Comparative Rates of Traumatic Physical Injury Among Concurrent Users of Opioid Analgesics and Skeletal Muscle Relaxants: Cohort Studies Using United States Medicaid Data

Background: Concomitant use of skeletal muscle relaxants (SMRs, a structurally diverse group of drugs that are used increasingly to treat pain) and opioid analgesics has been linked to an increased rate of physical injury, presumably driven by pharmacodynamic drug interactions between these medication classes. However, it remains unclear whether injury rates differ by specific SMR when combined with an opioid.

Objectives: To compare physical injury rates associated with different SMRs during person-time exposed to one of three very commonly-used opioids: hydrocodone, oxycodone, or tramadol

Methods: We conducted nine retrospective cohort studies using 1999-2012 Medicaid data from five populous United States (US) states. Each cohort consisted exclusively of person-time exposed to both an SMR (the exposure of interest) and one of three opioids: hydrocodone, oxycodone, or tramadol. Users were further divided into three subcohorts based on the ordering of drug initiation, i.e., opioid users newly-initiating an SMR, SMR users newly-initiating an opioid, and synchronous new use of an opioid and SMR. The outcome of interest was an International Classification of Diseases diagnosis for a traumatic physical injury present on an emergency department or inpatient hospitalization claim. Within each subcohort, we used Cox proportional hazards models to compare injury rates for eight different SMRs—each compared to methocarbamol (a commonly used SMR with debatably modest sedating effects)—adjusting for covariates (including but not limited to opioid dose and frailty) via overlap weighting on the propensity score.

Results: We identified 349 653, 139 458, and 218 967 concurrent users of SMRs with hydrocodone, oxycodone, and tramadol, respectively. Among oxycodone users with an SMR triggering concomitancy, adjusted hazard ratios (HRs) were 1.86 (95% CI, 1.23–2.82) for carisoprodol and 1.73 (1.09–2.73) for tizanidine. Among tramadol users with an SMR triggering concomitancy, adjusted HRs were 1.51 (1.01–2.26) for baclofen and 1.48 (1.03–2.11) for cyclobenzaprine. Among users in which tramadol and an SMR were initiated synchronously, adjusted HRs were 0.69 (0.49–0.97) for metaxalone and 0.62 (0.42–0.90) for tizanidine. All other adjusted HRs were consistent with the null value of 1.00.

Conclusions: Relative injury rates associated with concurrent use of SMRs and opioid analgesics greatly vary depending on the specific opioid, specific SMR, and/or the order in which such drugs are initiated. We provide preliminary findings on opioid-SMR combinations that may potentially exacerbate, and others that may reduce, the risk of injury. Future work is needed, especially in more contemporaneous data, to confirm these findings.