OTC Transdermal Analgesic Patches in Pain Management

US Pharm. 2019;44(3):15-21.

ABSTRACT: OTC topical analgesic patches offer both convenience and consistent drug administration. Among the active ingredients available in these products are lidocaine, capsaicin, methyl salicylate, and menthol. There is a paucity of studies about the efficacy and safety of these medications. Studies that are available are often of poor quality. While generally considered safe when used according to product labeling, these medications can also be associated with adverse effects. Pharmacists need to be familiar with the available evidence regarding the use of these products in order to help patients safely self-medicate.

According to the latest report from the CDC, 20.4% of adults in the United States experience chronic pain.¹ Among the therapeutic options for the management of pain are OTC or nonprescription topical analgesic patches. In the February 1983 Federal Register, the FDA published (48 FR 5852), the tentative final monograph on OTC external analgesic drug products, which included patch, plaster, and poultice dosage forms. In July 2003, the FDA reopened the administrative record for the rulemaking for OTC external analgesic to include more recent data on these medications.²

Patches offer advantages over oral analgesic medications (TABLE 1).^3-6 However, drawbacks to the use of topical analgesics exist, including local irritation or skin sensitization; interindividual variability of skin properties that can affect absorption (e.g., adult vs. pediatric patients); limited availability of medications that can be delivered via this route of administration; inappropriateness of the topical route of administration for patients with decreased peripheral blood flow (e.g., shock); and cost.^3,6 

Another caveat is that some transdermal products contain metallic backings, which can lead to excessive burns and local tissue damage if the patch is not removed prior to undergoing an MRI scan.⁴ Similarly, reports of severe burns have occurred when these products are used in conjunction with a heat source such as a heating pad or sauna or when the patch has been positioned over an implantable cardioverter defibrillator.^7,8 In 2012, the FDA issued a drug-safety communication stating that rare cases of serious burns (including second- and third-degree burns) have occurred with the use of OTC topical muscle and joint pain relievers. This problem was seen particularly with the use of products containing menthol as the single active ingredient or products containing both menthol and methyl salicylate (MS), in concentrations greater than 3% menthol and 10% MS (see TABLE 2).⁹ Few cases were described involving the use of capsaicin-containing products. Healthcare professionals should counsel patients about how to use these products appropriately, including discussing the risk of serious burns.⁹

These medications can also cause acute toxicity in children even when ingested in small amounts.¹⁰ The barrier function of the skin is incomplete in premature infants, putting them at increased risk from dermal exposure.¹¹ Medicated patches may retain up to 95% of the initial total amount of drug, even after the duration of use has passed, which can pose a risk to curious, unattended children.¹¹

A search of the National Institute of Health’s website, Daily Med, revealed the following active ingredients in topical OTC analgesic patches: lidocaine (up to 4%), capsaicin or capsicum (0.002%-3.75%), MS (0.04%-20%), menthol (0.2%-16%), camphor (0.13%-11%), wintergreen oil (0.5%), eucalyptus oil, l-menthol (1.25%-3%), peppermint (0.3%-1.95%), glycol salicylate (4.66%), nonivamide (0.01%), allantoin (2%), zinc oxide (18.77%), sulfur, petrolatum (30%), and tocopherol acetate (TABLE 2).¹² Among these agents, menthol, MS, wintergreen oil, camphor, and capsaicin are topical counterirritants. Counterirritants are medications that cause irritation and reddening of the skin that distract from more deep-seated pain.^13,14

Topical counterirritants are classified into four groups based on their properties: (1) rubefacients or those drugs that increase blood flow, such as MS; (2) those that produce a cooling sensation, such as camphor and menthol; (3) those that cause vasodilation, such as histamine dihydrochloride; and (4) those that incite irritation without an increase in blood flow, e.g., capsaicin.¹⁴ Trials involving rubefacients/counterirritants are fraught with difficulties, such as the inability to completely mask the drugs’ effects due to their irritant properties. Most trials involve few numbers of patients, are of short duration (i.e., longest trial 28 days; most were 14 days), and have questionable quality and validity.¹⁵

This article will focus on the OTC active ingredients that are commonly found in topical analgesic patches. Despite their prevalent use, there is a lack of clinical evidence supporting the efficacy of these topical nonprescription analgesic products.

Lidocaine

Lidocaine is a local anesthetic that acts by blocking voltage-gated sodium channels within the neuronal cell membrane. These channels are both increased and dysfunctional in patients with peripheral nerve damage, leading to chronic neuropathic pain. Lidocaine binds to the defective receptors, thereby blocking abnormal ectopic discharges. This results in the interruption of the transmission of the pain signal.¹⁶ These damaged nerve cells can lead to the sprouting of abnormal nerve fibers, which may lead to hyperirritability. Lidocaine is believed to decrease sympathetic nerve sprouting.¹⁶ It may also slow peripheral nociceptor sensitization and central hyperexcitability.⁶

Most studies involving the use of lidocaine for pain management have been conducted using the 5% lidocaine patch (Lidoderm, Endo Pharmaceuticals, Inc.), which is available only by prescription. Data for this more potent lidocaine preparation are conflicting. Even for this higher strength lidocaine patch, there is a lack of efficacy data from head-to-head comparison trials for neuropathic pain. The trials that are available are small and of limited quality.¹⁷

Most OTC patches contain 4% lidocaine. Even when the 5% patch is utilized, systemic absorption is low.³ Oni and colleagues compared the blood levels achievable from five commercially available lidocaine preparations (three OTC lidocaine 4% patches, two prescription lidocaine 5% patches, one compounded lidocaine patch) and found that there were significant interindividual differences.¹⁸ The OTC preparations produced the highest lidocaine and metabolite, monoethylglycinexylidide (MEGX), levels compared with the other preparations. The authors warned that although topical lidocaine products are safe, some patients may experience unpredictably high absorption, leading to elevated blood levels.¹⁸ This is important since lidocaine has both antiarrhythmic and proarrhythmic properties.¹⁹ Toxicity occurs at lidocaine levels greater than 5 mcg/mL.²⁰

Castro and Dent conducted a double-blind placebo-controlled trial involving 87 patients with back pain or arthritis who were administered either an OTC transdermal patch containing 3.6% lidocaine and 1.25% menthol, a 5% prescription lidocaine transdermal patch, or a placebo patch. The OTC product was found to be noninferior to the prescription lidocaine transdermal patch in terms of efficacy, side effects, and impact on quality of life. It was also found to be better than the placebo patch with respect to efficacy and the patient’s ability to engage in general activity and work. Both lidocaine patches were manufactured by JAR Laboratories, which partially funded this research.²¹

The treatment duration for OTC lidocaine patches is up to 7 days. The patches can be used every 6 to 8 hours as needed, not to exceed three applications within 24 hours.¹⁴

Due to their good safety profile, low incidence of systemic effects, and lack of drug-drug interactions during topical exposure, lidocaine patches may be especially useful for the management of focal neuropathic pain (with or without allodynia [heightened pain sensitivity to otherwise innocuous stimulation]) in older adults.⁶

Capsaicin or Capsicum Extract

Capsaicin is a resin derived from hot chili peppers of the Capsicum family. Commercially available preparations contain either capsaicin or capsicum oleoresin.¹⁴ It is used topically to treat both nociceptive and neuropathic pain.⁵

Capsaicin is thought to work via several mechanisms of action. Capsaicin interacts with sensory afferents via vanilloid receptors, which are cation channels from the transient receptor potential (TRP) family.²² There are at least 28 different mammalian TRP membrane channels, which can be activated by heat, cold, pain, tissue osmolarity, oxidative stress, lipids, intracellular calcium concentrations, and topical counterirritants.²² Vanilloid receptors (TRPV1) are activated by warmth and also by compounds that elicit sensations of heat.^6,23 TRPV3, TRPV4, TRPM (melastatin) 2, TRPM4, and TRPM5 are also activated by heat, whereas TRPA (ankyrin) 1 and TRPM8 detect cool temperatures.²² Chronic exposure to capsaicin initially stimulates TRPV1 but eventually desensitizes these channels. Capsaicin depletes substance P at nerve afferent endings and temporarily reduces the density of nerve fibers in the skin.^6,23 It also induces cellular degeneration of unmyelinated C fiber afferents; activation of neuronal proteases; interference of axonal transport; and a reduction in the absolute number of C fibers without affecting the number of myelinated fibers.²⁴

Due to capsaicin’s ability to initiate degeneration of cutaneous autonomic nerve fibers, caution is advised with the use of topical capsaicin in patients at risk of skin ulceration.²⁵ It can take about 6 weeks for the return of nociception following the discontinuation of capsaicin therapy.²⁶

Trials involving capsaicin are difficult to conduct because it is nearly impossible to disguise its unique burning sensation. A systematic review of topical capsaicin for the treatment of chronic pain found that while topical capsaicin was better than placebo for the management of neuropathic and musculoskeletal pain, its efficacy was moderate to poor. Nonetheless, the investigators recommended that topical capsaicin may be useful as an adjunct or as sole therapy for patients who are unresponsive or intolerant to other treatment modalities.²⁷ Patients in this systematic review were primarily receiving OTC capsaicin cream. No details are provided about the capsaicin patch employed.

An early phase 2, multicenter, randomized, semi–double-blind controlled study comparing the efficacy and safety of 0.625% and 1.25% capsaicin patches to 0.075% capsaicin cream or placebo patches in peripheral neuropathic pain found that only the 0.625%-strength patch and the cream produced a statistically significant improvement in pain after 6 weeks. The 1.25% patch was not effective in relieving pain. Over 90% of patients on the 0.625% patch reported improvement in pain, although this relief was only moderate at best. Minor skin irritation occurred in 47% of patients. The study, although promising, was faulted because of its small sample size (only 60 subjects initially enrolled) and a high dropout rate (23%).²⁸

Capsaicin patches 0.1% or 0.25% were not found to be effective in the management of myofascial pain.^29,30

Beside the stinging, burning, and erythematous reaction that is associated with capsaicin therapy, inhalation of the drug can produce respiratory irritation and cough. Due to its half-life of about 2 hours, the four-times-a-day application of capsaicin cream makes this form of therapy inconvenient; the capsaicin patch helps to ameliorate this problem.^6,28

Methyl Salicylate

MS is also referred to as oil of wintergreen, sweet birch oil, gaultheria oil, teaberry oil, and mountain tea.¹⁴ Medicinally, MS has been used an analgesic, an anti-inflammatory agent, a rubefacient/counterirritant, a fragrance in health and beauty aids, and a penetration enhancer for other topical medications.³¹ It possesses keratolytic, bacteriostatic, fungicidal, and photoprotective properties.³² It has both vasodilatory and thermogenic action, increasing local blood flow and skin temperature, respectively. It is by this mechanism that MS acts as a rubefacient.³¹

A systematic review found that while topically applied rubefacients containing salicylates may be effective for acute pain (NNT 2.1 for at least 50% pain relief), counterirritants have moderate to poor efficacy for musculoskeletal and arthritic pain (NNT 5.3).¹⁵ A Cochrane Database Systematic Review showed that that there is a lack of evidence to support the use of topical salicylate-containing rubefacients for the treatment of acute injuries (mostly sprains, strains, and acute low back pain) or chronic conditions (mostly osteoarthritis, bursitis, and chronic back pain).³³

A small placebo-controlled trial (N = 30) showed that both 10% MS/3% l-menthol patches and 5% lidocaine patches are effective in relieving myofascial pain. Whereas the lidocaine patch was associated with a slightly better reduction in pain intensity and a small increase in the degree of mouth opening and quality of life, the MS/menthol patch was more beneficial in increasing lateral movement compared with its competitors.³⁴ However, this study was of poor quality; demographic data of the study population were not even provided.

OTC topical products may contain up to 20% MS. The drug is lipophilic. There is appreciable dermal absorption via direct local tissue penetration when MS is applied topically.^35-37

Acute salicylate poisoning has occurred following dermal application of MS. Exercise and heat exposure (i.e., use of a heating pad, sauna, hot shower) increase percutaneous absorption. Absorption is also directly proportional to the amount of skin in contact with the drug. When coadministered, phenolic compounds such as camphor or menthol may damage the skin’s protective capacity and enhance the skin penetration of MS. Topical exposure of salicylates has been associated with fatalities from salicylism, especially in children.^32,38

MS demonstrates zero-order kinetics following dermal absorption.³¹ Topical MS also inhibits both central and peripheral prostaglandin synthesis.¹⁴ Similar to oral aspirin, topical MS can interact with oral warfarin, resulting in decreased platelet aggregation, prolongation of the international normalized ratio, and bleeding.^38,39  Because of its salicylate component, MS should not be given to children (over concern of Reye’s syndrome) or those who are allergic to aspirin.¹⁴

Severe urticaria, angioedema, and contact dermatitis have been reported with the use of MS.^38,40 Full-thickness skin and muscle necrosis has been reported with the use of combination MS and menthol products and the concomitant application of a heating pad.³⁸

Menthol

Menthol, which is a natural product from the peppermint plant, Mentha piperita, is a cyclic terpene alcohol.⁴¹ Menthol is metabolized via CYP 2A6.⁴¹ As opposed to MS, menthol has a cooling effect on the skin. However, this is temperature dependent with skin temperatures above 37°C producing feelings of warmth.²³ It is often used in combination with MS to produce a counterirritant effect.³¹

Menthol increases cutaneous blood flow. According to the gate control theory, menthol is thought to work by activating TRPM8 channels, which belong to a family of nonselective cation channels that open in response to cool temperatures (8-28°C). Activation of TRPM8 channels on sensory neurons of the trigeminal and dorsal root ganglia and on C (unmyelinated axons) and A (thinly myelinated axons) nociceptors reduce pain transmission.^23,42 Menthol acts as on TRPM8, TRP3, and TRPA1 channels. TRPV3 and TRPA1 are activated or inhibited by menthol.²³ TRPM8 receptors are expressed in neural and vascular cells. At warmer temperatures, menthol sensitizes TRPV3, and at cooler temperatures it activates TRPM8.²³  

Menthol also acts as a vasodilator by dose-dependently (up to a concentration of 4%) increasing blood flow in the microvasculature.⁴² At concentrations below 1%, menthol acts as an anesthetic; however, at concentrations greater than 1.25%, it functions as a counterirritant.¹⁴ This vasodilatory effect of menthol is attributed to nitric oxide, endothelium-derived hyperpolarizing factors, and sensory nerves.⁴² Additionally, menthol activates GABA_A and blocks voltage-gate sodium and calcium channels in the dorsal horn and preferentially binds to inactivated channels, producing a central analgesic effect.⁴³

Although concentrations of menthol peak in the skin within 30 minutes, vasoactive effects are seen within 15 minutes. The effects disappear after 45 minutes with the drug cleared from the skin by 60 minutes.⁴² Menthol acts as a penetration enhancer for other compounds.^23,41,44

There is a paucity of studies evaluating menthol patches. Icy Hot patches, which contain 5% menthol, were compared with ThermaCare HeatWraps with respect to effects on skin and deep-tissue temperature in healthy volunteers. The heat wraps increased skin temperature by 25.8% and underlying muscle tissue temperature by 7.7%, whereas the menthol patches decreased skin temperature by 5.4% and muscle temperature by 3.8%. Further, whereas ThermaCare HeatWraps caused a 109.7% and 148.5% increase in skin blood flow and in muscle blood flow, respectively, Icy Hot patches caused a reduction in both skin and muscle blood flow (16.7% and 7%, respectively). However, since this was not an efficacy study, the clinical implications of these findings for patients with pain are unclear.²²

Nonpatch dermal exposure to menthol has shown that menthol may attenuate cold allodynia (i.e., pain induced by normally innocuous cool stimuli) in patients with peripheral and central neuropathic pain.⁴⁵ 

Combination Methyl Salicylate and Menthol

There are very limited published clinical data on the use of MS in conjunction with menthol, despite the widespread use of this analgesic combination. In a placebo-controlled trial, an occlusive topical patch containing 10% MS and 3% l-menthol (Salonpas/Hisamitsu America) was found to produce significantly greater pain relief (40%) after initial application compared with placebo in adults with mild-to-moderate muscle strain. Pain relief was present during the 8 hours in which the patch was in contact with the skin; after removal of the patch, pain control dissipated. Salonpas patches are the first and only topically applied medication to receive FDA approval for the temporary relief of mild-to-moderate aches and pains of muscles and joints associated with arthritis, back pain, strains, bruises, and sprains.¹⁴ Side effects in the active treatment group were comparable with those seen in patients who had received the placebo patch.⁴⁶ 

Conclusion

Despite their widespread use, studies involving OTC analgesic patches are both lacking and are of poor quality. These trials, when available, vary in design and typically include small numbers of patients. For rubefacients, such as MS, there is a paucity of information supporting their use in either acute or chronic pain. There is conflicting evidence for the benefit of low-dose capsaicin in treating chronic neuropathic pain, but it may be useful for low back pain and osteoarthritis of the knees and hands. Pharmacists need to be familiar with both the efficacy data and adverse effects associated with topical OTC analgesics in order to help ensure their safe use, especially since these medications are often used as first-line therapy in the management of acute and chronic pain.

REFERENCES

1. Dahlhamer J, Lucas J, Zelaya, C, et al. Prevalence of chronic pain and high-impact chronic pain among adults — United States, 2016. MMWR Morb Mortal Wkly Rep. 2018;67(36):1001-1006. http://dx.doi.org/10.15585/mmwr.mm6736a2. Accessed December 20, 2018.
2. Department of Health and Human Services. U.S. Food and Drug Administration. External Analgesic Drug Products for Over-the-Counter Human Use; Reopening of the Administrative Record and Amendment of Tentative Final Monograph Federal Register/Vol. 68, No. 137 / Thursday, July 17, 2003 / Proposed Rules. 42324-42327. 21 CFR Part 348 [Docket No. 78N–0301] RIN 0910–AA01 www.govinfo.gov/content/pkg/FR-2003-07-17/pdf/03-17934.pdf. Accessed November 29, 2018.
3. Bajaj S, Whiteman A, Brandner B. Transdermal drug delivery in pain management. Continuing Education in Anaesth Crit Care Pain. 2011;11(2):39-43. https://doi.org/10.1093/bjaceaccp/mkq054. Accessed December 15, 2018.
4. Ball AM, Smith KM. Optimizing transdermal drug therapy. Am J Health-Syst Pharm. 2008;65:1337-1346.
5. Parhi R, Suresh P, Mondal S, et al. Novel penetration enhancers for skin applications: a review. Curr Drug Deliv. 2012;9:219-230.
6. Jorge LL, Feres CC, Teles VEP. Topical preparations for pain relief: efficacy and patient adherence. J Pain Res. 2010;4:11-24.
7. Rivard SC, Brelsford MA, Gibbs NF. Over-the-counter topical musculoskeletal pain relievers used with a heat source: a dangerous combination. Cutis. 2017;100(5):E22-E24.
8. Brown MR, Denman R, Platts D. Analgesic patches and defibrillators: a cautionary tale. Europace. 2009;11(11):1552-1553.
9. U.S. Food and Drug Administration. FDA Drug Safety Communication: Rare cases of serious burns with the use of over-the-counter topical muscle and joint pain relievers. September 13, 2012. www.fda.gov/Drugs/DrugSafety/ucm318858.htm. Accessed December 20, 2018 and February 9, 2019.
10. Parekh D, Miller MA, Borys D. Transdermal patch medication delivery systems and pediatric poisonings, 2002-2006. Clin Pediatr. 2008;47(7):659-663.
11. Pastore MN, Kalia YN, Horstmann M, et al. Transdermal patches: history, development and pharmacology. Br J Pharmacol. 2015;172:2179-2209.
12. National Institutes of Health. U.S. National Library of Medicine.  Daily Med website. Search “patch AND OTC AND (pain OR analgesia OR analgesic).” https://dailymed.nlm.nih.gov/dailymed/search.cfm. Accessed December 10, 2018 and February 9, 2019.
13. Topical rubefacients. Drugs.com. www.drugs.com/drug-class/topical-rubefacient.html. Accessed December 15, 2018.
14. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care. 19th ed. Krinsky DL, Ferreri SP, Hemstreet B, et al, eds. Olenak Julie L. Musculoskeletal injuries and disorders. Washington, DC: American Pharmacists Association; 2018:chap 7.
15. Mason L, Moore RA, Edwards JE, et al. Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. BMJ. 2004;328(7446):995.
|16. Zink KA, Mayberry JC, Peck EG, et al. Lidocaine patches reduce pain in trauma patients with rib fractures. Am Surg. 2011;77(4):438-442.
17. Wolff RF, Bala MM, Westwood M, et al. 5% lidocaine-medicated plaster vs other relevant interventions and placebo for post-herpetic neuralgia (PHN): a systematic review. Acta Neurol Scand. 2011;123:295-309.
18. Oni G, Brown S, Kenkel J. Comparison of five commonly-available lidocaine-containing topical anesthetics and their effect on serum levels of lidocaine and its metabolite monoethylglycinexylidide (MEGX). Aesthetic Surgery J. 2012;32(4):495-503.
19. Heist EK, Ruskin JN. Drug-induced arrhythmia. Circulation. 2010;122(14):1426-1435.
20. Mir F. Lidocaine level. https://emedicine.medscape.com/article/2090152-overview. December 5, 2013. Accessed December 10, 2018.
21. Castro E, Dent D. A comparison of transdermal over-the-counter lidocaine 3.6% menthol 1.25%, Rx lidocaine 5% and placebo for back pain and arthritis. Pain Manag. 2017;7(6):489-498.
22. Petrofsky JS, Laymon M, Berk L, et al. Effect of ThermaCare HeatWraps and Icy Hot cream/patches on skin and quadriceps muscle temperature and blood flow. J Chiropr Med. 2016;15(1):9-18.
23. Macpherson LJ, Hwang SW, Miyamoto T, et al. More than cool: promiscuous relationships of menthol and other sensory compounds. Mol Cell Neurosci. 2006;32:335-343.
24. Kamkaen N, Samee W, Nimkulrut S, et al. Development of new formulation and study on release of capsaicin from transdermal patch. J Health Res. 2010;24(4):151-154.
25. Gibbons CH, Wang N, Freeman R. Capsaicin induces degeneration of cutaneous autonomic nerve fibers. Ann Neurol. 2010;68(6):888-898.
26. Papoiu ADP, Yosipovitch G. Topical capsaicin. The fire of a ‘hot’ medicine is reignited. Expert Opin Pharmacother. 2010;11(8):1359-1371.
27. Mason L, Moore RA, Derry S, et al. Systematic review of topical capsaicin for the treatment of chronic pain. BMJ. 2004;328(7446):991.
28. Moon JY, Lee PB, Kim YC, et al. Efficacy and safety of 0.625% and 1.25% capsaicin patch in peripheral neuropathic pain: multi-center, randomized, and semi-double blind controlled study. Pain Physician. 2017;20(2):27-35.
29. Cho JH, Brodsky M, Kim EJ, et al. Efficacy of a 0.1% capsaicin hydrogel patch for myofascial neck pain: a double-blinded randomized trial. Pain Med. 2012;13:965-970.
30. Kim DH, Yoon KB, Park SH, et al. Comparison of NSAID patch given as monotherapy and NSAID patch in combination with transcutaneous electrical nerve stimulation, a heating pad, or topical capsaicin in the treatment of patients with myofascial pain syndrome of the upper trapezius: a pilot study. Pain Med. 2014;15:2128-2138.
31. Anderson A, McConville A, Fanthorpe L, et al. Salicylate poisoning potential of topical pain relief agents: from age old remedies to engineered smart patches. Medicines. 2017;4(3).
32. Madan RK, Levitt J. A review of toxicity from topical salicylic acid preparations. J Am Acad Dermatol. 2014;70(4):788-792.
33. Derry S, Matthews PR, Wiffen PJ, et al. Salicylate-containing rubefacients for acute and chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2014;(11):CD007403. Accessed February 7, 2019.
34. El-Sholkamy MA, Nasr TA. Evaluation of the efficacy of two different patches for the management of myofascial pain: a randomized controlled clinical study. Egyptian Dental J. 2018;64:177.
35. Morra P, Bartle WR, Walker SE, et al. Serum concentrations of salicylic acid following topically applied salicylate derivatives. Ann Pharmacother. 1996;30(9):935-940.
36. Cross SE, Anderson C, Thompson MJ, et al. Is there tissue penetration after application of topical salicylate formulations? Lancet. 1997;350(9078):636.
37. Cross SE, Anderson C, Roberts MS. Topical penetration of commercial salicylate esters and salts using human isolated skin and clinical microdialysis studies. Br J Clin Pharmacol. 1998;46:29-35.
38. Chan TYK. Potential dangers from topical preparations containing methyl salicylate. Hum Experiment Toxicol. 1996;15:747-750.
39. Tanen DA, Danish DC, Reardon JM, et al. Comparison of oral aspirin versus topical applied methyl salicylate for platelet inhibition. Ann Pharmacother. 2008;42:1396-1401.
40. Oiso N, Fukai K, Ishii M. Allergic contact dermatitis due to methyl salicylate in a compress. Contact Dermatitis. 2004;51:34-35.
41. Farco JA, Grundmann O. Menthol—pharmacology of an important naturally medicinal “cool.” Mini Rev Med Chem. 2013;13:124-131.
42. Craighead DH, McCartney NB, Tumlinson JH, et al. Mechanisms and time course of menthol-induced cutaneous vasodilation. Microvasc Res. 2017;110:42-47.
43. Pan R, Tian Y, Gao R, et al. Central mechanisms of menthol-induced analgesia. J Pharmacol Exp Ther. 2012;343:661-672.
44. Abu HMKM, Iimura N, Nabekura T, et al. Enhanced skin permeation of salicylate by ion-pair formation in non-aqueous vehicle and further enhancement by ethanol and l-menthol. Chem Pharm Bull. 2006;54(4):481-484.
45. Wasner G, Naleschinski D, Binder A, et al. The effect of menthol on cold allodynia in patients with neuropathic pain. Pain Med. 2008;9(3):354-358.
46. Higashi Y, Kiuchi T, Furuta K. Efficacy and safety profile of a topical methyl salicylate and menthol patch in adult patients with mild to moderate muscle strain: a randomized, double-blind, parallel-group, placebo-controlled, multicenter study. Clin Ther. 2010;32:34-43.

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