Concomitant use of prescription opioids and baclofen may increase the risk for opioid overdose, according to results of a study published in Neurology.

This active comparator cohort study was conducted using data from the Medicaid Analytic eXtract (2000-2014), Medicare fee-for-service beneficiaries (2012-2017), Optum© Clinformatics® Data Mart (2004-2019), and IBM® MarketScan® Research Database (2003-2018). The concomitant use of prescription opioids with muscle relaxant medications was evaluated for opioid overdose risk using a weighting approach to balance cohort characteristics. A negative control outcome of sepsis was used to account for potential overdose due to illicit opioid use, as illicit use is undercaptured in claims data and illicit use with injectable opioids may lead to sepsis.

A total of 552,649 patients initiated treatment with cyclobenzaprine, 214,838 initiated treatment with tizanidine, 136,650 initiated treatment with baclofen, 124,662 initiated treatment with methocarbamol, 117,633 initiated treatment with carisoprodol, 67,435 initiated treatment with metaxalone, and 32,152 initiated treatment with chlorzoxazone/orphenadrine. The mean age of the pooled study population was 53 years at the initiation of treatment with a muscle relaxant, and 62% were women. In the unweighted cohorts, individuals who initiated treatment with baclofen and tizanidine tended to be older than individuals receiving the other medications.

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For the intention-to-treat analysis, during the first 30 days after treatment initiation, 887 opioid overdoses occurred, with more overdoses occurring among individuals using cyclobenzaprine (n=278) and baclofen (n=266).

Compared with cyclobenzaprine, baclofen was associated with opioid overdose risk (adjusted weighted hazard ratio [awHR], 2.52; 95% CI, 1.29-4.90; P =.04), but there was no increased risk for opioid overdose with carisoprodol (awHR, 1.64; 95% CI, 0.81-3.34), chlorzoxazone/orphenadrine (awHR, 1.14; 95% CI, 0.53-2.46), tizanidine (awHR, 1.07; 95% CI, 0.49-2.33), methocarbamol (awHR, 1.00; 95% CI, 0.45-2.20), or metaxalone (awHR, 0.46; 95% CI, 0.17-1.24).

For the as-treated analysis, 1420 opioid overdose events occurred, with most events occurring in individuals undergoing treatment with baclofen (n=403) and cyclobenzaprine (n=388).

Compared with cyclobenzaprine, opioid overdose risk trended toward significance among individuals being treated with baclofen (awHR, 2.07; 95% CI, 1.18-3.64; P =.07) and remained nonsignificant for individuals being treated with other muscle relaxant medications.

During the first 30 days, 4324 sepsis events occurred, most often among individuals undergoing treatment with cyclobenzaprine (n=1810) and baclofen (n=907). Compared with cyclobenzaprine, no increased risk for sepsis was observed for any of the muscle relaxant medications.

In secondary analyses, opioid overdose risk was associated with baclofen use relative to tizanidine use (pooled weight hazard ratio [pwHR], 2.50; 95% CI, 1.95-3.21). Among patients without prior substance abuse, opioid overdose risk was associated with baclofen use relative to cyclobenzaprine use (pwHR, 2.48; 95% CI, 1.02-6.04).

A major limitation of this study is the lack of identification of the cause of opioid overdose, whether due to drug-drug interactions or opioid overuse.

The study authors conclude that concomitant use of baclofen and prescription opioids may increase the risk for opioid overdose, relative to cyclobenzaprine. “Greater awareness among clinicians about the risks of concomitant baclofen use may motivate discussions regarding prescribing of alternatives or ensuring access to opioid antagonists in patients for whom baclofen is the only option available.”

Disclosure: Multiple study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Khan N, Bykov K, Barnett M, Glynn R, Vine S, Gagne J. Comparative risk of opioid overdose with concomitant use of prescription opioids and skeletal muscle relaxants.Neurology. Published online July 14, 2022. doi:10.1212/WNL.0000000000200904

This article originally appeared on Clinical Pain Advisor