Cold aggravates abnormal excitability of motor axons in oxaliplatin‐treated patients

Abstract

Introduction Cold allodynia is often seen in the acute phase of oxaliplatin treatment, but the underlying pathophysiology remains unclear. Methods Patients scheduled for adjuvant oxaliplatin for colorectal cancer were examined with quantitative sensory testing and nerve excitability tests at baseline and after the second or third oxaliplatin cycle at different skin temperatures. Results Seven patients were eligible for examination. All patients felt evoked pain and tingling when touching something cold after oxaliplatin infusion. Oxaliplatin decreased motor nerve superexcitability (P < .001), increased relative refractory period (P = .011), and caused neuromyotonia‐like after‐activity. Cooling exacerbated these changes and prolonged the accommodation half‐time. Discussion The findings suggest that a combined effect of oxaliplatin and cooling facilitates nerve excitability changes and neuromyotonia‐like after‐activity in peripheral nerve axons. A possible mechanism is the slowing in gating of voltage‐dependent fast sodium and slow potassium channels, which results in symptoms of cold allodynia.

Predictive Biomarkers of Oxaliplatin-Induced Peripheral Neurotoxicity

“…Acute symptoms after OXA infusion correlate with nerve excitability findings [56]. This method can assess acute OXA-induced abnormalities in sensory or motor nerve function [56], and its cold-triggered aggravation [89].…”

“…Acute symptoms after OXA infusion correlate with nerve excitability findings [ 56 ]. This method can assess acute OXA-induced abnormalities in sensory or motor nerve function [ 56 ], and its cold-triggered aggravation [ 89 ]. Measurement of excitability parameters have been consistently shown to be a sensitive early biomarker of ongoing OXAIPN, even preceding the reduction in the SNAP and development of symptoms [ 76 , 90 , 91 ].…”

A test to determine the site of abnormal neuromuscular refractoriness

“…This study will focus on refractoriness, which is commonly expressed in terms of the relative refractory period (RRP), the interval between a supramaximal conditioning stimulus and the test stimulus at which excitability returns to its baseline value, and refractoriness switches to superexcitability. The RRP is prolonged by membrane depolarization and ischaemia ( Kiernan and Bostock, 2000 ) and prolongation is a common finding in nerve excitability tests of patients with axonal Guillain-Barre syndrome ( Kuwabara et al, 2003 ), uremic neuropathy ( Krishnan et al, 2005 ) and after treatment with oxaliplatin ( Park et al, 2011 , Heide et al, 2018 , Bennedsgaard et al, 2020 ). On the other hand it can also be decreased, as in episodic ataxia type 1 ( Tomlinson et al, 2010 ) and multifocal motor neuropathy ( Kovalchuk et al, 2020 ).…”

JI017 Attenuates Oxaliplatin-Induced Cold Allodynia via Spinal TRPV1 and Astrocytes Inhibition in Mice

“…According to a report, about 90% of oxaliplatin-treated patients suffered acute pain, which can be initiated only 24 h after a single injection of oxaliplatin [6]. Cold and mechanical allodynia are common occurring symptoms in animal models of oxaliplatin-induced neuropathic pain [7,8]. However, no optimal drug, without any side effects, has been developed, and the underlying mechanisms of this neuropathy still need to be elucidated [9].…”