Looking Back to Move Forward: The Current State of Research on the Clinical Applications of Camphor- and Menthol-Containing Agents

Topically applied compounds containing camphor and menthol have been used to alleviate pain, cold symptoms, and pruritus, historically predominantly in East Asia. Being not studied well, they are less recognized in Western medicine. Given the commonality of pain, pruritus, and cold symptoms in addition to the growing need for non-opioid treatment options, the authors investigated clinical applications of such compounds for their over-counter usage. The purpose was to analyze current clinical research and applications regarding the use of these topical agents. This study involved a bibliometric analysis of peer-reviewed articles, published in English and indexed in PubMed from 2010 to 2022, pertaining to camphor- and menthol-containing compounds. There were 103 results, of which 15 (14.6%) articles were related to the treatment of disorders related to health, such as upper respiratory infection, pain, and pruritus. Excluded were “non-research” articles (e.g., letters to the editor), articles that do not involve human subjects, reports of improper application or misuse (e.g., ingestion), and articles pertaining to intraoral, intranasal, and ophthalmic agents. Of these articles, the originating journals, respective journal impact factor scores, publication years, study designs, and study topics were identified. Underlying trends and themes regarding clinically relevant research on these compounds were subsequently discerned. Based on this analysis, topical agents containing camphor and menthol are potentially effective at treating pain, upper respiratory infection symptoms, and pruritus in addition to potentially functioning as an antimicrobial. However, with a limited number of studies addressing these compounds' uses in each application, no definitive recommendation can be made regarding their use. Given the promising results of earlier studies, the authors recommend that more primary research, particularly randomized, double-blind controlled studies, be done regarding clinical applications of these substances.


Introduction And Background
Back pain, arthritis, upper respiratory infection (URI) symptoms, and pruritus are among the most common complaints in developed countries [1]. Currently, there are limited safe and effective treatments for pain, URI symptoms, and chronic pruritus [2][3][4]. Consequently, research on alternative therapies and management strategies for these issues needs to be conducted.
Topical agents have emerged as promising alternative or complementary modalities of treatment for pain, pruritus, and URI symptoms over time [3,5,6]. Often lacking significant systemic effects, topical medications tend to be safer, have less addictive potential, and are more accessible than oral and parenteral therapies [7]. As such, topical medications are an appealing treatment option and have become a topic of research regarding the management of pain, pruritus, and URI symptoms.
The authors considered existing remedies that may not be as well recognized as the other topical agents. Camphor-and menthol-containing agents, in particular, stood out. From a pain standpoint, camphor activates TRPV1 and inhibits TRPA1, on which menthol also has a bimodal action, resulting in an analgesic effect [8]. For URI symptoms, camphor and menthol both activate inhibiting transient receptor potential (TRP) channel M8, which is believed to inhibit respiratory reflexes to alleviate irritation and cough. These compounds have deep roots in Eastern medicine and have historically been used for alleviating pain, cold symptoms, and pruritus in various cultures. However, as these compounds are not as well recognized in Western medicine, clinical research is sparse.
The bibliometric study seeks to evaluate the current research that exists on the clinical applicability of compounds containing camphor and menthol and make recommendations for future research regarding their use. This involved a comprehensive review of articles found in PubMed since 2010. McGranahan & Parker noted efforts to address the opioid epidemic starting in the early 2010s with opioid drug reformulation and declining prescription rates; as such, 2010 was chosen as the start date of the analysis [9]. The authors aimed to present general conclusions about these substances' application in clinical medicine and provide direction for future research regarding these topical compounds. This article was previously presented as a poster at PAINWeek 2022 on September 8, 2022.

Review Methods
This study involves a bibliometric analysis of English, peer-reviewed articles indexed in PubMed from 2010 to 2022 using the search term "Menthol AND Camphor". The journal, the journal impact factor score (acquired from the 2021 Journal Citation Reports), "clinical relevance," year of publication, study design, and study topic of each of the resulting articles were identified. Underlying themes regarding research on camphor-and menthol-containing compounds were reviewed independently by DH and AW, discrepancies were reviewed, and overarching themes were decided upon following discussion. Trends in research were evaluated by comparing the number of relevant publications from year to year and displayed using a bar graph. For the purpose of this analysis, "clinically relevant" articles included those that related to the treatment of disorders related to health. Articles that were not primary or secondary research (e.g., letters to the editor), articles that do not involve human subjects, reports of improper application or misuse (e.g., ingestion), and articles pertaining to intraoral, intranasal, and ophthalmic agents were excluded. Ultimately, counts of journals, study designs, and study topics were gathered, and the distribution of publication years was analyzed and displayed using a histogram.  The publication counts per year demonstrated no obvious trends in the total number of publications over time, with a maximum of three articles in 2014, or the type of journal to which these articles are published. Figure 1 displays the trend in publication counts over time.

FIGURE 1: Number of "clinically relevant" publications per year since 2010
Of the total 15 studies included in this review, five were reviews (33.3%), three were prospective case series (20.0%), two were non-randomized controlled studies (13.3%), two were randomized, double-blind controlled studies (13.3%), one was a cross-sectional study (6.7%), one was a qualitative case study (6.7%), and one was a case report (6.7%). Regarding discussed topics, pruritus in four articles (26.7%), adverse effects were discussed in three articles (20.0%), pain in three articles (20.0%), inflammation in three articles (20.0%), cold symptoms in three articles (20.0%), circulation effects in one article (6.7%), and antimicrobial activity in one article (6.7%). Antihistamine monotherapy has no clinically meaningful benefit, but combination therapy is beneficial in adults and older children. Decongestant has small benefit but uncertain clinical significance. Intranasal ipratropium has probable benefits. OTC cough treatment (e.g., antitussives, expectorants) has unclear benefit in adults and no benefit in children. Vapor rubs (containing camphor, menthol, and eucalyptus oil) have unclear benefits and demonstrated harm based on a "poorly described randomized, blinding limited, single study". NSAIDs are likely beneficial for pain. Acetaminophen is likely effective for fever and analgesia. Antibiotics have no benefits and clear harms. Combination of capsaicin (e.g., Myolaxin ointment containing oleoresin capsaicin, methylsalicylate, menthol, camphor, and eucalyptus oil) and eutectic mixture of local anesthetics is not significantly more effective than individual drugs alone, which demonstrate significant improvement in pain.
Menthol differs from other terpenic essential oil constituents Kolassa, 2013 [19] While convulsions have been seen and can be explained in camphor, thujone, and eucalyptus oil overdose/poisoning, no convulsions have been seen or explained in menthol overdose/poisoning. Therefore, menthol's side effect profile is not comparable to those of other terpenic derivatives.
Therapeutic options for acute cough due to upper respiratory infections in children Paul, 2012 [20] While there is not strong evidence supporting the use of narcotics OTC oral antitussives, and expectorants for upper-respiratory associated pediatric cough, honey, and topically applied vapor rubs (camphor, menthol, and eucalyptus oils in a petrolatum base) may be effective.
Tea tree oil attenuates experimental contact dermatitis Wallengren, 2011 [21] While compounds containing zinc, menthol and camphor have historically been used to relieve itching, no difference was found in the perception of itch from histamine.

Discussion
Camphor-and menthol-containing substances have been documented for their topical use for acute and chronic pain, pruritus, and cold symptoms relief as well as antimicrobial purposes. Proposed analgesic implementation included knee osteoarthritis [11], myalgias, neuralgias [13], and venipuncture pain [18], through possible improvements in blood circulation [15] among other mechanisms. These agents have shown potential in improving pruritus [10,14] through potential anti-inflammatory effects [16], but contradictory evidence does exist [21].
Other benefits of these agents include relieving nasal congestion and reducing nighttime cough frequency and severity, improving sleep for both the child and parents [3,17,20]. Additionally, antimicrobial properties were observed against onychomycosis [22]. Several of the excluded, "non-clinically relevant" articles (i.e., not involving human subjects) discussed other possible antimicrobial effects of menthol and camphor; however, they were not included in this analysis as they failed to meet criteria.
Potential side effects of these topical agents include contact dermatitis [23], allergic reactions, and camphor/menthol poisoning due to accidental ingestion, which could cause symptoms such as seizures [12,19]. That said, camphor, not menthol, is responsible for convulsions, so each compound's side effect profile should be considered separately [19].

Conclusions
Topical compounds containing camphor and menthol have traditionally been used to alleviate pain, cold symptoms, and pruritus, especially in East Asian cultures. As these symptoms are fairly common, this bibliometric analysis aimed to assess the presence of peer-reviewed publications to better guide evidencebased, clinical applications of these agents. As PubMed was the only search engine utilized, relevant literature from other platforms may have been excluded from the analysis. Similarly, while the authors tried to include all research pertaining to topical camphor-and menthol-containing agents with the nonspecific search terms, research articles referencing brand names of different formulations of these compounds, such as Tiger Balm, Eagle Balm, Vicks VapoRub, and Bengay, may have been excluded.
Based on existing literature, compounds containing camphor and menthol demonstrate potential in relieving pain, alleviating cold symptoms, lessening pruritus, and even functioning as an antimicrobial. Given the limited number of studies, however, a definitive recommendation cannot be made regarding their use. The authors recommend additional randomized, double-blind controlled studies be done to address the clinical application of these substances, particularly in the contexts of relieving localized pain, localized pruritus, and URI symptoms.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.