Comparative Risk of Opioid Overdose With Concomitant Use of Prescription Opioids and Skeletal Muscle Relaxants

Neurology. 2022 Sep 27;99(13):e1432-e1442. doi: 10.1212/WNL.0000000000200904. Epub 2022 Jul 14.


Background and objectives: The concomitant use of prescription opioids and skeletal muscle relaxants has been associated with opioid overdose, but little data exist on the head-to-head safety of these drug combinations. The objective of this study was to compare the risk of opioid overdose among patients on long-term opioid therapy who concurrently initiate skeletal muscle relaxants.

Methods: We conducted an active comparator cohort study spanning 2000 to 2019 using healthcare utilization data from 4 US commercial and public insurance databases. Individuals were required to have at least 180 days of continuous enrollment and at least 90 days of continuous prescription opioid use immediately before and on the date of skeletal muscle relaxant initiation. Exposures were the concomitant use of prescription opioids and skeletal muscle relaxants, and the main outcome was the hazard ratio (HR) and bootstrapped 95% CI of opioid overdose resulting in an emergency department visit or hospitalization. The primary analysis quantified opioid overdose risk across 7 prescription opioid-skeletal muscle relaxant therapies and a negative control outcome (sepsis) to assess potential confounding by unmeasured illicit opioid use. Secondary analyses evaluated two-group and five-group comparisons in patients with similar baseline characteristics; individuals without previous recorded substance abuse; and subgroups stratified by baseline opioid dosage, benzodiazepine codispensing, and oxycodone or hydrocodone use.

Results: Weighted HR of opioid overdose relative to cyclobenzaprine was 2.52 (95% CI 1.29-4.90) for baclofen; 1.64 (95% CI 0.81-3.34) for carisoprodol; 1.14 (95% CI 0.53-2.46) for chlorzoxazone/orphenadrine; 0.46 (95% CI 0.17-1.24) for metaxalone; 1.00 (95% CI 0.45-2.20) for methocarbamol; and 1.07 (95% CI 0.49-2.33) for tizanidine in the 30-day intention-to-treat analysis. Findings were similar in the as-treated analysis, 2-group and 5-group comparisons, and patients without previous recorded substance abuse. None of the therapies relative to cyclobenzaprine were associated with sepsis, and no subgroups indicated an increased risk of opioid overdose.

Discussion: Concomitant use of prescription opioids and baclofen relative to cyclobenzaprine is associated with opioid overdose. Clinical interventions may focus on prescribing alternatives in the same drug class or providing access to opioid antagonists if treatment with both medications is necessary for pain management.

MeSH terms

  • Amitriptyline / analogs & derivatives
  • Analgesics, Opioid
  • Baclofen
  • Benzodiazepines / adverse effects
  • Carisoprodol*
  • Chlorzoxazone
  • Cohort Studies
  • Humans
  • Hydrocodone
  • Methocarbamol*
  • Narcotic Antagonists / therapeutic use
  • Neuromuscular Agents* / adverse effects
  • Opiate Overdose*
  • Orphenadrine
  • Oxycodone
  • Prescriptions
  • Sepsis* / drug therapy
  • Substance-Related Disorders* / drug therapy


  • Analgesics, Opioid
  • Narcotic Antagonists
  • Neuromuscular Agents
  • Methocarbamol
  • Benzodiazepines
  • Amitriptyline
  • Carisoprodol
  • cyclobenzaprine
  • Hydrocodone
  • Orphenadrine
  • Oxycodone
  • Chlorzoxazone
  • Baclofen