Inhibition of In Vitro Metabolism of Opioids by Skeletal Muscle Relaxants

Abstract

The purpose of this study was to test the hypothesis that skeletal muscle relaxants could inhibit the in vitro metabolism of common comedications 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 ± pre-incubation, screened with pathway-specific cDNA-expressed cytochrome P450s (rCYP), and then IC values determined using either 8-concentration tests for those where the rCYP screen suggested an IC 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 (≥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 (≥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 comedications with skeletal muscle relaxants.

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

“…Our study suggests their potential to increase the risk of opioid overdose also varies. The positive finding with carisoprodol is consistent with existing pharmacokinetic data in which carisoprodol and its metabolite meprobamate showed weak and moderate potential to inhibit the deactivation of oxycodone . Pharmacodynamically, both carisoprodol and meprobamate can activate the GABA A receptor to suppress respiration, and potentially exacerbate opioid‐induced respiratory depression .…”

Isolated Hemopericardium after Initiation of Rivaroxaban: Implications and Potential Mechanisms

“…Given the above described pharmacokinetics of rivaroxaban, it is possible that the co-administration of Cyclobenzaprine and Pravastatin, both minor substrates of CYP 3A4. 10,11 and thus competitive compounds, lead to a higher serum concentration of metabolically active rivaroxaban and thus an increased bleeding risk.…”

Opioid toxicity due to CNS depressant polypharmacy: A case report

“…The addition of cyclobenzaprine at bedtime on day 10 seemed to have tipped the balance and contributed to the episode on day 11 although there is only 1 in vitro study to support cyclobenzaprine's potential to inhibit opioid metabolism. 16 Further, a number of CNS depressants were administered throughout this patient's hospital admission (see Figure ). Many of the medications have a moderately long half-life of 5 to 72 hours, and as complete elimination takes 4 to 5 half-lives, these medications could have remained in the patient's system and increased the risk of additive CNS depression.…”