Pharmacokinetics of Single Doses of Methadone and Buprenorphine in Blood and Oral Fluid in Healthy Volunteers and Correlation With Effects on Psychomotor and Cognitive Functions

Abstract

We aimed to study the pharmacokinetics of methadone and buprenorphine in blood and oral fluid after single-dose administration and investigate correlations between concentrations in blood and neurocognitive functions. A 5-way, double-blind, randomized, placebo-controlled, double-dummy, crossover study was performed to study the pharmacokinetics and neurocognitive effects of methadone (5 and 10 mg per oral) and buprenorphine (0.2 and 0.4 mg sublingual) in 22 healthy volunteers. Blood and oral fluid were collected throughout the test days, and drug concentrations in both matrices were analyzed using ultrahigh-performance liquid chromatography-tandem mass spectrometry. On-road driving testing, neurocognitive computerized tests, and subjective questionnaires were performed. Large individual variations in concentrations of methadone and buprenorphine in blood and oral fluid, and accordingly oral fluid/blood drug concentration ratios, were observed. The mean ratio 6.5 hours after drug administration was 2.0 (range, 0.49-7.39) for methadone after both doses. Buprenorphine was not detected above the limit of quantification in blood after 6.5 hours. No significant correlation between methadone concentration in blood and effect was found. Significant correlations were found between buprenorphine concentration in blood and standard deviation of lateral position in the driving test and some measures of reaction time, divided attention, balance, alertness, contentedness. and sleepiness. Concentrations of methadone and buprenorphine in blood and oral fluid showed large interindividual variations. No concentration-effect correlations were found for methadone, whereas low to moderate correlations were observed between buprenorphine concentration and driving, psychomotor function, and subjective rating of sleep and alertness.