P-088 - (Poster #88) Topical menthol for pain relief in humans: a scoping review

Pain is a leading cause of disability worldwide, and chronic conditions, neuropathic pain, and ‘everyday’ pains impact millions. Unfortunately, systemically delivered pharmacological analgesic treatments come with adverse effects, the possibility for misuse and abuse, limitations in administration (such as restrictions in oral delivery for those unable to swallow tablets, capsules, etc.), and potential drug-drug interactions. A potential solution is the use of topical analgesics, which limits systematic exposure by delivering the active agent locally.

Menthol is an organic compound derived from peppermint or other mint plants. It has a long history of use as a topical analgesic in the form of peppermint oil, and its well-established use has been documented; there are currently no reported interactions of topical peppermint oil with other medicinal products and other forms of interaction. Menthol is widely used in over-the-counter formulations due to its cooling and potential analgesic properties, as well as its relatively low cost. To date, dozens of studies have been conducted to assess the analgesic efficacy of menthol, across a variety of pain conditions, including tension headaches, migraine, dysmenorrhea, neuropathic pain, musculoskeletal pain, and sports injuries. Currently there are no systematically conducted reviews assessing the analgesic efficacy of topical menthol.


Purpose/Objectives:

Our objective was to identify all peer-reviewed and published clinical evidence assessing the analgesic efficacy of topically applied menthol. Our primary aim was to assess whether there is evidence for an analgesic effect. Additionally, we documented any recorded adverse events in the identified efficacy studies. Lastly, we aimed to get an overall perspective on the methodological and clinical heterogeneity in the published clinical literature, to inform the potential for a future systematic review and meta-analysis on the analgesic efficacy of topical menthol. Our research addressed the question: What is the clinical evidence that the topical application of menthol to the skin provides effective pain relief in humans?



Methods:

The eligibility criteria were: humans as population, topical application of menthol to the skin as intervention, any comparator, and a measure of pain relief as outcome.

Four electronic databases were searched on 8-April-2024 (MEDLINE, Embase, Cochrane Library, Web of Science) for relevant peer-reviewed studies, with no language or time restrictions. All search strategies were independently peer-reviewed. Additional information sources included reference lists of relevant reviews identified during screening, citation searching of all included studies, and studies known to the review authors. Screening was carried out by two independent reviewers and disagreements settled by discussion between both. Data extraction was performed by one reviewer, then verified by a second reviewer, with disagreements settled by discussion. A protocol was developed according to PRISMA-P guidelines and registered on the Open Science Framework on 24-May-2024, prior to data extraction: https://doi.org/10.17605/OSF.IO/QATKH.

Since the review was a scoping review, no formal risk of bias assessment was conducted, however, the absence or presence of pre-registration was documented for each study. Topical menthol analgesic efficacy was summarised using vote counting on the direction and the statistical significance of the effect. Data were synthesised via tabulation, bar plots, raincloud plots, and a global map.



Results:

The primary research outcome was the efficacy of menthol applied topically to skin for the relief of pain. Of the 5,229 reviews screened, 31 relevant publications were identified: 13 parallel-group trials, 7 cross-over trials, 9 pre-post studies, and 2 case reports. Most of the research has been conducted in the European Region with most sample sizes including between 1 and 181 participants. Most studies included mixed-sex populations, however ~42% of the studies were conducted on exclusively male or female populations.

Nine different pain scales were used to quantify pain and analgesic efficacy, with visual analogue scale (VAS) and numeric rating scales (NRS) being used in 23/31 studies. The type of pain studied was either pre-existing pain, or pain induced as part of the study, generally through exercise.

Most studies (24/31 studies) examined the analgesic efficacy of topical menthol by using inactive comparators, while the remaining used active comparators to compare menthol efficacy to other topical analgesics. Nine studies involved co-interventions to treat pre-existing conditions or for pain relief. Gels were the most common pharmaceutical form of menthol used in the reviewed studies, followed by solutions, creams, extracts, and finely ground peppermint, and the concentration of menthol used ranged between 1-10% for analgesic purposes, with only two studies using higher concentrations (40%) to achieve analgesic effects for specific pain types.

Overall, using vote counting on effect direction, the literature suggests a positive effect that topical menthol has analgesic properties: 87% positive analgesic effect, 10% negative effect, 3% unspecified effect.

A total of 12/31 studies reported adverse effects, with seven of the 12 studies explicitly reporting no adverse effects, while five reported some adverse effects, including stinging, burning or itching sensations at site of application; drying and reddening/erythema of skin at site of application; aggravation of pain; lacrimation when applied to forehead.

 


Some risk of bias concerns were raised on cross-over and parallel group studies, based on a single bias domain in the Cochrane RoB 2 tool. Only 6/31 studies had a pre-registration, but none provided statistical analysis plan details as part of the pre-registration.

Conclusions/Implications for future research and/or clinical care:

Across the studies, high methodological and clinical heterogeneity were observed, as well as a lack of detailed statistical reporting and a potential for high risk of bias. Several methodological limitations were noted across study designs, with case reports having limited capacity to provide inferences across larger populations, and pre-post designs identified to be sub-optimal experimental design.

Although more comprehensive meta-analyses could be conducted, potential barriers to conducting a systematic review or meta-analysis on this topic include a high degree of heterogeneity, limiting data synthesis; methodological limitations to some of the studies; and the sheer breath and thus clinical heterogeneity of the suggested use cases. As an alternative, this review provides an initial overview of the direction of effects, and a provides a significant body of evidence to suggest a relatively consistent positive effect that topical menthol has analgesic properties. Future large-scale, high-quality prospective RCT studies can further strengthen the results of this review.