U.S. flag

An official website of the United States government, Department of Justice.

Inhibition of In Vitro Metabolism of Opioids by Skeletal Muscle Relaxants

NCJ Number
Basic & Clinical Pharmacology & Toxicology Volume: 123 Issue: 3 Dated: September 2018 Pages: 327-334
Date Published
September 2018
8 pages

The purpose of this study was to test the hypothesis that skeletal muscle relaxants could inhibit the in vitro metabolism of common co-medications opioids buprenorphine, methadone, and oxycodone.


The compounds [solubility-limited concentration (µM) studied] were as follows: baclofen (1000), carisoprodol (200), its metabolite meprobamate (1000), chlorzoxazone (200), cyclobenzaprine (1000), metaxalone (50), methocarbamol (1000), orphenadrine (1000) and tizanidine (1000). Compounds were first incubated with human liver microsomes plus or minus pre-incubation, screened with pathway-specific cDNA-expressed cytochrome P450s (rCYP), and then IC50 values determined using either 8-concentration tests for those where the rCYP screen suggested an IC50 was achievable, or a 3-concentration test with downward extrapolation if screen suggested 50% inhibition was not achievable. These results were then extrapolated to determine an inhibitory potential. Six pathway inhibitor combinations were identified with a moderate inhibitory potential (greater than or equal to 2.0 < 5.0): five with chlorzoxazone, R-EDDP, S-EDDP and noroxycodone production by CYP3A4, and R- and S-EDDP production by CYP2B6; and one for the meprobamate effect on noroxycodone production by CYP3A4. An additional eleven combinations were found with a weak inhibitory potential (greater than or equal to 1.25 < 2.0): five with carisoprodol, two each with methocarbamol and meprobamate, and one each with metaxalone and orphenadrine. This represents the first comprehensive study of the inhibitory effect of this class of drugs and suggests that some of them may produce significant drug-drug interactions with opioids that are frequent co-medications with skeletal muscle relaxants. (publisher abstract modified)

Date Published: September 1, 2018