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NEUROPHARMACOLOGY

Using [¹¹C]Diprenorphine to Image Opioid Receptor Occupancy by Methadone in Opioid Addiction: Clinical and Preclinical Studies

Psychopharmacology Unit, University of Bristol, Bristol, United Kingdom (J.K.M., T.M.W., M.R.C.D., L.G.T., A.L.M., A.L.H., D.J.N.); Hammersmith Imanet Ltd., Hammersmith Hospital, London, United Kingdom (S.P.H., R.A.); Medical Research Council Clinical Sciences Centre and Division of Neuroscience, Faculty of Medicine, Imperial College, Hammersmith Hospital, London, United Kingdom (D.J.B.); and Bristol Specialist Drug Service, Blackberry Hill Hospital, Bristol, United Kingdom (J.S.M.)

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.

Address correspondence to: Professor David J. Nutt, Psychopharmacology Unit, University of Bristol, Dorothy Hodgkin Building, Whitson St., Bristol, BS1 3NY, UK. E-mail: david.j.nutt{at}bristol.ac.uk

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