Comparative Risk of Injury with Concurrent Use of Opioids and Skeletal Muscle Relaxants.

Concurrent use of skeletal muscle relaxants (SMRs) and opioids has been linked to an increased risk of injury. However, it remains unclear whether the injury risks differ by specific SMR when combined with opioids. We conducted nine retrospective cohort studies within a US Medicaid population. Each cohort consisted exclusively of person-time exposed to both an SMR and one of the three most dispensed opioids-hydrocodone, oxycodone, and tramadol. Opioid users were further divided into three cohorts based on the initiation order of SMRs and opioids-synchronically triggered, opioid-triggered, and SMR-triggered. Within each cohort, we used Cox proportional hazard models to compare the injury rates for different SMRs compared to methocarbamol, adjusting for covariates. We identified 349,543, 139,458, and 218,967 concurrent users of SMRs with hydrocodone, oxycodone, and tramadol, respectively. In the oxycodone-SMR-triggered cohort, the adjusted hazard ratios (HRs) were 1.86 (95% CI, 1.23-2.82) for carisoprodol and 1.73 (1.09-2.73) for tizanidine. In the tramadol-synchronically triggered cohort, the adjusted HRs were 0.69 (0.49-0.97) for metaxalone and 0.62 (0.42-0.90) for tizanidine. In the tramadol-SMR-triggered cohort, the adjusted HRs were 1.51 (1.01-2.26) for baclofen and 1.48 (1.03-2.11) for cyclobenzaprine. All other HRs were statistically nonsignificant. In conclusion, the relative injury rate associated with different SMRs used concurrently with the three most dispensed opioids appears to vary depending on the specific opioid and the order of combination initiation. If confirmed by future studies, clinicians should consider the varying injury rates when prescribing SMRs to individuals using hydrocodone, oxycodone, and tramadol.

Risk of Opioid Overdose Associated With Concomitant Use of Opioids and Skeletal Muscle Relaxants: A Population-Based Cohort Study.

The recent opioid prescribing guideline cautions about the concomitant prescribing of opioids and skeletal muscle relaxants (SMRs) given the additive central nervous system depressant effect. However, the clinical relevance remains unclear. In this retrospective cohort study, we compared the risk of opioid overdose associated with concomitant use of opioids and SMRs vs. opioid use alone. Adjusted hazard ratios were 1.09 (95% confidence interval (CI), 0.74-1.62) and 1.26 (95% CI, 1.00-1.58) in the incident and prevalent opioid user cohorts, respectively, generating a combined estimate of 1.21 (95% CI, 1.00-1.48). This risk seemed to increase with treatment duration (≤ 14 days: 0.91 and 95% CI, 0.67-1.22; 15-60 days: 1.37 and 95% CI, 0.81-2.37; >60 days: 1.80 and 95% CI, 1.30-2.48) and for baclofen (1.83 and 95% CI, 1.11-3.04) and carisoprodol (1.84 and 95% CI, 1.34-2.54). Concomitant users with daily opioid dose ≥50 mg (1.50 and 95% CI, 1.18-1.92) and benzodiazepine use (1.39 and 95% CI, 1.08-1.79) also had elevated risk. Clinicians should be cautious about these potentially unsafe practices to optimize pain care and improve patient safety.

Overlapping prescriptions of opioids, benzodiazepines, and carisoprodol: "Holy Trinity" prescribing in the state of Florida.

BACKGROUND: High-risk combinations of controlled medications, such as those involving opioid analgesics, are under increased scrutiny because of their contribution to the opioid epidemic in the United States. Responsible prescribing guidelines indicate that the triple drug combination--opioids, benzodiazepines and skeletal muscle relaxants, especially carisoprodol--should not be concurrently prescribed. METHODS: This pharmacoepidemiologic study was designed to primarily examine the characteristics of patients receiving this triple combination compared to the group receiving only opioids and benzodiazepines. RESULTS: Results show that, while the number of exposed patients has declined since 2012, approximately 17,000 Floridians were prescribed this combination in 2017 alone. Demographically, recipients of these prescriptions were younger, more likely to be female, and geographically-localized. Furthermore, these patients were more frequently associated with a prescriber in the top 1% of opioid and/or benzodiazepine prescribing, have more multiple provider episodes ("doctor shopping"), and receive higher mean daily opioid dosages. CONCLUSIONS: These findings raise important questions as to how frequently prescribers are checking prescription drug monitoring programs, following US Centers for Disease Control and Prevention opioid prescribing guidelines, and/or handling the clinical challenges associated with pharmaceutical management of patients with complex, painful health conditions.

The Pharmacology and Toxicology of the 'Holy Trinity'.

Combining opioids with benzodiazepines and skeletal muscle relaxants ('The Holy Trinity') has been reported to potentiate the 'high'. Through unique interactions with colocalized µ-opioid and GABAA receptors, the combined use of these agents induces a synergistic increase in dopamine in the nucleus accumbens (NAc) and depression of respiration. The inhibition of GABA release mediated by µ1 -opioid receptor activation results in a subsequent increase in dopamine in the NAc. Benzodiazepines activate the GABAA R to suppress respiration in the medullary respiratory centres. The skeletal muscle relaxant, carisoprodol, appears to bind to a unique binding domain within the GABAA R to further enhance the respiratory depressant effects of the benzodiazepines. Therefore, the opioids, the benzodiazepines and carisoprodol alone or in combination are capable of inducing respiratory depression. Current guidelines for opioid prescribing recommend against the concomitant use of benzodiazepines but do not recognize the potential risk associated with the addition of skeletal muscle relaxants.

Severe Carisoprodol Withdrawal After a 14-Year Addiction and Acute Overdose.

BACKGROUND: Carisoprodol, a centrally acting muscle relaxant with a high abuse potential, has barbiturate-like properties at the GABA-A receptor, leading to central nervous system depression and desired effects. Its tolerance and dependence has been previously demonstrated in an animal model, and withdrawal has been described in several recent case reports. Many cases can be effectively managed with a short course of benzodiazepines or antipsychotic agents. However, abrupt cessation in a patient with a history of long-term and high-dose carisoprodol abuse may result in symptoms that are more difficult for providers to treat. CASE REPORT: We present a case of a 34-year-old man with a long history of carisoprodol abuse who was found unresponsive after having ingested 7.5 grams of carisoprodol. He was intubated and admitted to the intensive care unit. He was given propofol, dexmedetomidine, fentanyl, ketamine, lorazepam, midazolam, quetiapine, and haloperidol, some at high-dose infusions, before his agitation and ventilator asynchrony could be controlled. His improvement coincided with the addition of carisoprodol and phenobarbital to his treatment regimen. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Trends show increasing emergency department presentations for drug-related disorders and treatment. This case highlights an uncommon case of carisoprodol withdrawal that may be encountered by emergency physicians, and demonstrates that benzodiazepines may not be sufficient to suppress severe withdrawal symptoms. Treatment with carisoprodol and phenobarbital provided additional benefit and can be considered in cases of severe carisoprodol withdrawal.

Carisoprodol: an underrecognized drug of abuse in north India.

BACKGROUND: There is limited literature on clinical profile of subjects abusing carisoprodol. METHODS: Our series of 34 subjects shows that a typical subject was an unmarried, unemployed, urban resident from a nuclear family set up; was a substance abuser before being introduced to carisoprodol by another substance abuser; initiated the use to get a better "kick" and after regular use reported craving and withdrawal symptoms. RESULTS: The effect of carisoprodol was dose dependent: a majority reported a feeling of general wellbeing on consuming up to three tablets; a hypomanic state with 4-10 tablets and confusion, disorientation and drowsiness with >10 tablets at a time. CONCLUSION: Thus being an underrecognized drug of abuse, carisoprodol is in need of wider awareness and regulatory measures to prevent its emergence as a greater menace in the future.

Effect of the market withdrawal of carisoprodol on use of other prescribed drugs with abuse potential.

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.

Bladder rupture after intentional medication overdose.

We report the case of a 51-year-old woman who had a medical history of diabetes, depression with past suicide attempts, and suicidal ideation. She was found unresponsive in a motel with multiple bottles of medicines (melatonin, carisoprodol, ativan, and clonazepam) and an unopened bottle of wine. She was transported to the local hospital and treated for benzodiazepine toxicity and aspiration pneumonitis.The decedent gradually became more alert and was extubated 3 days after hospital admission. The decedent was reportedly getting up to use the restroom when she became tachypneic and diaphoretic and complained of generalized body pain. Her condition quickly declined, and she was pronounced deceased. A postmortem examination revealed an acute bladder rupture and soft tissue hemorrhage.A review of the literature reveals that isolated bladder rupture after minimal or no trauma in association with alcohol or drug ingestion is an infrequently reported, but recognized, injury. The diagnosis of bladder rupture should be considered in a patient with lower abdominal pain, even without a history of trauma. A history of voiding or bladder dysfunction should increase the suspicion for this injury. If suspected, a retrograde cystogram should be obtained promptly. Failure to consider and recognize this injury may lead to significant morbidity.

Carisoprodol legal status and patterns of abuse.

OBJECTIVE: To review the current legal status and patterns of abuse of carisoprodol. DATA SOURCES: A literature search was conducted through MEDLINE (1950-August 2010), PubMed (1966-August 2010), EMBASE (1966-August 2010), and International Pharmaceutical Abstracts (1970-August 2010) using the search terms carisoprodol and abuse. In addition, reference citations from publications identified were reviewed. State laws and regulations were accessed through NABPLAW Online (2010) using the search term carisoprodol. Federal proposed rules were accessed through the Federal Register (1995 Volume 59-2010 Volume 75) using the search term carisoprodol. STUDY SELECTION AND DATA EXTRACTION: State laws and federal proposed rules regarding carisoprodol were examined. Case reports and studies involving carisoprodol abuse were evaluated. DATA SYNTHESIS: Carisoprodol is not federally scheduled under the Controlled Substances Act (CSA). However, carisoprodol is scheduled in 36% (n = 18) of states of the US. The Drug Enforcement Administration issued a Notice of Proposed Rulemaking in the Federal Register on November 17, 2009, to place carisoprodol into schedule IV of the CSA, with a deadline to submit written comments by December 17, 2009. Case reports, retrospective studies, and national reports, including reports from the American Association of Poison Control Centers and results from the Monitoring the Future national survey on drug use, have identified carisoprodol's abuse potential. CONCLUSIONS: Carisoprodol should be placed in schedule IV of the CSA based on its abuse potential and current state laws and regulations. Federally scheduling carisoprodol would lead to uniformity among the states and hopefully assist in preventing prescription drug abuse. Larger, well-designed studies evaluating carisoprodol abuse should be performed.

Carisoprodol withdrawal after internet purchase.

INTRODUCTION: Carisoprodol is a centrally acting muscle relaxant used in the treatment of various musculoskeletal disorders whose main metabolite, meprobamate, is a controlled substance in the United States due to its sedative properties and potential for abuse. CASE DESCRIPTION: We report a case of a 51-year-old man with cognitive impairment and tremor who developed worsening tremor, anxiety, myoclonus, ataxia, and psychosis on abrupt cessation of carisoprodol. At hospital discharge, his cognitive function significantly improved compared with when he was on carisoprodol. CONCLUSION: Carisoprodol withdrawal is an important and under-recognized syndrome that should be considered in patients presenting with neurologic symptoms who are taking the medication. Carisoprodol withdrawal can be successfully treated with the use of benzodiazepines, although further studies are needed to identify the most appropriate treatment protocol.

Carisoprodol: abuse potential and withdrawal syndrome.

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.

[Prescription shopping of addictive drugs in Norway]. / Legemiddelshopping av vanedannende medikamenter i Norge.

BACKGROUND: A Regular General Practitioner Scheme was introduced in Norway in 2001. One aim was to restrict patients from "shopping" doctors and prescription drugs. MATERIAL AND METHODS: Data from The Norwegian Prescription Database (NorPD) for 2004 were used to assess the following: number of physicians each patient had used to obtain prescriptions for a drug, the relationship between number of physicians used and amount of drugs prescribed, and concomitant prescription of opioids and benzodiazepines during the same period to the same patients. The drugs studied were the prescription drugs with potential for abuse; diazepam, carisoprodol and codeine combinations. The information retrieved was compared to that for the supposedly non-addictive drugs esomeprazole, metformine and salbutamol. RESULTS: More than 96 % (96.3 - 98.9) of the patients used one or two physicians for prescriptions of the same drug, and fewer than 0.5 % (0.01 - 0.26) used five or more physicians. However, the proportion of patients who used five or more physicians for the addictive drugs was 9.5 times higher than that for a comparable proportion of patients using the non-addictive drugs. The amount of dispensed drug increased considerably more with the number of physicians used for addictive drugs than for non-addictive drugs, as did the amount of concomitantly dispensed opioids and benzodiazepines. INTERPRETATION: The occurrence of prescription drug shopping in the Norwegian population was limited. Among the few patients who used many physicians for prescription of drugs, the phenomenon was much more frequent for users of addictive drugs than for users of the non-addictive drugs. The study suggests that prescription drug shopping may be an indicator of a drug abuse potential.

Introduction of low dose transdermal buprenorphine -- did it influence use of potentially addictive drugs in chronic non-malignant pain patients?

The aim was to study the introduction of the new low dose transdermal buprenorphine (LD-TD-BUP) in Norway, particularly with regard to former use and co-medication with other potentially addictive drugs. The nationwide Norwegian Prescription Database contains information on all prescription drugs dispensed to individual non-institutionalised patients, and we may follow all individuals who received LD-TD-BUP (Norspan) after marketing on the Norwegian market on 15/11/05. We studied all prescriptions of opioids and other potentially addictive drugs to patients receiving at least two LD-TD-BUP prescriptions during 2004-2006. Poisson regressions were run with concomitant use of addictive drugs (yes, no) as the endpoint. Overall, 1884, non cancer individuals received at least two prescription of LD-TD-BUP. Of these 91.7% received prescriptions of other opioids and 58.6% of them had also been prescribed benzodiazepines/carisoprodol before the prescription of LD-TD-BUP. Of the LD-TD-BUP users who received more than one prescription, 60% co-medicated with at least one other potentially addictive drug, and 24% with at least two. In the multivariate analysis, the variables associated with a higher likelihood of using co-medicated drugs were: previous use of benzodiazepines/carisoprodol relative risk RR=16.7 (95% CI 10.4-26.9), previous use of opioids RR=4.0 (1.9-8.7) and younger age 20-40 years RR=1.9 (1.6-2.3). So far, it is questionable whether the introduction of LD-TD-BUP actually has stabilised opioids consumption or whether it has complicated and increased the consumption of potentially addictive drugs.

High-dose carisoprodol during pregnancy and lactation.

OBJECTIVE: To report a case of use of high-dose carisoprodol during pregnancy and breast-feeding. CASE SUMMARY: A 28-year-old woman with severe back muscle spasm took carisoprodol 2800 mg/day before and throughout an uncomplicated pregnancy and while exclusively breast-feeding her infant during the first month after birth. Serum drug concentrations of carisoprodol and the active metabolite meprobamate were measured in the mother and infant. Concentrations of these agents also were measured in breast milk. Developmental toxicity was not observed in the near-term infant, whose birth weight was at the 10th percentile for gestational age. Only slight sedation was noted in the infant during breast-feeding, and no signs or symptoms of withdrawal were noted when nursing was stopped. DISCUSSION: Carisoprodol and meprobamate are excreted into breast milk. Although the published human pregnancy data are limited to 15 cases, carisoprodol does not appear to cause developmental toxicity (growth restriction, structural anomalies, functional/neurobehavioral deficits, or death), even when the mother is taking high doses. No signs or symptoms of withdrawal were noted in our infant or in a previously published case when breast-feeding was stopped. Long-term follow-up has not been conducted in exposed infants, and the possibility of functional/neurobehavioral l deficits appearing later in life cannot be excluded. CONCLUSIONS: Except for mild sedation, no other toxicity was observed in a near-term infant exposed to carisoprodol throughout gestation and during breast-feeding in the first month after birth.