Quantitation of Carisoprodol and Meprobamate in Urine and Plasma Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS).

Carisoprodol and meprobamate are centrally acting muscle relaxant/anxiolytic drugs that can exist in a parent-metabolite relationship (carisoprodol → meprobamate) or as a separate pharmaceutical preparation (meprobamate aka Equanil, others). The monitoring of the use of these drugs has both clinical and forensic applications in pain management applications and in overdose situations. LC-MS/MS is used to analyze urine or plasma/serum extracts with deuterated analogs of each analyte as internal standards to ensure accurate quantitation and control for any potential matrix effects. Positive ion electrospray is used to introduce the analytes into the mass spectrometer. Selected reaction monitoring of two product ions for each analyte allows for the calculation of ion ratios which ensures correct identification of each analyte, while a matrix-matched calibration curve is used for quantitation.

Factors affecting carisoprodol metabolism in pain patients using urinary excretion data.

Carisoprodol is a skeletal muscle relaxant prescribed to treat pain. Carisoprodol is metabolized to meprobamate, an active metabolite with anxiolytic effects, by the genetically polymorphic CYP2C19 enzyme. Concomitant use of CYP2C19 substrates or inhibitors may alter carisoprodol metabolism, with therapeutic and/or toxic implications for effectively treating patients with pain. This was a retrospective analysis of urinary excretion data collected from patients with pain from March 2008 to May 2011. Carisoprodol and meprobamate urine concentrations were measured by liquid chromatography-tandem mass spectrometry, and the metabolic ratio (MR) of meprobamate to carisoprodol concentrations was determined in 14,965 subjects. The MR geometric mean and 95% confidence interval (95% CI) of the young group (105, 95% CI = 99.1-113) were ∼47.4% higher than the middle-aged group (71.9, 95% CI = 70-73.8) and nearly two times higher than the elderly group (54.4, 95% CI = 51.3-57.6). Females had a 20.7% higher MR compared with males. No significant change in the MR was observed with overall CYP2C19 inhibitor or substrate use. However, evaluation of individual inhibitors showed co-administration with esomeprazole or fluoxetine was associated with a 31.8 and 24.6% reduction in MR, respectively, compared with controls (P < 0.05). Omeprazole did not significantly affect the MR. Patient-specific factors such as age, sex and co-medications may be important considerations for effective carisoprodol therapy.

Evaluating the relationship between carisoprodol concentrations and meprobamate formation and inter-subject and intra-subject variability in urinary excretion data of pain patients.

Using urinary carisoprodol data from pain patients, our objectives were to determine the relationship between carisoprodol concentration and its conversion to meprobamate, and quantify the intra-subject and inter-subject variability in carisoprodol metabolism. Liquid chromatography-tandem mass spectrometry was used to quantitate carisoprodol and meprobamate concentrations in urine specimens. The log creatinine-corrected carisoprodol versus log creatinine-corrected meprobamate showed a marginal positive relationship (R(2) = 0.395), with a 29.1-fold variance between subjects at the mean carisoprodol concentration. The geometric mean carisoprodol and meprobamate urine concentrations were 0.519 ± 3.38 mg and 28.2 ± 2.34 mg analyte per gram creatinine, respectively. The log metabolic ratio (MR) versus log creatinine-corrected carisoprodol displayed a marginal positive correlation. A subpopulation of outliers with higher carisoprodol and lower meprobamate levels were considered poor metabolizers and represented 0.483% (n = 21) of the study population. Using a curve-fit mathematical model, we estimated 0.318% (n = 10) to be ultra-rapid metabolizers. The inter-subject population geometric standard deviation (SD) of the MR was 3.64. The intra-subject geometric median and mean SD of the MR were 1.60 (interquartile range: 1.28, 2.07) and 1.72 ± 1.60, respectively. Inter-subject variability was 2.27 times greater than the median intra-subject variability. With a better understanding of urine carisoprodol and meprobamate concentrations and variability, urine drug testing provides a useful monitoring reference for clinicians.

Validation of a new homogeneous immunoassay for the detection of carisoprodol in urine.

The objective of this project was to validate a new high-throughput homogeneous enzyme immunoassay (HEIA) for the rapid detection of carisoprodol in human urine. Carisoprodol (Soma(®)) and meprobamate are widely prescribed as musculoskeletal pain relief drugs and are listed as one of the 10 most frequently identified drugs associated with DUI cases. Carisoprodol has a short elimination half-life of 1-3 h; however, its major active metabolite, meprobamate, has a longer elimination half-life of 6-17 h. As a result, it is important for an immunoassay to cross-react with both compounds. The advantage of this new assay is that cutoff concentrations can be adjusted between 100 and 500 ng/mL. The reportable range was 25 to 1000 ng/mL for carisoprodol and 50 to 10,000 ng/mL for meprobamate. The intraday coefficient of variation (% CV) for the semi-quantitative assay was less than 1%. The homogeneous assay was validated with a total of 86 urine samples previously analyzed by liquid chromatography-tandem mass spectrometry with carisoprodol concentrations ranging from 50 to 10,000 ng/mL. The accuracy was found to be 100% when immunoassay cutoff concentrations of carisoprodol and meprobamate were set at 100 and 1000 ng/mL, respectively.

Observations of medication compliance by measurement of urinary drug concentrations in a pain management population.

BACKGROUND: One of the major concerns of physicians treating pain patients with opioids is to determine whether the patients are compliant, and this is commonly determined by urine drug testing. There is limited information on which drugs these patients are most compliant with. There is also limited information as to how compliance is defined in terms of cutoffs. OBJECTIVE: To compare reported patient medication use with the presence of the drug in the patients' urine with defined cutoffs. METHOD: A retrospective study of the medications listed by the physicians' offices and the confirmed drug test findings. A Millennium Laboratories database of 20, 457 patient results was examined for the presence of the listed medications and was matched for the presence of the drugs above the analytical cutoffs. RESULTS: For oxycodone and hydrocodone, the authors observed 23 and 24 percent noncompliance, respectively. For carisoprodol, they observed 33 percent noncompliance. For morphine, they observed 14 percent noncompliance. For methadone, they observed 9 percent noncompliance. CONCLUSIONS: Noncompliance is prevalent in this patient population and varies with the prescribed drug.

Urine drug testing of chronic pain patients: licit and illicit drug patterns.

Chronic pain patients are frequently maintained on one or more powerful opioid medications in combination with other psychoactive medications. Urine tests provide objective information regarding patient compliance status. Little information is available on testing this unique population. The goal of this study was to characterize drug disposition patterns in urine specimens collected from a large population of pain patients. Confirmation data for 10,922 positive specimens were collated into 11 drug Classes. The number of drug/metabolites tested (#) and number of confirmed positive specimens were as follows: amphetamines (7), 160; barbiturates (5), 308; benzodiazepines (6), 2397; cannabinoids (1), 967; carisoprodol (2), 611; cocaine (1), 310; fentanyl (1), 458; meperidine (2), 58; methadone (2), 1209; opiates (7), 8996; and propoxyphene (2), 385. Subdivision into 19 distinct drug Groups allowed characterization of drug use patterns. Of the 10,922 positive specimens, 15,859 results were reported as positive in various drug Classes, and 27,197 drug/metabolites were measured by gas chromatography-mass spectrometry. The frequency of illicit drug use (cannabis, cocaine, ecstasy) was 10.8%. Being the first study of this type, these data present a large array of information on licit and illicit drug use, drug detection frequencies, drug/metabolite patterns, and multi-drug use combinations in pain patients.

Carisoprodol: an unrecognized drug of abuse.

During a 6-month monitoring period, carisoprodol was detected in the urine specimens of 19 patients for whom drug screening had been ordered for purposes of patient care. The clinical history suggested that in 7 cases the drug was abused or implicated in a suicide attempt or gesture. In another 7 cases, the drug was used primarily for medical purposes, and in 5 cases the reason for use could not be determined. One patient ingested homemade tablets that were found to contain carisoprodol. In an additional case, the drug was detected in breast milk. Physical findings, clinical history, and treatment are described, and the profile of a typical carisoprodol user is discussed. It seems that carisoprodol has become an unrecognized drug of abuse, at least in our community. This drug and its metabolite, meprobamate, should be included in comprehensive drug screening.