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Cancer treatment-related neuropathic pain: proof of concept study with menthol-a TRPM8 agonist

Fallon MT, Storey DJ, Krishan A, Weir CJ, Mitchell R, Fleetwood-Walker SM, Scott AC, Colvin LA

Support Care Cancer DOI 10.1007/s00520-015-2642-8, published online 15 February 2015

Editors‘ comment: Dr. Carla Ripamonti

Chemotherapy-induced peripheral neuropathy (CIPN) affects up to 96% of patients who receive potentially neurotoxic chemotherapy resulting in dose reduction or drug discontinuation for up to 50%. The use of adjuvant drugs such as antidepressants and anticonvulsants ± opioids is often not effective in relieving pain and can cause unpleasant adverse effects. A potential novel therapeutic approach has arisen as a result of basic science findings from the translational research Group at the University of Edinburgh. It demonstrated that endogenous neural circuitry underlying cooling-induced analgesia may represent a novel target for intervention. The researchers identified how the activation of the transient receptor potential melastatin (TRPM) 8 ion channel (a molecular receptor for cooling present in sensory nerves active in neuropathic pain) by topical agents such as topical menthol produced significant analgesia. In a proof-of-concept study 82% of patients with CIPN treated with topical 1% menthol cream twice daily had an improvement in total BFI scores (p<0.001), in mood (p=0.0004), catastrophising (p=0.001), walking ability (p=0.008) and sensation (p<0.01). The discovery of the TRP channels has provided an opportunity for the development of analgesics potentially more specific for certain pain syndrome and with a better side-effect profile than other interventions.

Abstract

PURPOSE:
Effective treatment of neuropathic pain without unacceptable side effects is challenging. Cancer sufferers increasingly live with long-term treatment-related neuropathic pain, resulting from chemotherapy-induced peripheral neuropathy (CIPN) or surgical scars. This proof-of-concept study aimed to determine whether preclinical evidence for TRPM8 ion channels in sensory neurons as a novel analgesic target could be translated to clinical benefit in patients with neuropathic pain, using the TRPM8 activator menthol.

PATIENTS AND METHODS:
Patients with problematic treatment-related neuropathic pain underwent a baseline assessment using validated questionnaires, psychophysical testing, and objective functional measures. The painful area was treated with topical 1 % menthol cream twice daily. Assessments were repeated at 4-6 weeks. The primary outcome was the change in Brief Pain Inventory total scores at 4-6 weeks. Secondary outcomes included changes in function, mood and skin sensation.

RESULTS:
Fifty-one patients (female/male, 32/19) were recruited with a median age of 61 (ranging from 20 to 89). The commonest aetiology was CIPN (35/51), followed by scar pain (10/51). Thirty-eight were evaluable on the primary outcome. Eighty-two per cent (31/38) had an improvement in total Brief Pain Inventory scores (median, 47 (interquartile range, 30 to 64) to 34 (6 to 59), P < 0.001). Improvements in mood (P = 0.0004), catastrophising (P = 0.001), walking ability (P = 0.008) and sensation (P < 0.01) were also observed.

CONCLUSION:
This proof-of-concept study indicates that topical menthol has potential as a novel analgesic therapy for cancer treatment-related neuropathic pain. Improvements in patient-rated measures are supported by changes in objective measures of physical function and sensation. Further systematic evaluation of efficacy is required.

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