RT Journal Article SR Electronic T1 Using [11C]Diprenorphine to Image Opioid Receptor Occupancy by Methadone in Opioid Addiction: Clinical and Preclinical Studies JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 309 OP 315 DO 10.1124/jpet.104.072686 VO 312 IS 1 A1 Jan K. Melichar A1 Susan P. Hume A1 Tim M. Williams A1 Mark R. C. Daglish A1 Lindsay G. Taylor A1 Rabia Ahmad A1 Andrea L. Malizia A1 David J. Brooks A1 Judith S. Myles A1 Anne Lingford-Hughes A1 David J. Nutt YR 2005 UL http://jpet.aspetjournals.org/content/312/1/309.abstract AB Substitute methadone prescribing is one of the main modes of treatment for opioid dependence with established evidence for improved health and social outcomes. However, the pharmacology underpinning the effects of methadone is little studied despite controversies about dosing in relation to outcome. We therefore examined the relationship between methadone dose and occupation of opioid receptors in brain using the positron emission tomography (PET) radioligand [11C]diprenorphine in humans and rats. Eight opioid-dependent subjects stable on their substitute methadone (18-90 mg daily) had an [11C]diprenorphine PET scan at predicted peak plasma levels of methadone. These were compared with eight healthy controls. No difference in [11C]diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy. Adult male Sprague-Dawley rats that had been given an acute i.v. injection of methadone hydrochloride (0.35, 0.5, 0.7, or 1.0 mg kg-1) before [11C]diprenorphine showed a dose-dependent increase in biodistribution but no reduction in [11C]diprenorphine binding. We suggest that the lack of a dose-dependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [11C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioid receptor occupancy. This has implications for understanding the actions of methadone in comparison with other opioid drugs such as partial agonists and antagonists. The American Society for Pharmacology and Experimental Therapeutics