Title page, table of contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / The current study aimed to assess the efficacy and safety of buprenorphine maintenance for the treatment of illicit opioid dependence during pregnancy. Parameters investigated assessed pregnancy progression and Neonatal Abstinence Syndrome (NAS) compared to methadone maintenance and non-opioid exposed control pregnancies. This is the first study to present results comparing the two treatment groups to a control population. The trial was a prospective, non-randomised, open-label, flexible dosing study (n=25 for each group). Women were recruited up to a gestational age of 28 weeks and their infants observed postnatally for 4 weeks. Methadone and buprenorphine doses did not change significantly from recruitment to delivery and were 48.40±5.95 mg.day⁻¹ and 7.46±O.84 mg.day⁻¹ respectively at delivery. Both subjective and objective measures of maternal withdrawal were significantly lower for buprenorphine compared to the methadone group (p<O.Ol and p<O.05, respectively) at the sub-optimal does observed in this study. Direct drug effects were similar between methadone and buprenorphine groups and did not change over the course of pregnancy. Additional substance use during pregnancy was significantly higher for methadone and buprenorphine groups compared to controls but was not significantly different between each other. Patterns of maternal symptom complaints during pregnancy were higher for methadone and buprenorphine compared to controls but were not significantly different to each other and raised several issues regarding maternal health, and re-dosing in the antenatal period. Obstetric complications in the antenatal period and during labour and delivery were similar between the three groups. There was no significant difference between the three groups for infant gestational age at delivery or their Apgar scores. However, methadone exposed infants were significantly smaller than control infants (birth weight p<O.05, body length p<O.05, head circumference p<O.05) while buprenorphine exposed infants did not differ to controls. There was no significant difference between methadone and buprenorphine exposed infants for the percentage of infants who required pharmacological treatment to control NAS (methadone 60%, buprenorphine 48%). However, significantly less morphine was required to control NAS in buprenorphine compared to methadone exposed infants (methadone: 40.07 ± 3.95 mg, buprenorphine: 22.77 ± 4.29 mg; p<0.05) and may have been due to reduced placental transfer of buprenorphine. The current study observed buprenorphine to be at least as efficacious as methadone for the treatment of opioid dependence during pregnancy while minimising NAS. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1259912 / Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2006

Title page, table of contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / The current study aimed to assess the efficacy and safety of buprenorphine maintenance for the treatment of illicit opioid dependence during pregnancy. Parameters investigated assessed pregnancy progression and Neonatal Abstinence Syndrome (NAS) compared to methadone maintenance and non-opioid exposed control pregnancies. This is the first study to present results comparing the two treatment groups to a control population. The trial was a prospective, non-randomised, open-label, flexible dosing study (n=25 for each group). Women were recruited up to a gestational age of 28 weeks and their infants observed postnatally for 4 weeks. Methadone and buprenorphine doses did not change significantly from recruitment to delivery and were 48.40±5.95 mg.day⁻¹ and 7.46±O.84 mg.day⁻¹ respectively at delivery. Both subjective and objective measures of maternal withdrawal were significantly lower for buprenorphine compared to the methadone group (p<O.Ol and p<O.05, respectively) at the sub-optimal does observed in this study. Direct drug effects were similar between methadone and buprenorphine groups and did not change over the course of pregnancy. Additional substance use during pregnancy was significantly higher for methadone and buprenorphine groups compared to controls but was not significantly different between each other. Patterns of maternal symptom complaints during pregnancy were higher for methadone and buprenorphine compared to controls but were not significantly different to each other and raised several issues regarding maternal health, and re-dosing in the antenatal period. Obstetric complications in the antenatal period and during labour and delivery were similar between the three groups. There was no significant difference between the three groups for infant gestational age at delivery or their Apgar scores. However, methadone exposed infants were significantly smaller than control infants (birth weight p<O.05, body length p<O.05, head circumference p<O.05) while buprenorphine exposed infants did not differ to controls. There was no significant difference between methadone and buprenorphine exposed infants for the percentage of infants who required pharmacological treatment to control NAS (methadone 60%, buprenorphine 48%). However, significantly less morphine was required to control NAS in buprenorphine compared to methadone exposed infants (methadone: 40.07 ± 3.95 mg, buprenorphine: 22.77 ± 4.29 mg; p<0.05) and may have been due to reduced placental transfer of buprenorphine. The current study observed buprenorphine to be at least as efficacious as methadone for the treatment of opioid dependence during pregnancy while minimising NAS. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1259912 / Thesis (Ph.D.) -- University of Adelaide, School of Medical Sciences, 2006

Opioid replacement therapy with methadone or buprenorphine has been recommended for managing opioid dependence during pregnancy. Although opioid replacement therapy decreases harmful consequences from maternal illicit drug seeking behaviors, the effects of methadone and buprenorphine on neurogenesis and myelination in the developing fetus have not been thoroughly reviewed. Methadone and buprenorphine may alter newborn neurobehavioral functions by impairing neurogenesis and changing the developmental pattern of myelination. This review found that therapeutic doses of methadone and buprenorphine disturb both neurogenesis and myelination in rodents. Methadone and buprenorphine may alter newborn neurobehavioral functions by impairing neurogenesis and changing the developmental pattern of myelination. However, further studies are required to bridge the gap in the understanding between changes in neural development and abnormalities in neurobehavioral functions in the newborn.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 6 uppsatser.

Objective: To describe the pharmacokinetics of buprenorphine in dogs following administration of a high-concentration formulation of buprenorphine. Study design: Prospective, randomized, crossover study. Animals: A total of six healthy male intact Beagle dogs, 9–13 months of age and weighing 10.3 ± 1.4 kg (mean ± standard deviation). Methods: Dogs were randomized to be administered buprenorphine (0.12 mg kg−1; Simbadol, 1.8 mg mL−1) via the intravenous (lateral saphenous) or subcutaneous (dorsal interscapular) route followed by the alternative route of administration after a 14 day interval. Blood was sampled before administration and at set times up to 72 hours after injection. Plasma buprenorphine concentration was measured using liquid chromatography–tandem mass spectrometry. Results: A 3-compartment model with zero or biphasic rapid and slow first order input in (intravenous or subcutaneous data, respectively) and first-order elimination from the central compartment best fitted the data. The rapid first order input accounted for 63% of the dosage absorption. Typical values (% interindividual variability) for the three compartment volumes were 900 (33), 2425 (not estimated) and 6360 (28) mL kg−1. The metabolic and two distribution clearances were 25.7 (21), 107.5 (74) and 5.7 (61) mL minute−1 kg−1. The absorption half-life for the fast absorption phase was 8.9 minutes with a 0.7 (103) minute delay. The absorption half-life for the slow absorption phase was 347 minutes with a 226 (42) minutes delay. Median (range) bioavailability calculated from noncompartmental analysis was 143 (80–239) %. Calculated terminal half-life was 963 minutes. Conclusions and clinical relevance: The high-concentration formulation of buprenorphine administered subcutaneously had a large volume of distribution and a rapid absorption phase followed by slower, delayed absorption. The high estimate of bioavailability should be interpreted with caution as values above 100% are most commonly related to experimental issues. / Master of Science / Opioids are ever-increasingly difficult to obtain for veterinary usage, although there is an FDA-approved and veterinary-specific formulation of buprenorphine (Simbadol) commercially available. Although only approved in cats, it has been used off-label in dogs due to its availability, despite minimal empirical evidence for its usage. Design: Six male beagle dogs were utilized in a randomized crossover study to evaluate the plasma concentrations of buprenorphine after intravenous and subcutaneous administration. Methodology: All dogs were anesthetized for central venous catheter placement. Following administration of the dosage (intravenous or subcutaneous), whole blood was sampled at set time points from one minute to three days. Blood was centrifuged and plasma removed for analysis of buprenorphine concentration, allowing pharmacokinetic modeling and creation of time-concentration curves. Results: Side effects were mild and associated with sedation. Appetite was transiently decreased in multiple dogs. A biphasic absorption model was determined from the subcutaneous data, with a rapid first phase accounting for the majority of absorption and a slower second phase occurring several hours later. Conclusions: The high-concentration formulation of buprenorphine administered subcutaneously resulted in a long terminal half-life and high estimate of bioavailability, although the latter should be interpreted cautiously. Relevance: The present study showed that the high-concentration formulation of buprenorphine is absorbed from subcutaneous administration in dogs with mild side effects. Further study is warranted on this formulation in dogs.

Relapse to drug taking is a major factor contributing to the low success rate of opioid addiction treatment programmes. Recently, studies have revealed a buprenorphine/naltrexone combination had successfully increased the treatment retention rate (compared to naltrexone alone) among heroin addicts (with history of cocaine abuse) who had undergone detoxification. However, buprenorphine and naltrexone could not be administered as a single formulation due to their different bioavailability, which could create compliance issues. Therefore, in this project, we aimed to synthesise a series of ligands each having the pharmacological profile of the buprenorphine/naltrexone combination (partial agonist (ORL-1 receptors), antagonist (u- and x-opioid receptors)). Based on the group's previous work, this profile can be achieved within the orvinols series. Compound BU127, a buprenorphine analogue with phenyl substituent (C20) is very close to the desired profile. Therefore, in order to optimize BU127's profile, we designed and synthesised a series of aromatic analogues, including analogues with a small group attached to the aromatic system to increase the ORL-1 receptor efficacy, while retaining the low efficacy / antagonist activity at the u-opioid receptor and antagonist activity at x-opioid receptor. However, [35S]GTPyS screening has shown a sudden increase of x-opioid receptor efficacy with these modifications. The related compound BU10119, having a Cv-methyl, met the desired profile at all targeted receptors in the [35S]GTPyS screen. A few analogues were selected for further evaluation in functional assays in the isolated tissue preparations (rat vas deferens (for the ORL-1 and u-opioid receptors) and mouse vas deferens (for the K-opioid receptor)) to estimate their binding affinity (Ks) and potency (pA2) of the compounds relative to buprenorphine, using Schild analysis and Schild equation. Of the analogues synthesised, only compounds BU127 and BU1 0119 have met the desired profile at the targeted receptors (competitive reversible at the ORL-1 and u-opioid receptors) and having binding affinity at each receptor similar to buprenorphine (ORL-1, ~- and K-opioid receptors). Based on these results, at this point, the optimum features of buprenorphine analogues in order to achieve the targeted profiles are having a small group at Cy and a 6-membered aromatic substituent at C . 20 Without any substituent group attached to the aromatic ring.

Opioid dependence is a chronic relapsing condition resulting in significant individual and community harms, for which the most effective treatment is long term opioid pharmacotherapy (OP). In contrast to other Australian states and territories, in Victoria, 80-85 % of OP prescribing is undertaken by GPs, and while demand for this treatment is difficult to estimate, all evidence indicates that the current and future GP workforce is inadequate to meet projected need. / GPs have shown a reluctance to become actively involved in the treatment of patients with drug dependence, especially where illicit drugs are involved. In order to prescribe OP, Australian medical practitioners are required to complete a specific training program. Little is known of the reasons why GPs decline to undertake this training, and why the majority who complete training, subsequently prescribe to very few or no patients. / Using in-depth interviews and an analysis of existing data from the Victorian Department of Human Services, this thesis not only explores why GPs are unwilling to complete OP training, and why many subsequently fail to prescribe, but also identifies both barriers and facilitators which influence GPs in their decisions regarding these issues. The results have not only provided new information on the reasons GPs decline the offer of training but also supported existing research.

During surgery, both anesthesia and tissue damage cause physiological stress responses in the body. The hypothalamic-pituitary-adrenal (HPA) axis is activated with increased levels of glucocorticoids. After surgical procedures the stress response may be a cause of postoperative morbidity and pre-emptive analgesic treatment can attenuate the stress response during the postoperative period. In laboratory animals, buprenorphine is a commonly used analgesic. Subcutaneous (s.c.) administration of buprenorphine is most common, but oral administration would be preferable in many cases, enabling administration without any handling of the rat. In this thesis we studied the surgical stress response in laboratory rats during surgery and in the postoperative period, and its modulation by s.c. injection and oral voluntary ingestion (VI) of buprenorphine. Corticosterone levels and the clinical parameters body weight, water intake and behavior were observed. The concentration of buprenorphine in plasma was measured as well as stock-related differences in postoperative recovery. During surgery and anesthesia there was a higher corticosterone release during a more severe surgery and corticosterone levels were reduced more effectively after buprenorphine treatment than after lidocaine treatment. Buprenorphine treatment, independent of the route of administration, led to better postoperative recovery in body weight and water intake compared to local anesthetics. VI of buprenorphine resulted in a suppression of plasma corticosterone levels compared to s.c. buprenorphine treatment and treatment with local anesthetics during the first day after surgical catheterization. The corticosterone levels of all buprenorphine treated groups had, by the second postoperative day, reverted to the normal diurnal rhythm of corticosterone secretion. Buprenorphine treatment increased locomotor activity in non-operated rats only. The effect of buprenorphine in operated rats could not be detected via the monitoring of locomotor activity or the time spent resting in the present study. Treatment with buprenorphine by VI has similar effects on postoperative plasma corticosterone levels in both Wistar and Sprague-Dawley rats. VI of buprenorphine resulted in a buprenorphine concentration in plasma at least as high as by s.c. treatment. Thus, administration by VI of buprenorphine appears to be an effective stress-reducing method for administrating postoperative analgesia to laboratory rats.

The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on July 13, 2010). Thesis advisor: Amy DeClue. "May 2010" Includes bibliographical references.

This study examined the state of the literature on the effectiveness of medication assisted treatment (MAT; methadone, buprenorphine, naltrexone) delivered in prisons and jails on community substance use treatment engagement, opioid use, recidivism, and health risk behaviors following release from incarceration. Randomized controlled trials (RCTs) and quasi-experimental studies published through December 2017 that examined induction to or maintenance on methadone (n = 18 studies), buprenorphine (n = 3 studies), or naltrexone (n = 3 studies) in correctional settings were identified from PsycINFO and PubMed databases. There were a sufficient number of methadone RCTs to meta-analyze; there were too few buprenorphine or naltrexone studies. All quasi-experimental studies were systematically reviewed. Data from RCTs involving 807 inmates (treatment n = 407, control n = 400) showed that methadone provided during incarceration increased community treatment engagement (n = 3 studies; OR = 8.69, 95% CI = 2.46; 30.75), reduced illicit opioid use (n = 4 studies; OR = 0.22, 95% CI = 0.15; 0.32) and injection drug use (n = 3 studies; OR = 0.26, 95% CI = 0.12; 0.56), but did not reduce recidivism (n = 4 studies; OR = 0.93, 95% CI = 0.51; 1.68). Data from observational studies of methadone showed consistent findings. Individual review of buprenorphine and naltrexone studies showed these medications were either superior to methadone or to placebo, or were as effective as methadone in reducing illicit opioid use post-release. Results provide the first meta-analytic summary of MATs delivered in correctional settings and support the use of MATs, especially with regard to community substance use treatment engagement and opioid use; additional work is needed to understand the reduction of recidivism and other health risk behaviors.