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 norbuprenorph ine plasma concentrations with subject-reported withdrawal symptomatol ogy during buprenorphine dose induction, maintenance treatment (daily and alternate-day dosing) and withdrawal. Design. Two groups of random ly assigned subjects inducted onto buprenorphine and maintained on 8 m g daily by the sublingual route for 18 days. Group 1 continued to rece ive 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 t he Addiction Research Center, Intramural Research Center, NIDA, Baltim ore, MD. Participants. Eleven male, heroin-dependent volunteers partic ipating in a research study. Intervention. Medications for treatment o f withdrawal symptoms were prescribed as needed after day 39 (72 hours after the last dose of buprenorphine). Measurements. Plasma concentra tions of buprenorphine and norbuprenorphine, withdrawal symptomatology and pupil diameter. Findings. The mean steady-state buprenorphine pla sma concentration (24 hours) after daily administration a sublingual b uprenorphine for study days 21-35 teas 0.80 ng/ml, and the mean altern ate day steady-stare buprenorphine plasma concentration (24 hours) was 0.77 ng/ml. Daily and alternate day steady-state norbuprenorphine pla sma concentrations were 1.10 and 0.90 ng/ml, respectively. Predicted a lternate day steady-state buprenorphine and norbuprenorphine plasma co ncentrations at 48 hours were 0.49 ng/ml and 0.57 ng/ml, respectively. Withdrawal scores varied inversely with plasma concentration. There w ere no significant differences between Groups 1 and 2 during steady-st ate (days 21-35) with regard to withdrawal scale scores or pupillary d iameter. The overall, mean terminal elimination half-lives for bupreno rphine and norbuprenorphine were 42 and 57 hours, respectively. Conclu sions. During daily buprenorphine maintenance, plasma concentrations g reater than 0.7 ng/ml of buprenorphine and norbuprenorphine were assoc iated with minimal withdrawal symptoms. The long elimination half-life of buprenorphine suggested that increasing the buprenorphine dose wit h alternate-day administration may provide an effective, flexible ther apy regimen for the treatment of opioid dependence.