PROJECT SYNOPSIS PAGE 1 519410 The project addresses a question of high practical and health relevance to increasing numbers of Australians, the answer to which is currently uncertain: whether opioids prescribed to treat heroin addiction or chronic persistent pain produce residual adverse cognitive and psychomotor effects comparable to those from alcohol? The project draws on expertise of leaders in the psychopharmacology of drug and alcohol dependence (White), pharmacogenetics (Somogyi), the role of processing speed/executive function to cognitive performance (Nettelbeck), psychometric theory, statistical modelling and analysis, and psychomotor skills relevant to driving (Burns). This research team therefore provides a unique opportunity to converge on questions about the nature and time-course of functional impairments when long-term use of opioid drugs applies, using as a standard for comparisons impairment produced at different blood level concentrations of alcohol. It also addresses whether effects are specific to methadone via comparison with buprenorphine and whether a modified methadone dosage regimen attenuates deleterious effects. Aims are three-fold: 1. To characterize cognitive and psychomotor impairment resulting from the peaks in plasma methadone concentration in patients maintained long-term. This will include: (i) The types of impairments produced; (ii) The time course of impairment relative to dosing; (iii)The magnitude of change relative to the effects of alcohol; 2. Determining whether the partial agonist buprenorphine produces less effect on performance than the full agonist methadone. 3. Determining if methadone effects are diminished by dividing the daily dose. To address these aims, four studies are planned: (i) The effects of alcohol intoxication on different domains of executive control processes responsible for higher order, everyday functioning, thereby setting comparison standards for drug- related performance; (ii) Evaluation in chronic pain and addiction subjects of methadone on cognitive and psychomotor functions across time and plasma concentration, from pre-dosing to 8 hours after dosing; (iii) Evaluation of buprenorphine compared to methadone on cognitive and psychomotor functions (iv) Assessing such functions when methadone dose is divided, to control release over time. Eight different but complementary tests based on current best practice for assessing cognitive and psychomotor functions will permit reliable repeated measures across time. The project is novel because it has the potential to resolve indeterminate and contradictory results thus far on impairment produced by opioid drugs. Specifically, by using repeated measures that track effects resulting from changing opioid plasma concentrations across time following drug administration, the research design avoids confounding opioid effects with pre-existing conditions associated with drug use (tolerance differences, polydrug use, associated trauma, various comorbidities, differences in IQ and social demographics, etc.). We will also assess plasma concentration-effect relationships and the pharmacogenomic contribution to intersubject variability in response measurements. Within a context where daily drug use is increasing, answering these questions has major significance for improved understanding of the cognitive/psychomotor performance of patients maintained long-term on opioids, particularly as this relates everyday functioning. Impaired functioning may affect capacities to work, study, drive a motor vehicle, and to maintain a reasonable quality of life. Impaired function may also impact on family and other community members, like co-workers and other road users. Improved knowledge, however, has potential for better management practices. Our work will have direct translational application, given the direct clinical nature of our study. The studies will also contribute to the Australian Government’s National Research Priorities in “Promoting and Maintaining Good Health” (Ageing well, ageing productively; Preventative healthcare) and the NHMRC Major Health Issue of Depression, dementia and addiction, as enunciated in their Strategic Plan 2007-2009.
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"A trial of therapeutic drug monitoring in methadone maintenance"Please download to view full document