camphor, menthol, methyl salicylate

Combination Topical Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Counterirritants (selected)

Do not apply to wounds or damaged, broken or irritated skin.
Do not use 1 hour before or within 30 minutes after a 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 camphor; menthol; methyl salicylate to heat (e.g., heating pad) or direct sunlight.
Do not use camphor; 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 camphor; 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.

Clean and dry affected area.
Remove patch from backing film and apply to skin.
Remove the used patch from the skin after at most 8-hour application.

Gel
Clean and dry affected area.
Apply a dime-sized portion to the affected area.
Massage thoroughly until absorbed into skin.
 
Solution (oil)
Apply a few drops then gently rub into the affected area.

erythema multiforme / Delayed / Incidence not known
cyanosis / Early / Incidence not known
anuria / Delayed / Incidence not known
spontaneous fetal abortion / Delayed / Incidence not known
apnea / Delayed / Incidence not known
seizures / Delayed / Incidence not known
interstitial nephritis / Delayed / Incidence not known
skin necrosis / Early / Incidence not known
GI bleeding / Delayed / Incidence not known

erythema / Early / Incidence not known
burns / Early / Incidence not known
contact dermatitis / Delayed / Incidence not known
delirium / Early / Incidence not known
urinary retention / Early / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hallucinations / Early / Incidence not known
excitability / Early / Incidence not known
respiratory depression / Rapid / Incidence not known
metabolic acidosis / Delayed / Incidence not known
dyspnea / Early / Incidence not known
respiratory alkalosis / Delayed / Incidence not known

pruritus / Rapid / Incidence not known
paresthesias / Delayed / Incidence not known
skin irritation / Early / Incidence not known
tremor / Early / Incidence not known
nausea / Early / Incidence not known
vomiting / Early / Incidence not known
tinnitus / Delayed / Incidence not known
diplopia / Early / Incidence not known

Bayer Muscle and Joint, BenGay Ultra Strength, Fordagel, MCM, Neuracin, Neuroxa, Pain Relieving Rub, RealLief, Salonpas, ValleGel Prep

OTC

Combination of topical analgesics
Used for the temporary relief of minor aches and pains of muscles and joints
Camphor ingestion associated with serious adverse events

Apply 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.

Apply 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.

Apply 1 patch to the affected area(s) up to 3 to 4 times daily as needed. Remove patch after 8 hours. Discontinue use if condition worsens or does not improve within 7 days.

Apply 1 patch to the affected area(s) up to 3 to 4 times daily as needed. Remove patch after 8 hours. Discontinue use if condition worsens or does not improve within 7 days.

Apply 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.

Apply 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.

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

There are no drug interactions associated with Camphor; Menthol; Methyl Salicylate products.

Bayer Muscle and Joint/BenGay Ultra Strength Topical Cream: 4-10-30%
Camphor, Menthol, Methyl Salicylate/MCM/Salonpas Topical Film: 3.1-6-10%, 96-76.8-57.6mg
Fordagel/Neuracin/Neuroxa/RealLief/Salonpas/ValleGel Prep Topical Gel: 3.1-10-15%, 4-10-30%
Salonpas Transdermal Film: 3.1-6-10%

4 applications/day.

4 applications/day.

4 applications/day.

12 years: 4 applications/day.
3 to 11 years: 4 applications/day of camphor 5%, menthol 16%, and methyl salicylate 15% solution; safety and efficacy of other cream, gel, patch, or solution have not been established.
1 to 3 years: Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Camphor is an irritant rubefacient, acting locally on the skin and mucous membranes to induce hyperemia and feelings of comfort and warmth, with sensations of coolness when its vapors are inhaled. Subjective relief of pain is obtained by an indirect counter irritation analgesic effect, representing a masking of moderate to severe deeper visceral pain by a milder pain arising from skin of the same segmented central nervous system level. 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.

Camphor; menthol; methyl salicylate is administered topically to the skin.
 
Affected cytochrome P450 isoenzymes and drug transporters: none

Camphor is highly lipophilic. It is rapidly absorbed across mucous membranes and has a large volume of distribution. It is oxidized to camphorol, which is conjugated in the liver with glucuronide. Active metabolites are stored in fat deposits and slowly cleared. Most camphor is excreted in the urine. Limited pharmacokinetic study has been conducted with cutaneous camphor; 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 camphor, menthol, and methyl salicylate systemic exposure in all study patients. Average maximum camphor plasma concentrations of 13.5 +/- 4.8 ng/mL, 26.8 +/- 17.2 ng/mL, and 41 +/- 5.8 ng/mL were measured after the use of 93.6 mg, 187.2 mg, and 374.4 mg of camphor; 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, and 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. Camphor, menthol, and methyl salicylate were no longer detectable at 8 to 12 hours after patch removal after the use of 93.6 mg of camphor, 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 camphor terminal half-life of 4 to 8 hours, 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.

Do not use camphor; 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.