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. 2026 Sep 22;20:100232. doi: 10.1016/j.ynpai.2026.100232

Cooling a burning mouth: is TRPM8 the therapeutically relevant target of clonazepam in burning mouth disorder?

Logan Elkin 1, Jonathan S Marchant 1,⁎
PMCID: PMC13635707  PMID: 42835698

Abstract

Burning mouth disorder (BMD) is an extremely painful oral condition that occurs at the highest prevalence in post-menopausal women. Treatment options remain limited and remission rates poor, highlighting a need for identification of relevant molecular targets that can be prosecuted for effective therapeutics. One treatment that realizes benefit in patients with burning mouth disorder is clonazepam, a benzodiazepine known to work by augmenting currents through gamma aminobutyric acid A (GABAA) ion channels to inhibit neuronal firing. Here, we highlight an ancillary target for clonazepam as the transient receptor potential melastatin 8 (TRPM8) ion channel. In this commentary, evidence supporting the idea that TRPM8 acts as the therapeutically relevant local mediator of clonazepam action in BMD is summarized, with the goal of spurring new treatments for this debilitating and painful condition.

Keywords: TRP channel, Polypharmacology, Pain, Benzodiazepine, Neuropathy

Highlights

  • •

    Burning mouth disorder (BMD) is an extremely painful oral condition.

  • •

    Clonazepam, a benzodiazepine, provides effective pain relief in BMD.

  • •

    We discuss whether the clinically relevant target of clonazepam is the TRPM8 ion channel.

Burning mouth disorder (BMD, (Chmieliauskaite et al., 2021)) or burning mouth syndrome, is a chronic condition associated with burning pain in the mouth in the absence of any clear mucosal abnormality (Tan et al., 2022; Rossella et al., 2022; Doyle et al., 2023). Sufferers experience burning and itching sensations in the tongue, lips, gums, and oral mucosa often with taste abnormalities (dysgeusia), dryness (xerostomia) and altered sensory perception (dysesthesia). This condition has been proposed to be a form of neuropathic pain associated with altered sensory thresholds (Kohorst et al., 2015; Forssell et al., 2002; Lauria et al., 2005). Disease prevalence has been reported at ∼1.7% in the general population (Wu et al., 2022). BMD rarely presents before the age of 30, but occurrence increases with age with the disorder presenting most frequently in older women as a peri−/post-menopausal condition (Kohorst et al., 2015; Bergdahl and Bergdahl, 1999; Grushka, 1987). Changes in sex hormone levels may therefore predispose to BMD, although no specific molecular mechanism has been defined. BMD also occurs as an adverse outcome of different types of cancer therapy (Normando et al., 2024).

While therapeutic management of BMD patients has proved challenging owing to the unclear pathogenesis, the drug clonazepam yields relief from BMD symptoms in most patients. Supporting evidence comes from primary studies, clinical trials and retrospective analyses (Table 1, (Tan et al., 2022; Rossella et al., 2022)). The mechanistic basis for symptomatic relief with clonazepam has long been assumed to solely result from the canonical action of benzodiazepines in augmenting GABA action at the GABAA ion channel to depress neuronal firing (Walters et al., 2000). This mechanism underpins the clinical utility of benzodiazepines as anti-seizure and anti-anxiety medications. However, there is little correlation between the effectiveness of benzodiazepines in treating BMD, bulk plasma concentration, and alleviation of anxiety or depressive symptoms. Rather clonazepam appears to be effective topically when administered orally as either a sublingual tablet (Gremeau-Richard et al., 2004)), or as a clonazepam-containing mouthwash (Kuten-Shorrer et al., 2017a; de Castro and Ribeiro-Rotta, 2014). The rapid onset of symptom relief and short duration of efficacy (inconsistent with the long systemic half-time of clonazepam) all hint at a localized, rather than central action of clonazepam in treating BMD symptoms (Gremeau-Richard et al., 2004; Woda et al., 1998). But the identity of the relevant local target, if not peripheral GABAA receptors, remained unclear.

Table 1.

Summary of studies examining the efficacy of clonazepam as a monotherapy to treat burning mouth disorder.

Study Administration, dose Sample (n) Study type & methods Conclusions
Sublingual tablet
Woda et al. (1998) Sublingual tablet; 0.5 or 1 mg CLZ for 3 min then expectorate, 2-3× daily 25 Enrolled patients, symptom intensity score 73% of patients experienced partial or complete remission of symptoms. Significant reduction in pain scores was reported after first and second appointments (3–29 months later). Immediate pain relief post CLZ administration was noted which lasted for 3-5 h.
Gremeau-Richard et al. (2004) Sublingual tablet; placebo vs 1 mg CLZ for 3 min then expectorate, 3× daily for 14 days 48 Enrolled patients, symptom intensity score, double blinded study Significant reduction in pain scores was reported between groups following 14 days of treatment. 72% of CLZ treated patients reported symptom improvement.
Rodriguez de Rivera Campillo et al. (2010) Sublingual tablet; placebo vs 0.5 mg CLZ for 3 min then expectorate, ≤4× daily 66 Enrolled patients, symptom intensity score, double blinded study 70% patients receiving CLZ reported a 50% reduction in symptom scores at 1- and 6- months post-treatment. 11% of patients receiving CLZ were asymptomatic at conclusion of study.
Amos et al. (2011) Sublingual tablet then swallow; 0.5 mg CLZ, 3× daily. 36 Retrospective chart review, symptom intensity score 80% of patients experienced >50% reduction in pain scores, with 33% showing complete resolution of symptoms.
Ko et al. (2012) Sublingual tablet; 0.5-1 mg CLZ, 1-2× daily for 4 weeks 100 Enrolled patients, symptom intensity score Patients with higher symptom severity scores experienced great therapeutic benefit with CLZ across a range of measures.
Zborowski and Konopka (2022) Sublingual tablet; escalating dose 0.5-3 mg CLZ, 1-3× daily for 4 weeks 57 Enrolled patients, symptom intensity score, quality of life score 82% of CLZ patients reported symptom relief. The CLZ group had a significant reduction in pain scores compared to baseline. 7% of CLZ patients experienced adverse effects.
Shin et al. (2023) Sublingual tablet then swallow, 0.75 mg CLZ, 3× daily for 2 weeks increasing to 1.5 mg for 4 weeks. 41 Enrolled patients, symptom intensity score 78% of patients reported improvement in oral pain scores,
with enhanced effect in patients with taste disturbances.
Jang et al. (2024) Sublingual tablet then swallow, 0.5 mg CLZ, 2× daily for 4 weeks. 23 Enrolled patients, symptom intensity score 43% of patients experienced a greater than 50% reduction in pain scores. Non-responders reported significantly reduced symptoms but this did not exceed the 50% threshold.



Systemic tablet
Grushka et al. (1998) Systemic tablet; 0.25 mg CLZ, 3× daily for at least 2 months, escalating dose (≤ 2.25 mg) if continued symptoms. 30 Enrolled patients, symptom intensity score 70% of patients experienced reduction in symptoms, although 27% stopped treatment in part due to side effects.
Barker et al. (2009) Systemic tablet; 0.25 mg CLZ or 2 mg diazepam, 2× daily. 90 Retrospective chart review and self-reporting of symptom intensity score Significant reduction in pain and symptomatic scores for CLZ and diazepam. 71% of patients receiving CLZ reported BMS symptom improvement compared with 55% of patients receiving diazepam.
Heckmann et al. (2012) Systemic tablet; 0.5 mg CLZ vs placebo, 1× daily 20 Enrolled patients, symptom intensity score Pain ratings were significantly different at subsequent visits (up to 10 weeks) between groups with a significant reduction in pain reported for CLZ-receiving patients.
Çınar et al. (2018) Systemic tablet; 2 mg CLZ, 1× daily 75 Enrolled patients, symptom intensity score Significant reduction in pain scores were reported for CLZ group. No adverse effects were reported. 32% of patients receiving CLZ experienced side effects.
Han et al. (2021) Systemic tablet; 0.25 mg CLZ for 2 months 37 Retrospective study, symptom intensity score, quality of life score Patients treated with CLZ reported significant improvement in symptom intensity and quality of life compared to baseline. 5% of CLZ patients reported side effects.



Mouthwash
de Castro and Ribeiro-Rotta (2014) Mouthwash; CLZ solution (0.1 mg/mL) for 3 min, 3× daily for 14 days 18 Enrolled patients, symptom intensity score A significant reduction in symptom scores with 66% of patients reporting symptom improvement with the CLZ mouthwash.
Kuten-Shorrer et al., 2017a, Kuten-Shorrer et al., 2017b Mouthwash; CLZ solution (0.1 or 0.5 mg/mL) for 5 min, 2-4× daily. 57 Retrospective chart review, symptom intensity score 88% of patients in 0.5 mg/mL CLZ cohort experienced symptom improvement which was superior to the 0.1 mg/mL CLZ cohort. Adverse reaction (sedation) in 15% of patients.
Fenelon et al. (2017) 10× drops; CLZ solution (0.1 mg/drop) before bed 39 Retrospective chart review, symptom intensity score Significant reduction in pain score after 6 weeks and 3 months of treatment compared to baseline. No serious adverse effects reported but 30% of patients experienced side effects with CLZ.
Rossella et al. (2022) Mouthwash; CLZ solution (0.1 mg/mL) for 5 min, ≤4× daily 82 Retrospective chart review, symptom intensity score Significant difference between baseline and initial follow-up pain scores. No side effects or adverse events reported.
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In this commentary, we contend that clonazepam efficacy in treating BMD relates to engagement of a previously unsuspected target, the transient receptor potential melastatin 8 ion channel (TRPM8). TRPM8 is a non-selective cation channel that functions as a sensor for noxious cold, as well as natural products such as menthol. TRPM8 activation underpins the menthol-induced cooling sensations beneficial for pain relief with TRPM8 activation being well established to confer analgesic outcomes (Liu et al., 2013; Proudfoot et al., 2006).

This new insight stems from recent work demonstrating that certain benzodiazepines, including clonazepam, act as agonists of the TRPM8 ion channel (Elkin et al., 2026). This discovery was surprising, as benzodiazepines have never previously been recognized as TRPM8 channel agonists, despite considerable scrutiny of both this channel and this chemotype in a neuronal signaling context. Clonazepam activated TRPM8 with robust efficacy and reasonable potency (EC50 = ∼600-800 nM, (Elkin et al., 2026)) compared with other TRPM8 agonists (Fig. 1). This sensitivity of TRPM8 channels to clonazepam is compatible with local concentrations of clonazepam attained after use of mouthwashes (‘swish and spit’, 0.1 mg/ml ∼300 μM clonazepam, (Kuten-Shorrer et al., 2017a; de Castro and Ribeiro-Rotta, 2014)) or sub-lingual administration of a clonazepam tablet (‘suck and spit’, 1 mg tablet held for 3 min in the mouth without swallowing (Gremeau-Richard et al., 2004)) to treat BMD symptoms. TRPM8 is robustly activated by several 7-nitrobenzodiazepines (e.g. clonazepam), as well as other benzodiazepines with much lower potency (e.g. diazepam), paralleling clinical outcomes in treating BMD where clonazepam was found superior to diazepam (Barker et al., 2009).

Fig. 1.

Fig. 1

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Clonazepam is a TRPM8 agonist. Top, chemical structures of various TRPM8 agonists. Bottom, Concentration response curves showing the effects of clonazepam (orange circle), icilin (blue square), WS-12 (magenta triangle) and menthol (green diamond) on Ca2+ signal amplitude in HEK293 cells expressing human TRPM8. Data is replotted from (Elkin et al., 2026). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

TRPM8 is expressed throughout the oral epithelium, tongue, and sensory nerve pathways where the painful symptoms of BMD occur. TRPM8 innervation of the tongue arises from the lingual posterior branch of the mandibular nerve, with histological studies evidencing TRPM8-positive sensory nerve fibers enriched around the fungiform papillae of the tongue (Dhaka et al., 2008; Abe et al., 2005; Moayedi et al., 2022; Simon and Gutierrez, 2017). BMD pain symptoms typically present in the anterior two-thirds of the tongue, where TRPM8-associated fungiform papillae are localized (Dhaka et al., 2008; Abe et al., 2005; Kichko et al., 2018). Sensory TRPM8 afferent fibers project to the trigeminal ganglion (Abe et al., 2005), and in vivo Ca2+ imaging studies evidence activation of various classes of cold- and menthol-responding neurons following oral stimulation with different temperature solutions (Leijon et al., 2019; Yarmolinsky et al., 2016). Discrete functional classes of TRPM8-expressing neurons have been mapped in the trigeminal ganglion, with these different types of neurons responding differently after thermal injury (Yarmolinsky et al., 2016). The majority of cold-sensing neurons projecting to the trigeminal ganglion are sensitive to menthol (Leijon et al., 2019), and therefore presumably to clonazepam also. Elkin et al. demonstrated clonazepam evoked Ca2+ responses in isolated mouse trigeminal neurons that were absent in neurons isolated from TRPM8 knockout mice (Elkin et al., 2026).

Not only is TRPM8 present in areas affected by BMD, but it is also wired correctly into signaling outcomes that counteract the triad of symptoms – oral pain, taste disturbances, decreased salivation – that are frequently associated with BMD. First, it is recognized that TRPM8 agonists confer analgesic effects. In the tongue, TRPM8-expressing trigeminal sensory neurons innervate fungiform papillae but immunoreactivity is not observed in TRPV1- or CGRP- positive nerve fibers (Abe et al., 2005). Menthol causes little CGRP release in buccal mucosa (Kichko et al., 2018). As CGRP is a mediator of neurogenic inflammation, this could be consistent with a model that neurons positive for nociceptive TRP channels may be functionally antagonized by activation of analgesic cold-and menthol-sensitive hTRPM8-containing neurons (Winchester et al., 2014). Indeed, tolerance of a TRPM8 antagonist in a human trial was limited by a side effect of perioral hotness in some individuals, consistent with TRPM8 blockade revealing an endogenous tone of TRP channels mediating heat sensitivity (Winchester et al., 2014). In other tissues, it is well appreciated that activation of TRPM8-expressing neurons (e.g. with menthol) relieves pain (Liu et al., 2013; Proudfoot et al., 2006). TRPM8 activation has also been shown to mitigate inflammatory and certain itching responses (Ramachandran et al., 2013; Lee et al., 2024). This is also likely true for sensory neurons within the mouth, with this rationale underpinning the symptomatic benefit of menthol-based mouthwashes (containing millimolar menthol, ∼2.7 mM in Listerine®) for oral pain relief. Clonazepam however appears superior to menthol in providing symptom relief for BMD. This may relate to the enhanced effect/potency of clonazepam on TRPM8 (Fig. 1), and/or the ability of menthol to stimulate opposing pathways through TRPA1 activity (Karashima et al., 2007).

Second, TRPM8 activation can confer pleasant sensations of flavor, based upon the ‘minty’ taste of the TRPM8 agonists menthol and eucalyptol, underpinning their use as flavors in foods, mouthwash and as an additive in nicotine-containing products to mask the bitter taste of nicotine. An older literature suggests that certain benzodiazepines, including clonazepam, can enhance food palatability and taste (Berridge and Pecina, 1995; Cooper and Yerbury, 1988). This may be an advantage in treating BMD symptoms given that BMD is known to be associated with taste abnormalities. A recent study documented taste disturbances (‘bitter taste’) in a majority of BMD patients (Shin et al., 2023). Interestingly, supertasters show a higher prevalence of BMD, and women are more likely to be supertasters than men. Patients with BMD who experience dysgeusia have been shown to respond well to treatment with clonazepam (Shin et al., 2023).

Finally, hyposalivation is an undesired BMD symptom (Shin et al., 2023). TRPM8 agonists, as well as clonazepam, cause hypersalivation (Houghton et al., 2020) potentially alleviating the symptoms of xerostomia in BMD patients. A similar outcome of enhanced secretion underpins the utility of TRPM8 agonists in treating symptoms and ocular pain in dry eye disease (Yang et al., 2017; Pattar et al., 2026; Parra et al., 2010). Indeed, a TRPM8 agonist (WS-12 or acoltremon, marketed as Tryptyr®) has been recently approved to treat this condition. We note that dry eye disease (DED), like BMD, increases in incidence with age. Changes in the terminal morphology and function of different populations of TRPM8-positive sensory neurons have been observed in a study of DED and tear flow in aged mice (Alcalde et al., 2018).

Future steps. Discovery of TRPM8 as a new target of clonazepam will prompt evaluation of whether established facets of TRP channel biology provide insights into BMD etiology. For example, age and sex are strong predisposing factors in BMD. If TRPM8 expression or functionality decreases with age, as seen in some tissues (Alcalde et al., 2018; Thapa et al., 2021), the concomitant decrease in TRPM8-mediated analgesic tone could then predispose to BMD in older patients. Of additional relevance are data showing TRP channel regulation by steroid hormones (Mendez-Resendiz et al., 2020). TRPM8 is regulated by steroid hormones that alter channel activity and/or expression (Asuthkar et al., 2015a; Asuthkar et al., 2015b; Chodon et al., 2010). These regulatory cues may be relevant as menopausal changes in steroid hormones could alter the balance of oral nociceptive (TRPA1, TRPV1) and analgesic (TRPM8) signals (Seol and Chung, 2022; Shinoda et al., 2022)). The strong prevalence of BMD in post-menopausal woman suggests reduced estrogen as a triggering factor (Seol and Chung, 2022). Estrogen depletion induced by ovariectomization in rats was shown to increase TRPA1 and TRPV1 currents in primary hippocampal and DRG neurons, and this effect reversed by hormone replacement therapy (Yazgan and Naziroglu, 2017). Progesterone has also been shown to downregulate TRPV1 expression (Ortiz-Renteria et al., 2018), providing another example of how menopausal changes can amplify relevant pain signaling pathways. A logical first step would be to examine changes in expression of TRPM8 and other TRP channels in the context of BMD.

Further research is also needed to probe whether other recognized physiological effects of clonazepam could also implicate ancillary TRPM8 signaling. One example is the utility of clonazepam for refractory cases of migraine and headache (Maizels, 2010; Smirne and Scarlato, 1977), where TRPM8 has emerged as a therapeutic target (Dussor and Cao, 2016). Benefit in other chronic pain conditions has also been reported (Fishbain et al., 2000). However, while this could be mechanistically insightful, the clinical utility of clonazepam is obviously tempered by side effects associated with chronic benzodiazepine administration, including risk of dependence and addiction.

Finally, this discovery provides another example of TRPM8 ‘off-target’ engagement by approved drugs. The growing list now encompasses antimycotics such as clotrimazole (a potent TRPM8 inhibitor (Meseguer et al., 2008)) as well as immunosuppressants such as rapamycin and tacrolimus (TRPM8 agonists, (Arcas et al., 2024; Tóth et al., 2025)). The broader polypharmacology of these agents at TRPM8 is likely also relevant when these drugs are applied to skin and mucous membranes.

In conclusion, the recent discovery that clonazepam activates TRPM8 provides momentum to further investigate TRPM8 as a relevant therapeutic target in BMD. Validation of this target would facilitate drug repurposing from within the current arsenal of TRPM8 activators to BMD therapy and potentially catalyze new design efforts based around the benzodiazepine scaffold in light of the robust efficacy seen with clonazepam at TRPM8 and in symptomatic relief for BMD patients. New treatments are certainly needed for this condition given the chronic pain and poorer quality of life endured by many BMD patients.

CRediT authorship contribution statement

Logan Elkin: Writing – review & editing, Writing – original draft. Jonathan S. Marchant: Writing – review & editing, Writing – original draft.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

Work was supported by NIH (R01 AI145871 to JSM). LE was supported by a Graduate Fellowship from the Medical College of Wisconsin Cancer Center.

Data availability

No data was used for the research described in the article.

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