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Glenn H Dillon - One of the best experts on this subject based on the ideXlab platform.
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A Single Amino Acid Residue at Transmembrane Domain 4 of the α Subunit Influences Carisoprodol Direct Gating Efficacy at GABAA Receptors.
The Journal of pharmacology and experimental therapeutics, 2017Co-Authors: Manoj Kumar, Manish Kumar, John M. Freund, Glenn H DillonAbstract:The muscle relaxant Carisoprodol has recently been controlled at the federal level as a Schedule IV drug due to its high abuse potential and consequences of misuse, such as withdrawal syndrome, delusions, seizures, and even death. Recent work has shown that Carisoprodol can directly gate and allosterically modulate the type A GABA (GABAA) receptor. These actions are subunit-dependent; compared with other GABAA receptors, Carisoprodol has nominal direct gating effects in α3β2γ2 receptors. Here, using site-directed mutagenesis and whole-cell patch-clamp electrophysiology in transiently transfected human embryonic kidney 293 cells, we examined the role of GABAA receptor α subunit transmembrane domain 4 (TM4) amino acids in direct gating and allosteric modulatory actions of Carisoprodol. Mutation of α3 valine at position 440 to leucine (present in the equivalent position in the α1 subunit) significantly increased the direct gating effects of Carisoprodol without affecting its allosteric modulatory effects. The corresponding reverse mutation, α1(L415V), decreased Carisoprodol direct gating potency and efficacy. Analysis of a series of amino acid mutations at the 415 position demonstrated that amino acid volume correlated positively with Carisoprodol efficacy, whereas polarity inversely correlated with Carisoprodol efficacy. We conclude that α1(415) of TM4 is involved in the direct gating, but not allosteric modulatory, actions of Carisoprodol. In addition, the orientation of alkyl or hydroxyl groups at this position influences direct gating effects. These findings support the likelihood that the direct gating and allosteric modulatory effects of Carisoprodol are mediated via distinct binding sites.
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JPET #151142 1 Title Page
2016Co-Authors: L A Gonzalez, Cynthia M Taylor, Cathy L Bell-Horner, Michael B Gatch, Michael J, Glenn H DillonAbstract:Carisoprodol-mediated modulation of GABAA receptors: in vitro and in vivo studie
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Carisoprodol: Update on Abuse Potential and Mechanism of Action
Molecular and Cellular Pharmacology, 2015Co-Authors: Manoj Kumar, Glenn H DillonAbstract:800x600 Carisoprodol is a centrally-acting skeletal muscle relaxant frequently prescribed for acute musculoskeletal conditions. Recreational use of Carisoprodol is an increasing problem. Tolerance to Carisoprodol develops quickly and abusers often take 10-20 times the normal dose, leading to intoxicating effects. Also, abrupt cessation of Carisoprodol results in severe withdrawal syndrome including delusions, seizures and even death. Considering its alarming rate of abuse and subsequent consequences, Carisoprodol was scheduled (schedule IV) at the federal level effective January 11, 2012 . Until recently, it was widely accepted that the sedative and muscle relaxant effects of Carisoprodol were due predominantly to its metabolite, meprobamate. However, it is now clear that Carisoprodol itself modulates and directly gates γ-aminobutyric acid type A receptors (GABA A Rs), the predominant inhibitory neurotransmitter receptors in mammalian brain. Recent work has provided additional insight into Carisoprodol’s interaction with GABA A Rs. This may underlie the ability of Carisoprodol in enhancing the sedative effects of CNS depressants, contributing to its potential for abuse. In this review, we discuss current understanding with regard to the abuse potential of Carisoprodol, therapeutic and abuse-related actions of this drug, and possible molecular actions that underlie these effects. Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman","serif";}
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Assessment of subunit-dependent direct gating and allosteric modulatory effects of Carisoprodol at GABAA receptors ☆
Neuropharmacology, 2015Co-Authors: Manoj Kumar, L A Gonzalez, Glenn H DillonAbstract:Abstract Carisoprodol is a widely prescribed muscle relaxant, abuse of which has grown considerably in recent years. It directly activates and allosterically modulates α1β2γ2 GABA A Rs, although the site(s) of action are unknown. To gain insight into the actions of Carisoprodol, subunit-dependent effects of this drug were assessed. Whole-cell patch clamp recordings were obtained from HEK293 cells expressing α1β2, α1β3 or αxβzγ2 (where x = 1–6 and z = 1–3) GABA A Rs, and in receptors incorporating the δ subunit (modeling extrasynaptic receptors). The ability to directly gate and allosterically potentiate GABA-gated currents was observed for all configurations. Presence or absence of the γ2 subunit did not affect the ability of Carisoprodol to directly gate or allosterically modulate the receptor. Presence of the β1 subunit conferred highest efficacy for direct activation relative to maximum GABA currents, while presence of the β2 subunit conferred highest efficacy for allosteric modulation of the GABA response. With regard to α subunits, Carisoprodol was most efficacious at enhancing the actions of GABA in receptors incorporating the α1 subunit. The ability to directly gate the receptor was generally comparable regardless of the α subunit isoform, although receptors incorporating the α3 subunit showed significantly reduced direct gating efficacy and affinity. In extrasynaptic (α1β3δ and α4β3δ) receptors, Carisoprodol had greater efficacy than GABA as a direct gating agonist. In addition, Carisoprodol allosterically potentiated both EC 20 and saturating GABA concentrations in these receptors. In assessing voltage-dependence, we found direct gating and inhibitory effects were insensitive to membrane voltage, whereas allosteric modulatory effects were affected by membrane voltage. Our findings demonstrate direct and allosteric effects of Carisoprodol at synaptic and extrasynpatic GABA A Rs and that subunit isoform influences these effects.
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Assessment of subunit-dependent direct gating and allosteric modulatory effects of Carisoprodol at GABAA receptors
Neuropharmacology, 2015Co-Authors: Lorie A. González, Glenn H DillonAbstract:Carisoprodol is a widely prescribed muscle relaxant, abuse of which has grown considerably in recent years. It directly activates and allosterically modulates α1β2γ2 GABAARs, although the site(s) of action are unknown. To gain insight into the actions of Carisoprodol, subunit-dependent effects of this drug were assessed. Whole-cell patch clamp recordings were obtained from HEK293 cells expressing α1β2, α1β3 or αxβzγ2 (where x = 1-6 and z = 1-3) GABAARs, and in receptors incorporating the δ subunit (modeling extrasynaptic receptors). The ability to directly gate and allosterically potentiate GABA-gated currents was observed for all configurations. Presence or absence of the γ2 subunit did not affect the ability of Carisoprodol to directly gate or allosterically modulate the receptor. Presence of the β1 subunit conferred highest efficacy for direct activation relative to maximum GABA currents, while presence of the β2 subunit conferred highest efficacy for allosteric modulation of the GABA response. With regard to α subunits, Carisoprodol was most efficacious at enhancing the actions of GABA in receptors incorporating the α1 subunit. The ability to directly gate the receptor was generally comparable regardless of the α subunit isoform, although receptors incorporating the α3 subunit showed significantly reduced direct gating efficacy and affinity. In extrasynaptic (α1β3δ and α4β3δ) receptors, Carisoprodol had greater efficacy than GABA as a direct gating agonist. In addition, Carisoprodol allosterically potentiated both EC20 and saturating GABA concentrations in these receptors. In assessing voltage-dependence, we found direct gating and inhibitory effects were insensitive to membrane voltage, whereas allosteric modulatory effects were affected by membrane voltage. Our findings demonstrate direct and allosteric effects of Carisoprodol at synaptic and extrasynpatic GABAARs and that subunit isoform influences these effects.
Michael J. Forster - One of the best experts on this subject based on the ideXlab platform.
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Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to meprobamate.
Neuropharmacology, 2020Co-Authors: Theresa M. Carbonaro, Michael B Gatch, Michael J. Forster, Vien Nguyen, Laszlo ProkaiAbstract:Abstract Carisoprodol (Soma®) is a centrally-acting skeletal-muscle relaxant frequently prescribed for treatment of acute musculoskeletal conditions. Carisoprodol's mechanism of action is unclear and is often ascribed to that of its active metabolite, meprobamate. The purpose of this study was to ascertain whether Carisoprodol directly produces behavioral effects, or whether metabolism to meprobamate via cytochrome P450 (CYP450) enzymatic reaction is necessary. Rats were trained to discriminate Carisoprodol (100 mg/kg) to assess time course and whether a CYP450 inhibitor (cimetidine) administered for 4 days would alter the discriminative effects of Carisoprodol. Additionally, pharmacokinetics of Carisoprodol and meprobamate with and without co-administration of cimetidine were assessed via in vivo microdialysis combined with liquid-chromatography–tandem mass spectrometry from blood and nucleus accumbens (NAc). The time course of the discriminative-stimulus effects of Carisoprodol closely matched the time course of the levels of Carisoprodol in blood and NAc, but did not match the time course of meprobamate. Administration of cimetidine increased levels of Carisoprodol and decreased levels of meprobamate consistent with its interfering with metabolism of Carisoprodol to meprobamate. However, cimetidine failed to alter the discriminative-stimulus effects of Carisoprodol. Carisoprodol penetrated into brain tissue and directly produced behavioral effects without being metabolized to meprobamate. These findings indicate that understanding the mechanism of action of Carisoprodol independently of meprobamate will be necessary to determine the validity of its clinical uses.
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Mass spectrometric analysis of Carisoprodol and meprobamate in rat brain microdialysates.
Journal of mass spectrometry : JMS, 2016Co-Authors: Laszlo Prokai, Vien Nguyen, Petr Fryčák, Michael J. ForsterAbstract:We report the evaluation of several mass spectrometry-based methods for the determination of Carisoprodol and meprobamate in samples obtained from the rat brain by in vivo intracranial microdialyis. Among the techniques that aspire to perform analyses without chromatographic separation and thereby increase throughput, chip-based nanoelectrospray ionization and the use of an atmospheric pressure solids analysis probe fell short of requirements because of insufficient detection sensitivity and hard ionization, respectively. Although direct analysis in real time provided the required soft ionization, shortcomings of a tandem mass spectrometry-based assay also included inadequate detection sensitivity and, in addition, poor quantitative reproducibility. Therefore, liquid chromatography coupled with atmospheric pressure chemical ionization tandem mass spectrometry was developed to determine Carisoprodol and meprobamate from artificial cerebrospinal fluid as the medium. No desalting and/or extraction of the samples was necessary. The assay, combined with in vivo sampling via intracranial microdialyis, afforded time-resolved concentration profiles for the drug and its major metabolite from the nucleus accumbens region of the brain in rats after systemic administration of Carisoprodol. Copyright © 2016 John Wiley & Sons, Ltd.
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Carisoprodol tolerance and precipitated withdrawal.
Drug and alcohol dependence, 2011Co-Authors: Michael B Gatch, Jacques D Nguyen, Theresa Carbonaro, Michael J. ForsterAbstract:Carisoprodol is a muscle relaxant that acts at the GABA(A) 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. 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 20-30 min 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 h after the last dose of Carisoprodol. The 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 15-30 min of administration. 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. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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Carisoprodol Tolerance and Precipitated Withdrawal
Drug and Alcohol Dependence, 2011Co-Authors: Michael B Gatch, Theresa M. Carbonaro, Jacques D Nguyen, Michael J. ForsterAbstract: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.
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Behavioral and toxicological effects of propofol
Behavioural pharmacology, 2011Co-Authors: Michael B Gatch, Michael J. ForsterAbstract:There is increasing concern about abuse of propofol, a widely-used surgical anesthetic and sedative that is currently not a controlled substance. The purpose of the present study was to establish a rat model of the psychoactive effect of sub-anesthetic doses of propofol that could be useful for confirming abuse liability and studying mechanisms of propofol abuse. Sprague-Dawley rats were trained to discriminate propofol (10 mg/kg, i.p.) from vehicle (2% methylcellulose). Carisoprodol (100 mg/kg), chlordiazepoxide (10 mg/kg) and dizocilpine (0.1 mg/kg) were tested for substitution for the discriminative-stimulus effects of propofol (10 mg/kg), whereas pentylenetetrazol (10 mg/kg) was tested for antagonism of the discriminative-stimulus effects. Propofol (10 mg/kg) was tested for substitution in rats trained to discriminate Carisoprodol from vehicle. Carisoprodol produced 59% propofol-appropriate responding, chlordiazepoxide 65%, and dizocilpine 34%. Pentylenetetrazol decreased propofol-appropriate responding to 41%. Propofol produced 52% Carisoprodol-appropriate responding. Mortality rate during training of 10 mg/kg propofol was 38%. Post-mortem examination revealed cardiovascular abnormalities similar to those observed in propofol-infusion syndrome in humans. The results demonstrate that propofol can be trained as a discriminative stimulus. Its discriminative-stimulus effects were more similar to compounds promoting GABA-A receptor activity than to a compound inhibiting NMDA receptor activity. Because propofol has discriminative-stimulus effects similar to known drugs of abuse and occasions a high mortality rate, its potential for continued abuse is of particular concern.
Jorgen G Bramness - One of the best experts on this subject based on the ideXlab platform.
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Drug and Alcohol Dependence 74 (2004) 311–318 Impairment due to intake of Carisoprodol
2015Co-Authors: Jorgen G Bramness, Svetlana Skurtveit, Jørg MørlAbstract:Background: Carisoprodol is a centrally acting muscle relaxant commonly used for lower back pain. It is a drug of abuse and has been detected among impaired drivers. Carisoprodol’s active metabolite meprobamate is thought to act through the GABAA receptor complex and produces a well-known impairing effect. It is unclear whether therapeutic intake of Carisoprodol leads to impairment, and the effect of supratherapeutic doses has not been investigated. Possible impairment could further be a product of the parent drug and/or the metabolite meprobamate. The present study aimed to investigate if Carisoprodol had an impairing effect by it self. Methods: From the database at the Norwegian Institute of Public Health, Division for Forensic Toxicology and Drug Abuse 62 cases containing Carisoprodol and meprobamate as only drugs were identified. These cases constituted our material. Results: Impaired drivers (73%) had higher blood Carisoprodol concentration than not impaired drivers (27%), but no difference in blood meprobamate concentration was found for all the drivers viewed together. Amongst occasional users of Carisoprodol, however, there was difference in blood meprobamate concentration between not impaired and impaired drivers. The risk of being judged impaired rose with increasing blood Carisoprodol concentration, but not with increasing blood meprobamate concentration. The clinical effects of Carisoprodol as measured by the clinical test for impairment (CTI) resembled those of benzodiazepines with some important differences such as tachycardia, involuntary movements, hand tremor and horizontal gaze nystagmus, which may be specific Carisoprodol effects. Conclusion: Carisoprodol probably has an impairing effect by itself, at least at blood concentration levels above which can be seen after therapeutic intake of the drug
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CYP2C19 genetics in fatal Carisoprodol intoxications
European journal of clinical pharmacology, 2012Co-Authors: Gudrun Høiseth, Jorgen G Bramness, Jørg Mørland, Umair Majid, Espen MoldenAbstract:Introduction Carisoprodol, a frequently used muscle relaxant, can cause potentially fatal intoxications. Conversion to its active metabolite meprobamate is almost solely mediated by cytochrome P450 2C19 (CYP2C19), and mutations in this enzyme could have significant effects on serum concentrations. The objective of this study was to investigate the role of CYP2C19 genetics in mortalities due to Carisoprodol intoxication.
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Effect of the market withdrawal of Carisoprodol on use of other prescribed drugs with abuse potential.
Clinical pharmacology and therapeutics, 2012Co-Authors: Jorgen G Bramness, Svetlana Skurtveit, Kari Furu, Anicee Van EngelandAbstract:Carisoprodol, a centrally acting muscle relaxant indicated for acute lower back pain, has been available in Europe and the United States since 1959. Studies indicating increased risk of abuse or addiction led to withdrawal of the drug from the market in Norway and other EU countries in 2008. In this nationwide longitudinal prescription study of 53,116 individuals in Norway, previous users of Carisoprodol switched, to a limited extent, to other prescribed drugs with abuse potential after the withdrawal.
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Can the total consumption of a medicinal drug be used as an indicator of excessive use? The case of Carisoprodol
Drugs Educ Prev Pol, 2010Co-Authors: Jorgen G Bramness, Ingeborg RossowAbstract:Background: The total consumption model implies a close relationship between the population mean of a health variable and prevalence of individuals at high risk concerning this variable in a population. The model applies well to alcohol consumption and prevalence of heavy drinkers, but has so far not been tested for prescription drugs with abuse potential. Carisoprodol is such a drug. Aim: To explore whether the total consumption model applies to the overall sales and prevalence of excessive use of the prescription drug Carisoprodol. Data and measures: Norwegian wholesale statistics for Carisoprodol were compared to data from the Norwegian prescription database on individuals’ use of the drug in 2004. Three different indicators of excessive use of Carisoprodol were applied. County was the unit of analysis. Findings: Log transformed data of total annual amount of Carisoprodol use showed a close to normal distribution. There was a close relationship between the sales figures and each of the three indicators...
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The role of pharmacoepidemiological studies in the market withdrawal of Carisoprodol (Somadril®) in Europe.
Norsk Epidemiologi, 2009Co-Authors: Jorgen G Bramness, Ingebjørg Buajordet, Svetlana SkurtveitAbstract:Carisoprodol is a centrally acting muscle relaxant that has been marketed in Europe for more than 45 years. In November 2007 the European Medicines Association recommended suspension of all Carisoprodol containing products in all EU countries. During recent years, several observational studies on Carisoprodol have been published by our group, which works in the field of traffic medicine and pharmacoepidemiological research in general. In this paper, we review the role pharmacoepidemiological studies on Carisoprodol played in providing evidence for the risk of psychomotor impairment and traffic accidents, intoxications and abuse. These issues have been important for decisions about the regulation of Carisoprodol. Key words: pharmacoepidemiology, Carisoprodol, drug abuse, impairment, intoxication
Michael B Gatch - One of the best experts on this subject based on the ideXlab platform.
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Carisoprodol pharmacokinetics and distribution in the nucleus accumbens correlates with behavioral effects in rats independent from its metabolism to meprobamate.
Neuropharmacology, 2020Co-Authors: Theresa M. Carbonaro, Michael B Gatch, Michael J. Forster, Vien Nguyen, Laszlo ProkaiAbstract:Abstract Carisoprodol (Soma®) is a centrally-acting skeletal-muscle relaxant frequently prescribed for treatment of acute musculoskeletal conditions. Carisoprodol's mechanism of action is unclear and is often ascribed to that of its active metabolite, meprobamate. The purpose of this study was to ascertain whether Carisoprodol directly produces behavioral effects, or whether metabolism to meprobamate via cytochrome P450 (CYP450) enzymatic reaction is necessary. Rats were trained to discriminate Carisoprodol (100 mg/kg) to assess time course and whether a CYP450 inhibitor (cimetidine) administered for 4 days would alter the discriminative effects of Carisoprodol. Additionally, pharmacokinetics of Carisoprodol and meprobamate with and without co-administration of cimetidine were assessed via in vivo microdialysis combined with liquid-chromatography–tandem mass spectrometry from blood and nucleus accumbens (NAc). The time course of the discriminative-stimulus effects of Carisoprodol closely matched the time course of the levels of Carisoprodol in blood and NAc, but did not match the time course of meprobamate. Administration of cimetidine increased levels of Carisoprodol and decreased levels of meprobamate consistent with its interfering with metabolism of Carisoprodol to meprobamate. However, cimetidine failed to alter the discriminative-stimulus effects of Carisoprodol. Carisoprodol penetrated into brain tissue and directly produced behavioral effects without being metabolized to meprobamate. These findings indicate that understanding the mechanism of action of Carisoprodol independently of meprobamate will be necessary to determine the validity of its clinical uses.
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JPET #151142 1 Title Page
2016Co-Authors: L A Gonzalez, Cynthia M Taylor, Cathy L Bell-Horner, Michael B Gatch, Michael J, Glenn H DillonAbstract:Carisoprodol-mediated modulation of GABAA receptors: in vitro and in vivo studie
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Carisoprodol tolerance and precipitated withdrawal.
Drug and alcohol dependence, 2011Co-Authors: Michael B Gatch, Jacques D Nguyen, Theresa Carbonaro, Michael J. ForsterAbstract:Carisoprodol is a muscle relaxant that acts at the GABA(A) 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. 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 20-30 min 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 h after the last dose of Carisoprodol. The 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 15-30 min of administration. 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. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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Carisoprodol Tolerance and Precipitated Withdrawal
Drug and Alcohol Dependence, 2011Co-Authors: Michael B Gatch, Theresa M. Carbonaro, Jacques D Nguyen, Michael J. ForsterAbstract: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.
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Behavioral and toxicological effects of propofol
Behavioural pharmacology, 2011Co-Authors: Michael B Gatch, Michael J. ForsterAbstract:There is increasing concern about abuse of propofol, a widely-used surgical anesthetic and sedative that is currently not a controlled substance. The purpose of the present study was to establish a rat model of the psychoactive effect of sub-anesthetic doses of propofol that could be useful for confirming abuse liability and studying mechanisms of propofol abuse. Sprague-Dawley rats were trained to discriminate propofol (10 mg/kg, i.p.) from vehicle (2% methylcellulose). Carisoprodol (100 mg/kg), chlordiazepoxide (10 mg/kg) and dizocilpine (0.1 mg/kg) were tested for substitution for the discriminative-stimulus effects of propofol (10 mg/kg), whereas pentylenetetrazol (10 mg/kg) was tested for antagonism of the discriminative-stimulus effects. Propofol (10 mg/kg) was tested for substitution in rats trained to discriminate Carisoprodol from vehicle. Carisoprodol produced 59% propofol-appropriate responding, chlordiazepoxide 65%, and dizocilpine 34%. Pentylenetetrazol decreased propofol-appropriate responding to 41%. Propofol produced 52% Carisoprodol-appropriate responding. Mortality rate during training of 10 mg/kg propofol was 38%. Post-mortem examination revealed cardiovascular abnormalities similar to those observed in propofol-infusion syndrome in humans. The results demonstrate that propofol can be trained as a discriminative stimulus. Its discriminative-stimulus effects were more similar to compounds promoting GABA-A receptor activity than to a compound inhibiting NMDA receptor activity. Because propofol has discriminative-stimulus effects similar to known drugs of abuse and occasions a high mortality rate, its potential for continued abuse is of particular concern.
Roy R Reeves - One of the best experts on this subject based on the ideXlab platform.
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Carisoprodol: update on abuse potential and legal status.
Southern medical journal, 2012Co-Authors: Roy R Reeves, Randy S Burke, Samet KoseAbstract:Carisoprodol is a centrally acting skeletal muscle relaxant of which meprobamate, a controlled substance, is the primary active metabolite. The abuse of Carisoprodol has increased dramatically in the last several years. A withdrawal syndrome occurs in some patients who abruptly cease Carisoprodol intake. The symptoms of this syndrome are similar to those seen with meprobamate withdrawal, suggesting that they may result from withdrawal from meprobamate accumulated with intake of excessive Carisoprodol; however, Carisoprodol is capable of modulating GABAA function, which may contribute to its abuse potential.There has been considerable debate about whether Carisoprodol should be considered a controlled substance. Carisoprodol was removed from the market in Norway on May 1, 2008, but may still be used by specially approved patients. Carisoprodol was classified as a controlled substance in several US states, and effective January 11, 2012, became a schedule IV controlled substance at the US federal level. This article updates the literature on abuse potential and examines recent developments regarding the legal status of Carisoprodol.
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Carisoprodol: abuse potential and withdrawal syndrome.
Current drug abuse reviews, 2010Co-Authors: Roy R Reeves, Randy S BurkeAbstract:Carisoprodol (N-isopropyl-2 methyl-2-propyl-1,3-propanediol dicarbamate; N-isopropylmeprobamate) is a centrally acting skeletal muscle relaxant whose primary active metabolite is meprobamate, a substance with well established abuse potential similar to that of benzodiazepines. A number of reports show that Carisoprodol has been abused for its sedative and relaxant effects, to augment or alter the effects of other drugs, and by the intentional combination of Carisoprodol and other noncontrolled medications because of the relative ease (as compared to controlled substances) of obtaining prescriptions. The diversion and abuse of Carisoprodol and its adverse health effects appear to have dramatically increased over the last several years. Clinicians have begun to see a withdrawal syndrome consisting of insomnia, vomiting, tremors, muscle twitching, anxiety, and ataxia in patients who abruptly cease intake of large doses of Carisoprodol. Hallucinations and delusions may also occur. The withdrawal symptoms are very similar to those previously described for meprobamate withdrawal, suggesting that what may actually be occurring is withdrawal from meprobamate accumulated as a result of intake of excessive amounts of Carisoprodol. However Carisoprodol itself is capable of modulating GABA(A) function, and this may contribute both to the drugs abuse potential and to the occurrence of a withdrawal syndrome with abrupt cessation of intake. Carisoprodol has been classified as a controlled substance in several states in the US and restrictions on the use of the drug have been imposed in some European countries. Carisoprodol is metabolized to a controlled substance, has clear evidence of abuse potential and increasing incidence of abuse, and has shown evidence of a withdrawal syndrome with abrupt cessation from intake. This article will discuss the abuse potential of Carisoprodol and the associated withdrawal syndrome, and consider implications for future use of the drug.
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Is the frequency of Carisoprodol withdrawal syndrome increasing?
Pharmacotherapy, 2007Co-Authors: Roy R Reeves, Jeffrey S Hammer, Richard O PendarvisAbstract:Carisoprodol is a commonly used centrally acting muscle relaxant. A number of case reports have suggested that the drug may have abuse potential, presumably because it is metabolized to the anxiolytic drug, meprobamate, which is a controlled substance at the federal level. Two recent case reports described symptoms of withdrawal after the cessation of Carisoprodol. We present two additional cases that support the concept of a withdrawal syndrome with this drug. Symptoms of Carisoprodol withdrawal include anxiety, tremulousness, insomnia, jitteriness, muscle twitching, and hallucinations. These symptoms are most likely caused by withdrawal from the meprobamate that accumulates after large amounts of Carisoprodol are ingested. Although Carisoprodol is not a controlled substance at the federal level, clinicians should be aware of its significant potential for abuse.
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Carisoprodol withdrawal syndrome.
Pharmacotherapy, 2004Co-Authors: Roy R Reeves, John J Beddingfield, James E. MackAbstract:A 43-year-old man with chronic back and shoulder pain was treated with hydrocodone. He began taking excessive amounts of the drug, so his physicians stopped prescribing it. The patient then obtained the muscle relaxant Carisoprodol on his own from several sources. He was consuming up to 30 or more tablets/day (> or =10,500 mg/day) for several weeks, then abruptly stopped taking the drug. Within 48 hours he developed anxiety, tremors, muscle twitching, insomnia, auditory and visual hallucinations, and bizarre behavior. The symptoms intensified and peaked on the fourth day after Carisoprodol cessation. The patient required brief treatment with olanzapine and tapering dosages of lorazepam while the symptoms gradually resolved. To our knowledge, this is the first documented case of a withdrawal syndrome with Carisoprodol. The symptoms most likely resulted because of accumulation of meprobamate, the active metabolite of Carisoprodol in humans. Clinicians prescribing Carisoprodol should be aware of the possibility for abuse or addiction. Further, we recommend that Carisoprodol be designated a controlled substance at the federal level.
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somatic dysfunction during Carisoprodol cessation evidence for a Carisoprodol withdrawal syndrome
The Journal of the American Osteopathic Association, 2003Co-Authors: Roy R Reeves, Jefferson D ParkerAbstract:: Carisoprodol is a commonly used skeletal muscle relaxant with potential for abuse because of its active metabolite, meprobamate, and several reports have suggested that patients abruptly stopping intake of Carisoprodol may have a withdrawal syndrome. The authors studied changes in the occurrence of somatic dysfunctions in five patients during an 8-day period following discontinuation from large doses of Carisoprodol. Results showed that the number of somatic dysfunctions changed significantly during the withdrawal period. Each patient had an increase in the number of somatic dysfunctions during the first 3 days after cessation of Carisoprodol with return to at or near baseline by the eighth day. This was reflected statistically in a significant-within-subjects effect for time. Results of supplemental analyses revealed a significant component of the effect and a trend for the quadratic component to be significant. Increases in the number of somatic dysfunctions during Carisoprodol discontinuation support the existence of a Carisoprodol withdrawal syndrome.