Lidocaine; menthol is a combination of a local anesthetic and a topical analgesic indicated for the temporary relief of minor aches and pains of muscles and joints, such as backache, low back pain, arthritis, neuralgia, muscle strains, bruises, cramps, and sprains. It can also be used for the temporary relief of pain and itching due to minor cuts, sunburns, scrapes, burns, insect bites and minor skin irritations. The lidocaine 5% patch may be used in combination with menthol for the treatment of postherpetic neuralgia. Lidocaine is a topical anesthetic and stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses, thereby effecting local anesthetic action. Menthol has local anesthetic and counterirritant qualities. It also acts as a weak kappa (k) opioid receptor agonist. Menthol chemically triggers the cold-sensitive TRPM-8 receptors in the skin, which are responsible for the well-documented cooling sensation that occurs when applied to the skin. Menthol's analgesic properties are not fully understood; however, they are mediated through a selective activation of k-opioid receptors. Menthol also blocks voltage-sensitive sodium channels, reducing neural activity that may stimulate muscle tissue. The lidocaine; menthol combination products are available over the counter in a number of different formulations.
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
Topical Cream or Lotion:
-For external use only. Avoid contact with eyes.
-Do not apply to large areas, open wounds/cuts, or irritated, infected, blistered, or swollen skin. Avoid applying to skin folds.
-Do not use at the same time as other topical analgesics or anesthetics.
-Prior to application, clean and dry the affected area.
-Apply a thin layer of medication to the affected area.
-Do not apply external heat, such as a heating pad, or occlusive dressings/bandages to treated areas.
-After application, wash hands with soap and water.
Transdermal Patch Formulations
Dermal Patch (Lidocaine; Menthol Combination Patch):
-For external use only. Avoid contact with eyes, genitals, mouth, or other mucous membranes.
-If eye contact occurs, immediately wash out eye with water or saline; protect eye until sensations return.
-Do not apply to open wounds or damaged, infected, irritated, or swollen skin.
-Do not use at the same time as other topical analgesics or anesthetics. Do not use with external heat, such as a heating pad.
-Clean and dry the affected area. If affected area is smaller than the patch, some patches may be cut into a smaller size to fit the application site; consult package labeling to determine if the patch may be cut.
-Remove the clear plastic backing (protective film) and apply patch to the affected area. Patch should be removed after 12 hours of continuous use and remain off for at least 12 hours.
-After 12 hours or wear, remove patch and safely discard to keep away from children and pets.
Dermal Lidocaine 5% Patch (Elemar 5% Patch):
-Keep the patches in their sealed envelopes until immediately before use.
-After removing the patch from the protective envelope, immediately apply to intact skin to cover the most painful area. Do not expose the eyes.
-Patches may be cut into smaller sizes prior to removal of the release liner.
-Adherence of the patch may be affected by contact with water; advise patients to avoid activities such as bathing, swimming, or showering while wearing the patch.
-Wash hands after handling the patches. Fold the sticky side of used patches together, and dispose of in such a way as to prevent accidental exposure to children or pets.
Other Topical Formulations
Topical Gel:
-For external use only. Avoid contact with eyes, genitals, or other mucous membranes.
-If eye contact occurs, rinse thoroughly with water.
-Do not apply to large areas, open wounds/cuts, or blistered, irritated, infected, inflamed, or swollen skin. Avoid applying to skin folds.
-Do not use at the same time as other topical analgesics or anesthetics.
-Prior to application, clean and dry the affected area.
-Apply a thin layer of medication to the affected area.
-Do not apply external heat (e.g., heating pad, electric blanket) or occlusive dressings/bandages to treated areas.
-After application, wash hands with soap and water.
Topical Liquid:
-For external use only. Avoid contact with eyes.
-Do not apply to large areas, open wounds/cuts, or irritated, infected, blistered, or swollen skin. Avoid applying to skin folds.
-Do not use at the same time as other topical analgesics or anesthetics.
-Prior to application, clean and dry the affected area.
-Apply a thin layer of medication to the affected area.
-Do not apply external heat, such as a heating pad, or occlusive dressings/bandages to treated areas.
-After application, wash hands with soap and water.
Topical Spray:
-For external use only. Avoid contact with eyes or face.
-Do not apply to large areas, open wounds/cuts, or irritated, infected, blistered, or swollen skin. Avoid applying to skin folds.
-Do not use at the same time as other topical analgesics or anesthetics.
-Prior to application, clean and dry the affected area.
-Spray onto affected area.
-Do not apply external heat, such as a heating pad, or occlusive dressings/bandages to treated areas.
-Spray products may be flammable; avoid heat, flame, or smoking during and immediately following application.
Allergic and anaphylactoid reactions have been infrequently associated with lidocaine administration. Allergic reactions may manifest as cutaneous lesions, urticaria, edema, angioedema, bronchospasm, dermatitis, dyspnea, laryngospasm, pruritus, or anaphylactic shock. Allergic reactions may occur as a result of sensitivity either to local anesthetic agents or to other components in the formulation. The detection of sensitivity by skin testing is of questionable value.
Compared to injectable local anesthetics, lidocaine; menthol has a lower likelihood of systemic adverse reactions due to topical application and lower systemic absorption. To decrease the potential for elevated systemic lidocaine blood concentrations, avoid application of lidocaine patches to large areas or wearing the patches for extended time periods. If systemic effects occur, they are similar to those observed with other amide local anesthetics, including CNS excitation and/or depression. CNS manifestations may be characterized by lightheadedness (dizziness), anxiety (i.e., nervousness or apprehension), restlessness, euphoria, confusion, drowsiness, tinnitus, blurred vision or double vision, vomiting, metallic taste, dysgeusia, sensations of heat (hot flashes), cold or numbness, twitching, tremors, convulsions (seizures), unconsciousness, respiratory depression, and respiratory arrest. The excitatory manifestations may be very brief or may not occur at all, in which case the first manifestation of toxicity may be drowsiness merging into unconsciousness. Cardiovascular manifestations may include bradycardia, hypotension, and cardiovascular collapse leading to cardiac arrest. Asthenia, confusion, disorientation, dizziness, headache, hyperesthesia, hypoesthesia, lightheadedness, metallic taste, nausea, nervousness, pain exacerbation, paresthesias, somnolence, taste alteration, vomiting, visual disturbances (e.g., blurred vision), flushing, tinnitus, and tremor have been reported with postmarketing use of lidocaine; menthol.
Methemoglobinemia has been reported with local anesthetic use. Signs and symptoms of methemoglobinemia may occur immediately or may be delayed some hours after local anesthetic exposure and are characterized by cyanotic skin discoloration and abnormal coloration of the blood. Other symptoms may include headache, rapid heart rate, shortness of breath, dizziness, lightheadedness, and drowsiness. Since methemoglobin concentrations may continue to rise, immediately discontinue lidocaine to avoid serious central nervous system and cardiovascular adverse events including seizures, coma, arrhythmias, and death. Depending on the severity of symptoms, patients may require supportive care, such as oxygen therapy and hydration. More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
Application site reactions can occur during or immediately after treatment with topical lidocaine; menthol. The skin at the site of application may develop blisters, bruising, burning sensation, depigmentation or skin hypopigmentation, contact dermatitis, skin discoloration, edema, erythema, exfoliative dermatitis/exfoliation, skin irritation, papules, petechiae, pruritus, vesicles, or may be the locus of abnormal sensation. These reactions are generally mild and transient, resolving spontaneously within a few minutes to hours.
Lidocaine; menthol is contraindicated in patients with amide local anesthetic hypersensitivity or hypersensitivity to any component of the product.
Avoid ocular exposure of lidocaine; menthol, as severe eye irritation and a loss of protective reflexes allowing for corneal irritation and potential abrasion may occur. If eye contact occurs, immediately wash the eye with water or saline, and protect the eye until sensation returns.
Lidocaine; menthol is for topical administration to intact skin, it is not recommended for use on irritated, infected, blistered, or swollen skin (e.g., eczema, burns), open or puncture wounds, or skin abrasions. Application to broken, inflamed, or irritated skin could lead to increased absorption of lidocaine; menthol resulting in higher plasma concentrations and potential systemic toxicity. Additional risks for systemic toxicity include application to large surface areas, application to warm skin (e.g., after exercise or applying thermal heat wraps or heating pads), use of large amounts of lidocaine; menthol, or covering application site with an occlusive dressing (e.g., skin wraps, bandages). Prolonged use of topical anesthetics is not recommended.
Patients with severe hepatic disease, such as hepatitis or hepatic encephalopathy, are at greater risk of developing toxic plasma concentrations of lidocaine and menthol. No data are available on the pharmacokinetic parameters of topically administered lidocaine; menthol in patients with hepatic impairment. However, higher plasma concentrations of lidocaine could theoretically occur in the presence of hepatic impairment, as lidocaine and some of its metabolites are enzymatically converted in the liver. Following systemic administration, the half-life of lidocaine generally may be prolonged two-fold or more in patients with hepatic impairment. Lidocaine; menthol should be used with caution in acutely ill, debilitated, or geriatric patients.
There are no adequate and well-controlled studies of lidocaine; menthol use in pregnant women. Lidocaine; menthol should not be used in pregnancy unless absolutely needed and discussed with a health care provider. Reproductive studies conducted in rats with lidocaine doses up to 30 mg/kg have not demonstrated fetal harm; however, animal studies are not always predictive of human response. Consider the total dose contributed by all lidocaine formulations if lidocaine is used during labor or obstetric delivery.
The effect of lidocaine; menthol on the nursing infant has not been evaluated. Caution should be exercised when lidocaine; menthol is administered to a breast-feeding patient. Lidocaine is excreted in breast milk with a milk:plasma ratio of 0.4. Previous recommendations from the American Academy of Pediatrics list lidocaine as usually compatible with breast-feeding. 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 maternal drug exposure, health care providers are encouraged to report the adverse effect to the FDA.
Methemoglobinemia has been reported with local anesthetic use. Although all patients are at risk for methemoglobinemia, patients with glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), preexisting (congenital or idiopathic) methemoglobinemia, cardiac or pulmonary compromise (cardiac disease or pulmonary disease), neonates and infants younger than 6 months, and those with concurrent exposure to oxidizing agents or their metabolites are more susceptible to developing methemoglobinemia. Monitor such patients closely for signs and symptoms of methemoglobinemia if a local anesthetic must be used. Signs of methemoglobinemia may occur immediately or may be delayed hours after exposure. Immediately discontinue the local anesthetic to avoid serious central nervous system and cardiovascular adverse events, as methemoglobin concentrations may continue to rise. Patients may require supportive care such as oxygen therapy and hydration. More severe symptoms may require treatment with methylene blue, exchange transfusion, or hyperbaric oxygen.
To avoid accidental exposure and/or ingestion, advise patients and/or their caregivers to store and dispose of all lidocaine; menthol products out of the reach of any pediatric-age person and pets. It is important to note that whether new or used, lidocaine 5% patches contain a large amount of lidocaine (at least 665 mg post-use). Pediatric patients or pets may experience serious adverse reactions from unintended lidocaine exposure including chewing or ingesting a new or used lidocaine patch.
For the treatment of temporary relief of mild pain associated with arthritis, muscles (myalgia), joints (arthralgia), simple backache, muscle strains, and sprains.:
Topical dosage (AvaLin-RX, Icy Hot Max, LidAll; lidocaine 4%; menthol 1% medicated topical patch):
Adults: Apply 1 patch to the affected area of intact skin for up to 8 hours as needed. May apply 1 patch, as needed, up to 3 to 4 times per day. Do not apply more than 1 patch at a time. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Adolescents and Children 12 years and older: Apply 1 patch to the affected area of intact skin for up to 8 hours as needed. May apply 1 patch, as needed, up to 3 to 4 times per day. Do not apply more than 1 patch at a time. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Topical dosage (CVS Cold and Hot Patch, Walgreens Cool n' Heat Patch; lidocaine 4%; Menthol 1% topical patch):
Adults: Apply 1 patch to the affected area of intact skin as needed. Patch should be removed after 12 hours of continuous use and remain off for at least 12 hours. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Adolescents and Children 12 years and older: Apply 1 patch to the affected area of intact skin as needed. Patch should be removed after 12 hours of continuous use and remain off for at least 12 hours. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Topical dosage (Atendia; lidocaine 4% and menthol 3% patch):
Adults: Apply 1 patch to the affected area of intact skin 1 to 3 times daily as needed. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Topical dosage (K2K Patch, LidoMet-10 Patch, MenthoReal-10 Patch, ValleMent Flex Patch; lidocaine 4% and menthol 4% patch):
Adults: Apply 1 patch to the affected area of intact skin for up to 12 hours as needed. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Adolescents and Children 12 years and older: Apply 1 patch to the affected area of intact skin for up to 12 hours as needed. Do not use more than 1 patch at a time. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Topical dosage (Limencin, Terocin; lidocaine 4%; menthol 4% topical patch):
Adults: Apply 1 patch to the affected area of intact skin 1 to 2 times daily as needed. Do not use more than 1 patch at a time. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Adolescents and Children 12 years and older: Apply 1 patch to the affected area of intact skin 1 to 2 times daily as needed. Do not use more than 1 patch at a time. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Topical dosage (Relyyks; lidocaine 4% and menthol 5% patch):
Adults: Apply 1 patch to the affected area 1 to 2 times daily as needed.
Adolescents and Children 12 years and older: Apply 1 patch to the affected area 1 to 2 times daily as needed.
Topical dosage (Gen7T Plus Patch; lidocaine 3.5% and menthol 7% patch):
Adults: Apply 1 patch to the affected area of intact skin for up to 12 hours as needed. Do not use more than 1 patch at a time. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Adolescents and Children 12 years and older: Apply 1 patch to the affected area of intact skin for up to 12 hours as needed. Do not use more than 1 patch at a time. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Topical dosage (Lidothol Patch; lidocaine 4.5% and menthol 5% patch):
Adults: Apply 1 to 2 patches to the affected area of intact skin for up to 12 hours as needed. Maximum is 4 patches per 24 hours.
Adolescents and Children 12 years and older: Apply 1 to 2 patches to the affected area of intact skin for up to 12 hours as needed. Maximum is 4 patches per 24 hours.
Topical dosage (topical cream):
Adults: Apply a thin layer to the affected skin area every 6 to 8 hours as needed. Do not exceed 3 applications in a 24-hour period.
Children and Adolescents 12 years and older: Apply a thin layer to the affected skin area every 6 to 8 hours as needed. Do not exceed 3 applications in a 24-hour period.
Topical dosage (topical lotion and topical solution):
Adults: Apply to the affected skin area no more than 3 to 4 times daily as needed. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Children and Adolescents 12 years and older: Apply to the affected skin area no more than 3 to 4 times daily as needed. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Topical dosage (topical gel):
Adults: Apply to the affected area up to 4 times a day as needed. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Adolescents and Children 12 years and older: Apply to the affected area up to 4 times a day as needed. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Topical dosage (topical spray):
Adults: Spray onto the affected skin area every 6 to 8 hours as needed. Do not exceed 3 to 4 applications per day. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Adolescents and Childrens 12 years and older: Spray onto the affected skin area every 6 to 8 hours. Do not exceed 3 to 4 applications per day. Discontinue use and seek medical care if symptoms persist for more than 7 days.
For the treatment of temporary relief of pain and itching (pruritus) due to minor cuts, sunburn, minor scrapes, minor burns, insect bites or stings, and minor skin irritations:
Topical dosage (lidocaine 4%; menthol 4% topical spray):
Adults: Spray onto the affected skin area no more than 3 to 4 times daily as needed. Discontinue use and seek medical care if symptoms persist for more than 7 days.
Children and Adolescents 12 years and older: Spray onto the affected skin area no more than 3 to 4 times daily as needed. Discontinue use and seek medical care if symptoms persist for more than 7 days.
For the treatment of pain associated with postherpetic neuralgia:
Topical dosage (lidocaine 5% topical patch; menthol 6% gel, Elemar Patch):
Adults: Apply up to 3 lidocaine patches to intact skin to cover the most painful area for up to 12 hours in a 24-hour period. Patches may be cut into smaller sizes with scissors before removal of the release liner. Apply menthol gel to the affected area up to 4 times daily.
Maximum Dosage Limits:
-Adults
Topical cream, gel, lotion, solution, and spray: 3 to 4 applications per day. Topical lidocaine; menthol patch: 1 to 4 patches patch per day. Maximum dose varies by product. Topical lidocaine 5% patch: 3 patches per 24 hours.
-Geriatric
Topical cream, gel, lotion, solution, and spray: 3 to 4 applications per day. Topical lidocaine; menthol patch: 1 to 4 patches patch per day. Maximum dose varies by product. Topical lidocaine 5% patch: 3 patches per 24 hours.
-Adolescents
Topical cream, gel, lotion, solution, and spray: 3 to 4 applications per day. Topical lidocaine; menthol patch: 1 to 4 patches patch per day. Maximum dose varies by product. Safety and efficacy have not been established for the lidocaine 5% topical patch.
-Children
12 years or older: Topical cream, gel, lotion, solution, and spray: 3 to 4 applications per day. Topical lidocaine; menthol patch: 1 to 4 patches patch per day. Maximum dose varies by product. Safety and efficacy have not been established for the lidocaine 5% topical patch.
2 to 11 years: Safety and efficacy have not been established.
Younger than 2 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
Adapalene; Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Benzoyl Peroxide; Clindamycin: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Benzoyl Peroxide; Erythromycin: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Benzoyl Peroxide; Sulfur: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Calamine; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Clindamycin; Adapalene; Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Dibucaine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Ethyl Chloride: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Hydrocortisone; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Menthol; Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Pramoxine: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Pramoxine; Zinc Acetate: (Moderate) Caution is advised if combining local anesthetics. The toxic effects of local anesthetics are additive. A major cause of adverse reactions appears to be excessive plasma concentrations, which may be due to accidental intravascular administration, slow metabolic degradation, or overdosage. In addition to additive toxic effects, rare and sometimes fatal cases of methemoglobinemia have been reported with the use of topical or oromucosal benzocaine-containing products. Clinicians should closely monitor patients for the development of methemoglobinemia when a combination local anesthetic is used during a procedure. If a patient becomes cyanotic or if elevated methemoglobin concentrations are suspected, immediately institute treatment to counteract methemoglobinemia (such as administration of methylene blue) as oxygen delivery is ineffective throughout the body until the condition is reversed. Patients who are receiving other drugs that can cause methemoglobin formation, such as prilocaine, are at greater risk for developing methemoglobinemia.
Tretinoin; Benzoyl Peroxide: (Moderate) Concurrent use of benzoyl peroxide and topical anesthetics may decrease the efficacy of the anesthetic. In a clinical study, an estimated 75% increase in patient-reported, prick-induced pain was noted in areas treated with both 5% benzoyl peroxide and 6% benzocaine cream as compared to areas treated with 6% benzocaine cream alone. Investigators attributed the decreased anesthetic effect to a breakdown of the benzocaine molecule by either or both benzoyl peroxide or benzoyl peroxide-derived free radicals. It is recommended that the skin area that is to be topically anesthetized have no previous treatment with benzoyl peroxide or that the skin is thoroughly washed prior to the application of the anesthetic.
Lidocaine: Lidocaine is an amide-type local anesthetic agent and is suggested to stabilize neuronal membranes by inhibiting the ionic fluxes required for the initiation and conduction of impulses. Dermal analgesia is achieved because lidocaine is released into the epidermal and dermal layers of the skin, and it accumulates in the vicinity of the dermal pain receptors and nerve endings. Lidocaine produces its analgesic effects through non-selective blockade of the voltage-gated sodium channels, which decreases the rate of membrane depolarization, thereby increasing the threshold for electrical excitability. Another mechanism that may contribute to lidocaine's analgesic effects is the possible activation of irritant receptors, TRPV1 and TRPA1, on keratinocytes and immune cells. The penetration of lidocaine into intact skin after application is sufficient to produce an analgesic effect, but less than the amount necessary to produce a complete sensory block.
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. 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.
Lidocaine; menthol; is administered topically to the skin.
-Lidocaine: Lidocaine is extensively metabolized in the liver into 2 active compounds, monoethylglycinexylidide (MEGX) and glycinexylidide (GX), which possess 100% and 25% of the potency of lidocaine, respectively. The major metabolic pathway, sequential N-deethylation to MEGX and GX, is primarily mediated by CYP1A2 with a minor role of CYP3A4. It is not known if lidocaine is metabolized in the skin. Following application of lidocaine; menthol topical gel, approximately 70% of the lidocaine dose is bound to plasma proteins, primarily alpha-1-acid glycoprotein.
-Menthol: Menthol acts on the transient receptor potential melastatin-8 (TRPM8) receptor, which are expressed in vascular and neural cells. Menthol is metabolized by CYP2A6. Menthol is rapidly metabolized to polyols and hydroxy acids that are excreted in these forms or as glucuronide conjugates.
Affected cytochrome P450 isoenzymes and drug transporters: CYP1A2, CYP2A6, CYP3A4
Lidocaine is extensively metabolized in the liver into 2 active compounds, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). The major metabolic pathway, sequential N-deethylation to MEGX and GX, is primarily mediated by CYP1A2 with a minor role of CYP3A4. Menthol is metabolized by CYP2A6.
-Route-Specific Pharmacokinetics
Topical Route
Lidocaine: The rate and extent of absorption after topical administration is dependent on the concentration, total dose, site of application, and duration of exposure. After topical administration of 60 grams of 4% lidocaine cream to 400 cm2 of skin or 3 hours, the measured blood levels of lidocaine were 0.05 to 0.16 micrograms/mL; toxicity occurs at levels greater than 5 micrograms/mL. In 20 healthy individuals, the Cmax values were 130 nanograms/mL and 153.8 nanograms/mL after once daily application of 3 or 4 lidocaine 5% patches, respectively, for 3 days. When the 5% dermal patch is used as directed, only 3% +/- 2% of the dose applied is expected to be absorbed transcutaneously with very little systemic absorption. After application of patches over a 420 cm2 area of intact skin for 12 hours, the absorbed dose of lidocaine was 64 mg resulting in a Cmax of 0.13 mcg/mL. The lidocaine concentration does not increase with daily use in patients with normal renal function.
Menthol: Limited pharmacokinetic studies have 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. Percutaneous penetration has been shown to increase with increasing menthol concentrations. Further, local and systemic toxicity has been reported following use of large doses of menthol; methyl salicylate and heat; the same may be possible if used with occlusive dressings.