Relationship of plasma buprenorphine and norbuprenorphine to withdrawal symptoms during dose induction, maintenance and withdrawal from sublingual buprenorphine

Aims. Examine the relationship between buprenorphine and norbuprenorphine plasma concentrations with subject-reported withdrawalsymptomatology during buprenorphine dose induction, maintenance treatment (daily and alternate-day dosing) and withdrawal . Design. Two groups of randomly assigned subjects inducted onto buprenorphine and maintained on 8 mg daily by the sublingual route for 18 days. Group 1 continued to receive daily buprenorphine to day 36. Group 2 subjects received alternate-day dosing of buprenorphine and placebo on days 19 to 36. Both groups received placebo on days 37 to 52 . Setting. Inpatient facilities at the Addiction Research Center, Intramural Research Center, NIDA, Baltimore, MD . Participants. Eleven male, heroin-dependent volunteers participating in a research study . Intervention. Medications for treatment of withdrawal symptoms were prescribed as needed after day 39 (72 hours after the last dose of buprenorphine) . Measurements. Plasma concentrations of buprenorphine and norbuprenorphine, withdrawal symptomatology and pupil diameter . Findings. The mean steady-state buprenorphine plasma concentration (24 hours) after daily administration of sublingual buprenorphine for study days 21-35 was 0.80 ng/ml, and the mean alternate day steady-state buprenorphine plasma concentration (24 hours) was 0.77 ng/ml. Daily and alternate day steady-state norbuprenorphine plasma concentrations were 1.10 and 0.90 ng/ml, respectively. Predicted alternate day steady-state buprenorphine and norbuprenorphine plasma concentrations at 48 hours were 0.49 ng/ml and 0.57 ng/ml, respectively. Withdrawal scores varied inversely with plasma concentration. There were no significant differences between Groups 1 and 2 during steady-state (days 21-35) with regard to withdrawal scale scores or pupillary diameter. The overall, mean terminal elimination half-lives for buprenorphine and norbuprenorphine were 42 and 57 hours, respectively . Conclusions. During daily buprenorphine maintenance, plasma concentrations greater than 0.7 ng/ml of buprenorphine and norbuprenorphine were associated with minimal withdrawal symptoms. The long elimination half-life of buprenorphine suggested that increasing the buprenorphine dose with alternate-day administration may provide an effective, flexible therapy regimen for the treatment of opioid dependence.