Menthol; methyl salicylate is a combination of topical analgesics indicated for the temporary relief of minor aches and pains of muscles and joints, such as simple backache, arthritis, muscle strains, sprains, bruises, and cramps. Methyl salicylate is an analgesic with anti-inflammatory and rubefacient/counterirritant properties. It has a vasodilatory action upon absorption resulting in an increased localised blood flow and a rise in tissue temperature. In contrast, menthol has a cooling effect, and the combination of menthol and methyl salicylate facilitates a counterirritant action. Methyl salicylate is also known as wintergreen oil or sweet birch oil. Historically, methyl salicylate was extracted from the wintergreen plant (Gaultheria procumbens) and birch trees (Betula lenta). Although prolonged use of methyl salicylate may cause dermatitis, methyl salicylate is generally safe in topical formulations.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Topical Administration
-Do not apply to wounds or damaged, broken or irritated skin.
-Do not use immediately after bath or shower.
-Avoid contact with the eyes or mucous membranes. If eye contact occurs, immediately wash out the eye with water or saline, and consult a health care provider if irritation persists.
-Avoid applying into skin folds.
-Do not expose the area treated with menthol; methyl salicylate to heat (e.g., heating pad) or direct sunlight.
-Do not use menthol; methyl salicylate when sweating, such as from exercise or heat.
-Do not bandage tightly. Do not bandage, wrap, or cover until after washing the areas where menthol; methyl salicylate has been applied.
-Do not recline on or cover treated area.
-Do not use at the same time as other topical analgesics.
-Wash hands with soap and water after application.
Cream/Ointment/Lotion Formulations
-Apply a thin layer to affected area(s).
-Massage into painful area until thoroughly absorbed into skin.
Transdermal Patch Formulations
-Clean and dry affected area.
-Remove patch from backing film and apply to skin.
-Remove the used patch from the skin when a new patch is applied.
Other Topical Formulations
Spray Formulations
-The spray is flammable; keep away from fire or flame. Do not use where sparks come out.
-Do not use in a confined space.
-Do not puncture or incinerate container; the contents are under pressure.
-Avoid inhalation.
-Shake the can very well before use.
-To avoid frostbite, hold the can 4 inches away from the skin, and spray each affected area for no longer than 1 second.
-Storage: Avoid storing product in direct sunlight and heat.
Use of menthol has been associated with transient erythema, skin irritation, and/or paresthesias (e.g., burning, stinging, warm sensation) at the site of application. This sensitivity generally diminishes with continued use. However, more serious hypersensitivity reactions may also occur. Contact dermatitis with disseminated pruritus and erythema multiforme lesions have been attributed to the topical application of menthol in a case report. Resolution of symptoms occurred after hospitalization and a 10-day taper of systemic corticosteroid therapy. Prolonged use of methyl salicylate may cause contact dermatitis. Rare cases of serious burns have been reported with menthol; methyl salicylate.
Toxicity including full-thickness skin necrosis, superficial muscle necrosis, transitory elevated hepatic enzymes, and persistent interstitial nephritis has been reported after the use of topical cream containing 18.3% methyl salicylate and 16% menthol to multiple sites. Upon presentation, the patient stated that periodic application of a heating pad was used on each treated area for no more than 15 to 20 minutes. Clinicians attributed effects to excessive percutaneous absorption and subsequent drug toxicity due in part to the application of heat. Local skin necrosis has been reported after the use of methyl salicylate and menthol along with periodic heating of the application area with a heating pad. Tinnitus, diplopia, dyspnea, mixed metabolic acidosis and respiratory alkalosis were also noted.
NSAIDs, including methyl salicylate, may cause GI bleeding. Discontinue methyl salicylate use and evaluate any patients with worsening or persistent stomach pain or upset or feeling faint with bloody or black tarry stools or vomit.
Do not use menthol; methyl salicylate in patients with salicylate hypersensitivity or NSAID hypersensitivity.
Menthol; methyl salicylate is for external use only. It is not for ophthalmic administration; avoid ocular exposure and contact with mucous membranes. Do not bandage skin tightly after menthol; methyl salicylate application; do not recline on or cover the treated area. Do not bandage, wrap, or cover until after washing the areas where menthol; methyl salicylate has been applied. Do not apply menthol; methyl salicylate to a skin abrasion, wounds, or damaged, broken, or irritated skin. Do not use menthol; methyl salicylate immediately after a bath or shower. Advise patients using menthol; methyl salicylate to avoid the application of heat, including the use of a heating pad, or direct sunlight (UV) exposure to the area of product application immediately before or after use. Do not use menthol; methyl salicylate when sweating, such as during strenuous exercise or with an ambient temperature increase.
NSAIDs, including methyl salicylate, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and GI perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a more than 10-fold increased risk for developing a GI bleed compared to patients without risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy, concomitant oral corticosteroid therapy, anticoagulant therapy, aspirin, or selective serotonin reuptake inhibitors (SSRIs), tobacco smoking, ethanol ingestion, geriatric age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease or coagulopathy are at increased risk for GI bleeding. To minimize GI risks in NSAID-treated patients, use the lowest effective dosage for the shortest possible duration, and avoid administration of more than 1 NSAID at a time. In the setting of concomitant low-dose aspirin use for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding. Avoid NSAID use in higher risk populations unless the benefits are expected to outweigh the risks of bleeding; consider alternate therapy other than NSAIDs in higher risk patients as well as those with active GI bleeding. Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy.
Do not use methyl salicylate right before or after heart surgery, including coronary artery bypass graft surgery (CABG). Use methyl salicylate with caution in patients with hypertension or cardiac disease. The risk of heart attack or stroke may increase if methyl salicylate is used at higher doses or for longer durations.
Use menthol; methyl salicylate with caution in patients with renal disease.
Because some transdermal systems (i.e., patches) contain aluminum or other metal components, advise patients to remove the menthol; methyl salicylate topical patch before undergoing magnetic resonance imaging (MRI). Metal components contained in the backing of some transdermal systems can overheat during an MRI scan and cause skin burns in the area where the patch is adhered.
Do not use menthol; methyl salicylate during the last 3 months of pregnancy because it may cause problems in the unborn child or complications during delivery. There is no conclusive evidence that methyl salicylate is teratogenic in humans during pregnancy. In animal studies, central nervous system teratogenicity, alteration in renal pelvis and urine formation, and increased litter size have been reported. Topical application of methyl salicylate did not cause congenital defects when used at doses up to 6,000 mg/kg/day. The methyl salicylate doses in these studies were significantly higher than the adult lethal human dose on mg/kg basis.
Previous American Academy of Pediatrics recommendations suggest salicylates be used with caution during breast-feeding.
For the treatment of minor arthralgia or myalgia associated with arthritis, bruises, simple backaches, sprains, and strains:
Topical dosage (menthol 2% and methyl salicylate 10% cream):
Adults: Apply a thin layer to the affected area(s) up to 3 to 4 times daily as needed. Discontinue use if condition worsens or does not improve within 7 days.
Children and Adolescents 2 to 17 years: Apply a thin layer to the affected area(s) up to 3 to 4 times daily as needed. Discontinue use if condition worsens or does not improve within 7 days.
Topical dosage (menthol 1% to 10% and methyl salicylate 14% to 30% cream, lotion, ointment, or spray):
Adults: Apply a thin layer to the affected area(s) up to 3 to 4 times daily as needed. Discontinue use if condition worsens or does not improve within 7 days.
Children and Adolescents 12 to 17 years: Apply a thin layer to the affected area(s) up to 3 to 4 times daily as needed. Discontinue use if condition worsens or does not improve within 7 days.
Topical dosage (menthol 3% and methyl salicylate 10% patch):
Adults: Apply 1 patch to the affected area and leave in place for up to 8 to 12 hours. May apply a second patch for up to another 8 to 12 hours if pain persists after removal of the first patch. Max: 1 patch/application and 2 patches/day. Discontinue use if condition worsens or does not improve within 3 days.
Maximum Dosage Limits:
-Adults
2 patches/day; 4 applications/day of cream, lotion, ointment, or spray.
-Geriatric
2 patches/day; 4 applications/day of cream, lotion, ointment, or spray.
-Adolescents
4 applications/day of cream, lotion, ointment, or spray; safety and efficacy of patch have not been established.
-Children
12 years: 4 applications/day of cream, lotion, ointment, or spray; safety and efficacy of patch have not been established.
2 to 12 years: 4 applications/day of menthol 2% and methyl salicylate 10% cream; safety and efficacy of other cream, lotion, ointment, patch, or spray 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 Menthol; Methyl Salicylate products.
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. Further, experts have theorized that menthol-induced activation of cold thermoreceptors in the skin may account for the sensation of cool, while activation of nociceptors evokes irritation or burning, and vasodilation. On a cellular level, menthol appears to alter calcium efflux from nerve-cell membranes of cold receptors. Investigators have termed these neurosensory receptors cold- and menthol-sensitive receptor-1 (CMR1), a subfamily of transient receptor potential channel M8 (TRPM8) receptors. The literature is unclear if menthol stimulation of nociceptors is mediated by alterations in cell wall calcium conduction or by, as yet, undefined mechanisms. However, the results of clinical study may explain the dose-dependent sensory effects of menthol. At low concentrations, menthol has been shown to have relative selectivity for CMR1, cold receptors, as compared to nociceptors, pain receptors, while at higher concentrations this selectivity is overcome and menthol acts at both. Methyl salicylate is a topical salicylate analgesic, with anti-inflammatory and rubefacient/counterirritant properties. It is lipophilic, and when applied topically, it readily penetrates the skin and is hydrolyzed to salicylic acid in the tissues. Once absorbed, the salicylate distributes throughout the tissue and transcellular fluids, primarily through passive pH-dependent processes. It also has a vasodilatory action upon absorption resulting in an increased localised blood flow and a rise in tissue temperature, its rubefacient action. In contrast, menthol has a cooling effect, and the combination of menthol and methyl salicylate facilitates a counterirritant action.
Menthol; methyl salicylate is administered topically to the skin.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Topical Route
Limited pharmacokinetic study has been conducted with cutaneous menthol; methyl salicylate. However, low concentrations of systemic exposure have been demonstrated after the use of camphor; menthol; methyl salicylate topical patches. Eight-hour application of various numbers of patches resulted in menthol and methyl salicylate 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 after the use of 74.88 mg, 149.76 mg, and 299.52 mg of menthol; average maximum methyl salicylate plasma concentrations of 8.6 +/- 3.8 ng/mL, 16.8 +/- 6.8 ng/mL, and 29.5 +/- 10.5 ng/mL were measured after the use of 149.76 mg, 299.52 mg, and 599.04 mg of methyl salicylate. Menthol and methyl salicylate were no longer detectable at 8 to 12 hours after patch removal after the use of 74.88 mg of menthol and 149.76 mg of methyl salicylate, a normal dose for these products. Based on data from each of the 3 administered doses, a menthol terminal half-life of 3 to 6 hours and a methyl salicylate terminal half-life of 2 to 4 hours were estimated. Percutaneous penetration has been shown to increase with increasing menthol concentrations. Further, local and systemic toxicity has been reported after use of large doses of menthol; methyl salicylate and heat; the same may be possible if used with occlusive dressings. Methyl salicylate is lipophilic, and when applied topically, it readily penetrates the skin and is hydrolyzed to salicylic acid in the tissues. Once absorbed, the salicylate distributes throughout the tissue and transcellular fluids, primarily through passive pH-dependent processes. Conjugation with glycine to from salicyluric acid and with glucuronic acid to form salicyl acyl and phenolic glucuronide are the major metabolic pathways. The metabolites are excreted in the urine with free salicylate accounting for 10% to 30%. The estimated plasma half-life for salicylate is 2 to 3 hours in low doses and 12 hours at anti-inflammatory doses.