Buprenorphine duration of action: mu-opioid receptor availability and pharmacokinetic and behavioral indices.
BACKGROUND
Buprenorphine (BUP) is effective in the treatment of opioid dependence when given on alternating days, probably as a result of long-lasting occupation of micro opioid receptors (microORs). This study examined the duration of action of BUP at microORs and correlations with pharmacokinetic and pharmacodynamic outcomes in 10 heroin-dependent volunteers.


METHODS
Availability of microOR (measured with positron emission tomography and [(11)C]-carfentanil), plasma BUP concentration, opioid withdrawal symptoms, and blockade of hydromorphone (HYD; heroin-like agonist) effects were measured at 4, 28, 52, and 76 hours after omitting the 16 mg/d dose of BUP in a study reported elsewhere.


RESULTS
Relative to heroin-dependent volunteers maintained on BUP placebo, whole-brain microOR availability was 30%, 54%, 67%, and 82% at 4, 28, 52, and 76 hours after BUP. Regions of interest showed similar effects. Plasma concentrations of BUP were time dependent, as were withdrawal symptoms, carbon dioxide sensitivity and extent of HYD blockade. Availability of microOR was also correlated with BUP plasma concentration, withdrawal symptoms, and HYD blockade.


CONCLUSIONS
Together with our previous findings, it appears that microOR availability predicts changes in pharmacokinetic and pharmacodynamic measures and that about 50%-60% BUP occupancy is required for adequate withdrawal symptom suppression (in the absence of other opioids) and HYD blockade.
Greenwald
Mark
M
Substance Abuse Research Division, Department of Psychiatry and Behavioral Neurosciences Wayne State University, Detroit, Michigan 48207, USA. mgreen@med.wayne.edu
Johanson
Chris-Ellyn
CE
Bueller
Joshua
J
Chang
Yan
Y
Moody
David E
DE
Kilbourn
Michael
M
Koeppe
Robert
R
Zubieta
Jon-Kar
JK
D000328:Adult; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000652:urine; D019540:Area Under Curve; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D001931:Brain Mapping; D002047:Buprenorphine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D005283:Fentanyl / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine; D006801:Humans; D004091:Hydromorphone / Q000494:pharmacology / Q000652:urine; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D009293:Opioid-Related Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D049268:Positron-Emission Tomography / Q000379:methods; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism*; D012119:Respiration / Q000187:drug effects; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics / Q000652:urine
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D017450:Receptors, Opioid, mu; D014316:Tritium; D002047:Buprenorphine; C017114:carfentanil; D004091:Hydromorphone; D005283:Fentanyl