Topical menthol for the management of peripheral neuropathic pain

Medical Research Scotland
PhD Studentship Award

This project is one of 13 four year PhD Studentships funded by Medical Research Scotland (http://www.medicalresearchscotland.org.uk) to be delivered jointly by the named University and Company. The Studentship will provide the first-class academic and commercial training needed to equip the successful candidate for a science career in an increasingly competitive market.

"Rapid translation from bench to bedside of topical menthol, a TRPM8 agonist, for management of peripheral neuropathic pain, using an RCT with fMRI" to be delivered by the University of Edinburgh [Supervisors: Professor Marie Fallon (Institute of Genetics and Molecualr Medicine), Dr Heather Whalley (Centre for Clinical Brain Sciences), Professor Susan Fleetwood-Walker and Dr Paul Mitchell (both Centre for Discovery Brain Sciences)] and The Mentholatum Company Ltd (https://www.mentholatum.co.uk/) [Company supervisor: Mr Colin Brown].

Chemotherapy-induced peripheral neuropathy (CIPN) occurs in up to 70% of patients receiving chemotherapy for cancer. CIPN frequently limits chemotherapy dose and results in poor quality of life and function. Current analgesic treatment options for CIPN are severely limited and include oral antidepressants and anticonvulsants, which display low efficacy and intolerable or dangerous side effects. At present the only effective long-term option is chemotherapy cessation or dose reduction, which may still not improve established CIPN and may impact on survival. Safe, effective analgesia for CIPN patients is an important unmet need.

Assessment of new analgesics by randomised controlled trials (RCTs) is complicated by the subjective nature of pain and the influence of an active placebo response, resulting in analgesic RCTs often describing small effect sizes, which are difficult to interpret clinically. Specifically in CIPN, the varied individual experiences of neuropathic pain, not easy to standardise clinically or with Quantitative Sensory Testing (QST), make the assessment of new analgesics particularly difficult.

The advent of fMRI as a research tool, with its ability to detect alterations in regional CNS activity underpinning behavioural changes, has greatly aided in unravelling processes of plasticity in the CNS.

In our earlier preclinical work we discovered that peripheral activation of non-nociceptive afferents, which express the TRPM8 ion channel (and normally participate in sensing innocuous cool temperatures) results in central suppression of hypersensitive neuropathic pain. The mechanism appears to involve non-opioid gating within the spinal dorsal horn, but how this impacts on supraspinal pain processing is unknown. Our group and others have provided case study and proof-of-concept open label trial data establishing the clinical efficacy of this strategy in neuropathic pain patients. Evolving this evidence is now very important clinically. Our RCT of topical menthol vs placebo for CIPN, with embedded fMRI should enhance the evidence base significantly. The study will provide important new opportunities to assess alignment between clinical, QST and fMRI evaluation of the efficacy of TRPM8 agonist treatment and further, gain insights into functional (and connectivity) changes in forebrain regions registering affective, as well as sensory-discriminitive pain responses.

As an integral member of our Translational Pain Research grouping, the successful candidate will be supported with full training courses in fMRI analysis and will learn how to develop fMRI paradigms, acquire fMRI scans and subsequently analyse them. He/she will be will be working alongside an experienced medical team and will be concentrating on the embedded fMRI part of the project. There will be a unique opportunity to link with industry and understand the process of drug development to approval.

Professor Marie Fallon leads a programme of clinical research in cancer related symptoms and links closely with translational and basic science colleagues: Prof Sue Fleetwood-Walker and Dr Rory Mitchell (who discovered analgesic activity of TRPM8 activation in neuropathic pain) and Dr Heather Whalley-Sibley, who is a Senior Fellow and expert in fMRI.

ENQUIRIES:

Enquiries should be sent by email to Professor Marie Fallon:
[Email Address Removed]

APPLICATIONS:

Candidates must have obtained, or expect to obtain, a minimum 2.1 undergraduate degree, or equivalent for degrees obtained outside the UK, in a relevant discipline. Previous experience with fMRI is desirable and good communication skills are required as the successful candidte will have direct patient contact around the time of scans.

Candidates should send a full Curriculum Vitae, the contact details of 2 academic references (including email addresses), and a covering letter, explaining why they wish to carry out this project, by email to Mrs Harriet Harris:
[Email Address Removed]

Interviews are expected to take place approximately 3-4 weeks after the closing date for applications.

It is anticipated that the PhD Studentship will start in September or October 2018.