Carisoprodol tolerance and precipitated withdrawal

Abstract

Aims Carisoprodol 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. Methods Carisoprodol (0, 100, 200, 300, or 500 mg/kg bid, i.p.) was administered to Swiss-Webster mice for 4 days and loss-of-righting reflex was measured 20 to 30 minutes following each administration. On the fourth day, bemegride (20 mg/kg), flumazenil (20 mg/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 24 hr after the last dose of carisoprodol. Results The righting reflex was dose-dependently impaired following the first administration of carisoprodol. A 75 to 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 24 hours following spontaneous withdrawal; however, bemegride and flumazenil each precipitated withdrawal within 15 to 30 min of administration. Conclusions Carisoprodol 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.

Assessment of subunit-dependent direct gating and allosteric modulatory effects of carisoprodol at GABAA receptors

“…The dangers associated with carisoprodol abuse, such as psychomotor impairment and severe withdrawal that may lead to seizures and death, are well-documented (Adams et al, 1975; Elder, 1991; Littrell et al, 1993; Reeves and Parker, 2003; Rust et al, 1993; Zacny et al, 2011, 2012). Precipitated withdrawal studies in mice have demonstrated tolerance to carisoprodol develops in as few as four doses (Gatch et al, 2012). In recent years, the ready availability of carisoprodol via internet pharmacies has led to increased recreational use of carisoprodol.…”

Mass spectrometric analysis of carisoprodol and meprobamate in rat brain microdialysates

“…N ‐Dealkylation of carisoprodol catalyzed by the cytochrome P450 (CYP) isoform CYP2C19 in the liver results in meprobamate, which also has the ability to enter the CNS . As the midbrain‐forebrain‐extrapyramidal circuit with its focus in the nucleus accumbens has been linked mechanistically to substance abuse, psychoactive drug and metabolite concentrations measured from this site were expected to yield the most relevant information regarding mechanistic and behavioral correlates studied in experimental animals …”

“…[31] As the midbrain-forebrain-extrapyramidal circuit with its focus in the nucleus accumbens has been linked mechanistically to substance abuse, [32] psychoactive drug and metabolite concentrations measured from this site were expected to yield the most relevant information regarding mechanistic and behavioral correlates studied in experimental animals. [10,11] NanoESI, DART and ASAP were evaluated regarding their applicability of chromatography-free MS to carisoprodol and meprobamate analyses in microdialysis samples. Desalting of brain microdialysates is essential for nanoESI; however, it can be done rapidly as part of sample preparation by using ZipTips.…”

“…[5] Based on a propensity to cause abuse, tolerance and physical dependence similar to meprobamate, [6] carisoprodol also was placed more recently to Schedule IV. [7] While it has been widely accepted that the therapeutic actions and abuse potential of carisoprodol can be attributed to its metabolism to meprobamate, [5] recent studies have confirmed that carisoprodol has meprobamate-independent intrinsic effects, [8][9][10] and is itself an active compound with significant barbiturate-like actions in the central nervous system (CNS). [11] One approach to discern how carisoprodol itself and meprobamate contribute to rewarding effects that confer abuse, and dependence, would be to compare the time course of each at relevant sites in the CNS.…”

A Single Amino Acid Residue at Transmembrane Domain 4 of the α Subunit Influences Carisoprodol Direct Gating Efficacy at GABAA Receptors

“…Carisoprodol abuse causes psychomotor impairment and severe withdrawal that may predispose to seizures and death (Bramness et al, 2004;Fass, 2010;Zacny and Gutierrez, 2011;Reeves et al, 2012). Tolerance to carisoprodol develops relatively quickly, facilitating the problems associated with withdrawal (Reeves and Burke, 2010;Gatch et al, 2012). Indeed, considering its alarming abuse rate, carisoprodol was controlled as a Schedule IV substance at the federal level effective January 2012 (Reeves et al, 2012).…”