Methadone is currently the most widely used agent to manage opioid dependence, but clinical experience has highlighted some limitations with its use. In particular, a relatively high proportion of patients complain of breakthrough withdrawal symptoms ( non - holding ) at apparently adequate methadone doses. Levo - alpha - acetylmethadol ( LAAM ) is a long acting opioid that is likely to benefit methadone non - holders ; however, relatively little is known about its pharmacology at steady state. The primary aim of this thesis was to evaluate LAAM as an alternative maintenance pharmacotherapy to methadone for the treatment of non - holders ; subsidiary aims were to elucidate the pharmacodynamics and pharmacokinetics of LAAM and its active metabolites ( nor - and dinor - LAAM ), and to examine the in vitro activity of LAAM, nor - and dinor - LAAM. Sixteen methadone maintenance patients ( non - holders = 8 ) were recruited to participate in a randomised, crossover trial of LAAM and methadone. At steady state there were two testing sessions ( 24 h for methadone and 48 h for LAAM ) that featured the concurrent measurement of plasma drug concentrations and both subjective and physiological indices of opioid effect. Cognitive and psychomotor functions were also assessed once during each inter - dosing interval study. Ten age - and gender - matched controls were also tested. The peak magnitude of methadone ' s and LAAM ' s effects were similar. Compared to methadone, LAAM was associated with more stable and less severe withdrawal and mood disturbance. The general pattern of symptom complaints and cognitive function was similar for both drugs. Severity of mood disturbance and withdrawal was similar in holders on methadone and LAAM, but was greater in non - holders when they were taking methadone than LAAM. In comparison to plasma ( R ) - ( - ) methadone, plasma nor - and dinor - LAAM concentrations fluctuated little over the dosing interval. Furthermore, nor - and dinor - LAAM were both more potent in the guinea - pig ileum bioassay, and had greater affinity for mu opioid receptors in receptor binding studies, than LAAM. In conclusion, LAAM converted methadone non - holders into LAAM holders. It is proposed that it is the relatively flat plasma concentration - time profile for nor - and dinor - LAAM that confer stability of opioid effect, minimising withdrawal. Therefore, LAAM may have a role in selected patients, whose response to methadone is suboptimal. / Thesis (Ph.D.)--School of Medical Sciences, 2006.
| Identifer | oai:union.ndltd.org:ADTP/263760 |
| Date | January 2006 |
| Creators | Newcombe, David A.L. |
| Source Sets | Australiasian Digital Theses Program |
| Language | en_US |
| Detected Language | English |
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