TABLE 2.
Human models of menthol and its products.
| Compound | Route of administration | Indication | Effects | Clinical trial number | References |
| 10 mM menthol | Oral | Healthy subjects | Transiently desensitize capsaicin-sensitive fibers | NA | Proudfoot et al., 2006 |
| 40% Menthol | Topical | Healthy subjects | Topical menthol induced cold allodynia | NA | Wasner et al., 2004, 2008; Namer et al., 2005, 2008; Seifert and Maihöfner, 2007; Altis et al., 2009; Flühr et al., 2009; Binder et al., 2011; Mahn et al., 2014 |
| 30% Menthol | Topical | Healthy subjects | 30% Topical menthol can induce cold hyperalgesia with effectively and safely | NA | Hatem et al., 2006 |
| 10% Menthol | Topical | Healthy subjects | No significant to histamine-induced itch and pain sensation | NA | Yosipovitch et al., 1996 |
| Tetracaine gel with vs. without menthol | Topical | Healthy subjects | Improved the analgesic efficacy of the tetracaine gel in part through enhanced percutaneous permeation | NA | Liu et al., 2005 |
| Menthol smokers vs. non-menthol smokers | NA | Healthy subjects | Less pain and pain-related functional interference | NA | Kosiba et al., 2019 |
| 0%, 10%, 20% and 30% menthol | Topical | Healthy subjects | The concentration-dependent grading response elicits a range of sensations | NA | Wright et al., 2019 |
| Topical pain-relieving patch (containing 6% menthol) vs. placebo | Topical | Mild to moderate pain condition | Significant relief of pain | NA | Gudin et al., 2020 |
| 40% Menthol | Topical | Upper limb amputees | Induce hypersensitivity | NA | Vase et al., 2013 |
| 40% Menthol vs. placebo | Topical | Healthy subjects, Trans-cinnamaldehyde-induced hyperalgesia | No Results Posted | NCT02653703 | Andersen et al., 2016 |
| 5% Menthol cream vs. placebo | Topical | After photodynamic therapy | No Results Posted | NCT02984072 | |
| Menthol (Biofreeze) vs. placebo | Topical | Acute LBP | Significant relief of pain | NA | Zhang J. et al., 2008 |
| Menthol (Biofreeze) vs. placebo | Topical | Non-radicular mechanical neck pain | No Results Posted | NCT03012503 | |
| 3.5% Menthol gel vs. inert placebo gel | Topical | OA | No significant improvement | NA | Topp et al., 2013 |
| Menthol (Biofreeze) vs. placebo | Topical | OA | No Results Posted | NCT03888807, NCT04351594, NCT01565070 | |
| Menthol (Biofreeze) vs. placebo | Topical | EIMD | Menthol may reduce the sensation of muscle soreness and may influence recovery of lower-body power | NA | Gillis et al., 2020 |
| Menthol (Biofreeze) vs. placebo | Topical | DOMS | Significant relief of pain associated with increased corticospinal inhibition | NA | Stefanelli et al., 2019 |
| 3.5% menthol gel vs. application of ice | Topical | DOMS | Decreased perceived discomfort to a greater extent and permitted greater tetanic forces to be produced. | NA | Johar et al., 2012 |
| 3.5% menthol gel vs. inert placebo gel | Topical | Soft tissue injuries | Significant relief of pain | NA | Airaksinen et al., 2003 |
| 3% menthol + ibuprofen vs. gel ibuprofen gel alone/diclofenac gel | Topical | Soft tissue injuries | Significant relief of pain | NA | Wade et al., 2019 |
| Mentholated cream only vs. MC containing oxygenated glycerol triesters | Topical | Acute musculoskeletal pain | The combination resulted in a gradual reduction in pain, lower VAS scores, and greater improvements in lifestyle and mobility improvements | NCT01387750 | Taylor et al., 2012 |
| 3.5% Menthol patch vs. placebo patch | Topical | Mild to moderate musculoskeletal strain | Significant relief of pain | NA | Higashi et al., 2010 |
| 1% Diclofenac/3% menthol gel vs. inert placebo gel | Topical | Acute ankle sprain | No significant improvement | NCT02100670 | Lai et al., 2017 |
| Menthol (Biofreeze) vs. placebo | Topical | CTS | No Results Posted | NCT01716767 | |
| Menthol (Biofreeze) vs. placebo | Topical | CTS | Significant relief of pain | NA | Sundstrup et al., 2014 |
| Neat peppermint oil (containing 10% menthol)* | Topical | Postherpetic neuralgia | Significant relief of pain | NA | Davies et al., 2002 |
| Menthol (Biofreeze) vs. placebo | Topical | MPS | Increase in the mouth opening size | NA | Yaman et al., 2021 |
| 1% Menthol cream | Topical | CIPN, PMPS | Significant relief of pain | NA | Fallon et al., 2015 |
| 1% Menthol cream* | Topical | CIPN | Significant relief of pain | NA | Cortellini et al., 2017 |
| 5% Menthol cream* | Topical | CIPN | Significant relief of pain | NA | Brid et al., 2015 |
| 7.5% Methyl salicylate/2% menthol lotion vs. placebo | Topical | CIPN | No Results Posted | NCT01855607 | |
| 3.5% Menthol gel vs. inert placebo gel | Topical | CIPN | No Results Posted | NCT04276727 | |
| Mannitol + menthol cream vs. menthol cream | Topical | PDPN | No Results Posted | NCT02728687 | |
| No cooling vs. menthol-containing cooling bandage vs. ice containing cold pack | Topical | Undergoing anterior cruciate ligament reconstruction | Positive subjective comfort feedback | NA | Engelhard et al., 2019 |
| Menthol 10% solution vs. menthol 0.5% solution | Topical | Migraine | Significant relief of pain | NA | Borhani Haghighi et al., 2010 |
| 6% Menthol gel (STOPAIN) | Topical | Migraine | Significant relief of pain | NCT01687101 | St Cyr et al., 2015; Kayama et al., 2018 |
| 40% Menthol | Topical | Histamine-induced itch | An inhibitory effect on histaminergic itch | NA | Andersen et al., 2017; Engelhard et al., 2019 |
| Menthol based aromatic therapy vs. placebo | NA | Second trimester genetic amniocentesis | No significant improvement | NA | Hanprasertpong et al., 2015 |
* Case reports. CTS, carpal tunnel syndrome; CIPN, chemotherapy-induced peripheral neuropathy; DOMS, delayed-onset muscle soreness; EIMD, exercise-induced muscle damage; LBP, low back pain; MPS, Masticatory myofascial pain syndrome; OA, osteoarthritis; PDPN, painful diabetic peripheral neuropathy; PMPS, post-mastectomy pain syndrome; VAS, Visual Analog Scale.