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From Bench to Bedside: A Case of Rapid Reversal of Bortezomib-Induced Neuropathic Pain by the TRPM8 Activator, Menthol

Departments of Anaesthesia, Critical Care & Pain Medicine, Western General Hospital, Edinburgh Cancer Centre, Edinburgh, Scotland

Peter R.E. Johnson

Departments of Haematology, Western General Hospital, Edinburgh Cancer Centre, Edinburgh, Scotland

Rory Mitchell

Centre for Integrative Physiology (Membrane Biology Group), School of Biomedical Sciences, University of Edinburgh, Edinburgh, Scotland

Susan M. Fleetwood-Walker

Centre for Neuroscience Research, Division of Veterinary Biomedical Sciences, the Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh, Scotland

Marie Fallon

Department of Palliative Medicine, Western General Hospital, Edinburgh Cancer Centre, Edinburgh, Scotland

To the Editor:

Chemotherapy-induced neuropathic pain can be a major treatment-limiting factor, causing a significant reduction in quality of life. Improved management of chemotherapy-induced peripheral neuropathy is high on the supportive and palliative care research agenda.

Bortezomib, a proteasome inhibitor, is an important new treatment for multiple myeloma, with potential application in the treatment of other malignancies. Unfortunately a treatment-emergent neuropathy has been reported in 35% of patients, with up to 15% suffering from severe neuropathic pain, often requiring the cessation of treatment.¹

We report a case of severe bortezomib-induced neuropathy in a 69-year-old man with a 39-month history of multiple myeloma. Previous treatment included melphalan, cyclophosphamide, dexamethasone, and thalidomide (which was discontinued because of attainment of stable partial response, with no neuropathic symptoms). After a symptomatic increase in paraprotein levels, bortezomib was commenced as third-line antimyeloma treatment. Unfortunately, after two cycles of bortezomib, the patient complained of paraesthesia, numbness, and "lightning-like" pains in both hands, which did not resolve despite a 50% dose reduction for the third cycle.

A month later, he developed an extremely painful peripheral neuropathy (grade 4) in his lower limbs, in a stocking distribution, while his hand symptoms remained mild and unchanged. The pain was characteristic of that found in bortezomib-induced neuropathy.² The predominant feature was severe burning, with significant sleep disturbance, high levels of distress, and reduced general function, such that he was virtually bed-bound. Bortezomib was therefore discontinued, despite a more than 90% reduction in the paraprotein level (36 g/L to 3 g/L).

Treatment for neuropathic pain was limited by significant adverse effects with systemic agents including opioids, gabapentin, pregabalin, and ketamine and increased burning pain after topical capsaicin. When standard treatments for neuropathic pain failed, we decided to use a new approach, based on our recent preclinical discovery of marked analgesic effects of topical transient receptor potential melastatin (TRPM8) receptor activators, icilin and the related agent, menthol, in neuropathy.³ Topical 0.5% menthol in calamine cream was applied to the lower limb stocking distribution (area of pain or sensory disturbance) and to the skin over the lumbosacral region of the spine corresponding with the affected nerve root origins.

Before application, we carried out a detailed pain assessment, with further assessments 90 minutes after menthol application, then 2 weeks later. Bedside Quantitative Sensory Testing was used to give an objective assessment of evoked sensations, using a modification of the German Research Network on Neuropathic Pain protocol.⁴ Briefly, this included assessment for mechanical dynamic allodynia (calibrated brush [SenseLab 0.5N]); establishing mechanical detection threshold and mechanical pain threshold (von Frey filaments [Somedic, Sweden]); assessing thermal responses to warm (40°C) and cool (25°C) stimuli (Rolltemp device [Somedic; Hornby, Sweden]); and a Visual Analog Score (VAS) to quantify response to suprathreshold stimuli and to temporal summation (windup) with rapidly repeated pin-prick stimuli (Neurotips; Owen Mumford; Oxford, United Kingdom). Both affected lower limbs and a control area on the left thigh were tested.

Despite no reduction in global pain score being reported by the patient, profound changes in Quantitative Sensory Testing were detected 90 minutes after menthol application. Spontaneous pain, mechanical detection threshold, and thermal responses were not significantly altered. He did not have thermal allodynia. There was a marked increase in mechanical pain threshold (from 0.145 to 17 g on the right and 0.085 to 5.1 g on the left) with decreased pain in response to suprathreshold stimulus (VAS score changed from 8 to 2 for both right and left side) and complete reversal of wind-up (VAS reduced from 8 to 0). The patient was able to walk without a stick for the first time since the lower limb neuropathy started. These changes were consistently maintained at the 2-week assessment.

The patient continued to apply 0.5% menthol twice daily. After 5 days, he reported a sustained improvement in pain control, sleep, mobility, general function, and mood. This was maintained at 2 weeks with his total Brief Pain Inventory score reduced from 56 to 14 and his Hospital Anxiety and Depression scores reduced from 22 to 16. His hand symptoms, which were not treated with menthol, remained unchanged, suggesting no spontaneous resolution of his neuropathy.

We have demonstrated a rapid and significant therapeutic response using topical menthol to counteract bortezomib-induced neuropathic pain. The rationale for using this therapy was based on our recent findings indicating that the TRPM8 receptor may offer a potential new target for the treatment of neuropathic pain. A prominent analgesic effect of cooling compounds that activate TRPM8 was demonstrated in a rodent model of neuropathic pain. Moderate concentrations of menthol are selective for TRPM8, whereas higher concentrations act on other molecular targets, and adverse effects may predominate.^5,6 TRPM8 forms one of the main transduction mechanisms for moderate cooling, whereas noxious cold involves the TRPA1 receptor. An increase in TRPM8 receptor expression occurs in some sensory neurons after nerve injury, possibly contributing to enhanced sensitivity to cooling agents.³

Of particular interest is the rapid reduction in wind-up and improvement in mechanically evoked responses seen here in a neuropathic state, which were not seen in the volunteer studies.^5,6 This particular effect on mechanical responses correlates well with the specific antineuropathic analgesia found in laboratory studies. One other group has used peppermint oil, containing 10% menthol, for a case of postherpetic neuralgia, where a rapid improvement in pain was also found.⁷

Treatment-related neuropathies can limit successful disease control in cancer care. This is relevant to several classes of therapy, including the proteasome inhibitor, bortezomib. This case demonstrates the value of close collaboration in translational research, with novel laboratory findings being rapidly translated to a direct clinical application.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Richardson PG, Briemberg H, Jagannath S, et al: Frequency, characteristics and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. J Clin Oncol 24:3113-3120, 2006[Abstract/Free Full Text]

2. Cata JP, Weng HR, Burton AW, et al: Quantitative sensory findings in patients with bortezomib-induced pain. J Pain 8:296-306, 2007[CrossRef][Medline]

3. Proudfoot CJ, Garry EM, Cottrell DF, et al: Analgesia mediated by the TRPM8 cold receptor in chronic neuropathic pain. Curr Biol 16:1591-1605, 2006[CrossRef][Medline]

4. Rolke R, Baron R, Maier C, et al: Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values. Pain 123:231-243, 2006[Medline]

5. Hatem S, Attal N, Willer JC, et al: Psychophysical study of the effects of topical application of menthol in healthy volunteers. Pain 122:190-196, 2006[CrossRef][Medline]

6. Wasner G, Schattschneider J, Binder A, et al: Topical menthol: A human model for cold pain by activation and sensitization of C nociceptors. Brain 127:1159-1171, 2004[Abstract/Free Full Text]

7. Davies SJ, Harding LM, Baranowski AP, et al: A novel treatment of postherpetic neuralgia using peppermint oil. Clin J Pain 18:200-202, 2002[CrossRef][Medline]

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