Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy

Flatters, Sarah J.L; Bennett, Gary J

doi:10.1016/j.pain.2004.01.029

Cited by 576Cancer Treatment and PharmacologyPain Mechanisms and TreatmentsPain Management and Opioid Use

Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy

Flatters, Sarah J.L, Bennett, Gary J·2004·Pain

DOI 10.1016/j.pain.2004.01.029

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Abstract

Paclitaxel (Taxol) is one of the most effective and frequently used chemotherapeutics for the treatment of solid tumours. However, paclitaxel produces peripheral neurotoxicity with patients reporting sensory abnormalities and neuropathic pain during and often persisting after paclitaxel therapy. The mechanisms underlying this dose-limiting side effect are currently unknown and there are no validated drugs for its prevention or control. Male Sprague-Dawley rats received four intraperitoneal (i.p.) injections on alternate days of 2 mg/kg paclitaxel. Behavioural assessment using von Frey filaments and acetone showed that such paclitaxel treatment induced a pronounced mechanical and cold allodynia/hyperalgesia. Thus these studies aim to test potential analgesics on established paclitaxel-induced pain. Paclitaxel-induced pain appears to be relatively resistant to opioid therapy i.p. 4 mg/kg morphine was ineffective and i.p. 8 mg/kg morphine only elicited up to a 50% reversal of mechanical allodynia/hyperalgesia. Interestingly, a maximally tolerated dose (i.p. 0.2 mg/kg) of the potent NMDA receptor antagonist MK-801 produced no significant reversal of the mechanical allodynia/hyperalgesia suggesting that NMDA receptors have little role in paclitaxel-induced pain. Ethosuximide (i.p. 450 mg/kg) an anti-epileptic and relatively selective T-type calcium channel blocker elicited a near complete reversal of mechanical allodynia/hyperalgesia. Repetitive dosing with ethosuximide (i.p. 100 or 300 mg/kg daily for 3 days) showed a dose-related consistent reversal of mechanical allodynia/hyperalgesia with no evidence of tolerance. Ethosuximide (i.p. 300 mg/kg) also reversed paclitaxel-induced cold allodynia and vincristine-induced mechanical allodynia/hyperalgesia. These data suggest that T-type calcium channels may play a role in chemotherapy-induced neuropathy and moreover identify ethosuximide as a new potential treatment for chemotherapy-induced pain.

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Using the Flatters and Bennett paclitaxel dosing paradigm, mechanical allodynia but not thermal hyperalgesia was observed.
“Using the paclitaxel dosing paradigm described by Flatters and Bennett,120 mechanical allodynia, but not thermal hyperalgesia, was observed.”
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Authors: Flatters, S. J. L., & Bennett, G. J.
Affiliations: McGill University (CA)
Corresponding author: Flatters, Sarah J.L
ORCID: Flatters, Sarah J.L
Venue: Pain
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2004-05
Volume: 109
Issue: 1
Pages: 150-161
ISSN: 0304-3959 (ISSN-L)
DOI: 10.1016/j.pain.2004.01.029
OpenAlex: W2094267095
Cited by: 576
References: 67
Citations by year: 2026: 9 · 2025: 17 · 2024: 17 · 2023: 25 · 2022: 39 · 2021: 35 · 2020: 34 · 2019: 30 · 2018: 25 · 2017: 28 · 2016: 24 · 2015: 39 · 2014: 40 · 2013: 26 · 2012: 27
FWCI: 11.27
Type: journal article
Language: en
Open access: closed
Locations: Pain (publishedVersion)
PubMed (publishedVersion)
Research Portal (King's College London) (submittedVersion)
Topics: Health Sciences › Medicine › Oncology › Cancer Treatment and Pharmacology
Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
Keywords: ethosuximide, paclitaxel, vincristine, chemotherapy-induced peripheral neuropathy, neuropathic pain, T-type calcium channels, mechanical allodynia, cold allodynia, hyperalgesia, morphine, antiepileptic drugs
MeSH terms: Animals, Behavior, Animal, Calcium Channel Blockers, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Interactions, Ethosuximide, Male, Morphine, Narcotics, Neuralgia, Pain Measurement, Physical Stimulation, Time Factors, Vincristine, Dizocilpine Maleate, Rats, Sprague-Dawley, Paclitaxel, Excitatory Amino Acid Antagonists, Rats

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Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy

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