, psoriasis, toothache, chronic rheumatic pains, rheumatoid arthritis, lumbago, chilblains. Can be used to promote circulation and tissue repair in gum disease, pharyngitis and hoarseness (gargle).

specific indications: Debility and weakness in the elderly, especially with deficient circulation. Topically, neuralgic pain and sore throat (as a gargle).

AHPA Botanical Safety Rating:
• internal: 1
• external : 2d

toxicity:
• Commision E states without explanation that external use should be restricted to two days duration with 14 days between each two day application. Evidence for this is lacking, and commercial preparations such as Zostrex state the need for continuous use for several weeks.
(Blumenthal M, et al. 1998, 178; McGuffin M, et al.(eds.) 1997, 23.)
• Inhalation of capsaicin has been reported to cause allergic alveolitis.
(Brinker F. 1998.)

contraindications:
• internal : Excessive doses contraindicated in acute or chronic stomach inflammation.
• external: Local Irritant: Not to be applied to injured or broken skin, or near the eyes.

constituents:
• Capsaicinoids: (0.05 - 1.5 %) Pungent phenolic amides including mostly capsaicin, dihydrocapsaicin and derivatives.
• Carotenoids: Carotene, capsanthin
• Volatile oil: trace
• Other: Proteins, vitamins A, C, coumarins, steroidal alkaloids including solanidine, flavonoids.

pharmacology:
Capsaicin inhibits release of neurotransmitter substance P (sensory afferents, including nocioceptors, after an initial stimulation. It stimulates adrenal secretion from the medulla (adrenaline) and cortex (cortisol). It reduces serum triglycerides. Inhibits gastric motility, increases duodenal motility. Increases mucosal blood flow and vascular permeability. Stimulates areas in stomach and duodenum which afford protection against ulcers (also when stimulated by acid). Animal and human studies are conflicting on increase of gastric secretion levels. There is considerable literature on neurotransmitter research using capsaicin as a diagnostic tool. Early evidence suggested a fibrinolytic and anti-platelet activity, later studies on this are lacking.

clinical trials:
Topical capsaicin based creams have relieved pain symptoms in both rheumatoid and osteoarthritic joint pains compared to controls, as well as diabetic neuropathy, post herpetic neuralgia, migraine and cluster headaches. A problem with all placebo controlled studies is the lack of a similar "hot" remedy that is inactive. Capsicum extracts cause increase acid secretion and DNA content in duodenal cells of gastric aspirates in ulcer patients, but has been reported to have little effect on gastric secretions in normal patients.(Newall, 1996). A recent review of 33 clinical trials on capsicum/capsaicin concluded capsaicin is effective for psoriasis, pruritus, and cluster headache; it is often helpful for the itching and pain of postmastectomy pain syndrome, oral mucositis, cutaneous allergy, loin pain/hematuria syndrome, neck pain, amputation stump pain, and skin tumor; and it may be beneficial for neural dysfunction (detrusor hyperreflexia, reflex sympathetic dystrophy, and rhinopathy).
(Hautkappe, 1998: see also Fusko, 1997).



Interactions

herb/nutrient affecting drug toxicity: Acetylsalicylic Acid

• mechanism: Capsaicin is a key constituent of cayenne known for its potent effect on special neurons found in the stomach lining.

• research: Studies using rats found that capsaicin stimulated these nerves in the stomach lining in a way that reduced the harmful effects of aspirin in the stomach. After conducting a human trial Yeoh et al concluded that eating 20 grams of Cayenne peppers before taking aspirin could protect against gastroduodenal mucosal injury and ulcer formation.
(Abdel Salam OMB, et al. Pharmacol Res 1995;32:209-215; Holzer P, et al. Gastroenterol 1989;96:1425-1433; Yeoh KG, et al. Dig Dis Sci 1995;40:580-583.)

• nutritional support: Despite this supportive evidence it would be wise to consult a healthcare provider trained in herbal medicine before relying on cayenne peppers or extracts to counteract the effects of frequent or excessive use of aspirin.

herb/nutrient possibly affecting drug performance and toxicity: Warfarin

• mechanism: Some herbs that inhibit platelet aggregation could conceivably potentiate the anticoagulant activity of warfarin or similar drugs. Generally, adverse effects would not be likely to appear unless relatively large doses of these herbs or their combinations were consumed for an extended period of time. The combination of these plants with anticoagulant drugs such as warfarin inherently increases the risk of excessive bleeding or other adverse side effects. In order for several of these plants, some being common foods, to produce a significant risk or interaction the consumption of sizable amounts would most likely be required.

herb/nutrient possibly affecting drug class performance and toxicity: ACE Inhibitors

• mechanism: Capscium has the ability to normalize both low and high blood pressure and is often used to equalize blood pressure, hence capsaicin may interfere with the blood-pressure regulating functions of ACE inhibitors. The production of 'substance P' by Cayenne has the known effect of dilating the arteries, thereby lowering blood pressure. Capsaicin may also aggravate cough due to ACE-inhibitor drugs according to studies using rats and humans.
(Yeo WW, et al. Br J Clin Pharmacol. 1995 Nov;40(5):423-429; Takahama K, et al. J Pharm Pharmacol. 1996 Oct;48(10):1027-1033; Damas J, et al. Naunyn Schmiedebergs Arch Pharmacol. 1996 Nov;354(5):662-669; Baluk P, et al. Br J Pharmacol. 1999 Jan;126(2):522-528; Brinker F. 1998, 51.)

herbal constituent affecting drug performance and toxicity: Major Anesthetics

• mechanism: Possible potentiation of anesthetic by capsaicin.

• herbal concern: Usage of cayenne at therapeutic dosages warrants physician supervision pre-operatively and possible avoidance for two to four weeks before surgery.

herb/nutrient with potential pharmacokinetic activity: Absorption modifier

See also under Herb Groups: Pharmacokinetic: GI Modifiers: Irritants

• mechanism: Due to its secretomotor and stimulant activity, Capsicum may affect the gastro-intestinal absorption of drugs.

• research: Capsicum has been found to increase the absorption and bioavaliability of theophylline.
(Bouraoui A, et al. Thérapie 1986; 41: 467-471, cited in Fugh-Berman A. Lancet 2000; 355: 134-138.)

• herbal support: Herbalists traditionally use Capsicum as an adjuvant in prescriptions to aid distribution of the remedies to the target areas and tissues of the body.

• herbal concern: Individuals who have been prescribed theophylline should avoid internal consumption of Capsicum in significant amounts until they have discussed this potential interaction with the prescribing physician.

Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

References

Abdel Salam OMB, Moszik O, Szolcsanyi J. Studies on the effect of intragastric capsaicin on gastric ulcer and on the prostacyclin-induced cytoprotection in rats. Pharmacol Res 1995 Oct;32(4):209-215.
Abstract: The effect of intragastric (i.g.) capsaicin on experimental gastric ulcer was studied in the 1 h pylorus-ligated rats. Capsaicin applied in 40 ng ml-1 concentration (0.1 microgram kg-1) protected against gastric mucosal injury evoked by i.g. application of acidified aspirin, 96% ethanol or 0.6 M HCl. After a capsaicin concentration of 400 micrograms ml-1 (1 mg kg-1) protection occurred initially, while several hours later mucosal damage evoked by acidified aspirin was enhanced. Capsaicin in 2 and 6 ml kg-1 (10 and 30 mg kg-1) invariably aggravated the aspirin and ethanol-induced gastric mucosal damage. Capsaicin in 0.1 microgram kg-1 did not modify the mucosal protective action of prostacyclin (5 micrograms kg-1) on gastric mucosal injury produced by i.g. application of acidified aspirin, 96% ethanol or 0.6 M HCl. Local capsaicin desensitization induced by application of capsaicin in 2 mg ml-1 (10 mg kg-1) did not interfere with the mucosal cytoprotective effects of prostacyclin against ethanol and aspirin-induced mucosal damage. It is concluded that i.g. capsaicin exerts a dual dose-dependent effect on development of experimental gastric ulcer. Neither i.g. capsaicin in small doses nor local capsaicin desensitization modify the mucosal cytoprotective effects of prostacyclin.

Baron R, Baron Y, Disbrow E, Roberts TP. Brain processing of capsaicin-induced secondary hyperalgesia: a functional MRI study. Neurology. 1999 Aug 11;53(3):548-557.
Abstract: OBJECTIVE: To investigate, using functional MRI (fMRI), the neural network that is activated by the pain component of capsaicin-induced secondary mechanical hyperalgesia. BACKGROUND: Mechanical hyperalgesia (i.e., pain to innocuous tactile stimuli) is a distressing symptom of neuropathic pain syndromes. Animal experiments suggest that alterations in central pain processing occur that render tactile stimuli capable of activating central pain-signaling neurons. A similar central sensitization can be produced experimentally with capsaicin. METHODS: In nine healthy individuals the cerebral activation pattern resulting from cutaneous nonpainful mechanical stimulation at the dominant forearm was imaged using fMRI. Capsaicin was injected adjacent to the stimulation site to induce secondary mechanical hyperalgesia. The identical mechanical stimulation was then perceived as painful without changing the stimulus intensity and location. Both activation patterns were compared to isolate the specific pain-related component of mechanical hyperalgesia from the tactile component. RESULTS: The pattern during nonpainful mechanical stimulation included contralateral primary sensory cortex (SI) and bilateral secondary sensory cortex (SII) activity. During hyperalgesia, significantly higher activation was found in the contralateral prefrontal cortex: the middle (Brodmann areas [BAs] 6, 8, and 9) and inferior frontal gyrus (BAs 44 and 45). No change was present within SI, SII, and the anterior cingulate cortex. CONCLUSIONS: Prefrontal activation is interpreted as a consequence of attention, cognitive evaluation, and planning of motor behavior in response to pain. The lack of activation of the anterior cingulate contrasts with physiologic pain after C-nociceptor stimulation. It might indicate differences in the processing of hyperalgesia and C-nociceptor pain or it might be due to habituation of affective sensations during hyperalgesia compared with acute capsaicin pain.

Bernstein JE, Parish LC, Rapaport M, Rosenbaum MM, Roenigk HH Jr. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986;Sep;15(3):504-507.
Abstract: Alterations in the cutaneous vascular system are prominent in psoriasis and may play an important role in the pathogenesis of this disorder. We evaluated the effects of topically applied capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a known inhibitor of cutaneous vasodilatation, on moderate and severe psoriasis. Under a double-blind paradigm, forty-four patients with symmetrically distributed psoriatic lesions applied topical capsaicin to one side of their body and identical-appearing vehicle to the other side for 6 weeks. After 3 and 6 weeks of treatment, we performed ratings on changes in scaling and erythema, as well as overall improvement of the psoriasis. Over the course of the study, significantly greater overall improvement was observed on sides treated with capsaicin compared to sides treated with vehicle. Similarly, significantly greater reductions in scaling and erythema accompanied capsaicin application. Burning, stinging, itching, and redness of the skin were noted by nearly half of the patients on initial applications of study medication but diminished or vanished upon continued application. These results suggest that topical application of capsaicin may be a useful new approach in the treatment of psoriasis.
Blumenthal M, Gruenwald J, Hall T, & Riggins CW, (eds.) German Commission E Monographs: Therapeutic Monographs on Medicinal Plants for Human Use. Austin, TX: American Botanical Council, 1998.

Blumenthal M, Busse WR, Goldberg A, et al, eds. The Complete Commission E Monographs: Therapeutic Guide to Herbal Medicines. Boston, MA: Integrative Medicine Communications, 1998.

Bouraoui A, Brazier JL, Zouaghi H, Rousseau M. Theophylline pharmacokinetics and metabolism in rabbits following single and repeated administration of Capsicum fruit. Eur J Drug Metab Pharmacokinet. 1995 Jul-Sep;20(3):173-178.
Abstract: Pharmacokinetics and metabolism of theophylline were studied in three groups of male rabbits, after intravenous administration (12 mg/kg), with and without oral ground Capsicum fruit suspension. Compared with control values, plasma theophylline half-life of distribution and of elimination, areas under plasma curves, clearance and volume of distribution did not show any significant difference. On the contrary, the elimination rate constant (k1,0) is significantly different (0.01 < P < 0.05) after a single dose of capsicum and remained unchanged after a repeated dose. Concerning the metabolism of theophylline in rabbits, the results showed that the oral administration of a single dose of Capsicum fruit suspension does not significantly affect the urinary excretion of theophylline and its metabolites--1,3-dimethyluric acid (1,3-DMU) and 1-methyluric acid (1-MU). On the other hand, after a repeated dose of Capsicum fruit for 7 days, the quantity of 1-MU was significantly reduced (0.01 < P < 0.05). In conclusion, it was found that a single dose of Capsicum fruit could affect pharmacokinetic parameters of theophylline (k1,0), while a repeated dose affected the metabolic pathway of xanthine oxidase.

Bouraoui A, Toumi A, Ben Mustapha H, Brazier JL. Effects of capsicum fruit on theophylline absorption and bioavailability in rabbits. Drug Nutr Interact. 1988;5(4):345-350.
Abstract: Absorption and bioavailability of theophylline from a sustained-release gelatin capsule were investigated in 10 male rabbits after oral administration (20 mg/kg), with and without a ground capsicum fruit suspension. Comparison of pharmacokinetic parameters showed that the concomitant absorption of capsicum increases areas under plasma curves (from 86.06 +/- 9.78 mg H/liter to 138.32 +/- 17.27 mg H/liter, P less than 0.001), peak plasma levels (from 6.65 +/- 0.76 to 8.78 +/- 0.98 mg/liter, P less than 0.01), and mean residence times (from 14.94 +/- 2.97 to 20.98 +/- 5.75 H, P less than 0.001). A second administration of the capsicum suspension, 11 hours after dosing, produced a new rise of theophylline plasma levels in every rabbit. The variations in pharmacokinetic and bioavailability parameters are discussed in accordance with the mechanisms of action of capsaicin, an active compound present in capsicum fruit.

Bradley PR, ed. British Herbal Compendium, vol 1. Bournemouth, Dorset, UK: British Herbal Medicine Association, 1992.

Brinker F. Herb Contraindications and Drug Interactions. Second edition., Sandy, OR: Eclectic Institute Inc, 1998.

Brooks S. (ed.). 1995. Botanical Toxicology. Protocol J Bot. Med, 1:147-158.

Buiatti E, Palli D, Decarli A, Amadori D, Avellini C, Bianchi S, Biserni R, Cipriani F, Cocco P, Giacosa A, et al. A case-control study of gastric cancer and diet in Italy. Int J Cancer 1989 Oct 15;44(4):611-616.

Capsaicin Study Group. Effect of treatment with capsaicin on daily activities of patients with painful diabetic neuropathy. The capsaicin study group. Diabet Care 1992;15:159-165.

Capsaicin Study Group. Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. The capsaicin study group. Arch Int Med 1991;151:2225-2229.

Chandiramani VA, Peterson T, Duthie GS, Fowler CJ. Urodynamic changes during therapeutic intravesical instillations of capsaicin. Br J Urol 1996 Jun;77(6):792-797.
Abstract: OBJECTIVE: To describe the technique for and urodynamic changes during therapeutic instillations of intravesical capsaicin in patients with detrusor hyper-reflexia. PATIENTS AND METHODS: Ninety intravesical instillations of capsaicin were performed as a therapeutic procedure in 30 patients; 21 patients had various causes of non-traumatic spinal cord disease, five patients were very severely neurologically impaired and were bed-bound with an indwelling catheter, and four were neurologically normal. Simultaneous cystometry was performed in 25 patients during the instillation of capsaicin; 100 mL of 1 or 2 mmol/L capsaicin in 30% ethanol/saline was instilled into the bladder for 30 min and two patients received 30% ethanol/saline only. The last 56 capsaicin treatments were preceded by the instillation of 40 mL of 2% lignocaine for 20 min. Detrusor hyper-reflexia was decreased and urinary continence improved for 3-6 months after a single instillation; the instillation was then repeated. Two patients who received only ethanol/saline showed no clinical or urodynamic improvement. RESULTS: The treatment was not abandoned in any patient due to discomfort and there were no short- or medium-term complications. All patients with spinal cord disease and phasic detrusor hyper-reflexia had similar, frequent and repetitive detrusor contractions during the instillation of capsaicin. These acute reactive contractions did not occur in the neurologically normal patients. Similarly, the instillation of intravesical lignocaine only caused no phasic detrusor contractions. Intravesical lignocaine instillation before capsaicin markedly reduced and sometimes abolished the detrusor overactivity and lessened the discomfort for the patients. The instillation of lignocaine before capsaicin did not alter the benefit from each instillation of intravesical capsaicin. CONCLUSION: A method has been developed for administering capsaicin intravesically which diminishes discomfort for the patient and in the short- and medium-term is free of complications. The study also provides functional evidence of the role of capsaicin-sensitive afferents in phasic detrusor hyper-reflexia due to spinal cord disease.

Deal CL, Schnitzer TJ, Lipstein E, Seibold JR, Stevens RM, Levy MD, Albert D, Renold F. Treatment of arthritis with topical capsaicin: A double-blind trial. Clin Ther 1991 May-Jun;13(3):383-395.
Abstract: The neuropeptide substance P has been implicated in the pathogenesis of inflammation and pain in arthritis. In this double-blind randomized study, 70 patients with osteoarthritis (OA) and 31 with rheumatoid arthritis (RA) received capsaicin (a substance P depletor) or placebo for four weeks. The patients were instructed to apply 0.025% capsaicin cream or its vehicle (placebo) to painful knees four times daily. Pain relief was assessed using visual analog scales for pain and relief, a categorical pain scale, and physicians' global evaluations. Most of the patients continued to receive concomitant arthritis medications. Significantly more relief of pain was reported by the capsaicin-treated patients than the placebo patients throughout the study; after four weeks of capsaicin treatment, RA and OA patients demonstrated mean reductions in pain of 57% and 33%, respectively. These reductions in pain were statistically significant compared with those reported with placebo (P = 0.003 and P = 0.033, respectively). According to the global evaluations, 80% of the capsaicin-treated patients experienced a reduction in pain after two weeks of treatment. Transient burning was felt at the sites of drug application by 23 of the 52 capsaicin-treated patients; two patients withdrew from treatment because of this side effect. It is concluded that capsaicin cream is a safe and effective treatment for arthritis.

De Smet PAGM, et al. (eds.) Adverse Effects of Herbal Drugs 2, Berlin: Springer-Verlag, 1993.

Ellison N, Loprinzi CL, Kugler J, Hatfield AK, Miser A, Sloan JA, Wender DB, Rowland KM, Molina R, Cascino TL, Vukov AM, Dhaliwal HS, Ghosh C. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol. 1997 Aug;15(8):2974-2980.
Abstract: PURPOSE: A minority of cancer survivors develops long-term postsurgical neuropathic pain. Based on evidence that capsaicin, the pungent ingredient in hot chili peppers, might be useful for treating neuropathic pain, we developed the present clinical trial. PATIENTS AND METHODS: Ninety-nine assessable patients with postsurgical neuropathic pain were entered onto this study. After stratification, patients were to receive 8 weeks of a 0.075% capsaicin cream followed by 8 weeks of an identical-appearing placebo cream, or vice versa. A capsaicin/placebo cream was to be applied to the painful site four times daily. Treatment evaluation was performed by patient-completed weekly questionnaires. RESULTS: During the first 8-week study period, the capsaicin-cream arm was associated with substantially more skin burning, skin redness, and coughing (P < .0001 for each). Nonetheless, treatment was stopped for patient refusal or toxicity just as often while patients were receiving the placebo as compared with the capsaicin. The capsaicin cream arm had substantially more pain relief (P = .01) after the first 8 weeks, with an average pain reduction of 53% versus 17%. On completion of the 16-week study period, patients were asked which treatment period was most beneficial. Of the responding patients, 60% chose the capsaicin arm, 18% chose the placebo arm, and 22% chose neither (P = .001). CONCLUSION: A topical capsaicin cream decreases postsurgical neuropathic pain and, despite some toxicities, is preferred by patients over a placebo by a three-to-one margin among those expressing a preference.

Felter HW, Lloyd JU. King's American Dispensatory, Vols. I and II. Portland, OR: Eclectic Medical Publications, 1983.

Felter HW, Scudder JK. The Eclectic Materia Medica, Pharmacology and Therapeutics. Cincinnati, Ohio. Reprinted in 1985 by Eclectic Medical Publications, Portland, OR, 1983.

Fox AJ, Lalloo UG, Belvisi MG, Bernareggi M, Chung KF, Barnes PJ. Bradykinin-evoked sensitization of airway sensory nerves: a mechanism for ACE-inhibitor cough. Nat Med 1996 Jul;2(7):814-817.
Abstract: Cough accompanied by an increased sensitivity of the cough reflex is the most common symptom of inflammatory airway disease. This symptom is also frequently reported in patients receiving angiotensin-converting enzyme (ACE) inhibitors as therapy for heart failure or hypertension, although the underlying mechanism is unknown. We have investigated the possibility that the inflammatory peptide bradykinin, normally degraded by ACE, causes sensitization of airway sensory nerves and an enhancement of the cough reflex in conscious guinea pigs. Treatment of guinea pigs for two weeks with captopril led to an increased cough response to inhaled citric acid, which was prevented by concomitant treatment with the bradykinin receptor antagonist icatibant. A similar icatibant-sensitive enhancement of citric acid-evoked cough was seen in untreated animals after prior inhalation of bradykinin, although cough evoked by hypertonic saline was unaffected. In electrophysiological studies performed in vitro, responses of single vagal C fibers to capsaicin, applied to receptive fields of single-fiber units in the trachea, were also markedly increased after perfusion with bradykinin, whereas A delta fiber responses to hypertonic saline were unaffected. These results indicate that bradykinin-evoked sensitization of airway sensory nerves may underlie the pathogenesis of ACE-inhibitor cough. Bradykinin receptor antagonists may be of benefit in treating chronic cough seen with this and other inflammatory conditions.

Fugh-Berman A. Herb-drug interactions. Lancet 2000; 355: 134-138.
Abstract: Concurrent use of herbs may mimic, magnify, or oppose the effect of drugs. Plausible cases of herb-drug interactions include: bleeding when warfarin is combined with ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai (Angelica sinensis), or danshen (Salvia miltiorrhiza); mild serotonin syndrome in patients who mix St John's wort (Hypericum perforatum) with serotonin-reuptake inhibitors; decreased bioavailability of digoxin, theophylline, cyclosporin, and phenprocoumon when these drugs are combined with St John's wort; induction of mania in depressed patients who mix antidepressants and Panax ginseng; exacerbation of extrapyramidal effects with neuroleptic drugs and betel nut (Areca catechu); increased risk of hypertension when tricyclic antidepressants are combined with yohimbine (Pausinystalia yohimbe); potentiation of oral and topical corticosteroids by liquorice (Glycyrrhiza glabra); decreased blood concentrations of prednisolone when taken with the Chinese herbal product xaio chai hu tang (sho-saiko-to); and decreased concentrations of phenytoin when combined with the Ayurvedic syrup shankhapushpi. Anthranoid-containing plants (including senna [Cassia senna] and cascara [Rhamnus purshiana]) and soluble fibres (including guar gum and psyllium) can decrease the absorption of drugs. Many reports of herb-drug interactions are sketchy and lack laboratory analysis of suspect preparations. Health-care practitioners should caution patients against mixing herbs and pharmaceutical drugs.

Fusco BM; Giacovazzo M 1997, Peppers and pain. The promise of capsaicin. Drugs 1997 Jun;53(6):909-914 ABSTRACT: Capsaicin, the most pungent ingredient in red peppers, has been used for centuries to remedy pain. Recently, its role has come under reinvestigation due to evidence that the drug acts selectively on a subpopulation of primary sensory neurons with a nociceptive function. These neurons, besides generating pain sensations, participate through an antidromic activation in the process known as neurogenic inflammation. The first exposure to capsaicin intensely activates these neurons in both senses (orthodromic: pain sensation; antidromic: local reddening, oedema etc.). After the first exposure, the neurons become insensitive to all further stimulation (including capsaicin itself). This evidence led to the proposal of capsaicin as a prototype of an agent producing selective analgesia. This perspective is radically different from previous 'folk medicine' cures, where the drug was used as a counter-irritating agent (i.e. for muscular pain). The new concept requires that capsaicin be repeatedly applied on the painful area to obtain the desensitisation of the sensory neurons. Following this idea, capsaicin has been used successfully in controlling pain in postherpetic neuralgia, diabetic neuropathy and other conditions of neuropathic pain. Furthermore, evidence indicates that capsaicin could also control the pain of osteoarthritis. Finally, repeated applications of the drug to the nasal mucosa result in the prevention of cluster headache attacks. On the basis of this evidence, capsaicin appears to be a promising prototype for obtaining selective analgesia in localised pain syndromes.

Hautkappe M, Roizen MF, Toledano A, Roth S, Jeffries JA, Ostermeier AM. Review of the effectiveness of capsaicin for painful cutaneous disorders and neural dysfunction. Clin J Pain 1998 Jun;14(2):97-106. (Review)
Abstract: BACKGROUND: Topical capsaicin is known to be a safe and effective pain management adjunct for rheumatoid arthritis, osteoarthritis, neuralgias, and diabetic neuropathy. However, studies and case reports in the literature have indicated that other conditions may also benefit from capsaicin: painful or itching cutaneous disorders from operations, injuries, or tumors; neural dysfunction; or inflammation of the airways and urinary tract. METHODS: To determine the effectiveness of capsaicin for painful cutaneous disorders and neural dysfunction, the authors analyzed data from 33 reports (MEDLINE search of 1966-96) on the efficacy of capsaicin. Outcome measures consisted of the response rate and degree of pain relief. Results from placebo-controlled trials were pooled when possible; effect of treatment was estimated by the method of DerSimonian and Laird. RESULTS: Pain relief for postmastectomy syndrome and cluster headache was greater with capsaicin than with placebo; also, psoriasis and pruritus responded better to capsaicin. Uncontrolled studies and case reports have indicated that pain or dysfunction was less at the end of capsaicin therapy for neck pain, loin pain/hematuria syndrome, oral mucositis, rhinopathy, reflex sympathetic dystrophy syndrome, detrusor hyperreflexia, and cutaneous pain due to tumor of the skin. CONCLUSIONS: Capsaicin is effective for psoriasis, pruritus, and cluster headache; it is often helpful for the itching and pain of postmastectomy pain syndrome, oral mucositis, cutaneous allergy, loin pain/hematuria syndrome, neck pain, amputation stump pain, and skin tumor; and it may be beneficial for neural dysfunction (detrusor hyperreflexia, reflex sympathetic dystrophy, and rhinopathy). A universal problem for many of the studies analyzed was the absence of a "burning placebo" such as camphor.

Holzer P, Pabst MA, Lippe IT. Intragastric capsaicin protects against aspirin-induced lesion formation and bleeding in the rat gastric mucosa. Gastroenterol 1989 Jun;96(6):1425-1433.
Abstract: Previous work has indicated that capsaicin-sensitive afferent neurons are involved in gastric mucosal defense mechanisms. The present study investigated whether stimulation of these neurons by intragastric administration of capsaicin would protect against aspirin-induced mucosal damage in the luminally perfused rat stomach. Capsaicin (25-640 microM), administered together with acidified (pH 1.5) aspirin (25 mM), inhibited macroscopically visible lesion formation and gastric bleeding in a concentration-dependent fashion. Capsaicin (160 microM) also attenuated the aspirin-induced fall in the gastric potential difference. An inhibitory effect of capsaicin (160 microM) on aspirin-induced gastric injury was also seen by light and scanning electron microscopy. Aspirin alone caused a vast ablation of the gastric surface epithelium, resulting in exposure of the lamina propria. In the presence of capsaicin, the depth of mucosal injury, the area totally deprived of surface epithelial cells, and the severity of surface desquamation were diminished. As capsaicin is a selective stimulant of thin afferent neurons, it would appear that these neurons participate in mechanisms of gastric defense against aspirin injury. Prevention of hemorrhagic damage seems to be the primary effect of afferent nerve-mediated gastroprotection, although injury to the surface epithelium is also reduced to some degree.

Ko F, Diaz M, Smith P, Emerson E, Kim YJ, Krizek TJ, Robson MC. Toxic effects of capsaicin on keratinocytes and fibroblasts. J Burn Care Rehabil. 1998 Sep-Oct;19(5):409-413.
Abstract: Pain management for partial-thickness burns and split-thickness skin graft donor sites remains a persistent problem. Topical capsaicin (trans-b-methyl-N-vanillyl-noneamide) has been successful for pain relief in postherpetic neuralgia, arthritis, and diabetic neuropathy. It is thought to work by inhibiting type C cutaneous factors and by releasing substance P, which is essential for wound healing. To evaluate the effects of topical capsaicin treatment on burn wounds and donor sites, an in vitro study was designed to consider cytotoxic effects of commercial concentrations of capsaicin on keratinocytes and fibroblasts. Human keratinocytes and human fibroblasts were grown in tissue culture and exposed to varying concentrations of capsaicin (0.025% weight/volume to 0.2% weight/volume). In addition, fibroblast-seeded collagen matrixes were exposed to capsaicin to evaluate the compound's ability to cause cytotoxic effects beneath the surface. Keratinocyte growth was reduced 21% to 31% in commercial concentrations of capsaicin 0.025% to 0.20% weight/volume. Fibroblasts were reduced 5% to 10% during the first 6 hours of exposure to capsaicin and 30% after 24 hours across the full range of concentrations tested. At concentrations of at least 0.1% weight/volume, capsaicin penetrated the collagen matrixes, resulting in fibroblast degeneration not only on the surface but also in the inner layers. On the basis of the fact that capsaicin was demonstrated to be cytotoxic to keratinocytes and fibroblasts and on the basis of its known detrimental effect on wound healing, it does not appear that topical capsaicin is indicated for the treatment of burns.

Levy RL. Intranasal capsaicin for acute abortive treatment of migraine without aura. Headache 1995;35(5):277. (Letter)

Lopez-Carrillo L, Avila M, Dubrow R. Chili pepper consumption and gastric cancer in Mexico: A case-control study. Amer J Epidem 1994;139(3):263-271.

Lynn B. Capsaicin: actions on nociceptive C-fibres and therapeutic potential. Pain. 1990 Apr;41(1):61-69. (Review)
Abstract: Recent work on the excitatory action of capsaicin on somatic and visceral afferent neurones shows that depolarization is selective for C-fibre polymodal nociceptor afferents and involves opening a non-selective cation channel. Exposure to significantly suprathreshold amounts of capsaicin causes permanent degeneration of C-fibre afferents in adult rats. Functional changes in rats (hypalgesia, diminished neurogenic inflammation) are likely to be a direct consequence of the loss of C-fibre nociceptors, and so are the reductions in neuropeptide levels that follow adult capsaicin treatment. Clinical trials of topical capsaicin treatment for post-herpetic neuralgia have yielded promising results. The selective nature of the action of capsaicin in reducing just C-nociceptor activity may make it particularly useful for treating pain states triggered by C-fibre input.

Marciniak BH, Brown B, Peterson B, Boult L, Guay D. Adverse consequences of capsaicin exposure in health care workers. J Am Geriatr Soc. 1995 Oct;43(10):1181-1182. (Letter)

Markovits E, Gilhar A. Capsaicin - an effective topical treatment in pain. Int J Dermatol. 1997 Jun;36(6):401-404. (Review)

Marks DR, Rapoport A, Padla D, Weeks R, Rosum R, Sheftell F, Arrowsmith F. A double-blind placebo-controlled trial of intranasal capsaicin for cluster headache. Cephalalgia 1993 Apr;13(2):114-116.
Abstract: It has been suggested that treatment of cluster headache (CH) patients with topical capsaicin may desensitize sensory neurons by depleting the nerve terminals of substance P. We attempted to determine whether capsaicin is effective in aborting CH attacks. Patients in acute cluster were randomized to receive either capsaicin or placebo in the ipsilateral nostril for 7 days. Patients recorded the severity of each headache for 15 days. Headaches on days 8-15 of the study were significantly less severe in the capsaicin group vs the placebo group. There was also a significant decrease in headache severity in the capsaicin group on days 8-15 compared to days 1-7, but not in the placebo group. Episodic CH patients appeared to benefit more than chronic CH patients. These results indicate that intranasal capsaicin may provide a new therapeutic option for the treatment of this disease.

Mathias BJ, et al. Topical capsaicin for chronic neck pain. A pilot study. Am J Phys Med Rehabil. 1995 Jan-Feb;74(1):39-44.

McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol. 1992 Apr;19(4):604-607.
Abstract: Topical capsaicin 0.075% was evaluated for the treatment of the painful joints of rheumatoid arthritis (RA) and osteoarthritis (OA) in a 4 week double blind, placebo controlled randomized trial. Twenty-one patients were selected, all of whom had either RA (n = 7) or OA (n = 14) with painful involvement of the hands. Assessments of pain (visual analog scale), functional capacity, morning stiffness, grip strength, joint swelling and tenderness (dolorimeter) were performed before randomization. Treatment was applied to each painful hand joint 4 times daily with reassessment at 1, 2 and 4 weeks after entry. One subject did not complete the study. Capsaicin reduced tenderness (p less than 0.02) and pain (p less than 0.02) associated with OA, but not RA as compared with placebo. A local burning sensation was the only adverse effect noted. These findings suggest that topical capsaicin is a safe and potentially useful drug for the treatment of painful OA of the hands.

McCarty DJ. Treatment of pain due to fibromyalgia with topical capsaicin: A pilot study. Semin Arth Rhem 1986;23(suppl 3):41-47.

McGuffin M, et al.(eds.) AHPA Botanical Safety Handbook . CRC Press, 1997.

Morris VH, Cruwys SC, Kidd BL. Characterisation of capsaicin-induced mechanical hyperalgesia as a marker for altered nociceptive processing in patients with rheumatoid arthritis. Pain. 1997 Jun;71(2):179-186.
Abstract: Rheumatoid arthritis (RA) is characterised by pain and tenderness not only over inflamed or damaged joints, but also over apparently normal tissues. Experimental models suggest that these features results from changes of sensitivity within both peripheral and central neurones, but direct evidence from human disease is lacking. At present, most clinical studies have evaluated overall pain experience rather than activity within components of the nociceptive pathway. Therefore, the aim of this study was to assess the use of a capsaicin-based technique to quantify changes of neuronal sensitivity in patients with RA. First 20 microliters of capsaicin in solution (0.03 mg/ml) was applied topically for 30 min to apparently normal skin on the forearm of control subjects and patients with RA. The subsequent development of mechanical hyperalgesia to pinprick stimuli was then measured at various time points using a 74.4-mN von Frey hair. The relationship between the area of hyperalgesia and a number of clinical measures was determined. Capsaicin-induced mechanical hyperalgesia was found to decline with age in normal subjects (r = 0.47, P < 0.01). The development of hypearlgesia had a similar time course in normal subjects and patients with RA. The maximum area of hyperalgesia, however, was substantially larger in 35 RA patients; 254.3 +/- 20.7 cm2, compared with 35 normal controls; 109 +/- 7.5 cm2 (P < 0.001). An association was apparent between hyperalgesic area and a composite score of joint tenderness (r = 0.47, P < 0.01), but not with overall pain score or a systemic marker of inflammation. These results provide evidence for enhanced sensitisation of a population of sensory fibres in RA. Peripheral sensory activity over the forearms of rheumatoid patients has previously been shown to be normal and the results suggest the presence of enhanced central mechanisms in this disorder. The correlation between capsaicin-induced hyperalgesia and joint tenderness in the RA patients implies that joint symptoms arise partially as a result of central, and not exclusively peripheral, factors. The study supports the use of capsaicin-based techniques to explore nociceptive mechanisms in clinical disorders characterised by chronic pain.

Morris V, Cruwys S, Kidd. Increased capsaicin-induced secondary hyperalgesia as a marker of abnormal sensory activity in patients with fibromyalgia. Neurosci Lett. 1998 Jul 10;250(3):205-207.
Abstract: In this study, capsaicin-induced secondary hyperalgesia was assessed as a marker of abnormal nociceptive processing in patients with fibromyalgia (FM). The area of mechanical secondary hyperalgesia induced by a standard solution of capsaicin placed on the volar forearm was measured in ten patients with FM and the results compared to those obtained in ten patients with rheumatoid arthritis (RA) and ten normal subjects. The area of secondary hyperalgesia was found to be substantially increased in both the FM and RA groups compared with controls. In the FM group the area of hyperalgesia correlated with the overall pain score and with the joint tenderness score. The results suggest that in FM there is enhanced sensitivity of nociceptive neurones at a spinal level, thereby supporting the concept of a generalised disturbance of pain modulation in this disorder.

Newall CA, Anderson LA, Phillipson DJ., Herbal Medicines: A Guide for Healthcare Professionals. The Pharmaceutical Press, London, 1996.

Ogata K, Masaki T, Takao F, Kunimoto M, Inoue K. [Therapeutic trials with topical capsaicin cream and iontophoretically applied lidocaine for diabetic painful truncal neuropathy]. Rinsho Shinkeigaku. 1996 Jan;36(1):30-33. [Article in Japanese]
Abstract: We report a 63-year-old man with a history of diabetes mellitus for 23 years. Painful dysesthesia developed in his toes and trunk with weight loss of 2kg in two months, after the therapy for diabetes mellitus. Truncal painful dysesthesia was symmetrically distributed in the bilateral posterior and anterior T8-11 dermatomes, sparing the bilateral lateral tholacic areas. Electromyography showed denervation potentials in bilateral abdominal rectus muscles at the levels of Th8-10. Histopathological study of the biopsied right sural nerve revealed small fiber neuropathy. We suspected the truncal painful dysesthesia of this patient resulted from diabetic small fiber polyneuropathy, which was resistant to ordinary medical treatments such as non-steroidal anti-inflammatory drugs. Capsaicin cream containing 0.075% capsaicin, and lidocaine delivered by iontophoresis were both effective for his painful dysesthesia.

Phillips CD. 1879. Materia Medica and Therapeutics: Vegetable Kingdom. New York: William Wood and Company.

Rains C, Bryson HM. Topical capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs Aging. 1995 Oct;7(4):317-28. (Review)
Abstract: Capsaicin, the active principle of hot chili pepper, is thought to selectively stimulate unmyelinated C fibre afferent neurons and cause the release of substance P. Prolonged application of capsaicin reversibly depletes stores of substance P, and possibly other neurotransmitters, from sensory nerve endings. This reduces or abolishes the transmission of painful stimuli from the peripheral nerve fibres to the higher centres. In clinical studies of patients with post-hepatic neuralgia, diabetic neuropathy or osteoarthritis, adjunctive therapy with topical capsaicin achieved better relief than its vehicle in most studies. In a single trial, topical capsaicin in demonstrated similar efficacy to oral amitriptyline in patients with diabetic neuropathy. Topical capsaicin is not associated with any severe systemic adverse effects. However, stinging and burning, particularly during the first week of therapy, is reported by many patients. Topical capsaicin merits consideration as adjuvant therapy in conditions such as post-herpetic neuralgia, diabetic neuropathy and osteoarthritis, where the pain can be chronic and difficult to treat.

Shin HC, Park HJ, Raymond SA. Potentiation by capsaicin of lidocaine's phasic impulse block in isolated rat sciatic nerve. Pharmacol Res 1994 Jul;30(1):73-79.
Abstract: Compound action potentials (CAPs) of A- and C-fibres were recorded from isolated sciatic nerves of the rat to determine whether lidocaine-induced phasic impulse block was affected by low doses of capsaicin. Preceding impulse activity produced phasic reductions of the amplitudes of both A- (5.7 +/- 1.3%) and C-CAPs (20.7 +/- 7.0%) in drug-free solution. Capsaicin alone (50 microM) did not change the activity-induced reductions of the heights of both CAPs (A-CAP: 6.2 +/- 1.7%, C-CAP: 22.3 +/- 8.0%). Lidocaine (100 microM) caused differential phasic blocks between the A-CAP (20.1 +/- 3.7%; n = 7) and the C-CAP (33.8 +/- 4.9% n = 7). Lidocaine's phasic impulse block was potentiated after 30 min of subsequent capsaicin administration (A-CAP: 40.6 +/- 4.7%, n = 7; C-CAP: 48.8 +/- 5.5% n = 9). Capsaicin's phasic potentiating effects were reversed after 30 min of washing. These results suggest that capsaicin may be a useful agent for the reversible potentiation of phasic impulse blockade by lidocaine.

Siften DW, ed. Physicians’ Desk Reference for Nonprescription Drugs. Montvale, NJ: Medical Economics, 1998, 790-791.

Surh YJ, Lee SS. Capsaicin in hot chili pepper: Carcinogen, co-carcinogen or anticarcinogen? Food Chem Toxic 1996 Mar;34(3):313-316.
Abstract: Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a major pungent ingredient of the Capsicum fruits such as hot green and red peppers. Besides its use as a food additive in various spicy cuisines, capsaicin is currently utilized for therapeutic purposes to treat various peripheral painful conditions such as rheumatoid arthritis and diabetic neuropathy. Considering consumption of capsaicin as a food additive and its current medicinal application in humans, correct evaluation and precise assessment of any harmful effects of this compound are essential from the public health standpoint. Numerous investigations have been conducted to determine the potential mutagenic and carcinogenic activity of capsaicin and chili pepper, but results are discordant. This review briefly examines findings in the literature of studies testing mutagenicity and tumorigenicity of capsaicin and presents a possible mechanistic basis for the dual effects exerted by the compound.

Vickers ER, Cousins MJ, Walker S, Chisholm K. Analysis of 50 patients with atypical odontalgia. A preliminary report on pharmacological procedures for diagnosis and treatment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998 Jan;85(1):24-32.
Abstract: Atypical odontalgia is a distressing and unusual chronic orofacial pain condition. It is often difficult to diagnose because it is associated with a lack of clinical and radiographic abnormalities. The condition is poorly understood on a pathophysiological basis, and patients often undergo repetitive and unnecessary dental procedures in attempts to alleviate pain. In this study, 50 patients diagnosed with odontalgia were evaluated by pharmacological procedures, including topical anesthetic application and phentolamine infusion. Results of these pharmacological procedures suggest that atypical odontalgia is a neuropathic pain of the oral cavity that may have a component of sympathetically maintained pain. Therapeutic trials of topical capsaicin were carried out to assess its efficacy for pain reduction. Topical capsaicin was effective in most patients.

Wallace MS, Laitin S, Licht D, Yaksh TL. Concentration-effect relations for intravenous lidocaine infusions in human volunteers: effects on acute sensory thresholds and capsaicin-evoked hyperpathia. Anesthesiology 1997 Jun;86(6):1262-1272.
Abstract: BACKGROUND: Preclinical studies have emphasized that persistent small afferent input will induce a state of central facilitation that can be regulated by systemically administered lidocaine. The authors extended these preclinical studies to human volunteers by examining the concentration-dependent effects of intravenous lidocaine on acute sensory thresholds and facilitated processing induced by intradermal capsaicin. METHODS: Fifteen healthy persons received a lidocaine or a placebo infusion. A computer-controlled infusion pump targeted sequential stepwise increases in plasma lidocaine concentration steps of 1, 2, and 3 microg/ml. At each plasma concentration, neurosensory testing (thermal and von Frey hair test stimulation) were performed. After completing the tests at the 3 microg/ml plasma lidocaine level, intradermal capsaicin was injected into the volar aspect of the left forearm, and the flare response and hyperalgesia to von Frey hair stimulation, stroking, and heat was assessed. RESULTS: The continuous infusion of lidocaine and placebo had no significant effect on any stimulus threshold. Although intravenous lidocaine resulted in a decrease in all secondary hyperalgesia responses, this was only significant for heat hyperalgesia. Intravenous lidocaine resulted in a significant decrease in the flare response induced by intradermal capsaicin. CONCLUSIONS: These studies suggest that the facilitated state induced by persistent small afferent input human pain models may predict the activity of agents that affect components of nociceptive processing that are different from those associated with the pain state evoked by "acute" thermal or mechanical stimuli. Such insight may be valuable in the efficient development of novel analgesics for both neuropathic and post-tissue-injury pain states.

Watson CP, Evans RJ, Watt VR, Birkett N. A randomized vehicle-controlled trial of topical capsaicin in the treatment of postherpetic neuralgia. Clin Ther 1993;15:510-523.

Yeoh KG, Kang JY, Yap I, Guan R, Tan CC, Wee A, Teng CH. Chili protects against aspirin-induced gastroduodenal mucosal injury in humans. Dig Dis Sci. 1995 Mar;40(3):580-583.
Abstract: Capsaicin, the pungent ingredient of chili, has a gastroprotective effect against experimental gastric mucosal injury in animals. Such an effect has not, however, been documented in humans to date. Eighteen healthy volunteers with normal index endoscopies underwent two studies four weeks apart. Each subject took 20 g chili orally with 200 ml water in one study and 200 ml water in another study. In each case this was followed half an hour later by 600 mg aspirin BP with 200 ml water. Endoscopy was repeated 6 hr later. Gastroduodenal mucosal damage was assessed by a previously validated scoring system. The median gastric injury score after chili was 1.5 compared to 4 in the control group (P < 0.05), demonstrating a gastroprotective effect of chili in human subjects.

Yeo WW, Chadwick IG, Kraskiewicz M, Jackson PR, Ramsay LE. Resolution of ACE inhibitor cough: changes in subjective cough and responses to inhaled capsaicin, intradermal bradykinin and substance-P. Br J Clin Pharmacol 1995 Nov;40(5):423-429.
Abstract: 1. In eight hypertensive patients with ACE inhibitor-induced cough the resolution of the cough was examined in a prospective observational study over 4 weeks duration. Resolution of cough was measured by visual analogue scales and questionnaire at baseline and days 3, 7, 14 and 28. In addition changes in cough sensitivity to inhaled capsaicin, and skin responses to bradykinin and substance-P were measured at the same time points. 2. All patients recorded significant subjective improvement in cough questionnaire scores for severity and night time waking, and by visual analogue scales for severity and frequency of cough (all P < 0.0005 for trend from day 0-28). Significant changes in subjective measures were recorded by 3 to 7 days for most measures, but further reductions were observed up to day 28 (all P < 0.01 day 28 vs day 0). 3. The sensitivity to inhaled capsaicin fell over the 28 days of study after stopping enalapril. The potency of capsaicin relative to day 0 was reduced to 0.25 (95% CI 0.07-0.87) by day 14, and to 0.20 (95% CI 0.06-0.67) by 28 days. 4. After stopping enalapril there was a highly significant reduction in wheal area produced by intradermal bradykinin, with the majority of the effect seen by day 3 (P < 0.0005). The wheal area to intradermal substance-P also declined with time after stopping enalapril, but significant changes were not observed until 14 days (P < 0.01). 5. Multiple regression analysis of the rates of decline for the subjective and objective measures of cough showed significant associations between the response to inhaled capsaicin and the VAS scores for severity of cough (P = 0.005) and frequency of cough (P = 0.011). Capsaicin response was not related significantly to the severity of cough measured by self-administered questionnaire. 6. There was a significant association between bradykinin response and VAS scores for frequency of cough (P < 0.04) and severity of cough (P < 0.05), but not with cough by questionnaire or the capsaicin response. The response to substance-P did not relate significantly to any of the measures of cough. 7. Cough caused by enalapril improved markedly by 14 days but took up to 28 days to resolve. It was associated with increased sensitivity to inhaled capsaicin which decreased over 28 days, and which paralleled changes in subjective cough scores.