Carisoprodol tolerance and precipitated withdrawal

Abstract

AimsCarisoprodol is a muscle relaxant that acts at the GABAA receptor. Concerns about the abuse liability of carisoprodol are increasing, but evidence that carisoprodol produces tolerance and a significant withdrawal syndrome has yet to be established. The purpose of the current study was to determine if repeated administration of carisoprodol produces tolerance and withdrawal signs in a mouse model. MethodsCarisoprodol (0, 100, 200, 300, or 500mg/kg bid, i.p.) was administered to Swiss-Webster mice for 4 days and loss-of-righting reflex was measured 20–30min following each administration. On the fourth day, bemegride (20mg/kg), flumazenil (20mg/kg), or vehicle was administered following carisoprodol and withdrawal signs were measured. Separate groups of mice receiving the same treatment regimen and dose range were tested for spontaneous withdrawal at 6, 12 and 24h after the last dose of carisoprodol. ResultsThe righting reflex was dose-dependently impaired following the first administration of carisoprodol. A 75–100% decrease in the magnitude of the impairment occurred over the four days of exposure, indicating the development of tolerance to the carisoprodol-elicited loss-of-righting reflex. Withdrawal signs were not observed within 24h following spontaneous withdrawal; however, bemegride and flumazenil each precipitated withdrawal within 15–30min of administration. ConclusionsCarisoprodol treatment resulted in tolerance and antagonist-precipitated withdrawal, suggesting it may have an addiction potential similar to that of other long-acting benzodiazepine or barbiturate compounds.