It was hypothesized that a metabolite of morphine, morphine-3-glucuronide (M3G), contributes to the expression of symptoms seen during withdrawal from morphine. To test this hypothesis, the behaviors observed during precipitated withdrawal from morphine and sufentanil were compared. Sufentanil was chosen because, like morphine, it acts primarily at the mu opioid receptor, but has different metabolites. Differences in the abstinence syndromes produced by the two drugs may therefore be attributable to the actions of metabolites, rather than the primary opioid actions of morphine and sufentanil. Although there were some differences in the occurrence of symptoms, morphine and sufentanil withdrawal were very similar. Therefore, the evidence was inconclusive as to the contribution of metabolites during withdrawal. / Systemic administration of M3G alone and in combination with morphine produced no withdrawal-like behaviors. However, when these drugs were given centrally, withdrawal-like behaviors were observed in conjunction with seizures. The seizures were not attenuated by naloxone (but were alleviated by an anti-convulsant), indicating that they were not mediated by opioid receptors. The behaviors resembled those seen by previous investigators following high doses of morphine. The results suggest that M3G may play a role in the toxic effects of high doses of morphine.

No description available.

Policy-makers, funding bodies and treatment providers need current, comparable and accurate information on the activities and outcomes of alcohol and other drug (AOD) treatment services to respond to the needs of the sector. If meaningful comparisons are to be made at the jurisdictional level, a standardised treatment outcome monitoring system must be developed and implemented, that takes into account differences in client characteristics, treatment settings and modes of service provision. A brief, multi-dimensional instrument, the Brief Treatment Outcome Measure (BTOM) has been developed for routine, ongoing treatment outcome monitoring with clients receiving opioid maintenance pharmacotherapy (OMP) services in New South Wales (NSW), and for use in treatment evaluation research. This is the first time in Australia that an attempt has been made to integrate outcome monitoring into routine clinical practice across an AOD treatment sector. The BTOM contains thirty-three items across the domains of dependence, blood-borne virus exposure risk, drug use, health/psychological functioning and social functioning. The internal reliability of the BTOM is satisfactory; retest reliabilities for the measures are good to excellent and concurrent validation of BTOM scales yielded acceptable agreement. Average completion times of the BTOM were 14.5 minutes when administered by researchers and 21 minutes by clinicians. A 30-month feasibility trial was conducted in selected NSW OMP treatment agencies to determine the practicability of implementing an OMS; to identify issues that would impact on the quality of the data; and identify administrative processes that could facilitate implementation whilst minimising the burden on agency staff. In addition, clinicians who had administered the BTOM were surveyed 18 months into the trial to ascertain their attitudes towards the clinical utility, acceptability of content and the level of support given to them to administer the BTOM as part of routine clinical practice. Results from the trial indicate that the BTOM measures are sensitive to change over time; that the change observed is consistent with that reported in the OMP treatment outcome literature; and that clinicians, whilst generally being positively predisposed towards using the instrument, express concerns relating to the burden of administering and the clinical utility of conducting outcome monitoring.

Suicide attempts and opioid dependence are important clinical issues, as both are associated with a high degree of psychiatric morbidity and elevated risk of mortality. Research has identified a number of risk factors for suicide attempts among the general population, and to a lesser extent, among heroin users. Due to a lack of case-control studies, however, it is still not known to what extent opioid dependence per se is a risk factor for suicide attempts. This thesis comprised the first study to directly examine whether opioid dependence is a unique risk factor of suicide attempts. This thesis examined suicide attempts, associated risk factors, and related comorbidity among an opioid-dependent case group and a non-opioid-dependent control group. A structured interview was used to collect data from 726 opioid-dependent cases and 399 non-opioid-dependent controls. This thesis identified a number of important findings. Firstly, although opioid-dependent individuals were more likely to report lifetime suicide attempts compared to controls, the risk factors were largely the same for both groups. It appeared that opioid-dependent individuals were characterised by a higher likelihood of the same risk factors for suicide attempts, rather than having different risks. Cases appeared to be at increased risk of suicide attempts because of increased levels of multiple risk factors. Secondly, borderline personality disorder (BPD) and impulsivity were identified as important risk markers for suicidal behaviour, especially among opioid-dependent individuals. The study concluded that the treatment of BPD should be prioritised among this group. Third, self-mutilation was identified as a clinically significant problem in its own right, however, when combined with a history of attempted suicide, the psychological dysfunction observed was found to be very high. Fourth, non-fatal opioid overdose and suicide attempts were found to be distinct behaviours. The risk factors for each were completely different. While drug-related risks were associated with non-fatal overdose, the risk markers for suicide attempts were related to the presence of psychological disorders. This thesis has highlighted important areas of concern for clinical interventions as well as for future research to explore. Considering this is the first study of its kind, future research should focus on its replication.

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.

Suicide attempts and opioid dependence are important clinical issues, as both are associated with a high degree of psychiatric morbidity and elevated risk of mortality. Research has identified a number of risk factors for suicide attempts among the general population, and to a lesser extent, among heroin users. Due to a lack of case-control studies, however, it is still not known to what extent opioid dependence per se is a risk factor for suicide attempts. This thesis comprised the first study to directly examine whether opioid dependence is a unique risk factor of suicide attempts. This thesis examined suicide attempts, associated risk factors, and related comorbidity among an opioid-dependent case group and a non-opioid-dependent control group. A structured interview was used to collect data from 726 opioid-dependent cases and 399 non-opioid-dependent controls. This thesis identified a number of important findings. Firstly, although opioid-dependent individuals were more likely to report lifetime suicide attempts compared to controls, the risk factors were largely the same for both groups. It appeared that opioid-dependent individuals were characterised by a higher likelihood of the same risk factors for suicide attempts, rather than having different risks. Cases appeared to be at increased risk of suicide attempts because of increased levels of multiple risk factors. Secondly, borderline personality disorder (BPD) and impulsivity were identified as important risk markers for suicidal behaviour, especially among opioid-dependent individuals. The study concluded that the treatment of BPD should be prioritised among this group. Third, self-mutilation was identified as a clinically significant problem in its own right, however, when combined with a history of attempted suicide, the psychological dysfunction observed was found to be very high. Fourth, non-fatal opioid overdose and suicide attempts were found to be distinct behaviours. The risk factors for each were completely different. While drug-related risks were associated with non-fatal overdose, the risk markers for suicide attempts were related to the presence of psychological disorders. This thesis has highlighted important areas of concern for clinical interventions as well as for future research to explore. Considering this is the first study of its kind, future research should focus on its replication.

Includes copies of articles co-authored by the author during the preparation of this thesis. / Includes bibliographical references (leaves 334-376). / viii, 376 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Aims to increase understanding of the metabolism and disposition of methadone in humans, in particular in subjects receiving methadone maintenance treatment for opioid dependence, and to identify factors which may contribute to inter-subject variability in these processes, with respect to stereoselectivity / Thesis (Ph.D.)--Adelaide University, Dept. of Clinical and Experimental Pharmacology, 2001