Title: A phase II RCT of topical menthol gel versus placebo in cancer chemotherapy-related peripheral neuropathic pain
Funder: Marie Curie

Abstract: Cancer-related pain is the commonest reason for out of hours emergency contact with cancer patients1. Neuropathic pain is a common cause for poorly controlled cancer pain. It is becoming more complex and difficult to manage, because of chemotherapy-induced peripheral neuropathy(CIPN). CIPN has emerged over the last decade as a major clinical challenge. CIPN is painful and predominantly sensory, affecting up to 90% of patients and persisting in about 50% of all patients who have received neurotoxic chemotherapy (120,000 per year in UK). There are no effective preventive treatments nor predictable management strategies. The sequelae which evolve as patients reach the terminal phase are underpinned by an exacerbation of all other pains by this neuropathy2. We have been working on this challenge for 10 years, and identified in a laboratory model of neuropathic pain a novel yet simple way to manage this problem, using the topical transient receptor potential melastatin (TRPM8) channel agonist; menthol3. We translated this to the clinic and have several publications refelecting our work, including a successful phase 1/Proof of Concept study with topical levomenthol cream (1%)4. We have refined the treatment since the PoC, with identification of optimum and safe menthol dose (at 5% rather than 1%), frequency (twice daily) and formulation (gel is easier to use than cream). We have also developed a robust placebo gel, which looks, smells and has the same texture as menthol gel and does not have any measurable activity at the TRPM8 receptor5. We are now ready to conduct an exploratory randomised,double blind placebo-controlled phase 2 study. Embedded fMRI analysis will enable correlation to effects on central nervous system regions activated during pain processing. In neuropathic pain in particular, assessment of new analgesics in RCTs is compromised by both poor characterisation of pain and increased active placebo response6-10. Such analgesic RCTs often describe small effect sizes, difficult to interpret clinically7.This contributes to the current situation of often poorly controlled neuropathic pain in cancer patients. The advent of fMRI as a research tool, with its ability to objectively detect pain-associated changes in specific brain regions, has greatly aided in elucidating neuropathic pain perception11-13. In particular the subjective non-standardised nature of pain has become more readily understood using fMRI12. Over the last decade fMRI has also been implemented in drug discovery and drug efficacy assessment14. We have completed successful studies using fMRI in peripheral neuropathic pain15,16. To overcome barriers with neuropathic pain trials, we will embed fMRI in the proposed phase 2 double-blind placebo-controlled RCT of topical menthol gel, in patients with chronic CIPN for independent corroboration. Using established understanding of central mechanisms of analgesia and of the placebo response, fMRI will facilitate the assessment of a potentially centrally-mediated analgesic effect of menthol and distinguish this from a placebo response. We will recruit oncology patients with chronic stable CIPN, as this is a major problem, both in itself and in its impact on accentuating other cancer related pain(s). Consenting patients fulfilling inclusion/exclusion criteria, would (following baseline assessments) apply a gel themselves to the affected areas twice daily. Primary outcome: 4 weeks. Clinically significant reduction in pain (at least a 30% decrease in BPI SF as relates to index neuropathic pain). Secondary outcomes: 4 weeks. BPI SF Combined sensory and motor scales for CIPN (CIPN-20) Functional interference (BPI scale) Anxiety and depression (HADS) Side-effects Psychophysical testing (QST) (fMRI analysis related tests DSST,GCOS,NART) fMRI baseline and 4 weeks. Patients will have a 12 week follow-up to assess ongoing analgesic response (BPI-SF). Methods and analysis: Single centre, randomised, double blind, placebo-controlled phase 2 study (with embedded fMRI) of topical menthol gel versus placebo gel in cancer treatment-induced neuropathy. Forty patients (to allow for at least 32 completed patients) will be randomised in a 1:1 ratio to receive 5% levomenthol or placebo gel for 4 weeks. Patients will undergo fMRI scan prior to treatment allocation with a repeat scan at 4 weeks. The primary end point, which is a patient reported outcome of pain, will be compared to identification of diminished activation of established pain brain networks and to placebo networks. Exploration of ongoing analgesia at 12 weeks. This work will allow us to decide very efficiently if a phase 3 study is justified.


Research activity codes: 7.2 END OF LIFE CARE;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS