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 withdrawal symptomatology 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 a sublingual buprenorphine for study days 21-35 teas 0.80 ng/ml, and the mean alternate day steady-stare 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.