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Rachelle Buchbinder - One of the best experts on this subject based on the ideXlab platform.
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muscle relaxants for pain management in rheumatoid arthritis
Cochrane Database of Systematic Reviews, 2012Co-Authors: Bethan Richards, Samuel L Whittle, Rachelle BuchbinderAbstract:Background: Pain management is a high priority for patients with rheumatoid arthritis (RA). Muscle relaxants include drugs that reduce muscle spasm (for example benzodiazepines such as diazepam (Valium), alprazolam (Xanax), lorazepam (Ativan) and non-benzodiazepines such as metaxalone (Skelaxin) or a combination of paracetamol and orphenadrine (Muscol)) and drugs that prevent increased muscle tone (baclofen and dantrolene). Despite a paucity of evidence supporting their use, antispasmodic and antispasticity muscle relaxants have gained widespread clinical acceptance as adjuvants in the management of patients with chronic musculoskeletal pain. Objectives: The aim of this review was to determine the efficacy and safety of muscle relaxants in pain management in patients with RA. The muscle relaxants that were included in this review are the antispasmodic benzodiazepines (alprazolam, bromazepam, chlordiazepoxide,cinolazepam, clonazepam, cloxazolam, clorazepate, diazepam, estazolam, flunitrazepam, flurazepam, flutoprazepam, Halazepam, ketazolam, loprazolam, lorazepam, lormetazepam, medazepam, midazolam, nimetazepam, nitrazepam, nordazepam, oxazepam, pinazepam, prazepam, quazepam, temazepam, tetrazepam, triazolam), antispasmodic non-benzodiazepines (cyclobenzaprine, carisoprodol, chlorzoxazone, meprobamate, methocarbamol, metaxalone, orphenadrine, tizanidine and zopiclone), and antispasticity drugs (baclofen and dantrolene sodium). Search methods: We performed a search of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 4th quarter 2010), MEDLINE (1950 to week 1 November 2010), EMBASE (Week 44 2010), and PsycINFO (1806 to week 2 November 2010). We also searched the 2008 to 2009 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) abstracts and performed a handsearch of reference lists of relevant articles. Selection criteria: We included randomised controlled trials which compared a muscle relaxant to another therapy (active, including non-pharmacological therapies, or placebo) in adult patients with RA and that reported at least one clinically relevant outcome. Data collection and analysis: Two blinded review authors independently extracted data and assessed the risk of bias in the trials. Meta-analyses were used to examine the efficacy of muscle relaxants on pain, depression, sleep and function, as well as their safety. Main results: Six trials (126 participants) were included in this review. All trials were rated at high risk of bias. Five cross-over trials evaluated a benzodiazepine, four assessed diazepam (n = 71) and one assessed triazolam (n = 15). The sixth trial assessed zopiclone (a non-benzodiazepine) (n = 40) and was a parallel group study. No trial duration was longer than two weeks while three single dose trials assessed outcomes at 24 hours only. Overall the included trials failed to find evidence of a beneficial effect of muscle relaxants over placebo, alone (at 24 hrs, 1 or 2 weeks) or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) (at 24 hrs), on pain intensity, function, or quality of life. Data from two trials of longer than 24 hours duration (n = 74) (diazepam and zopiclone) found that participants who received a muscle relaxant had significantly more adverse events compared with those who received placebo (number needed to harm (NNTH) 3, 95% CI 2 to 7). These were predominantly central nervous system side effects, including dizziness and drowsiness (NNTH 3, 95% CI 2 to 11). Authors' conclusions: Based upon the currently available evidence in patients with RA, benzodiazepines (diazepam and triazolam) do not appear to be beneficial in improving pain over 24 hours or one week. The non-benzodiazepine agent zopiclone also did not significantly reduce pain over two weeks. However, even short term muscle relaxant use (24 hours to 2 weeks) is associated with significant adverse events, predominantly drowsiness and dizziness.
W R Martin - One of the best experts on this subject based on the ideXlab platform.
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chronic administration of and dependence on Halazepam diazepam and nordiazepam in the dog
Drug and Alcohol Dependence, 1991Co-Authors: J W Sloan, W R Martin, E Wala, K M DickeyAbstract:Abstract Halazepam administered chronically to dogs in oral doses of 180 and 450 mg/kg/day produced physical dependence which was revealed by a flumazenil precipitated abstinence syndrome and measured by the Nordiazepam Precipitated Abstinence Scale score (NPAS) (McNicholas et al., 1988; Sloan et al., 1990). This abstinence as measured by the NPAS score was more severe in diazepam- and Halazepam-dependent than in nordiazepam-dependent dogs whereas the incidence of precipitated clonic seizures was greater in the diazepam- and nordiazepam-dependent than in the Halazepam-dependent dogs. Pharmacokinetic studies showed that in the dog the major conversion of Halazepam, like diazepam, was to nordiazepam and an oxazepam conjugate. Appreciable quantities of oxazepam, 3-OH Halazepam and its conjugated metabolite were also identified in plasma. The NPAS score obtained in the Halazepam-dependent dogs, however, was greater than the NPAS score obtained in nordiazepamdependent dogs who had nordiazepam plasma levels over three times higher than those obtained in the Halazepam-dependent dogs. Further, the precipitated abstinence observed in the Halazepam-, diazepam- and nordiazepam-dependent dogs differed in qualitative as well as in quantitative aspects including marked differences in the time course of abstinence signs. These data argue that the different dependencies produced by Halazepam, diazepam and nordiazepam are not due solely to either the parent compound or to a single metabolite but most likely to their combined effects.
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pharmacokinetics and metabolism of Halazepam in naive and dependent dogs
Pharmacology Biochemistry and Behavior, 1991Co-Authors: Elzbieta P Wala, W R Martin, Jewell W Sloan, Terry A PruittAbstract:The pharmacokinetic profiles of Halazepam (HL) and its metabolites, desmethyldiazepam (DMDZ), oxazepam (OX), 3-hydroxyHalazepam (OH-HL), and conjugates of oxazepam (OX-CONJ) and 3-hydroxyHalazepam (OH-HL-CONJ) were studied in 4 naive dogs following single intravenous (2 mg/kg) and oral (112.5 mg/kg) administrations of HL and in 5 dependent dogs chronically dosed with HL (450 mg/kg/day q.i.d.). HL is rapidly metabolized to DMDZ as the principal metabolite but appreciable levels of HL, OX and OH-HL were measured in plasma and the brain tissue. High levels of conjugated metabolites were measured in plasma. The steady-state plasma concentrations of HL and its unconjugated metabolites can be predicted from the single dose study. Halazepam does not serve as a simple prodrug for DMDZ in producing physical dependence in dogs.
S-k Yang - One of the best experts on this subject based on the ideXlab platform.
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stereoselective metabolism of prazepam and Halazepam by human liver microsomes
Drug Metabolism and Disposition, 1991Co-Authors: X L Lu, S-k YangAbstract:Metabolism of prazepam [PZ, 7-chloro-1,3-dihydro-5-phenyl-1- (cyclopropylmethyl)-2H-1,4-benzodiazepin-2-one] and Halazepam [HZ,7- chloro-1,3-dihydro-5-phenyl-1-(2,2,2-trifluoroethyl)-2H-1,4- benzodizepin-2-one] was investigated in microsomes prepared from the livers of two male and one female subjects who died of head injuries. PZ (or HZ) and its metabolites were analyzed by normal phase and chiral stationary phase HPLC. The relative amount of products formed in the metabolism of PZ was found to be N-desalkylprazepam (NDZ, also known as N-desmethyldiazepam and nordiazepam) greater than 3-hydroxy-PZ (3-OH-PZ) much greater than oxazepam (OX). In contrast, the relative amount of products formed in the metabolism of HZ was found to be 3-OH-HZ much greater than NDZ greater than OX. Enantiomers of 3-OH-PZ and 3-OH-HZ were resolved by HPLC on an analytical column packed with the chiral stationary phase R-N-(3,5-dinitrobenzoyl)phenylglycine covalently bound to spherical particles of gamma-aminopropylsilanized silica. The 3-OH-PZ formed in the metabolism of PZ by three human liver microsomal preparations were found to have 3R/3S enantiomer ratios of 65:35, 61:39, and 62:38. In the metabolism of HZ, the enzymatically formed 3-OH-HZ had 3R/3S enantiomer ratios of 67:33, 60:40, and 62:38. N-Dealkylations of racemic 3-OH-PZ and 3-OH-HZ by human liver microsomal preparations were substrate-enantioselective; 3S-OH-PZ and 3R-OH-HZ were each N-dealkylated slightly faster than the corresponding antipode. The results indicated that both C3-hydroxylation of PZ and HZ as well as N-dealkylation of 3-OH-PZ and 3-OH-HZ catalyzed by human liver microsomes were stereoselective, resulting in the formation of a C3-hydroxylated product enriched (60-67%) in the 3R-enantiomer.
K M Dickey - One of the best experts on this subject based on the ideXlab platform.
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chronic administration of and dependence on Halazepam diazepam and nordiazepam in the dog
Drug and Alcohol Dependence, 1991Co-Authors: J W Sloan, W R Martin, E Wala, K M DickeyAbstract:Abstract Halazepam administered chronically to dogs in oral doses of 180 and 450 mg/kg/day produced physical dependence which was revealed by a flumazenil precipitated abstinence syndrome and measured by the Nordiazepam Precipitated Abstinence Scale score (NPAS) (McNicholas et al., 1988; Sloan et al., 1990). This abstinence as measured by the NPAS score was more severe in diazepam- and Halazepam-dependent than in nordiazepam-dependent dogs whereas the incidence of precipitated clonic seizures was greater in the diazepam- and nordiazepam-dependent than in the Halazepam-dependent dogs. Pharmacokinetic studies showed that in the dog the major conversion of Halazepam, like diazepam, was to nordiazepam and an oxazepam conjugate. Appreciable quantities of oxazepam, 3-OH Halazepam and its conjugated metabolite were also identified in plasma. The NPAS score obtained in the Halazepam-dependent dogs, however, was greater than the NPAS score obtained in nordiazepamdependent dogs who had nordiazepam plasma levels over three times higher than those obtained in the Halazepam-dependent dogs. Further, the precipitated abstinence observed in the Halazepam-, diazepam- and nordiazepam-dependent dogs differed in qualitative as well as in quantitative aspects including marked differences in the time course of abstinence signs. These data argue that the different dependencies produced by Halazepam, diazepam and nordiazepam are not due solely to either the parent compound or to a single metabolite but most likely to their combined effects.
Terry A Pruitt - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics and metabolism of Halazepam in naive and dependent dogs
Pharmacology Biochemistry and Behavior, 1991Co-Authors: Elzbieta P Wala, W R Martin, Jewell W Sloan, Terry A PruittAbstract:The pharmacokinetic profiles of Halazepam (HL) and its metabolites, desmethyldiazepam (DMDZ), oxazepam (OX), 3-hydroxyHalazepam (OH-HL), and conjugates of oxazepam (OX-CONJ) and 3-hydroxyHalazepam (OH-HL-CONJ) were studied in 4 naive dogs following single intravenous (2 mg/kg) and oral (112.5 mg/kg) administrations of HL and in 5 dependent dogs chronically dosed with HL (450 mg/kg/day q.i.d.). HL is rapidly metabolized to DMDZ as the principal metabolite but appreciable levels of HL, OX and OH-HL were measured in plasma and the brain tissue. High levels of conjugated metabolites were measured in plasma. The steady-state plasma concentrations of HL and its unconjugated metabolites can be predicted from the single dose study. Halazepam does not serve as a simple prodrug for DMDZ in producing physical dependence in dogs.
