511: Topical Menthol Cream for Refractory Localized Neuropathic Pain: A Multicenter Retrospective Study

Topic: Clinical Science
Subtopic: Pain category (ICD-11), Chronic neuropathic pain, Pharmacological treatments

Background and Aims: Neuropathic pain, caused by a lesion or disease of the somatosensory nervous system, remains a major therapeutic challenge. First-line systemic treatments — gabapentinoids, tricyclic antidepressants, and serotonin–norepinephrine reuptake inhibitors — provide modest average benefit (NNT 4.6–8.9) and are frequently limited by dose-dependent adverse effects such as sedation, dizziness, and cognitive impairment. Topical therapies have therefore gained attention for localized neuropathic pain, targeting peripheral generators while minimizing systemic exposure. Current options include lidocaine 5% patches and capsaicin 8% patches, but each has limitations in efficacy or tolerability. Menthol, a natural TRPM8 agonist, exerts analgesic effects through desensitization of nociceptive nerve endings and additional multi-target mechanisms including TRPA1 inhibition, sodium channel blockade (Nav1.8/1.9), and GABA-A receptor potentiation. Despite this pharmacological rationale, clinical evidence remains scarce. We aimed to evaluate the real-world effectiveness and tolerability of a standardized stepwise titration strategy using compounded topical menthol (1%–10%) in refractory localized neuropathic pain.

Methods: We conducted a multicenter retrospective chart review across two chronic pain centers between March 2022 and September 2023. All consecutive adult patients (≥18 years) were included if they had localized neuropathic pain confirmed by a pain specialist, baseline NRS >4/10, DN4 ≥4, and documented failure or intolerance of prior analgesic therapies.

Patients received pharmacy-compounded menthol cream (Excipial® Hydrocream base) titrated from 1% to 10% over approximately 60 days, with concentration escalated every 10–15 days according to analgesia and tolerability. Application frequency was two to four times daily.

The primary endpoint was the responder rate at the final concentration, defined as ≥30% NRS reduction and/or ≥30% self-reported pain relief.
Secondary outcomes included NRS evolution, Patient Global Impression of Change (PGIC), Neuropathic Pain Symptom Inventory (NPSI) total and subscores, and adverse effects.

Statistical analyses were performed using R (v4.3.1), with t-tests for NRS comparisons and ANOVA for subgroup analyses.

Results: Twenty-one patients were analyzed (76% female, mean age 60.7 ± 12.8 years); 71% had chemotherapy-induced peripheral neuropathy (CIPN). Patients had previously failed a mean of 3.6 analgesic treatments.

Mean baseline NRS was 6.83 and decreased progressively during titration: 6.25 at 1% (p = 0.326), 6.00 at 3% (p = 0.010), 5.47 at 5% (p = 0.018), and 4.82 at 10% (p = 0.018), with statistical significance from 3% onward. At 10% menthol, 12 patients (57.1%) met the predefined response criterion. PGIC improved from 4 ("no change") to 3 ("slightly improved"). NPSI subscores showed reductions in burning pain, evoked pain, paroxysmal pain, and dysesthesia, while constrictive pain increased slightly.

Patients with Deep Pain phenotype showed significantly greater benefit (p = 0.035), with a trend in Evoked Pain (p = 0.070). Treatment was well tolerated: four patients reported transient discomfort at 1%, one experienced palpitations at 5% leading to discontinuation, and one had mild erythema at 10%.

Conclusions: This two-center retrospective study provides initial real-world evidence that progressively titrated topical menthol (1%–10%) is effective and well tolerated in refractory localized neuropathic pain. The concentration–response pattern observed across titration steps, together with a responder rate (~60%) exceeding typical placebo responses in neuropathic pain trials (30–40%), supports a genuine pharmacological contribution beyond contextual factors alone. The preferential response observed in Deep Pain and Evoked Pain phenotypes suggests that TRPM8-mediated modulation may be particularly relevant when peripheral sensitization predominates, supporting phenotype-informed treatment selection. Menthol's favorable tolerability and accessibility profile positions it as a pragmatic intermediate therapeutic option between standard topical treatments and high-concentration capsaicin. These findings warrant prospective controlled studies to confirm efficacy, refine titration schedules and dosing frequency, identify responder phenotypes using symptom-based clustering, and evaluate multimodal topical combinations to enhance magnitude and duration of analgesia.

References: Bouhassira D. Neuropathic pain: definition, assessment and epidemiology. Rev Neurol 2019;175(1–2):16–25.
Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment. Physiol Rev 2021;101(1):259–301.
Soliman N et al. Pharmacotherapy and non-invasive neuromodulation for neuropathic pain: a systematic review and meta-analysis. Lancet Neurol 2025;24(5):413–28.
Kocot-Kępska M et al. Topical treatments and their molecular/cellular mechanisms in patients with peripheral neuropathic pain. Pharmaceutics 2021;13(4):450.
Moisset X et al. Pharmacological and non-pharmacological treatments for neuropathic pain. Rev Neurol 2020.
Li Z et al. The distinctive role of menthol in pain and analgesia. Front Mol Neurosci 2022;15:1006908.
Liu B et al. TRPM8 is the principal mediator of menthol-induced analgesia. Pain 2013;154(10):2169–77.
Davies SJ et al. A novel treatment of postherpetic neuralgia using peppermint oil. Clin J Pain 2002;18(3):200–2.
Bouhassira D et al. Stratification of patients based on the NPSI. Pain 2021;162(4):1038–46.
Fallon MT et al. Cancer treatment-related neuropathic pain: proof of concept with menthol. Support Care Cancer 2015;23(9):2769–77.
Frisaldi E et al. Placebo and nocebo responses in painful diabetic neuropathy. Pain 2024;165(1):29–43.

Presenting Author: Erwan Treillet
Submitting Author: Erwan Treillet

Senior Author: Erwan Treillet

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Gregoire Oudot: MD - Godinot Institute
• Yacine Hadjiat: MD, PhD - Mohammed Bin Rashid University of Medicine and Health Sciences, College of Medicine, Dubai Healthcare City, United Arab Emirates