Follow-Up Psychophysical Studies in Bortezomib-Related Chemoneuropathy Patients

Abstract

Many frontline chemotherapeutic agents produce robust neuropathy as a dose-limiting side effect; however, the persistence of chemotherapy-related sensory disturbances and pain are not well-documented. We have previously investigated the qualities of bortezomib-induced pain, and now seek to determine the ongoing nature of this pain. Twenty-six control subjects and eleven patients who had previously been treated with bortezomib and who were experiencing ongoing pain consented to recurring quantitative sensory testing. A pilot immunohistochemistry study of skin innervation was also performed on patient obtained biopsies. Psychophysical testing in patients revealed persistent changes including decreased skin temperature in the area of pain, diminished touch and sharpness detection, increased pegboard completion times, and decreased sensitivity to skin heating. Additionally, the intensity of pain, as captured by the use of a visual analog scale and pain descriptors, was reported by patients to be unchanged during the retest despite similar morphine equivalent daily doses. The patient skin biopsies displayed a marked decrease in the density of epidermal nerve fibers and Meissner’s corpuscles. These results signify a persistent and severe impairment of Aβ, Aδ, and C fibers in patients with chronic bortezomib-induced chemoneuropathy. Further, this study reports a loss of both epidermal nerve fibers and Meissner’s corpuscles. Perspective The results of this article indicate a persistent, painful peripheral neuropathy in patients treated with bortezomib. Pilot data indicates a loss of nerve fibers innervating the area of pain. This is the first paper to address the persistence, and potential contributing factors, of bortezomib chemoneuropathy.

A Quantitative Sensory Analysis of Peripheral Neuropathy in Colorectal Cancer and Its Exacerbation by Oxaliplatin Chemotherapy

“…Three sites were tested in each subject, the tip of the index finger, the thenar eminence, and the volar surface of the forearm to encompass the areas of skin that are typically affected in chronic CIPN patients (2-5). QST were conducted by two clinical data coordinators with many years’ experience and with previously verified excellent inter-rater reliability (2-5). The specific tests that were performed included the following and were performed in the order described.…”

“…Touch detection threshold was determined using von Frey monofilaments (Semmes-Weinstein) in an up/down manner as previously described (2). The filaments were applied for 1 second at each testing site starting with a force of 0.5 g and the patients unable to see the stimulus application.…”

“…Thermal detection threshold was determined using a 3.6 x 3.6cm Peltier probe set at a baseline temperature of 32°C (2). The probe temperature was ramped upward at a rate of 0.30°C/s for detection of warmth and heat pain thresholds, whereas cool detection and cold pain threshold was determined using a decreasing ramp of 0.50°C/s.…”

“…The mechanism for chemotherapy induced peripheral neuropathy (CIPN) is poorly understood. Primary afferent neurons appear to be the most vulnerable as most commonly sensory symptoms alone start in the tips of the toes and fingers and then advance over time proximally in a “stocking-glove” distribution (2-5). More specifically, pain is typically reported in the tips of the toes and fingers; numbness and tingling, but not necessarily pain is present in the soles of the feet and palms; while hairy skin is typically outside the areas of patient complaint (3'6).…”

Quantitative Sensory Testing in Pain Management

“…However, due to the immense variety of musculoskeletal disorders, several QST test batteries are needed to analyze the associated pathologies. Another use of QST takes advantage of its selectivity to assess the toxic effects of neurotoxic agents on specific small fibers in cancer therapy [23]. This use of QST has expanded our understanding of the adverse effects of certain chemotherapies.…”