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Background: Long-acting injectable depot buprenorphine has become an important treatment option for the management of opioid dependence. However, little is known about patients' experiences of depot buprenorphine and its embodied effects. This qualitative study aims to explore patients' experiences of depot buprenorphine treatment, including how it feels within the body, experiences of dosing cycles across time, and how this form of treatment relies on wider ecologies of care beyond the clinical encounter., Methods: Participants were recruited from sites in Sydney, regional New South Wales, and Melbourne, Victoria, Australia. Thirty participants (16 men, 14 women) participated in semi-structured interviews. Participants had histories of both heroin and prescription opioid consumption, and opioid agonist therapy including daily dosing of buprenorphine and methadone., Results: Our analysis illuminates: (1) how patients' expectations and concerns about treatment are linked to past embodied experiences of withdrawal and uncertainty about the effectiveness of depot buprenorphine; (2) the diverse meanings patients attribute to the depot buprenorphine substrate 'under the skin'; and, (3) how depot buprenorphine is embedded within wider ecologies of care, such as counselling and social supports., Conclusion: Our analysis destabilises commonplace assumptions about a linear, causal relationship between the pharmacological action of depot buprenorphine and experiences of treatment. Instead, it highlights patients' variable experiences of depot buprenorphine, tracing the everyday practices, embodied feelings, expectations and wider networks of care that shape patient experiences. We conclude with some reflections on the implications of our analysis for alcohol and other drug treatment, specifically how they might inform the design of client education materials and care., Competing Interests: Declaration of competing interest ROLE OF FUNDING SOURCE This research was supported by funding from Camurus AB. SA is supported by a National Health and Medical Research Council Investigator Grant (GNT2008193). SA has received honoraria for advisory board attendance from Camurus and Indivior, and speaker honoraria from Camurus, Indivior, Gilead, Janssen and Servier unrelated to this work. VH has received funding from Camurus AB and ViiV Healthcare to provide training. NL has received honoraria for attendance on Advisory Boards for Indivior, Mundipharma and Chiesi Pharmaceuticals, and has received research funding from Camurus AB for unrelated research. DL has previously received speaking honoraria from AstraZeneca, Camurus, Indivior, Janssen, Servier, Shire and Lundbeck and has provided consultancy advice to Lundbeck and Indivior. DL is supported by a NHMRC Investigator grant (1196892). Other than support received from Camurus AB for this project, AB, MS, KP and VP have no funding disclosures to declare., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The most recent formulation of buprenorphine treatment is extended-release depot injections (BUP-XR) that are administered subcutaneously by health care professionals. This study aimed to observe treatment outcomes of BUP-XR delivered in standard practice during a 96-week follow-up period in a community setting., Methods: This study is an extension of the CoLAB study, a prospective single-arm, multicentre, open label trial (N=100, 7 sites in Australia) among people with opioid dependence who received monthly injections of BUP-XR to evaluate the retention in treatment. Participants were followed for 96 weeks, comprising 48 weeks of the CoLAB study followed by a 48-week extension., Results: Of 100 participants at baseline, 47 were retained on BUP-XR at 96 weeks. The median time retained on monthly depot was 90 weeks. Heroin use (adjusted OR=0.19, P=0.012) in the month prior to baseline was associated with lower odds of retention on BUP-XR. Older age at first opioid use (adjusted OR= 1.08, P=0.009) and longer duration in OAT at baseline (adjusted OR= 1.12, P=0.001) were associated with increased retention. Prevalence of past four-weeks opioid use was estimated at 4% at 96 weeks of treatment (prevalence 0.04, 95%CI: 0.00-0.11) compared to 15% at baseline. Quality of life and medication treatment satisfaction improved over time for those retained in treatment., Conclusion: This is one of the few studies to describe long term (96 week) retention in treatment with BUP-XR in a community setting. It displayed retention rates with 47% of participants completing 96 weeks of treatment with BUP-XR. Patient reported outcomes suggest improvements in client wellbeing., Funding: Indivior., Competing Interests: Declaration of competing interest This study was supported by an Externally Sponsored Collaborative Research grant from Indivior PLC (MF, BL, LD, NL, AD, RA, SN, GD, J Grebely). In the past three years, MF and LD have received funding from Indivior for studies of new opioid medications in Australia. J Grebely reports grants and personal fees from Abbvie, bioLytical, Camurus, Cepheid, Hologic, Indivior, and Gilead Sciences. NL has received reimbursement for participation in Advisory Boards for Mundipharma, Indivior and Chiesi Pharmaceuticals; he received funding from Camurus for a company-sponsored trial of BUP-XR. RA has received untied educational grants from Reckitt Benckiser and an untied educational grant from Mundipharma. AJD reports grants from Braeburn/Camurus AB, to conduct clinical studies with buprenorphine products and travel support to Hunter New England Local Health District, which employs AJD. GJD has received research grant funding from Gilead and Abbvie. MM has served as an honorary on advisory boards for Pfizer and AbbVie. MC, JS, MB, JG, and EZ have no conflicts to declare. SN has received untied research funding from Seqirus to conduct research on prescription opioid related harms., (Crown Copyright © 2024. Published by Elsevier B.V. All rights reserved.)

Background: In April 2020, in response to the COVID-19 public health emergency, South Eastern Sydney Local Health District (SESLHD) Drug and Alcohol services modified their delivery of opioid dependency treatment (ODT) to reduce spread of COVID-19 and maintain continuity of care by increasing use of takeaway doses (TADs), transferring clients to local community pharmacies for dosing and encouraging the use of long-acting depot buprenorphine (LADB) which enabled once a month dosing., Methods: This study was a retrospective longitudinal case-control study conducted from August 1st, to November 30th, 2021. Eligible clients were those admitted for treatment with SESLHD ODT Services prior to August 1st,2021 and who remained in treatment beyond November 30th, 2021. COVID-19 diagnoses were determined by a COVID-19 PCR and extracted from the electronic Medical Records (eMR) Discern Reporting Portal. Demographic, clinical and dosing related data were collected from eMR and the Australian Immunisation Register (AIR)., Results: Clients attending SESLHD ODT services had significantly greater odds of acquiring COVID-19 than the NSW adult population at large (OR: 13.63, 95%CI: 9.64,18.88). Additionally, amongst SESLHD ODT clients, being of Aboriginal and Torres Strait Islander origin was associated with greater odds of acquiring COVID-19 (OR = 2.18, CI: 1.05,4.53); whilst being employed (OR = 0.06, CI:0.01,0.46), receiving doses at pharmacy (OR = 0.43, CI: 0.21,0.89), and being vaccinated (OR = 0.12, CI: 0.06,0.26) were associated with lower odds. Every additional day of attendance required for dosing was associated with a 5% increase in odds of acquiring COVID-19 (OR = 1.05, CI: 1.02,1.08)., Conclusions: Clients attending SESLHD ODT services are significantly more likely to acquire COVID-19 than the NSW population at large. Promoting vaccination uptake, transferring clients to pharmacy, and reducing the frequency of dosing (by use of takeaway doses or long-acting depot buprenorphine) are all potential methods to reduce this risk., (© 2024. The Author(s).)

Background: In 2019 daily liquid methadone and sublingual buprenorphine-naloxone were primary opioid agonist treatments for correctional centres in New South Wales, Australia. However, both had significant potential for diversion to other patients, and their daily administration was resource intensive. An alternative treatment in the form of subcutaneous depot buprenorphine became a viable option following a safety trial in 2020 - the UNLOC-T study. Depot preparation demonstrated advantages over current treatments as more difficult to divert and requiring fewer administrations. This paper reports the results of economic modelling of staffing costs in medication administration comparing depot buprenorphine, methadone, and sublingual buprenorphine provision in UNLOC-T trial facilities., Methods: The costing study adopted a micro-costing approach involving the synthesis of cost data from the UNLOC-T clinical trial as well as data collected from Justice Health and Forensic Mental Health Network records. Labour and materials data were collected during site observations and interviews. Costs were calculated from two payer perspectives: a) the New South Wales (state) government which funds custodial and health services; and b) the Australian Commonwealth government, which pays for medications. The analysis compared the monthly-per-patient cost for each of the three medications in trial-site facilities during July 2019. This was followed by simulation of depot buprenorphine implementation across the study population. Costs associated with medical assessment and reviews were excluded., Results: The monthly-per-patient New South Wales government service costs of depot buprenorphine, methadone and sublingual buprenorphine were: $151, $379 and $1,529 respectively while Commonwealth government medication costs were $434, $80 and $525. The implementation simulation found that service costs of depot buprenorphine declined as patients transitioned from weekly to monthly administration. Costs of treatment using the other medications increased as patient numbers decreased alongside fixed costs. At 12 months, monthly-per-patient service costs for depot buprenorphine, methadone and sublingual buprenorphine-which would be completely phased out by month 13-were $92, $530 and $2,162 respectively., Conclusions: Depot buprenorphine was consistently the least costly of the treatment options. Future modelling could allow for dynamic patient populations and downstream impacts for participants and the state health system., Trial Registration: ACTRN12618000942257 . Registered 4 June 2018., (© 2022. The Author(s).)

Introduction: In early 2020, many services modified their delivery of opioid treatment in response to the COVID-19 pandemic, to limit viral spread and maintain treatment continuity. We describe the changes to treatment and preliminary analysis of the association with patients' substance use and well-being., Methods: A pre-post comparison of treatment conditions and patient self-reported outcomes using data extracted from electronic medical records in the 5 months before (December 2019-April 2020) and after (May 2020-September 2020) changes were implemented in three public treatment services in South Eastern Sydney Local Health District., Results: Data are available for 429/460 (93%) patients. Few (21, 5%) dropped out of treatment. In the 'post' period there was significantly more use of depot buprenorphine (12-24%), access to any take-away doses (TAD; 24-69%), access to ≥6 TAD per week (7-31%), pharmacy dosing (24-52%) and telehealth services. There were significant reductions in average opioid and benzodiazepine use, increases in cannabis use, with limited group changes in social conditions, or quality of life, psychological and physical health. At an individual level, 22% of patients reported increases in their use of either alcohol, opioids, benzodiazepines or stimulants of ≥4 days in the past 4 weeks. Regression analysis indicates increases in substance use were associated with higher levels of supervised dosing., Discussion and Conclusions: These preliminary findings suggest that the modified model of care continued to provide safe and effective treatment, during the pandemic. Notably, there was no association between more TAD and significant increases in substance use. Limitations are discussed and further evaluation is needed., (© 2021 Australasian Professional Society on Alcohol and other Drugs.)

The mainstay of treatment for opioid use disorder are medications, methadone (a full opioid agonist), or buprenorphine (a partial opioid agonist), in conjunction with psychosocial interventions. Both treatments are effective but safety, efficacy, and patient preference can lead to a decision to change from one treatment to the other. Transfer from buprenorphine to methadone is not clinically challenging; however, changing from methadone to buprenorphine is more complex. Published reports describe varied approaches to manage this transfer to both minimize patient symptoms associated with withdrawal from methadone and reduce risk of precipitating withdrawal symptoms with introduction of the partial agonist buprenorphine [Lintzeris et al. J Addict Med. 2020; in press]. There is no single approach for methadone to buprenorphine that is superior to others and no approach that is suitable for all case presentations. This case conference describes three different approaches to achieve a successful methadone to buprenorphine transfer and provides commentary on how the case may be managed based on published transfer "strategies.", Competing Interests: Duncan Hill and Apo Demirkol have no conflicts of interest to disclose. Victoria Hayes has received money from Camurus and Viiv for providing education and training sessions. Nicholas Lintzeris has served on Advisory Boards for Mundipharma, Indivior, GW Pharmaceuticals and Camurus, and has received funding for conducting research from Camurus., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.)

Objectives: To review the currently available evidence on transfer strategies from methadone to sublingual buprenorphine used in clinical trials and observational studies of medication for opioid use disorder treatment, and to consider whether any strategies yield better clinical outcomes than others., Methods: Six medical and public health databases were searched for articles and conference abstracts. The Cochrane Central Register of Controlled Trials and the World Health Organization International Clinical Trials Registry Platform were used to identify unpublished trial results. Records were dually screened, and data were extracted and checked independently. Results were summarized qualitatively and, when possible, analyzed quantitatively., Results: Eighteen studies described transfer from methadone to buprenorphine. Transfer protocols were extremely varied. Most studies reported successful rates of transfer, even among studies involving transfer from high methadone doses, although lower pretransfer methadone dose was significantly associated with higher rate of successful transfer. Precipitated withdrawal was not reported frequently. A range of innovative approaches to transfer from methadone to buprenorphine remains untested., Conclusions: Few studies have used designs that enable comparison of different approaches to transfer patients from methadone to buprenorphine. Most international clinical guidelines provide recommendations consistent with the available evidence. However, clinical guidelines should be perceived as providing "guidance" rather than "protocols," and clinicians and patients need to exercise judgment when attempting transfers., Competing Interests: Nicholas Lintzeris has served on Advisory Boards for Mundipharma, Indivior, GW Pharmaceuticals, and Camurus, and has received funding for conducting research from Camurus. Baher Mankabady reports no conflicts of interest. Carlos Rojas-Fernandez completed the work as a paid consultant to Venebio. Halle Amick reports receipt of consulting fees from Indivior during the conduct of this review., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.)

Background: Opioid agonist treatment (OAT) is an effective intervention for opioid dependence. Extended-release buprenorphine injections (BUP-XR) may have additional potential benefits over sublingual buprenorphine. This single-arm trial evaluated outcomes among people receiving 48 weeks of BUP-XR in diverse community healthcare settings in Australia, permitting examination of outcomes when BUP-XR is delivered in standard practice., Methods: Participants were recruited from a network of specialist public drug treatment services, primary care and some private practices in three states. Following a minimum 7 days on 8-32 mg of sublingual buprenorphine (±naloxone), participants received monthly subcutaneous BUP-XR injections administered by a healthcare practitioner and completed monthly research interviews. The primary endpoint was retention in treatment at 48 weeks., Findings: Participants (n = 100) were 28% women, mean age 44 years with a long history of OAT (median 5.8 years); heroin was the most common opioid of concern (58%). Treatment retention at 24 and 48 weeks was 86% and 75%, respectively. Participants with past-month injecting drug use (OR 0.23; 95%CI: 0.09-0.61) or heroin use (OR 0.23; 95%CI: 0.08-0.65) at baseline had lower odds of being retained in treatment to 48 weeks. Reductions in multiple forms of extra-medical drug use were observed. Improvements in quality of life, participation in employment, and treatment satisfaction measures were also observed., Interpretation: This real-world implementation study of BUP-XR demonstrated high retention and treatment satisfaction. This study provides important additional data on the uptake and experience of clients, with relevance for policy makers, health service planners, administrators, and practitioners., Funding: Indivior., Trial Registration: ClinicalTrials.gov Identifier: NCT03809143., Competing Interests: Declarations of Interest This study was supported by an Externally Sponsored Collaborative Research grant from Indivior PLC (MF, BL, LD, NL, AD, RA, SN, GD, JG). In the past three years, MF and LD have received funding from Indivior, Seqirus for studies of new opioid medications in Australia. JG reports grants and personal fees from Abbvie, Camurus, Cepheid, Hologic, Indivior, Gilead Sciences, and Merck. NL has received reimbursement for participation in Advisory Boards for Mundipharma, Indivior and Chiesi Pharmaceuticals; he received funding from Camurus for a company-sponsored trial of BUP-XR. RA has received untied educational grants from Reckitt Benckiser and an untied educational grant from Mundipharma. AJD reports grants from Braeburn/Camurus AB, to conduct clinical studies with buprenorphine products and travel support to Hunter New England Local Health District, which employs AJD. He has served as an honorary on advisory boards for Mundipharma and Seqiris. GJD has received research grant funding from Gilead and Abbvie. MM has served as an honorary on advisory boards for Pfizer and AbbVieMC. JS and MB have no conflicts to declare. SN has received untied research funding from Seqirus to conduct research on prescription opioid related harms., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: Opioid agonist treatment is effective but resource intensive to administer safely in custodial settings, leading to significant under-treatment of opioid dependence in these settings world-wide. This study assessed the safety of subcutaneous slow-release depot buprenorphine in custody., Design: Open-label, non-randomized trial., Setting: Correctional centres in New South Wales, Australia., Participants: Sixty-seven men and women, aged ≥ 18 years of various security classifications with a diagnosis of moderate to severe DSM-5 opioid use disorder currently serving a custodial sentence of ≥ 6 months were recruited between November 2018 and July 2019. Patients not in opioid agonist treatment at recruitment commenced depot buprenorphine; patients already stable on oral methadone treatment were recruited to the comparison arm., Intervention and Comparator: Depot buprenorphine (CAM2038 weekly for 4 weeks then monthly) and daily oral methadone., Measurements: Safety was assessed by adverse event (AE) monitoring and physical examinations at every visit. Participants were administered a survey assessing self-reported diversion and substance use at baseline and weeks 4 and 16., Findings: Retention in depot buprenorphine treatment was 92.3%. Ninety-four per cent of patients reported at least one adverse event, typically mild and transient. No diversion was identified. The prevalence of self-reported non-prescribed opioid use among depot buprenorphine patients decreased significantly between baseline (97%) and week 16 (12%, odds ratio = 0.0035, 95% confidence interval = 0.0007-0.018, P < 0.0001)., Conclusions: This first study of depot buprenorphine in custodial settings showed treatment retention and outcomes comparable to those observed in community settings and for other opioid agonist treatment used in custodial settings, without increased risk of diversion., (© 2021 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Long-acting injectable depot buprenorphine is an important new treatment option for the management of opioid dependence, delivering therapeutic doses in weekly or monthly formulations. Depot buprenorphine aims to overcome challenges associated with traditional opioid agonist therapy (OAT), including: poor patient adherence; inconvenience of regular attendance for dosing; and, risk of non-medical use of takeaway doses. However, little is known about patients' experiences of depot buprenorphine. This qualitative study aimed to explore patients' experiences of the practical and social affordances of depot buprenorphine., Methods: Participants were recruited from sites in Sydney, regional New South Wales, and Melbourne, Victoria, Australia. Thirty participants (16 men, 14 women; mean age 47.3 years) participated in semi-structured interviews. Participants had histories of both heroin and prescription opioid use, and previous OAT including daily dosing of buprenorphine and methadone., Findings: Depot buprenorphine afforded positive benefits for many participants, including: opportunities to avoid stigma experienced at pharmacies/clinics; time to engage in activities (e.g., travel, work) by releasing participants from previous OAT treatment regimens; and, cost savings by not having to pay pharmacy fees associated with daily dosing. However, for some participants, moving to depot buprenorphine: disrupted engagements with important social/practical supports available at pharmacies/clinics; constrained their control over dosing; and, constrained their ability to generate income via the sale of takeaway doses., Conclusions: While generally experienced as affording benefits, depot buprenorphine can have differing social and practical impacts. Clinicians should monitor patients receiving depot buprenorphine to reduce the risk of unintended consequences including disruption to clinical supports., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Importance: Patient-reported outcomes in the treatment of opioid dependence may differ between subcutaneously administered depot buprenorphine and daily sublingual buprenorphine., Objective: To compare patient satisfaction between depot buprenorphine and sublingual buprenorphine in adult outpatients with opioid dependence., Design, Setting, and Participants: This open-label, randomized clinical trial was conducted among adult patients with opioid dependence at 6 outpatient clinical sites in Australia from October 2018 to September 2019. Data analysis was conducted from October 2019 to May 2020., Interventions: Participants were randomized to receive treatment with weekly or monthly depot buprenorphine or daily sublingual buprenorphine over 24 weeks., Main Outcomes and Measures: The primary end point was the difference in global treatment satisfaction, assessed by the Treatment Satisfaction Questionnaire for Medication (TSQM) version 1.4 (range, 0-100; higher score indicates greater satisfaction) at week 24. Secondary end points included other patient-reported outcomes, including quality of life, treatment burden, and health-related outcomes, as well as measures of opioid use, retention in treatment, and safety., Results: A total of 119 participants (70 [58.8%] men; mean [SD] age, 44.4 [10.5] years) were enrolled, randomized to, and received either depot buprenorphine (60 participants [50.4%]) or sublingual buprenorphine (59 participants [49.6%]). From the initial sample of 120, a participant (0.8%) in the sublingual buprenorphine group withdrew consent and did not receive study treatment. All participants were receiving sublingual buprenorphine when enrolled. The mean TSQM global satisfaction score was significantly higher for the depot group compared with the sublingual group at week 24 (mean [SE] score, 82.5 [2.3] vs 74.3 [2.3]; difference, 8.2; 95% CI, 1.7 to 14.6; P = .01). Improved outcomes were also observed for several secondary end points after treatment with depot buprenorphine (eg, mean [SE] treatment burden assessed by the Treatment Burden Questionnaire global score, on which lower scores indicate lower burden: 13.2 [2.6] vs 28.6 [2.5]; difference, -15.4; 95% CI, -22.6 to -8.2; P < .001). Thirty-nine participants (65.0%) in the depot buprenorphine group experienced 117 adverse drug reactions, mainly injection site reactions of mild intensity following subcutaneous administration, and 12 participants (20.3%) in the sublingual buprenorphine group experienced 21 adverse drug reactions. No participants withdrew from the trial medication or the trial due to adverse events., Conclusions and Relevance: In this study, participants receiving depot buprenorphine reported improved treatment satisfaction compared with those receiving sublingual buprenorphine. The results highlight the application of patient-reported outcomes as alternative end points to traditional markers of substance use in addiction treatment outcome studies., Trial Registration: anzctr.org.au Identifier: ANZCTR12618001759280.

Buprenorphine is a partial opioid agonist commonly used to treat opioid dependence. The pharmacology of buprenorphine increases the risk of a precipitated opioid withdrawal when commencing patients on buprenorphine treatment, particularly when transferring from long acting opioids (e.g. methadone). There is little documented experience regarding the management of precipitated withdrawal. In our case, a patient developed a significant precipitated opioid withdrawal following buprenorphine administration, and was able to be successfully treated in hospital with further buprenorphine. This demonstrates that rapid increases in buprenorphine dose can be used as an effective treatment for buprenorphine-induced precipitated opioid withdrawal. The use of buprenorphine to manage withdrawal then allows the individual to continue on this highly effective treatment., (© 2021 The Authors. Drug and Alcohol Review published by John Wiley & Sons Australia, Ltd on behalf of Australasian Professional Society on Alcohol and other Drugs.)

The COVID-19 pandemic has presented challenges for traditional models of opioid use disorder treatment worldwide. Depot buprenorphine became available in Australia shortly before the height of the COVID-19 pandemic. This timing provided us an opportunity to examine the utilization and uptake of depot buprenorphine, and to understand the particular benefits and implementation challenges associated with this new formulation of opioid agonist treatment., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: Opioid agonist treatment is effective for opioid dependence and newer extended-release buprenorphine (BUP-XR) injections represent a significant development. The Community Long-Acting Buprenorphine (CoLAB) study aims to evaluate client outcomes among people with opioid dependence receiving 48 weeks of BUP-XR treatment, and examines the implementation of BUP-XR in diverse community healthcare settings in Australia., Methods and Analysis: The CoLAB study is a prospective single-arm, multicentre, open-label trial of monthly BUP-XR injections in people with opioid dependence. Participants are being recruited from a network of general practitioner and specialist drug treatment services located in the states of New South Wales, Victoria and South Australia in Australia. Following a minimum 7 days on 8-32 mg of sublingual buprenorphine (±naloxone), participants will receive monthly subcutaneous BUP-XR injections administered by a healthcare practitioner at intervals of 28 days (-2/+14 days). The primary endpoint is participant retention in treatment at 48 weeks after treatment initiation. Secondary endpoints will evaluate dosing schedule variations, craving, withdrawal, substance use, health and well-being, and client-reported treatment experience. Qualitative and costing substudies will examine implementation barriers and facilitators at the client and provider level., Ethics and Dissemination: The study has received ethics approval from the St Vincent's Hospital Sydney Human Research Ethics Committee (Ref. HREC/18/SVH/221). The findings will be disseminated via publication in peer-reviewed journals, presentations at national and international scientific conferences, and in relevant community organisation publications and forums., Trial Registration Number: NCT03809143 PROTOCOL IDENTIFIER: CoLAB1801, V.4.0 dated 01 August 2019., Competing Interests: Competing interests: Many of the investigators have received investigator-initiated, untied educational grants for opioid-related studies from: Indivior (Briony Larance, Louisa Degenhardt, Nicholas Lintzeris, Michael Farrell, Suzanne Neilsen); Reckitt Benckiser (Briony Larance, Louisa Degenhardt, Nicholas Lintzeris, Michael Farrell, Suzanne Nielsen, Robert Ali, Adrian Dunlop); Mundipharma (Briony Larance, Louisa Degenhardt, Nicholas Lintzeris, Michael Farrell); and Seqirus (Briony Larance, Louisa Degenhardt, Michael Farrell, Suzanne Nielsen)., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The study objective was to identify the analgesic efficacy of three different pharmacological strategies in patients receiving methadone or buprenorphine as opioid agonist treatment (OAT). The three pharmacological approaches, a) increasing maintenance methadone/buprenorphine dose by 30%, b) adding oxycodone, or c) adding a single dose of gabapentin, were compared with a control condition of the participant's usual OAT dose., Design: A randomized, controlled, double-blinded, double-dummy, within-subject crossover study., Subjects: Nine participants on stable doses of methadone and eight participants on stable doses of buprenorphine were recruited., Setting: An outpatient opioid treatment clinic in inner city Sydney, Australia., Methods: The cold pressor tolerance test was used to examine experimental pain threshold and tolerance. Ratings of subjective drug effects and safety measures (physiological and cognitive) were assessed., Results: There was no difference in the primary outcome measures of pain thresholds or tolerance between the conditions examined. Interindividual variability was evident. Differences in some subjective measures were identified, including lower pain recall, lower "bad effects," and higher global satisfaction in the additional methadone condition. In the buprenorphine arm, increased drug liking and "bad effects" were detected with oxycodone administration, while increased subjective intoxication was identified with gabapentin., Conclusions: There was no evidence of an objective improvement in analgesia with any condition compared with control. Further research is required to optimize pain management strategies in this population., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Buprenorphine is widely used in the treatment of opioid use disorder and pain management. Little is known about the analgesic effects of high-dose sublingual buprenorphine, particularly in doses of >8 mg. The aim of this study was to examine the effect of ascending doses of buprenorphine upon acute pain measures in patients stabilized on buprenorphine as treatment for opioid dependence., Methods: The pilot study (n = 7) was a randomised, controlled, double-blind, double-dummy, within-subject crossover study examining cold-pressor threshold and tolerance testing under different buprenorphine dose conditions. Each participant attended three sessions to test the analgesic effect of buprenorphine in their usual dose (100%), 150% and 200% of their usual daily dose., Results: No significant effects of increased dose were seen on experimental pain measures. Expected physiological effects on pupil size and pulse were observed with increasing dose. No effect of buprenorphine condition was seen on subjective ratings of drug strength, or self-reported sedation, though lower ratings drug liking were seen with 150% and 200% conditions, and lower ratings of 'bad effects' and intoxication were reported with the 200% buprenorphine dose condition. No safety concerns with the 150 and 200% buprenorphine dose condition were observed., Discussion: This pilot study suggests that a ceiling effect on analgesia may be observed in people maintained on buprenorphine, though larger studies may confirm this finding. Clinical Trial Number: ACTRN12614001038684., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aims: To assess the long-term safety of subcutaneous buprenorphine (CAM2038) weekly and monthly depots., Design: Phase 3, open-label, observational, multi-centre 48-week trial (ClinicalTrials.gov NCT02672111)., Setting: Twenty-six out-patient sites (United States, United Kingdom, Hungary, Denmark, Sweden, Germany, Australia) between 14 December 2015 and 12 April 2017., Participants: Two hundred and twenty-eight adults with opioid use disorder; 227 received CAM2038 (37 initiated onto CAM2038 and 190 converted from sublingual buprenorphine)., Interventions: CAM2038 weekly (8, 16, 24 or 32 mg) or monthly (64, 96, 128 or 160 mg) with flexible dosing and individualized titration utilizing multiple CAM2038 weekly and monthly doses., Measurements: Safety variables, urine toxicology samples and self-reported illicit opioid use were collected at each visit. Participants were administered a patient satisfaction survey at months 6 and 12, completed by 162 of 227 (71.4%) participants., Findings: The study treatment period was completed by 167 of 227 (73.6%) participants. At least one treatment-emergent adverse event (TEAE) was reported by 143 of 227 (63.0%) participants, of whom 60 of 227 (26.4%) reported as being drug-related. Most of the TEAEs, reported by 128 of 227 (56.4%) of participants, were mild or moderate in intensity. Injection-site reactions were reported by 46 of 227 (20.3%) participants, with most [45 of 46 (97.8%)] reported as mild to moderate. Five participants (2.2%) discontinued the study drug due to a TEAE, two cases (0.9%) of which were injection-site-related. No serious adverse events were attributed to the study drug. Among those remaining in the study, the percentage of opioid-negative urine tests combined with self-reports was 63.0% (17 of 27) in new-to-treatment participants and 82.8% (111 of 134) for those converted from sublingual buprenorphine. Participants reported high levels of satisfaction with CAM2038., Conclusions: Subcutaneous buprenorphine delivered weekly or monthly (CAM2038) was well tolerated, with a systemic safety profile consistent with the known profile of sublingual buprenorphine. CAM2038 weekly and monthly was associated with high retention rates and low levels of illicit opioid use throughout this study., (© 2019 Braeburn Inc. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Background: Insomnia and excessive daytime sleepiness (EDS) are reported to be common in methadone maintenance treatment (MMT) but much less is known about these symptoms in buprenorphine maintenance treatment (BMT) and in women compared with men. Methods: Cross sectional study of recipients of BMT ( n  = 113, 47 women), MMT ( n  = 184, 94 women), people using opioids nonmedically (nonopioid agonist treatment, non-OAT: n  = 87, 31 women) and a reference group with no opioid use (RG; n  = 105, 53 women) in Australia. Measures included Athens Insomnia Scale, Epworth Sleepiness Scale, the Hospital Anxiety and Depression Scale, and other substance use. Results: Insomnia (Athens Insomnia Scale, total ≥10) was highly prevalent among all people who use opioids (BMT 46.0-68.1%; MMT 55.4-69.6%; non-OAT 58.6-80.5%), did not differ significantly among these groups, and was significantly associated with anxiety and depression. EDS (Epworth score >10) was found in 14.2% of BMT, 22.8% of MMT, 35.6% of non-OAT groups, and 11.4% of the RG, and was significantly associated with depression overall. Fewer people had Epworth score >15 indicating more severe EDS (BMT 4.4%, MMT 6.0%; non-OAT 13.8%; RG 1.9%). Insomnia and EDS did not differ by sex or by opioid dose, nor were they significantly associated with other drug use, housing stress or social security status. Conclusions: Insomnia was common in people receiving OAT and using opioids non-medically, and associated with anxiety and depression. Clinicians should consider the possibility of daytime sleepiness in people receiving BMT and MMT, and in people using opioids nonmedically.

Introduction and Aims: Transfer from methadone to buprenorphine is problematic for many opioid-dependent patients, with limited documented evidence or practical clinical guidance, particularly for the range of methadone doses routinely prescribed for most patients (>50 mg). This study aimed to implement and evaluate recent national Australian guidelines for transferring patients from methadone to buprenorphine., Design and Methods: A multisite prospective cohort study. Participants were patients who transferred from methadone to buprenorphine-naloxone at 1 of 4 specialist addiction centers in Australia and New Zealand. Clinicians were trained in the guidelines, and medical records were reviewed to examine process (eg, transfer setting, doses, and guideline adherence) and safety (precipitated withdrawal) measures. Participants completed research interviews before and after transfer-assessing changes in substance use, health outcomes, and side effects., Results: In all, 33 participants underwent transfer, 9 from low methadone doses (<30 mg), 9 from medium doses (30-50 mg), and 15 from high doses (>50 mg). The majority of high-dose transfers occurred in inpatient settings. There was reasonable guideline adherence, and no complications identified in the low and medium-dose transfers. Three high-dose transfers (20%) experienced precipitated withdrawal, and 7/33 participants (21%) returned to methadone within 1 week of attempted transfer., Discussions and Conclusions: Transfer is feasible in outpatient settings for those transferring from methadone doses below 50 mg; however, inpatient settings and specialist supervision is recommended for higher-dose transfers. The Australian clinical guidelines appear safe and feasible, although further research is required to optimize high-dose transfer procedures.

Background: Opioid substitution treatment (OST) is often continued long-term and, therefore, opioid-associated symptoms are of interest. Symptoms associated with methadone maintenance treatment (MMT) in men are well described, but there are fewer reports concerning symptoms associated with buprenorphine maintenance treatment (BMT) and very few reports among women., Method: Recipients of BMT (n=113) and MMT (n=184), non-opioid users (n=105) and opioid users not receiving OST (n=87) completed the Patient Assessment of Constipation (PAC-SYM) and a general symptom checklist. Multivariate analysis included other potential moderators of opioid-associated symptoms., Findings: Opioid users reported a higher frequency and severity of symptoms than non-opioid users. Constipation, dry mouth, decreased appetite, sweating and fatigue were highly prevalent in the previous 30days (51-80%). Nausea, itchy skin, trouble urinating, menstrual problems, lightheadedness, blurred vision, heart racing were also common (30-50%). Non-OST opioid users had significantly higher frequency and severity than OST recipients of nausea, vomiting, diarrhoea, decreased appetite, sweating and itchy skin. Sweating was significantly more common in MMT than BMT. Constipation scores were higher in women, otherwise most sex differences were small. Higher PAC-SYM scores were associated with vomiting (OR=1.04) and sweating (OR=1.06). Cannabis use was associated with vomiting (OR=2.19). Constipation (OR=1.07), insomnia (OR=2.5) and depression (OR=2.82) were associated with fatigue., Conclusion: Men and women receiving OST report similarly high rates of somatic symptoms, though less than opioid users not receiving OST. There were few differences between BMT and MMT. Buprenorphine might be preferred where sweating is problematic. Several modifiable factors were identified., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: There are increasing concerns regarding pharmaceutical opioid harms including overdose and dependence, with an associated increase in treatment demand. People dependent on pharmaceutical opioids appear to differ in important ways from people who use heroin, yet most opioid agonist treatment research has been conducted in people who use heroin., Objectives: To assess the effects of maintenance agonist pharmacotherapy for the treatment of pharmaceutical opioid dependence., Search Methods: The search included the Cochrane Drugs and Alcohol Group's Specialised Register of Trials; the Cochrane Central Register of Controlled Trials (CENTRAL, 2015, Issue 5); PubMed (January 1966 to May 2015); EMBASE (Ovid) (January 1974 to May 2015); CINAHL (EBSCOhost) (1982 to May 2015); ISI Web of Science (to May 2014); and PsycINFO (Ovid) (1806 to May 2014)., Selection Criteria: We included randomised controlled trials examining maintenance opioid agonist treatments that made the following two comparisons:1. full opioid agonists (methadone, morphine, oxycodone, levo-alpha-acetylmethadol (LAAM), or codeine) versus different full opioid agonists or partial opioid agonists (buprenorphine) for maintenance treatment and2. full or partial opioid agonist maintenance versus placebo, detoxification only, or psychological treatment (without opioid agonist treatment)., Data Collection and Analysis: We used standard Cochrane methodological procedures., Main Results: We identified six randomised controlled trials that met inclusion criteria (607 participants).We found moderate quality evidence from two studies of no difference between methadone and buprenorphine in self reported opioid use (risk ratio (RR) 0.37, 95% confidence interval (CI) 0.08 to 1.63) or opioid positive urine drug tests (RR 0.81, 95% CI 0.56 to 1.18). There was low quality evidence from three studies of no difference in retention between buprenorphine and methadone maintenance treatment (RR 0.69, 95% CI 0.39 to 1.22). There was moderate quality evidence from two studies of no difference between methadone and buprenorphine on adverse events (RR 1.10, 95% CI 0.64 to 1.91).We found low quality evidence from three studies favouring maintenance buprenorphine treatment over detoxification or psychological treatment in terms of fewer opioid positive urine drug tests (RR 0.63, 95% CI 0.43 to 0.91) and self reported opioid use in the past 30 days (RR 0.54, 95% CI 0.31 to 0.93). There was no difference on days of unsanctioned opioid use (standardised mean difference (SMD) -0.31, 95% CI -0.66 to 0.04). There was moderate quality evidence favouring buprenorphine maintenance over detoxification or psychological treatment on retention in treatment (RR 0.33, 95% CI 0.23 to 0.47). There was moderate quality evidence favouring buprenorphine maintenance over detoxification or psychological treatment on adverse events (RR 0.19, 95% CI 0.06 to 0.57).The main weaknesses in the quality of the data was the use of open-label study designs., Authors' Conclusions: There was low to moderate quality evidence supporting the use of maintenance agonist pharmacotherapy for pharmaceutical opioid dependence. Methadone or buprenorphine appeared equally effective. Maintenance treatment with buprenorphine appeared more effective than detoxification or psychological treatments.Due to the overall low to moderate quality of the evidence and small sample sizes, there is the possibility that the further research may change these findings.

Introduction and Aims: Buprenorphine-naloxone (BNX) film for opioid dependence treatment was introduced in Australia in 2011. A key difference in State policy approaches saw transfer from BNX tablets to BNX film mandated in South Australia (SA) with New South Wales (NSW) and Victoria (VIC) having less stringent policies. This study examined (i) how initiations and transfers were implemented, (ii) the profile and predictors of adverse effects as self-reported by BNX film clients, and (iii) dosing issues., Design and Methods: Survey of 334 buprenorphine (BPN), BNX tablet and BNX film clients and semi-structured interviews with 39 key experts (KEs) in 2012. Comparisons are made between clients interviewed in SA versus NSW and VIC combined., Results: Among the 180 current BNX film clients, 23% started treatment on BNX film, 18% requested a transfer to BNX film and 59% (n = 106) reported their clinic/prescriber recommended transfer to BNX film. Among clients who were offered but refused a transfer to BNX film (n = 66), the most common reason was 'I am happy with my current treatment and do not see a reason to change' (53%). Some opioid substitution therapy clients and KE viewed transfers as 'forced' (i.e. no choice of buprenorphine formulation). Multivariable regression showed residing in SA (vs. NSW/VIC) and a shorter length of current treatment episode were associated with more BNX film-attributed adverse effects but clinic/prescriber-recommended transfer was not., Discussion and Conclusions: The introduction of BNX film in Australia varied across States. A perception of restricted choice in medication may have undermined initial acceptance in SA., (© 2015 Australasian Professional Society on Alcohol and other Drugs.)

Aims: To develop a stability typology among opioid substitution therapy patients using a range of adherence indicators derived from clinical guidelines, and determine whether stable patients receive more unsupervised doses., Methods: An interviewer-administered cross-sectional survey was used in opioid substitution therapy programmes in three Australian jurisdictions, totalling 768 patients in their current treatment episode for ≥4 weeks. A structured questionnaire collated data from patients about their demographics, treatment characteristics, past 6-month drug use and medication adherence, psychosocial stability, comorbidity, child welfare concerns and levels of supervised dosing. Latent class analysis (LCA) was used to derive a stability typology. Linear regression models examined predictors of unsupervised dosing in the past month., Results: LCA identified two classes: (i) a higher-adherence group (67%) who had low-moderate probabilities of endorsing the opioid substitution therapy stability indicators and (ii) a lower-adherence group (33%) who had moderate-high probabilities of endorsing the stability indicators. There was no association between adherence profile and the number of unsupervised doses. Significant predictors of receiving larger numbers of unsupervised doses included being older, living in New South Wales or South Australia (vs. Victoria), receiving methadone (vs. mono-buprenorphine), being prescribed in private clinic or general practice (vs. public clinic), reporting a longer current treatment episode, not receiving a urine drug screen in the past month, being currently employed and not having a prison history., Conclusions: This study suggested that system-level factors and observable indicators of social functioning were more strongly associated with the receipt of less supervised treatment. Future research should examine this issue using prospectively collected data., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

This case is an amalgamation of several real patients in office-based treatment for prescription opioid dependence synthesized into a single theoretical case. The case illustrates the various ways in which medication diversion and misuse may be encountered in clinical practice and therapeutic responses designed to maximize positive treatment outcomes. It is followed by discussions from several expert addiction medicine providers from 3 different countries, giving their perspectives on the salient aspects of this case. This case conference should be of particular interest to clinicians working with opioid-dependent patients in an outpatient setting.

Background: We compared the diversion and injection of a new formulation of buprenorphine, a buprenorphine-naloxone film product (BNX film), with buprenorphine-naloxone tablets (BNX tablets), mono-buprenorphine (BPN) and methadone (MET) in Australia., Methods: Surveys were conducted with people who inject drugs regularly (PWID) (2004-2012) and opioid substitution treatment (OST) clients (2012, N=543). Key outcome measures: the unsanctioned removal of supervised doses, diversion, injection, motivations, drug liking and street price. Levels of injection among PWID were adjusted for background availability of medication using sales data. Doses not taken as directed by OST clients were adjusted by total number of daily doses dispensed., Results: Among out-of-treatment PWID, levels of injection for BNX film were comparable to those for MET and BNX tablet formulations, adjusting for background availability; BPN injecting levels were higher. Among OST clients, recent injecting of one's medication was similar among clients in all OST types; weekly or more frequent injection of prescribed doses was reported by fewer BNX film clients (3%; 95% CI: 1-6) than BPN clients (11%; 95% CI: 3-17), but at levels similar to those observed among MET and BNX tablet clients. The proportion of BNX film doses injected was lower than that for BPN and BNX tablets, and equivalent to that for MET. The majority of BNX film doses injected by OST clients were unsupervised doses, although some injection of supervised doses of BNX film did occur. The median price of all buprenorphine forms on the illicit market was the same., Conclusions: Non-adherence and diversion of the BNX film formulation was similar to MET and BNX tablet formulations; BPN had higher levels of all indicators of non-adherence and diversion., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Background: Buprenorphine-naloxone sublingual film was introduced in 2011 in Australia as an alternative to tablets. This study compared the two formulations on subjective dose effects and equivalence, trough plasma levels, adverse events, patient satisfaction, supervised dosing time, and impact upon treatment outcomes (substance use, psychosocial function)., Methods: 92 buprenorphine-naloxone tablet patients were recruited to this outpatient multi-site double-blind double-dummy parallel group trial. Patients were randomised to either tablets or film, without dose changes, over a 31 day period., Results: No significant group differences were observed for subjective dose effects, trough plasma buprenorphine or norbuprenorphine levels, adverse events and treatment outcomes. Buprenorphine-naloxone film took significantly less time to dissolve than tablets (173±71 versus 242±141s, p=0.007, F=7.67)., Conclusions: The study demonstrated dose equivalence and comparable clinical outcomes between the buprenorphine-naloxone film and tablet preparations, whilst showing improved dispensing times and patient ratings of satisfaction with the film., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: These studies compared the diversion and injection of buprenorphine-naloxone (BNX), buprenorphine (BPN) and methadone (MET) in Australia., Methods: Surveys were conducted with regular injecting drug users (IDUs) (2004-2009, N=881-943), opioid substitution treatment (OST) clients (2008, N=440) and authorised OST prescribers (2007, N=291). Key outcome measures include the unsanctioned removal of supervised doses, diversion, injection, motivations, drug liking and street price. Levels of injection among IDUs were adjusted for background availability of medications. Doses not taken as directed by OST clients were adjusted by total number of daily doses dispensed., Results: Among regular IDUs, levels of injection were lower for BNX relative to BPN, but comparable to those for MET, adjusting for background availability. Among OST clients, fewer BNX clients (13%) reported recently injecting their medication, than BPN (28%) and MET clients (23%). Fewer MET clients (10%) reported removal of supervised doses, than BPN (35%) and BNX clients (22%). There were no differences in prevalence of recent diversion (28% of all OST clients). Adjusting for the total doses dispensed, more BPN was injected (10%), removed (12%) and diverted (5%), than MET (5%, <1% and 2% respectively) and BNX (5%, 9% and <1% respectively). In 2009, the median street price of BNX was equivalent to that for BPN., Conclusions: BNX was less commonly and less frequently injected than BPN, but both sublingual medications were diverted more than liquid MET., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Introduction and Aims: The use of opioid substitution therapy (OST) is a widely used and effective treatment for opioid dependence, yet many Australian general practitioners (GPs) authorised to administer OST, prescribe to very few or no patients. This is a particular issue within Victoria that places greater reliance on a small number of active OST prescribing GPs, compared with other jurisdictions. Given the unmet demand for treatment, the provision of accurate figures on the OST prescribing practices of Victorian GPs is necessary for workforce planning. This study aimed to ascertain information on the prescribing patterns of Victorian GPs in their first 5 years after training, and elicit any trends that may explain their reluctance to prescribe OST., Design and Methods: The prescribing patterns over a 5 year period of 168 Victorian GPs who became first authorised to prescribe OST during the years 2001-2004 were examined by accessing the Victorian Department of Human Services OST individual patient treatment permit data., Results: Forty-six per cent of these GPs never held a patient permit, and at any one time, approximately two-thirds did not hold a permit. The majority of active prescribers were treating fewer than 10 patients and only 12.5% ever prescribed to more than 50 patients., Discussion and Conclusions: The study suggests the Victorian GP workforce is inadequate to address the demand for OST. Many more GPs will need to be recruited, and encouraged to prescribe for more patients. Further research is required to identify barriers to GP OST prescribing., (© 2010 Australasian Professional Society on Alcohol and other Drugs.)

Background: This study aimed to investigate patient perspectives regarding coming off maintenance opioid substitution treatment (OST). The study explored previous experiences, current interest and concerns about stopping treatment, and perceptions of how and when coming off treatment should be supported., Methods: A cross-sectional survey was used. Participants were 145 patients receiving OST at public opioid treatment clinics in Sydney, Australia., Results: Sixty-two percent reported high interest in coming off treatment in the next 6 months. High interest was associated with having discussed coming off treatment with a greater number of categories of people (OR=1.72), not citing concern about heroin relapse (OR=3.18), and shorter duration of current treatment episode (OR=0.99). Seventy-one percent reported previous withdrawal attempts and 23% had achieved opioid abstinence for ≥3 months following a previous withdrawal attempt. Attempts most commonly involved jumping off (59%), and doctor-controlled (52%) or self-controlled (48%) gradual reduction. For future attempts respondents were most interested in doctor-controlled (68%) or self-controlled (41%) gradual reduction. Concerns regarding coming off treatment included withdrawal discomfort (68%), increased pain (50%), and relapse to heroin use (48%)., Conclusion: While some patients may require lifetime maintenance, the issue of coming off treatment is important to many patients and should be discussed regularly throughout treatment and where appropriate supported by a menu of clinical options., (Crown Copyright © 2010. Published by Elsevier B.V. All rights reserved.)

Benzodiazepines (BZDs) are widely used by heroin users not in treatment, and by patients in methadone and buprenorphine (BPN) treatment. This review examines the epidemiology of BZD use by opioid users, and the range of harms that are associated with BZD use in this group, including the association of BZD use with opioid-related mortality. Preclinical and clinical data regarding pharmacokinetic and pharmacodynamic interactions between methadone, buprenorphine, and BZDs are reviewed. An overview of treatment approaches for managing BZD use in this population is presented, including strategies for minimizing abuse and addressing BZD dependence.

Background: Buprenorphine (Subutex) is the most abused opioid in Finland. In order to curb the abuse potential of this drug, many treatment centers and prisons crush Subutex tablets before administering them to patients. To date, there are no published studies comparing the efficacy and bioavailability of crushed and whole Subutex tablets., Methods: A total of 16 opioid-dependent patients stabilized on 24 mg of buprenorphine were enrolled in a double-blind, double-dummy, randomized cross-over study comparing crushed and whole buprenorphine tablets on a range of pharmacokinetic and pharmacodynamic variables. Buprenorphine tablets (either crushed or whole) and placebo tablets (either crushed or whole) were administered to subjects simultaneously. Buprenorphine and norbuprenorphine serum levels were measured at 30, 60, 90, 120, 180, 240 and 360 min, as well as 24 h, after tablet administration. After 1 week, the experiment was repeated in a cross-over design so that, by the end of the study, each patient had received the active drug (buprenorphine) as both crushed and whole tablets., Results: Pharmacokinetic parameters (mean serum levels, C(max), T(max), AUC) of buprenorphine or norbuprenorphine did not differ significantly between crushed and whole tablets, although serum levels were slightly higher after administration of the crushed tablets. There were also no significant differences in dissolution/absorption time, withdrawal signs or opiate craving., Conclusion: We conclude that crushing Subutex tablets does not significantly alter serum buprenorphine or norbuprenorphine levels or the drug's clinical effect. Our results indicate that crushing Subutex tablets may be used as an alternative method to counter the risk of buprenorphine diversion., (2010 S. Karger AG, Basel.)

Objectives: To examine the levels and predictors of injection of buprenorphine-naloxone (BNX)--a combination of a partial opioid agonist and an opioid antagonist for treating opioid dependence--which was specifically developed to limit injecting. Comparison was made with injecting of two other opioid substitution treatment medications, methadone and buprenorphine (BPN); severe harms have been documented after injection of the latter., Design and Participants: Injecting was studied in regular injecting drug users ("IDUs") and current opioid substitution treatment clients ("clients"). Regular IDUs are interviewed annually in each Australian capital city (about 900 per year) and data for 2003-2007 were used; 399 clients were interviewed in 2007. Data on injection of opioid substitution treatment medications between 2003 and 2007 were adjusted for availability of medications (from national sales data for methadone, BPN and BNX). Predictors of injecting were analysed by multiple regression analyses., Setting: Capital cities of all Australian states and territories., Main Outcome Measure: Injection of opioid substitution treatment medications among individuals both in and out of treatment., Results: In the year after its introduction in Australia, BNX was injected less frequently and by fewer regular IDUs and clients compared with BPN, particularly when differences in the availability of medications were taken into account. Some individuals did nonetheless regularly inject BNX. Injection of methadone, BPN and BNX was more likely to occur among those injecting other pharmaceutical opioids., Conclusions: A partial opioid agonist-antagonist combination appears to be less commonly and less frequently injected by clients in treatment and IDUs who are not. Further studies are needed to evaluate longer-term trends in use and harms.

The study investigates patient preferences and beliefs and treatment program factors related to the decision to prescribe either buprenorphine or methadone to opiate-dependent patients. The sample (N = 192) was recruited from 10 addiction treatment services in London. Data were collected by means of a single structured interview conducted with patients commencing a treatment episode at the participating agencies. Data on patient demographics, beliefs, attitudes, and preferences were collected using a structured interview. Data regarding treatment goals and prescribed medication were collected from interviews with clinical staff. Oral methadone had a higher preference rating than buprenorphine. Clinical prescribing practices were influenced by patient preferences (both positive and negative), by prior treatment experiences, and by current treatment goals. Patient preferences and beliefs about opioid agonist medications served as an important influence upon clinical prescribing practices. The odds of being prescribed buprenorphine were three times greater among those patients who reported a preference for buprenorphine. The odds of receiving a prescription for methadone were about twice as great among those for whom methadone was the more preferred medication. Preferences were related to previous treatment experiences with these opioid agonists, and for patients in both groups, personal experience was the most important source of information about the treatment options. Buprenorphine was more likely to be prescribed for short-term detoxification and methadone for maintenance treatment.

Objectives: We investigated how a randomised controlled trial (RCT) could be designed to incorporate features known or thought likely to enhance the uptake of the new treatment into clinical practice post-trial., Method and Results: Between 1999 and 2001, we trialled buprenorphine treatment for heroin dependence in community settings throughout Victoria, using 28 experienced methadone prescribers and 34 pharmacists across 19 sites. In this case study, we describe how we incorporated seven features considered important in treatment uptake: skilled and experienced practitioners, government and policy support, incentives to prescribe the new treatment, specialist support services, clinical guidelines, training programs and patient involvement and information. We also present information showing that uptake of buprenorphine treatment was substantially boosted in Victoria compared with other Australian jurisdictions immediately after the trial in 2001 and that this increase was sustained until at least 2006., Conclusion: While we cannot prove that our trial design was responsible for the increased uptake of buprenorphine treatment in Victoria, we do show that design has been a neglected aspect of clinical trials in terms of enhancing post-trial uptake of the treatment being tested., Implications: Those interested in closing the 'know-do' gap between research and practice may wish to further explore this very promising lead. Imaginative linking of features known to enhance treatment uptake to pressing research questions may lead to new information on efficacy, as well as getting valuable drugs into the treatment system more rapidly.

Background: Benzodiazepine abuse is common among methadone- and buprenorphine-maintained patients; however interactions between these drugs under high dose conditions have not been adequately examined under controlled conditions., Objective: To investigate the effects of co-administering diazepam with methadone or buprenorphine under high dose conditions., Design: Double-blind, randomly ordered, 2 x 2 cross-over design in which the effects of diazepam dose (0mg versus 40 mg) and opioid dose (100% versus 150% normal dose) were examined over four sessions in methadone- and buprenorphine-maintained patients., Participants: Four methadone- and seven buprenorphine-prescribed patients without concurrent dependence on other substances or significant medical co-morbidity., Measures: Physiological (pulse rate, blood pressure, pupil size, respiratory rate and peripheral SpO2), subjective (ARCI, VAS ratings) and performance (reaction time, cancellation task and Digit Symbol Substitution Test, DSST) measures were taken prior to and for 6h post-dosing., Results: High dose diazepam was associated with time-dependent increases in the intensity of subjective drug effects (strength of drug effect, sedation) and decreases in psychological performance (reaction time, DSST) for both methadone and buprenorphine patients. These effects were generally independent of the opioid dose administered. High dose opioid administration (150% normal dose) was associated with reductions in overall SpO2 levels and performance (reaction time, DSST) in the methadone patients, but had virtually no impact on pharmacodynamic responses in the buprenorphine group., Conclusion: High dose diazepam significantly alters subjective drug responses and psychological performance in patients maintained on methadone and buprenorphine.

Objectives: To assess the clinical effectiveness and cost-effectiveness of buprenorphine maintenance therapy (BMT) and methadone maintenance therapy (MMT) for the management of opioid-dependent individuals., Data Sources: Major electronic databases were searched from inception to August 2005. Industry submissions to the National Institute for Health and Clinical Excellence were accessed., Review Methods: The assessment of clinical effectiveness was based on a review of existing reviews plus an updated search for randomised controlled trials (RCTs). A decision tree with Monte Carlo simulation model was developed to assess the cost-effectiveness of BMT and MMT. Retention in treatment and opiate abuse parameters were sourced from the meta-analysis of RCTs directly comparing flexible MMT with flexible dose BMT. Utilities were derived from a panel representing a societal perspective., Results: Most of the included systematic reviews and RCTs were of moderate to good quality, and focused on short-term (up to 1-year follow-up) outcomes of retention in treatment and the level of opiate use (self-report or urinalysis). Most studies employed a trial design that compared a fixed-dose strategy (i.e. all individuals received a standard dose) of MMT or BMT and were conducted in predominantly young men who fulfilled criteria as opiate-dependent or heroin-dependent users, without significant co-morbidities. RCT meta-analyses have shown that a fixed dose of MMT or BMT has superior levels of retention in treatment and opiate use than placebo or no treatment, with higher fixed doses being more effective than lower fixed doses. There was evidence, primarily from non-randomised observational studies, that fixed-dose MMT reduces mortality, HIV risk behaviour and levels of crime compared with no therapy and one small RCT has shown the level of mortality with fixed-dose BMT to be significantly less than with placebo. Flexible dosing (i.e. individualised doses) of MMT and BMT is more reflective of real-world practice. Retention in treatment was superior for flexible MMT than flexible BMT dosing but there was no significant difference in opiate use. Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT. A pooled RCT analysis showed no significant difference in serious adverse events with MMT compared with BMT. Although treatment modifier evidence was limited, adjunct psychosocial and contingency interventions (e.g. financial incentives for opiate-free urine samples) appeared to enhance the effects of both MMT and BMT. Also, MMT and BMT appear to be similarly effective whether delivered in a primary care or outpatient clinic setting. Although most of the included economic evaluations were considered to be of high quality, none used all of the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. One company (Schering-Plough) submitted cost-effectiveness evidence based on an economic model that had a 1-year time horizon and sourced data from a single RCT of flexible-dose MMT compared with flexible-dose BMT and utility values obtained from the literature; the results showed that for MMT vs no drug therapy, the incremental cost-effectiveness ratio (ICER) was pound 12,584/quality-adjusted life-year (QALY), for BMT versus no drug therapy, the ICER was pound 30,048/QALY and in a direct comparison, MMT was found to be slightly more effective and less costly than BMT. The assessment group model found for MMT versus no drug therapy that the ICER was pound 13,697/QALY, for BMT versus no drug therapy that the ICER was pound 26,429/QALY and, as with the industry model, in direct comparison, MMT was slightly more effective and less costly than BMT. When considering social costs, both MMT and BMT gave more health gain and were less costly than no drug treatment. These findings were robust to deterministic and probabilistic sensitivity analyses., Conclusions: Both flexible-dose MMT and BMT are more clinically effective and more cost-effective than no drug therapy in dependent opiate users. In direct comparison, a flexible dosing strategy with MMT was found be somewhat more effective in maintaining individuals in treatment than flexible-dose BMT and therefore associated with a slightly higher health gain and lower costs. However, this needs to be balanced by the more recent experience of clinicians in the use of buprenorphine, the possible risk of higher mortality of MMT and individual opiate-dependent users' preferences. Future research should be directed towards the safety and effectiveness of MMT and BMT; potential safety concerns regarding methadone and buprenorphine, specifically mortality and key drug interactions; efficacy of substitution medications (in particular patient subgroups, such as within the criminal justice system, or within young people); and uncertainties in cost-effectiveness identified by current economic models.

Benzodiazepine use by patients in methadone and buprenorphine substitution treatment is common, despite safety concerns regarding these drug interactions. The relative safety of diazepam use by methadone- or buprenorphine-treated patients has not been systematically examined. This study aimed to examine the effect of single diazepam doses, within normal therapeutic range (doses: 0, 10, and 20 mg), upon physiological, subjective, and performance measures in stable methadone and buprenorphine-treated patients. In a double-blind, randomized crossover design, methadone- or buprenorphine-treated patients were administered their normal opioid dose and either placebo, 10-, or 20-mg diazepam, in balanced order over 3 sessions. Eight methadone- and 8 buprenorphine-prescribed patients with no concurrent benzodiazepine dependence or significant comorbidity were recruited from an outpatient addiction clinic in London. Measures were taken at baseline and for 6 hours after dosing, and included physiological responses (pulse rate, blood pressure, pupil size, respiratory rate, and peripheral pO2), subjective drug effects (Addiction Research Center Inventory subscales, visual analog scales of strength of drug effect, drug-liking, and sedation), and performance measures (simple reaction time, cancellation task, digit symbol substitution task, and balance). The 10- and 20-mg diazepam doses resulted in comparable subjective experiences of greater sedation and strength of drug effects in both patient groups, and had minimal impact on physiological parameters. However, diazepam had greater peak effects on performance measures (simple reaction time, digit symbol substitution task, and cancellation time) in methadone-treated than in buprenorphine-treated patients. Diazepam may significantly alter the response to opioid substitution treatment with methadone or buprenorphine.

Buprenorphine was registered in Australia as a maintenance and detoxification agent for the management of opioid dependence in November, 2000, and became widely available in August, 2001. This paper provides an overview of key developments in the introduction of buprenorphine treatment in Australia, with an emphasis upon the delivery of services in community-based (primary care) settings. A central study in this work was the Buprenorphine Implementation Trial (BIT), a randomized, controlled trial comparing buprenorphine and methadone maintenance treatment delivered under naturalistic conditions by specialist and community-based service providers (general practitioners and community pharmacists) in 139 subjects across nineteen treatment sites. In addition to conventional patient outcome measures (treatment retention, drug use, psychosocial functioning, and cost effectiveness), the BIT study also involved the development and evaluation of clinical guidelines, training programs for clinicians, and client literature, which are described here. Integration of treatment systems (methadone with buprenorphine, specialist and primary-care programs) and factors thought to be important in the uptake of buprenorphine treatment in Australia since registration are discussed.

Background: Buprenorphine is used in the treatment of opioid dependence. Due to its pharmacology, the transfer from methadone to buprenorphine may precipitate withdrawal symptoms., Methods: Methadone maintained patients with clinical indicators of stability who were seeking withdrawal from methadone were recruited from three Australian states. Patients on methadone doses between 30 and 40 mg were randomised to transfer to buprenorphine by a fixed dose (transfer at 30 mg methadone) or by a variable dose induction (transfer when 'uncomfortable'). A third group of patients with methadone doses less than 30 mg were transferred to buprenorphine at their entry methadone dose. Fifty-one patients were inducted onto buprenorphine using the same dosing protocol with the first dose of 4 mg buprenorphine. Following stabilisation on buprenorphine, patients gradually reduced the buprenorphine dose to 0 mg. Withdrawal severity and drug use was monitored., Results: There were no significant difference between the transfer at 30 mg and transfer when 'uncomfortable' dosing protocols in severity of withdrawal on transfer from methadone to buprenorphine. Those on doses less than 30 mg reported significantly less withdrawal discomfort at transfer. All but one patient stabilised on buprenorphine. Thirty-eight of the 51 patients inducted onto buprenorphine reached 0 mg., Conclusions: Transfer from methadone to buprenorphine can safely occur from doses of around 30 mg of methadone. Buprenorphine dose reductions were well tolerated. Thirty-one percent of patients were not using heroin or methadone at 1-month follow-up.

Objective: To compare outcomes, costs and incremental cost-effectiveness of heroin detoxification performed in a specialist clinic and in general practice., Design and Setting: Randomised controlled trial set in a specialist outpatient drug treatment centre and six office-based general practices in inner city Sydney, Australia., Participants: 115 people seeking treatment for heroin dependence, of whom 97 (84%) were reinterviewed at Day 8, and 78 (68%) at Day 91., Interventions: Participants were randomly allocated to primary care or a specialist clinic, and received buprenorphine for 5 days for detoxification, then were offered either maintenance therapy with methadone or buprenorphine, relapse prevention with naltrexone, or counselling alone., Main Outcome Measures: Completion of detoxification, engagement in post-detoxification treatment, and heroin use assessed at Days 8 and 91. Costs relevant to providing treatment, including staff time, medication use and diagnostic procedures, with abstinence from heroin use on Day 8 as the primary outcome measure., Results: There were no significant differences in the proportions completing detoxification (40/56 [71%] primary care v 46/59 [78%] clinic), participating in postwithdrawal treatment (28/56 [50%] primary care v 36/59 [61%] clinic), reporting no opiate use during the withdrawal period (13/56 [23%] primary care v 13/59 [22%] clinic), and in duration of postwithdrawal treatment by survival analysis. Most participants in both groups entered postwithdrawal buprenorphine maintenance. On an intention-to-treat basis, self-reported heroin use in the month before the Day 91 interview was significantly lower than at baseline (27 days/month at baseline, 14 days/month at Day 91; P < 0.001) and did not differ between groups. Buprenorphine detoxification in primary care was estimated to be $24 more expensive per patient than treatment at the clinic. The incremental cost-effectiveness ratio reveals that, in this context, it costs $20 to achieve a 1% improvement in outcome in primary care., Conclusions: Buprenorphine-assisted detoxification from heroin in specialist clinic and primary care settings had similar efficacy and cost-effectiveness. Buprenorphine treatment can be initiated safely in primary care settings by trained GPs.

The study aimed to identify the range of buprenorphine doses required to comfortably alleviate symptoms in patients undergoing inpatient heroin withdrawal using a symptom-triggered titration dosing regime, and to identify the patient characteristics that impact upon the buprenorphine dose requirements. The study was conducted in two Australian inpatient withdrawal units, recruiting 63 dependent, injecting heroin users with no recent methadone treatment, dependence on other drugs, or other active medical or psychiatric conditions. In a single (patient) blinded case series, placebo or 2 mg sublingual buprenorphine tablets was administered four times a day according to severity of withdrawal (assessed with Subjective Opiate Withdrawal Scale). Up to 16 mg buprenorphine was available over the first 4 days of the admission, up to 8 mg on day 5, and placebo continued until day 6. Thirty-two subjects completed the dosing regime, with mean (+/-S.D.) daily doses of 3.8+/-2.8 on day 1, 5.8+/-3.2 on day 2, 4.8+/-3.3 on day 3, 2.3+/-2.6 on day 4, 0.8+/-1.3 on day 5, and a total dose of 17.4+/-9.7. Higher buprenorphine doses were required by those patients with more severe psychosocial dysfunction, women, those with more frequent heroin use, and those with more severe dependence on heroin at intake. A dosing regime using sublingual buprenorphine tablets for short inpatient heroin withdrawal is proposed.

This paper describes the development and implementation of training programs for primary care medical practitioners and pharmacists in the delivery of buprenorphine and LAAM treatment in the management of opiate dependence. Separate training programs were developed for each medication. Each training package included learning objectives, training materials, and assessment instruments. Findings of the evaluation of these initiatives and the subsequent Australian postregistration training program for buprenorphine are described.

Aim: To determine whether buprenorphine is more effective than clonidine and other symptomatic medications in managing ambulatory heroin withdrawal., Design: Open label, prospective randomized controlled trial examining withdrawal and 4-week postwithdrawal outcomes on intention-to-treat., Setting: Two specialist, out-patient drug treatment centres in inner city Melbourne and Sydney, Australia., Participants: One hundred and fourteen dependent heroin users were recruited. Participants were 18 years or over, and with no significant other drug dependence, medical or psychiatric conditions or recent methadone treatment. One hundred and one (89%) participants completed a day 8 research interview examining withdrawal outcomes, and 92 (81%) completed day 35 research interview examining postwithdrawal outcomes., Interventions: Participants randomized to control (n = 56) (up to 8 days of clonidine and other symptomatic medications) or experimental (n = 58) (up to 5 days of buprenorphine) withdrawal groups. Following the 8-day withdrawal episode, participants could self-select from range of postwithdrawal options (naltrexone, substitution maintenance, or counselling)., Measurements: Retention in withdrawal; heroin use during withdrawal; and retention in drug treatment 4 weeks after withdrawal., Secondary Outcomes: Withdrawal severity; adverse events, and heroin use in the postwithdrawal period., Findings: The experimental group had better treatment retention at day 8 (86% versus 57%, P = 0.001, 95% CI for numbers needed to treat (NNT) = 3-8) and day 35 (62% versus 39%, P = 0.02, 95% CI for NNT = 4-18); used heroin on fewer days during the withdrawal programme (2.6 +/- 2.5 versus 4.5 +/- 2.3, P < 0.001, 95% CI = 1-2.5 days) and in the postwithdrawal period (9.0 +/- 8.2 versus 14.6 +/- 10, P < 0.01, 95% CI = 1.8-9.4); and reported less withdrawal severity. No severe adverse events reported., Conclusions: Buprenorphine is effective for short-term ambulatory heroin withdrawal, with greater retention, less heroin use and less withdrawal discomfort during withdrawal; and increased postwithdrawal treatment retention than symptomatic medications.

This study aimed to establish a buprenorphine regime suitable for the short-term management of out-patient heroin withdrawal using an open-label, single-group case series. Eighteen dependent injecting heroin users underwent an 8-day withdrawal episode with supervised dosing of sublingual Subutex tablets. Buprenorphine doses were titrated daily over a 5-day period. Fifteen subjects (83%) completed the 5-day regime, and 14 (78%) completed the 8-day withdrawal episode. The mean doses ((SD) were 6.1 (1.2) mg on day 1; 9.6 (1.7) mg on day 2; 10.1 (1.9) mg on day 3; 8.9 (2.0) mg on day 4; 4.1 (1.5) mg on day 5; and a total regime dose of 38.9 (5.8) mg. Withdrawal severity was mild, with minimal rebound upon the cessation of dosing. Five subjects reported no heroin use, and five subjects reported using on only one occasion during the 8 days. An out-patient buprenorphine regime is recommended.

By diverting his dispensed medication, our patient collected 11 buprenorphine tablets (8 mg each), which he took in one day. The result was not respiratory depression, but instead severe opiate withdrawal lasting four days--this scenario has not previously been reported. This case highlights features of the unique pharmacology of buprenorphine and some key issues for its use in the management of heroin dependence.

Buprenorphine is safe and effective for short-term ambulatory heroin withdrawal. Compared to clonidine and other symptomatic medications, buprenorphine was associated with greater retention, less heroin use and less discomfort during withdrawal. People receiving buprenorphine had significantly greater retention, less heroin use and less withdrawal discomfort compared with clonidine. The intervention was provided for an extended period, and the sample size was large, providing sufficient power.