STRENGTHS AND LIMITATIONS OF THIS STUDY
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This study provides both quantitative and in-depth qualitative data to assess the feasibility of integrated, time-limited supervised injectable opioid treatment (SIOT).
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The treatment occurs within an existing opioid treatment programme, where clinic staff and other clinic attendees on conventional opioid agonist treatment are interviewed to determine the impact on existing clinic operations.
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The open-label design of the study and the small sample size preclude determination of ‘efficacy’.
Introduction
Australia has a well-developed system of providing opioid agonist treatment (OAT) to people with opioid use disorder (OUD), but the currently available forms of OAT, primarily methadone and buprenorphine, do not deliver optimal benefits to all people. From the estimated 1% of the Australian population dependent on opioids,1 about half can be retained in methadone treatment long term, and of those, about 5%–15% continue injecting illicit opioids2 and experience severe harms such as premature death, non-fatal overdose, bloodborne infections, violence and arrest,2 3 indicating that the current treatment system is not meeting the needs of all individuals affected by OUD.
An indication of the potential demand for a different form of OAT in Australia, and the catalyst to undertaking this project, is the existence of, and evidence from, a cohort of people who inject drugs attending the Uniting Medically Supervised Injecting Centre (MSIC) in inner-Sydney. MSIC is the only supervised injecting centre in New South Wales (NSW) and only one of two such overdose prevention services nationally. Data from MSIC client registrations indicate the potential need for SIOT: when MSIC records were reviewed in 2017 for development of this study, approximately 10% of the clients who visited MSIC to use opioids had first registered with the service in 2001–2002. In addition, an MSIC client survey, also performed in 2017, found 43% of respondents were currently prescribed and taking methadone, and a further 35% had been on methadone previously, indicating potentially treatment-refractory OUD.
Prescription of heroin for people who misuse opioids, referred to as ‘heroin-assisted treatment’, has been available in places such as the UK since the early 1900s4 and while an Australian heroin trial was proposed in the Australian Capital Territory (ACT) in 1996,5 it did not proceed.6
Supervised injectable opioid treatment (SIOT), as it is now known, has since been compared with treatment with oral methadone in seven randomised controlled trials,7 and is internationally recognised as a second-line treatment option for those individuals who do not benefit from standard OAT.8 9 It involves prescribing injectable opioids, usually diacetylmorphine (pharmaceutical heroin), but hydromorphone has also been used,10 for people who continue with illicit opioid injecting despite access to standard treatments (eg, methadone, buprenorphine). Opioids delivered intravenously are more ‘rewarding’ in terms of providing a more rapid and euphoric effect than oral OAT, and can attract and retain people in structured treatment where methadone and buprenorphine have not been effective.11
SIOT is now available as a treatment option for eligible patients in Switzerland, Denmark, the Netherlands and Canada.7 As of 2012, there were about 1000 patients receiving SIOT treatment with diacetylmorphine in the European Union (Denmark, Germany and the Netherlands) and about 1400 in Switzerland.12
Although SIOT is considered an effective treatment, there are several issues that are of concern, especially to policy makers and governments. SIOT is an intensive and highly structured treatment, requiring daily or several times daily attendance as opposed to the daily (or less) attendance requirements of current OAT. This, combined with medication costs, means that compared with standard OAT, SIOT is relatively expensive. Governments around the world are therefore often reluctant to fund indefinite, high-cost treatment when there are cheaper alternatives available.
In light of long-term follow-up studies showing that the strongest benefits of SIOT are achieved within the first 2 years,13 14 there is a case for testing the feasibility and acceptability of time-limited SIOT, as an adjunct to oral methadone or other standard OAT, with the objective of reducing the use of illicit drugs and associated harms. Furthermore, there is opportunity to assess the delivery of SIOT from an existing public clinic, where normally there are a higher proportion of ‘non-responding’ clients. This would support a potential scale-up of SIOT into other public opioid treatment programmes if the study results were positive.
Objectives
The primary aim of this study is to investigate whether it is feasible to implement SIOT in an Australian clinic using injectable hydromorphone; and to investigate whether a 2-year intervention, followed by continuation on standard OAT alone, is feasible and acceptable to participants and staff.
Secondary aims of this study are to assess safety, cost and changes in other outcomes such as: non-prescribed/unsanctioned opioid use; other non-prescribed drug use; quality of life; mental and physical health; social connectedness and well-being and crime.
Methods and analysis
Trial design
This is a single-site, uncontrolled, open-label study. Eligible adults with a treatment-refractory OUD and who currently inject opioids are offered up to 24 months two times per day supervised injectable hydromorphone plus standard OAT (methadone or buprenorphine). Following cessation of injectable hydromorphone, participants will then be offered ongoing OAT and followed up as per routine clinical care.
Hydromorphone is currently not registered for the treatment of opioid dependence in Australia. All consenting participants are registered with the NSW Pharmaceutical Regulatory Unit and receive parenteral hydromorphone plus oral methadone or buprenorphine.
Patient and public involvement
Early on in the development of the project, key stakeholder interviews were conducted with people who inject drugs, specifically clients of the Sydney MSIC, as well as representatives from other user organisations. MSIC clients, through their Consumer Group, were informed about the project’s evolution and had the opportunity to ask questions and provide input. This included a recommendation to ensure that the clients’ voices were represented in the research.
The project Steering Committee and Clinical Working Group included a Consumer Worker as a member who participated in the initial discussions of the study and reviewed the protocol prior to implementation. The Consumer Worker was available to speak to potential participants about the trial and to support both participants and non-participants attending the public opioid treatment programme during the implementation of the trial.
The Consumer Worker has participated in discussions and presentations of the trial and its outcomes, as well as inclusion as an author on relevant publications, including this publication.
The Consumer Worker will also write a plain language summary of the trial results.
Furthermore, the study is designed to incorporate the views of all participants through qualitative interviews and focus groups, as well as the views of non-participants who continued attending the clinic for OAT.
Study setting
Participants are enrolled in the study at a single site, Rankin Court Treatment Centre (RCTC), the outpatient opioid treatment programme operated by St Vincent’s Hospital Sydney, NSW, Australia.
Eligibility criteria
To be eligible, adults must be 21–60 years of age; have a minimum of 5 years living with OUD: demonstrate current physical dependence, as assessed by an Addiction Medicine Specialist, using International Classification of Diseases 10th Revision criteria15; have previous unsuccessful episodes of treatment (ie, either not retained on past OAT or self-report of injecting illicit opioids while on current OAT); currently injecting illicit opioids >3 times weekly (as measured by self-report); demonstrate evidence of harm (health, mental health, social functioning) due to their opioid use; have the ability to provide written, informed consent to participate and be willing to participate and comply with the study protocol.
Exclusion criteria for the study are pregnant, breastfeeding or planning to become pregnant; advanced liver disease (Child-Pugh B)16; chronic airflow limitation or other respiratory compromise producing dyspnoea on mild exertion; other severe and active medical condition as assessed by a study medical officer; concurrent monoamine oxidase inhibitors (MAOIs) or within 14 days of treatment with MAOIs; require other prescribed medication, which interacts with trial medication in ways which make treatment unsafe; previous adverse reaction to hydromorphone; severe psychiatric disorder (eg, acute psychosis, severe anxiety and/or mood disorder, intent to harm self or others assessed by study medical officer and/or psychiatrist); severe cognitive impairment and inability to provide informed consent, even with a registered medical interpreter.
Intervention
Participants self-administer (intravenously or intramuscularly) parenteral hydromorphone up to two times per day for 24 months, onsite under direct observation of nursing staff. All injections must be in the upper limbs only, completed within 5 min and with the maximum dosage of 200 mg/dose (a maximum 400 mg/day). Participants are required to receive supervised OAT (with methadone or buprenorphine) between 3 and 7 days prior to their first hydromorphone dose and will be required to have their regular dose of OAT prior to their injection of parenteral hydromorphone. Participants are initially commenced on only 10 mg of hydromorphone and the dose is slowly escalated to prevent any adverse events (AEs). Participants will then be transitioned to standard OAT only after 24 months as per routine care. A timeline of participants’ progress through the trial is outlined in figure 1.
Trial schema. OAT, opioid agonist treatment.
Recruitment
Recruitment for the study has already been completed with a 6-month recruitment phase from April to September 2022; however, final data collection will not be concluded until January 2025. MSIC and other local drug services identified potential participants among their client group. Participants who fulfilled the eligibility criteria based on their clinical records at these services were informed about the trial. If the client expressed an interest in learning more, they were given an appointment to meet trial staff and at that appointment were given detailed written information about the study.
A second appointment was offered at least 24 hours after being given the written information with the trial medical officer; allowing the potential participant as much time as they wished to discuss the study with other healthcare providers, family or friends.
Following provision of informed consent, eligibility screening was performed. The trial medical officer evaluated each patient for eligibility according to the inclusion and exclusion checklist, including a formal medical assessment, history and physical examination and review of investigations as required. If eligibility criteria were met, participants were enrolled and proceeded to a baseline visit.
Baseline data were collected comprising medical history; concomitant medications and contraception (people of childbearing potential). A focused physical examination was performed, along with a Mental State Examination (including appearance, behaviour, speech, mood, affect, thought stream, thought content, thought form, perception, cognition, insight and judgement),17 measurement of body mass index, urine drug screening and a urine pregnancy test for individuals of childbearing potential.
Participants consenting to the study had regulatory paperwork completed (if not already on the OAT programme at RCTC) and approved by the jurisdictional authorities, pharmaceutical services, NSW Health, prior to commencing OAT and hydromorphone. This paperwork consists of an ‘application for authority to prescribe methadone, buprenorphine or other opioid agonist therapy treatment under the NSW Opioid Treatment Programme’, which is a regulatory requirement for medical practitioners in NSW to provide such treatment.18
The study has now been operational for over 12 months and in these first 12 months of the study, participants who ceased SIOT were able to recommence if they returned within 3 months. This is consistent with standard practice at the clinic to allow for disruptions to OAT and SIOT that may be incurred due to involvement with the criminal justice system or other complex social issues.
Data collection
The dataset will include all participants enrolled in the study and who received at least one dose of the study medication.
Primary outcomes
Feasibility will be assessed by recruitment, as well as retention and participation in treatment over the 27 months of possible inclusion in the study. Recruitment will be determined by the number of people screened and who are eligible for the trial as well as the final number of participants enrolled in the study. Retention and participation in treatment will be assessed by the number of days of supervised injectable treatment; number of days of oral medication only; number of missed days of dosing and number of participants transferred to standard OAT only.
Baseline descriptive characteristics including age, gender, sexual identity, Aboriginal and/or Torres Strait Islander Status, income, living arrangements and current postal code will be described. Descriptive statistics will be presented as the median for continuous parametric measures and as proportions for categorical variables; however, given the small sample size, it is assumed that the data will not be evenly distributed and non-parametric tests will be used.
Acceptability will be assessed by qualitative interviews, which will be offered to all participants at baseline, 12 months and at 3 months following the last injection of hydromorphone. These semi-structured interviews will be conducted by an independent researcher from the University of NSW recording such topics as positive and negative experiences due to treatment; any negative effects; perceived mechanisms of change and treatment journey; practical issues associated with receiving treatment and other themes. Qualitative data analysis to assess acceptability will be conducted using the framework by Sekhon et al19 and the updated Consolidated Framework for Implementation Research.20
To further assess programme acceptability, qualitative interviews with clinic staff, other attendees at the clinic and other stakeholders such as policy makers will be undertaken during and at completion of the trial. Clinic staff will be asked to describe the main operational features and difficulties pertaining to SIOT such as issues that have arisen, strengths and weaknesses of the programme and help answer key questions regarding transferability and scale-up. Stakeholders, such as policy makers, will be asked to discuss the broader acceptability of this treatment as well as barriers to implementation more widely.
Secondary outcomes
To assess secondary outcomes, quantitative surveys will be conducted at baseline, 12 months and 3 months post the final injection of hydromorphone, and will monitor changes in mental health, quality of life and non-prescribed drug use. These interviews will document self-reported prescribed and non-prescribed drug use (using the Time Line Follow Back21), involvement in crime, changes in mental health (measured by K1022 and Symptom checklist 90 (SCL-90)),23 quality of life (measured by Assessment of Quality of Life-8 (AQoL-8)),24 physical health and social functioning (assessed using Australian Treatment Outcomes Profile).25 26
Safety will be assessed by treatment emergent AEs, using Therapeutic Goods Administration criteria.27 For the purposes of the study, a ‘serious AE’ will also include an event where airway management is required, and any event where naloxone is administered. A Data Safety Monitoring Board (DSMB) was convened for the purposes of ensuring participant safety for the duration of the study. The DSMB will meet to review the trial data following the first participant’s visit and every 3 months thereafter. The DSMB will review the number and severity of AEs including if airway management or the administration of naloxone is required.
And finally, to estimate the costs associated with SIOT in the Australian setting, a comprehensive cost assessment will be undertaken to determine both the unit cost of SIOT and minimum feasible number per site to inform scaling-up the treatment.
Statistical methods
No sample size calculation was conducted as this is a feasibility study28 and is not powered to detect differences in treatment efficacy. A population sample size of between 20 and 30 participants was chosen, based on clinical capacity, to provide sufficient data on the study’s objectives. If, at the end of the feasibility study, a more formal test of time-limited SIOT is deemed necessary, the current study will provide the basis for an appropriate power calculation needed to conduct a full randomised controlled trial.
Ethics and dissemination
This study received ethical approval from the St Vincent’s Hospital Human Research Ethics Committee (2019/ETH00418) and was prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621001729819).
This will be the first study of SIOT in Australia since it was first proposed by Bammer and Douglas in 1996.5 This is also the first study worldwide on time-limited SIOT. We aim to determine if SIOT will be feasible and acceptable in the Australian setting, as it is in other countries, and also whether it is possible to deliver SIOT within the restrictions of a time-limited framework.
Findings from the trial will be submitted to peer-reviewed journals and other articles will be produced for media to promote public discussion as well as scientific and community fora.
Once completed, a preliminary report on outcomes will be prepared and forwarded to respective Federal and State Health policy makers. If the findings of this trial indicate support for scaling up, the project team (Uniting ACT/NSW, University of NSW, St Vincent’s) will be able to support these activities with an implementation toolkit including training for clinicians, an operations manual and community engagement guidelines.
Ethics statements
Patient consent for publication
Acknowledgments
This project is a partnership between Uniting NSW/ACT, the organisation which runs the Sydney Medically Supervised injecting Centre (MSIC), St Vincent’s Hospital Sydney (SVHS) and the University of New South Wales (UNSW). The authors would also like to thank the study participants for their contribution to research, as well as current and past researchers and staff: Katerina Zavitsanou, Anna McVinish, Ruthy McIver, Teodora Zanesheva-Karamanlieva, Nader Malek and all the nursing staff working in the clinic. We would also like to extend our thanks to Marian Shanahan who is currently leading the health economic assessment and Jake Rance, who is undertaking the quantitative and qualitative surveys.
This post was originally published on https://bmjopen.bmj.com