The mechanism of action of carisoprodol in relieving discomfort associated with acute painful musculoskeletal conditions has not been clearly identified.
In animal studies, muscle relaxation induced by carisoprodol is associated with altered interneuronal activity in the spinal cord and in the descending reticular formation of the brain.
Carisoprodol is a centrally acting skeletal muscle relaxant that does not directly relax skeletal muscles.
A metabolite of carisoprodol, meprobamate, has anxiolytic and sedative properties. The degree to which these properties of meprobamate contribute to the safety and efficacy of carisoprodol is unknown.
The pharmacokinetics of carisoprodol and its metabolite meprobamate were studied in a crossover study of 24 healthy subjects (12 male and 12 female) who received single doses of 250 mg and 350 mg carisoprodol (see Table 2 ). The exposure of carisoprodol and meprobamate was dose proportional between the 250 mg and 350 mg doses. The Cmax of meprobamate was 2.5 ± 0.5 μg/mL (mean ± SD) after administration of a single 350 mg dose of carisoprodol, which is approximately 30% of the Cmax of meprobamate (approximately 8 μg/mL) after administration of a single 400 mg dose of meprobamate.
|250 mg Carisoprodol||350 mg Carisoprodol|
|Cmax (μg/mL)||1.2 ± 0.5||1.8 ± 1.0|
|AUC inf (μg*hr/mL)||4.5 ± 3.1||7.0 ± 5.0|
|Tmax (hr)||1.5 ± 0.8||1.7 ± 0.8|
|T 1/2 (hr)||1.7 ± 0.5||2.0 ± 0.5|
|Cmax (μg/mL)||1.8 ± 0.3||2.5 ± 0.5|
|AUC inf (μg*hr/mL)||32 ± 6.2||46 ± 9.0|
|Tmax (hr)||3.6 ± 1.7||4.5 ± 1.9|
|T 1/2 (hr)||9.7 ± 1.7||9.6 ± 1.5|
Absorption: Absolute bioavailability of carisoprodol has not been determined. The mean time to peak plasma concentrations (Tmax) of carisoprodol was approximately 1.5 to 2 hours. Co-administration of a high-fat meal with carisoprodol (350 mg tablet) had no effect on the pharmacokinetics of carisoprodol. Therefore, carisoprodol may be administered with or without food.
Metabolism: The major pathway of carisoprodol metabolism is via the liver by cytochrome enzyme CYP2C19 to form meprobamate. This enzyme exhibits genetic polymorphism (see Patients with Reduced CYP2C19 Activity below).
Elimination: Carisoprodol is eliminated by both renal and non-renal routes with a terminal elimination half-life of approximately 2 hours. The half-life of meprobamate is approximately 10 hours.
Gender: Exposure of carisoprodol is higher in female than in male subjects (approximately 30-50% on a weight adjusted basis). Overall exposure of meprobamate is comparable between female and male subjects.
Patients with Reduced CYP2C19 Activity: Carisoprodol should be used with caution in patients with reduced CYP2C19 activity. Published studies indicate that patients who are poor CYP2C19 metabolizers have a 4-fold increase in exposure to carisoprodol, and concomitant 50% reduced exposure to meprobamate compared to normal CYP2C19 metabolizers. The prevalence of poor metabolizers in Caucasians and African Americans is approximately 3-5% and in Asians is approximately 15-20%.
Long term studies in animals have not been performed to evaluate the carcinogenic potential of carisoprodol.
Carisoprodol was not formally evaluated for genotoxicity. In published studies, carisoprodol was mutagenic in the in vitro mouse lymphoma cell assay in the absence of metabolizing enzymes, but was not mutagenic in the presence of metabolizing enzymes. Carisoprodol was clastogenic in the in vitro chromosomal aberration assay using Chinese hamster ovary cells with or without the presence of metabolizing enzymes. Other types of genotoxic tests resulted in negative findings. Carisoprodol was not mutagenic in the Ames reverse mutation assay using S. typhimurium strains with or without metabolizing enzymes, and was not clastogenic in an in vivo mouse micronucleus assay of circulating blood cells.
Carisoprodol was not formally evaluated for effects on fertility. Published reproductive studies of carisoprodol in mice found no alteration in fertility although an alteration in reproductive cycles characterized by a greater time spent in estrus was observed at a carisoprodol dose of 1200 mg/kg/day. In a 13-week toxicology study that did not determine fertility, mouse testes weight and sperm motility were reduced at a dose of 1200 mg/kg/day. In both studies, the no effect level was 750 mg/kg/day, corresponding to approximately 2.6 times the human equivalent dosage of 350 mg four times a day, based on a body surface area comparison. The significance of these findings for human fertility is not known.
The safety and efficacy of carisoprodol for the relief of acute, idiopathic mechanical low back pain was evaluated in two, 7-day, double blind, randomized, multicenter, placebo controlled, U.S. trials (Studies 1 and 2). Patients had to be 18 to 65 years old and had to have acute back pain (≤ 3 days of duration) to be included in the trials. Patients with chronic back pain; at increased risk for vertebral fracture (e.g., history of osteoporosis); with a history of spinal pathology (e.g., herniated nucleus pulposis, spondylolisthesis or spinal stenosis); with inflammatory back pain, or with evidence of a neurologic deficit were excluded from participation. Concomitant use of analgesics (e.g., acetaminophen, NSAIDs, tramadol, opioid agonists), other muscle relaxants, botulinum toxin, sedatives (e.g., barbiturates, benzodiazepines, promethazine hydrochloride), and anti-epileptic drugs was prohibited.
In Study 1, patients were randomized to one of three treatment groups (i.e., carisoprodol 250 mg, carisoprodol 350 mg, or placebo) and in Study 2 patients were randomized to two treatment groups (i.e., carisoprodol 250 mg or placebo). In both studies, patients received study medication three times a day and at bedtime for seven days.
The primary endpoints were the relief from starting backache and the global impression of change, as reported by patients, on Study Day 3. Both endpoints were scored on a 5-point rating scale from 0 (worst outcome) to 4 (best outcome) in both studies. The primary statistical comparison was between the carisoprodol 250 mg and placebo groups in both studies.
The proportion of patients who used concomitant acetaminophen, NSAIDs, tramadol, opioid agonists, other muscle relaxants, and benzodiazepines was similar in the treatment groups.
The results for the primary efficacy evaluations in the acute, low back pain studies are presented in Table 3.
|Table 3. Results of the Primary Efficacy Endpoints a in Studies 1 and 2|
|Study||Parameter||Placebo||Carisoprodol 250 mg||Carisoprodol 350 mg|
|1||Number of Patients||n=269||n=264||n=273|
|Relief from Starting Backache, Mean (SE) b||1.4 (0.1)||1.8 (0.1)||1.8 (0.1)|
|Difference between Carisoprodol and Placebo, Mean (SE) b (95% CI)||0.4 (0.2, 0.5)||0.4 (0.2, 0.6)|
|Global Impression of Change, Mean (SE) b||1.9 (0.1)||2.2 (0.1)||2.2 (0.1)|
|Difference between Carisoprodol and Placebo, Mean (SE) b (95% CI)||0.2 (0.1, 0.4)||0.3 (0.1, 0.4)|
|2||Number of Patients||n=278||n=269|
|Relief from Starting Backache, Mean (SE) b||1.1 (0.1)||1.8 (0.1)|
|Difference between Carisoprodol and Placebo, Mean (SE) b (95% CI)||0.7 (0.5, 0.9)|
|Global Impression of Change, Mean (SE) b||1.7 (0.1)||2.2 (0.1)|
|Difference between Carisoprodol and Placebo, Mean (SE) b (95% CI)||0.5 (0.4, 0.7)|
a. The primary efficacy endpoints (Relief from Starting Backache and Global Impression of Change) were assessed by the patients on Study Day 3.These endpoints were scored on a 5-point rating scale from 0 (worst outcome) to 4 (best outcome). b. Mean is the least squared mean and SE is the standard error of the mean. The ANOVA model was used for the primary statistical comparison between the carisoprodol 250 mg and placebo groups. Patients treated with carisoprodol experienced improvement in function as measured by the Roland-Morris Disability Questionnaire (RMDQ) score on Days 3 and 7.
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