Capsaicin, menthol, and methyl salicylate are used together in an external preparation for the temporary relief of minor aches and pains associated with arthritis, simple backache, strains, bruises, and sprains. Capsaicin, naturally derived from peppers, acts as a topical analgesic. Menthol and methyl salicylate are counterirritants. They stimulate nerve endings in the skin that respond to pain, warmth, and coolness. Menthol is extracted from peppermint oil or prepared synthetically. When combined, capsaicin, menthol, and methyl salicylate act together to provide a paradoxical pain-relieving effect by producing a sensation that counters a more intense feeling of pain. Methyl salicylate (wintergreen oil or sweet birch oil) is synthetically prepared by esterification of salicylic acid with methyl alcohol.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Topical Administration
Cream/Ointment/Lotion Formulations
Muscular Balm Ointment
-Apply to affected area.
-Do not apply to wound or damaged skin.
-Do not bandage tightly.
-Do not use if excessive irritation of the skin develops.
Pain Relief Lotion
-Shake bottle well before each use.
-Wash and dry affected area, then gently rub over area of pain.
-Do not apply to open wounds, damaged skin, eyes, mouth, genitals, or other mucous membranes.
-Wash hands immediately after application.
The most common adverse effect associated with use of capsaicin; menthol; methyl salicylate is transient skin irritation, application site reactions including dermatitis, pruritus (greater than or equal to 10% of patients), scaling (greater than or equal to 10% of patients), erythema (greater than or equal to 10% of patients) and/or paresthesias (e.g., burning, stinging, warm sensation) at the site of application; the severity of this effect appears to be dose related. With the use of capsaicin 0.025% or 0.075% cream, this sensation usually disappears after the first several days of continuous treatment; however, it may persist for 2 to 4 weeks or longer. Factors such as exposure of the treated area to heat or humidity, direct sunlight, wrappings (e.g., clothing or bandages), bathing in warm water, or sweating may intensify the sensation. The burning or stinging sensation produced during initial administration may be prolonged if capsaicin cream is applied less than 3 to 4 times per day. During clinical trials, the use of the capsaicin 8% topical patch was associated with application site reactions including erythema (63%), pain (42%), pruritus (6%), papules or maculopapular rash (6%), edema (4%), swelling (2%), and dryness, xerosis (2%), and drug-induced body odor. The majority of reactions were considered mild to moderate. Reactions may necessitate local anesthetic pretreatment; even with such pretreatment, application site reactions may still occur.
In September 2012, the FDA warned healthcare providers, and consumers about the rare risk of serious skin injuries, including first to third degree burns, with the use of over the counter topical analgesics used for mild muscle and joint pain. Post-marketing surveillance and medical literature review detected 43 cases of burns on application sites with the use of topical analgesic patches, balms, and creams. Few cases have been reported with capsaicin containing products. Many burns appeared in areas where the product was applied following 1 application, with severe burning or blistering occurring within 24 hours. Some burns resulted in hospitalization. Patients should not apply topical analgesics such as capsaicin or menthol to wounds or broken, irritated skin, and the area should not be tightly wrapped or bandaged. Contact with mucous membranes and application of heat to the affected area should be avoided. Items such as heating pads, lamps, or hot water bags and bottles may increase the risk of burns. Discuss the risk of burns with patients, as warnings on over the counter topical analgesics for joint or muscle pain are not required. Patients who experience pain, skin blistering, or swelling should stop use and contact their healthcare provider for treatment.
Capsaicin is a known respiratory irritant. Cough has been reported rarely upon removal of clothing or bed sheets that have covered the site of application. This effect has been attributed to respiratory irritation from inhalation of the residue of the dried cream. In addition, cough, sneezing, nasal irritation, and throat irritation have been reported in patients treated with capsaicin. Do not hold capsaicin products or any treatment materials near the face. Infections that have been reported during use include bronchitis, naso-pharyngitis, and sinusitis.
Capsaicin and capsaicin-containing products should not be used in patients who are known to be sensitive to the fruits of capsicum plants (e.g., hot peppers).
Capsaicin; menthol; methyl salicylate should not be applied to areas with skin abrasion, irritation, infection, or inflammation. Due to the potential for enhanced absorption, capsaicin and capsaicin-containing preparations should not be used with a heating pad or applied after strenuous exercise. In the days following treatment, treated areas may become more heat sensitive; patients may wish to avoid external heat from heating pads, hot baths or showers, artificial or natural sunlight (UV) exposure, and strenuous exercise until sensitivity resolves. When used for self-medication, if a person's condition worsens or if symptoms persist for more than 7 days, or clear up and occur again within a few days, capsaicin therapy should be discontinued, and a physician should be consulted.
Capsaicin is an irritant; avoid mucous membrane and ocular exposure to drug product, dried residue, or any treatment materials. Do not hold capsaicin products or treatment materials near the face. If capsaicin comes in contact with the eyes, rinse well with water; advise patients to seek medical help if irritation persists. Handle all capsaicin products with care, using appropriate precaution to avoid accidental exposure to non-treatment areas of skin.
When treated with topical products that contain 8% capsaicin patients may experience substantial procedural pain, even after use of a local anesthetic; acute pain should be treated with local cooling and appropriate analgesic medications. During the procedure, some patients experienced an elevation in blood pressure, likely induced by pain. Patients with poorly controlled hypertension, a recent cardiovascular event (e.g., myocardial infarction), or a recent cerebrovascular event (e.g., stroke) may be at an increased risk for an adverse cardiovascular event during treatment with capsaicin 8% topical patch because of the associated transient increase in blood pressure. In clinical trials, blood pressure elevations averaged less than 10 mmHg and appeared to be related to treatment-related increases in pain and not to pretreatment blood pressure. Further, blood pressure returned to baseline within two hours of patch removal with no lasting effect measured at the 4, 8, or 12 week follow-up visits. Monitor blood pressure and manage pain during treatment.
Adequate and well-controlled studies of capsaicin; menthol; methyl salicylate in pregnant women have not been conducted. No evidence of fetal teratogenicity was demonstrated in rats using capsaicin patches at doses of up to 11 times the recommended human maximum dose or in rabbits using capsaicin liquid at doses of up to 37 times the recommended human maximum dose. During use of capsaicin patches in pregnant rats, there were no adverse effects observed on survival, growth, learning and memory tests, sexual maturation, mating, pregnancy, or fetal development. Because animal studies are not always predictive of human response, capsaicin topical products should be used during pregnancy only when clearly indicated. The effects of capsaicin during labor and obstetric delivery are unknown. Adequate and well controlled studies of topical menthol use during pregnancy have not been conducted. Consider the potential for risks and benefits to both mother and fetus.
It is not known if capsaicin is excreted in human milk. An adequate study has not been conducted in infants exposed to capsaicin, a natural component of peppers, via breast milk or direct administration. Adverse effects, including erythematous rash with desquamation, have been reported in nursing infants whose mothers ingested foods flavored with red pepper. Because mild to severe skin irritation may occur following topical application of capsaicin, the infant's skin should not come into direct contact with areas of the mother's skin that have been treated.
Adequate and well controlled study of topical menthol use during pregnancy has not been conducted. The American Academy of Pediatrics has not made a determination regarding the use of menthol and breast-feeding. Do not use menthol on or near the breast where baby might ingest it during breast-feeding, and use care not to make contact with the skin of an infant or very young child. There have been cases where the direct application of menthol topical products to an infant's skin resulted in severe breathing difficulties.
Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Capsaicin; menthol; methyl salicylate should not be used in patients sensitive to aspirin, with salicylate hypersensitivity, or in conditions associated with aspirin sensitivity.
For the temporary relief of minor musculoskeletal pain and arthralgia:
Topical dosage:
Adults, Adolescents, and Children 12 years and older: Apply topically to affected area 3 to 4 times daily.
Maximum Dosage Limits:
-Adults
4 topical applications per day
-Geriatric
4 topical applications per day
-Adolescents
4 topical applications per day
-Children
12 years: 4 topical applications per day
1 to 11 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Capsaicin; Menthol; Methyl Salicylate products.
Mechanism of Action:
-Capsaicin: Capsaicin depletes and prevents reaccumulation of substance P in peripheral sensory neurons. Substance P is found in slow-conducting, unmyelinated type C neurons that innervate the dermis and epidermis. Substance P is thought to be the primary chemical mediator of pain impulses from the periphery to the central nervous system. Substance P can also be released into joint tissues, where it activates inflammatory substances involved in the development of rheumatoid arthritis. By depleting substance P, capsaicin renders skin and joints insensitive to pain since local pain impulses cannot be transmitted to the brain. When capsaicin therapy is discontinued, substance P reaccumulates and neuronal sensitivity returns to normal. Capsaicin is not a traditional counterirritant since it does not produce vasodilation.
-Menthol: Local effects including mild analgesia, cooling sensation, irritant/counter-irritant effect, and vasodilation have been attributed to topical menthol application. The exact mechanism of these actions is not well defined and primarily based on observation. Analgesia may occur directly through interaction with kappa-opioid receptors or indirectly through nociceptor activation and resultant counter-irritant effect.
-Methyl Salicylate: The exact mechanism of action of methyl salicylate is unknown. When applied topically to the skin, methyl salicylate induces redness and irritation at the site of application followed by an analgesic effect. It is readily absorbed from intact skin and can produce effects typical of systemic salicylates. When applied topically, methyl salicylate is thought to penetrate the skin and underlying tissues where it reversibly inhibits cyclooxygenase enzyme and locally and peripherally prevents the production of inflammatory mediators such as prostaglandin and thromboxane A2.
Capsaicin; menthol; methyl salicylate is administered topically. Menthol targets the kappa opioid receptor on the TRPM8 neuron. Menthol is rapidly metabolized to polyols and hydroxy acids that are excreted in these forms or as glucuronide conjugates. Capsaicin binds to the TRPV1 proteins located on pain and heat neurons. Capsaicin is metabolized by CYP450 enzymes and carboxylesterase class enzymes; metabolites possess less potential at VR1 receptors.
Affected cytochrome P450 isoenzymes: CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4
Capsaicin is extensively metabolized by CYP450 isoenzymes; however, clinically significant drug interactions are not expected.
-Route-Specific Pharmacokinetics
Topical Route
-Capsaicin: Following the topical application of capsaicin, the duration of action is 4 to 6 hours; maximal relief of neuropathic and arthritic pain is usually noted with 2 weeks of continuous therapy, although may not be observed for 4 to 6 weeks. Application of a single capsaicin 8% topical patch resulted in systemic exposure to capsaicin in 1/3 of an unstated number of studied patients; Cmax was less than 5 ng/ml in all patients and occurred at 60 minutes after patch application. The capsaicin plasma concentration of most patients was undetectable within 3 to 6 hours following patch removal. Use of a single 60 minute patch results in greater than or equal to 30% relief of postherpetic neuralgia in as soon as 1 week and persisting for up to 12 weeks following application.
-Menthol: Limited pharmacokinetic study has been conducted with cutaneous menthol. However, low levels of systemic exposure have been demonstrated following the use of menthol; camphor; methyl salicylate combination topical patches. Eight hour application of various numbers of patches resulted in menthol systemic exposure in all study patients. Average maximum menthol plasma concentrations of 7.6 +/- 2.6 ng/mL, 19 +/- 5.4 ng/mL, and 31.9 +/- 8.8 ng/mL were measured following the use of 74.88 mg, 149.76 mg, and 299.52 mg of menthol. Menthol was no longer detectable 8 to 12 hours after patch removal following the use of 74.88 mg of menthol, a normal dose for this product. Based on data from each of the 3 administered doses, a menthol terminal half-life of 3 to 6 hours was estimated.