CLASSES
Combination Topical Nonsteroidal Anti-inflammatory Drugs (NSAIDs) and Counterirritants (selected)
DESCRIPTION
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
COMMON BRAND NAMES
Bayer Muscle and Joint, BenGay Ultra Strength, Fordagel, MCM, Neuracin, Neuroxa, Pain Relieving Rub, RealLief, Salonpas, ValleGel Prep
HOW SUPPLIED
Bayer Muscle and Joint/BenGay Ultra Strength Topical Cream: 4-10-30%
Camphor, Menthol, Methyl Salicylate/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%
DOSAGE & INDICATIONS
For the treatment of minor arthralgia or myalgia associated with arthritis, bruises, simple backaches, sprains, and strains.
Topical dosage (camphor 3.1% to 4%, menthol 10%, and methyl salicylate 15% to 30% cream or gel)
Adults
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.
Children and Adolescents 12 to 17 years
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.
Topical dosage (camphor 3.1%, menthol 6%, and methyl salicylate 10% patch)
Adults
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.
Children and Adolescents 12 to 17 years
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.
Topical dosage (camphor 5%, menthol 16%, and methyl salicylate 15% solution)
Adults
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.
Children and Adolescents 3 to 17 years
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.
MAXIMUM DOSAGE
Adults
4 applications/day.
Geriatric
4 applications/day.
Adolescents
4 applications/day.
Children
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.
Infants
Safety and efficacy have not been established.
Neonates
Safety and efficacy have not been established.
DOSING CONSIDERATIONS
Hepatic Impairment
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Renal Impairment
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
ADMINISTRATION
Topical Administration
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.
Transdermal Patch Formulations
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.
Other Topical Formulations
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.
STORAGE
Generic:
- Protect from direct sunlight
- Protect from moisture
- Store at controlled room temperature (between 68 and 77 degrees F)
Bayer Muscle and Joint:
- Store between 68 to 77 degrees F
BenGay Ultra Strength:
- Store between 68 to 77 degrees F
FLEXALL Plus:
- Storage information not listed
Fordagel:
- Store at controlled room temperature (between 68 and 77 degrees F)
MCM:
- Protect from direct sunlight
- Protect from moisture
Neuracin:
- Protect from heat
- Store between 68 to 77 degrees F
Neuroxa:
- Protect from heat
- Store at controlled room temperature (between 68 and 77 degrees F)
Pain Relieving Rub :
- Store between 68 to 77 degrees F
RealLief:
- Avoid exposure to heat
- Store at controlled room temperature (between 68 and 77 degrees F)
Salonpas:
- Avoid direct heat and sunlight
- Protect from moisture
- Store between 68 to 77 degrees F
ValleGel Prep:
- Protect from heat
- Store between 68 to 77 degrees F
CONTRAINDICATIONS / PRECAUTIONS
NSAID hypersensitivity, salicylate hypersensitivity
Do not use camphor; menthol; methyl salicylate in patients with salicylate hypersensitivity or NSAID hypersensitivity.
Ambient temperature increase, heating pad, ocular exposure, ophthalmic administration, skin abrasion, strenuous exercise, sunlight (UV) exposure
Camphor; 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, wrap, or cover the areas where camphor; menthol; methyl salicylate has been applied. Do not apply camphor; menthol; methyl salicylate to a skin abrasion, wounds, or damaged, broken, or irritated skin. Do not use camphor; menthol; methyl salicylate 1 hour before or within 30 minutes after a bath or shower. Advise patients using camphor; 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 camphor; menthol; methyl salicylate when sweating, such as during strenuous exercise or with an ambient temperature increase.
Anticoagulant therapy, coagulopathy, corticosteroid therapy, ethanol ingestion, geriatric, GI bleeding, peptic ulcer disease, tobacco smoking
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.
Cardiac disease, coronary artery bypass graft surgery (CABG), hypertension
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.
Potential for overdose or poisoning
Camphor ingestion is associated with potential for overdose or poisoning and serious adverse events, including death. Because alternative therapies exist for all indications for camphor therapy, a previous American Academy of Pediatrics (AAP) statement recommended consideration of other therapies that do not contain camphor.
Magnetic resonance imaging (MRI)
Because some transdermal systems (i.e., patches) contain aluminum or other metal components, advise patients to remove the camphor; 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.
Pregnancy
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.
Breast-feeding
Previous American Academy of Pediatrics recommendations suggest salicylates be used with caution during breast-feeding.
ADVERSE REACTIONS
Severe
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
Moderate
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
Mild
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
DRUG INTERACTIONS
There are no drug interactions associated with Camphor; Menthol; Methyl Salicylate products.
PREGNANCY AND LACTATION
Pregnancy
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.
MECHANISM OF ACTION
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.
PHARMACOKINETICS
Camphor; menthol; methyl salicylate is administered topically to the skin.
Affected cytochrome P450 isoenzymes and drug transporters: none
Topical Route
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.