Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy.

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.

• Authors: Sarah J L Flatters, Gary J Bennett
• Journal: Pain (Pain) Vol. 109 Issue 1-2 Pg. 150-61 (May 2004) ISSN: 0304-3959 [Print] United States
• PMID: 15082137 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calcium Channel Blockers
• Excitatory Amino Acid Antagonists
• Narcotics
• Vincristine
• Ethosuximide
• Dizocilpine Maleate
• Morphine
• Paclitaxel

Topics

• Animals
• Behavior, Animal
• Calcium Channel Blockers (administration & dosage, therapeutic use)
• Dizocilpine Maleate (administration & dosage)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Drug Interactions
• Ethosuximide (administration & dosage, therapeutic use)
• Excitatory Amino Acid Antagonists (administration & dosage)
• Male
• Morphine (administration & dosage)
• Narcotics (administration & dosage)
• Neuralgia (chemically induced, drug therapy)
• Paclitaxel (adverse effects)
• Pain Measurement (drug effects)
• Physical Stimulation (methods)
• Rats
• Rats, Sprague-Dawley
• Time Factors
• Vincristine (adverse effects)