Effect of Intranasal vs Intramuscular Naloxone on Opioid Overdose: A Randomized Clinical Trial.

Importance: Previous unblinded clinical trials suggested that the intranasal route of naloxone hydrochloride was inferior to the widely used intramuscular route for the reversal of opioid overdose. Objective: To test whether a dose of naloxone administered intranasally is as effective as the same dose of intramuscularly administered naloxone in reversing opioid overdose. Design, Setting, and Participants: A double-blind, double-dummy randomized clinical trial was conducted at the Uniting Medically Supervised Injecting Centre in Sydney, Australia. Clients of the center were recruited to participate from February 1, 2012, to January 3, 2017. Eligible clients were aged 18 years or older with a history of injecting drug use (n = 197). Intention-to-treat analysis was performed for all participants who received both intranasal and intramuscular modes of treatment (active or placebo). Interventions: Clients were randomized to receive 1 of 2 treatments: (1) intranasal administration of naloxone hydrochloride 800 µg per 1 mL and intramuscular administration of placebo 1 mL or (2) intramuscular administration of naloxone hydrochloride 800 µg per 1 mL and intranasal administration of placebo 1 mL. Main Outcomes and Measures: The primary outcome measure was the need for a rescue dose of intramuscular naloxone hydrochloride (800 µg) 10 minutes after the initial treatment. Secondary outcome measures included time to adequate respiratory rate greater than or equal to 10 breaths per minute and time to Glasgow Coma Scale score greater than or equal to 13. Results: A total of 197 clients (173 [87.8%] male; mean [SD] age, 34.0 [7.82] years) completed the trial, of whom 93 (47.2%) were randomized to intramuscular naloxone dose and 104 (52.8%) to intranasal naloxone dose. Clients randomized to intramuscular naloxone administration were less likely to require a rescue dose of naloxone compared with clients randomized to intranasal naloxone administration (8 [8.6%] vs 24 [23.1%]; odds ratio, 0.35; 95% CI, 0.15-0.66; P = .002). A 65% increase in hazard (hazard ratio, 1.65; 95% CI, 1.21-2.25; P = .002) for time to respiratory rate of at least 10 and an 81% increase in hazard (hazard ratio, 1.81; 95% CI, 1.28-2.56; P = .001) for time to Glasgow Coma Scale score of at least 13 were observed for the group receiving intranasal naloxone compared with the group receiving intramuscular naloxone. No major adverse events were reported for either group. Conclusions and Relevance: This trial showed that intranasally administered naloxone in a supervised injecting facility can reverse opioid overdose but not as efficiently as intramuscularly administered naloxone can, findings that largely replicate those of previous unblinded clinical trials. These results suggest that determining the optimal dose and concentration of intranasal naloxone to respond to opioid overdose in real-world conditions is an international priority. Trial Registration: anzctr.org.au Identifier: ACTRN12611000852954.

An overview of take-home naloxone programs in Australia.

INTRODUCTION AND AIMS: Take-home naloxone (THN) programs commenced in Australia in 2012 in the Australian Capital Territory and programs now operate in five Australian jurisdictions. The purpose of this paper is to record the progress of THN programs in Australia, to provide a resource for others wanting to start THN projects, and provide a tool for policy makers and others considering expansion of THN programs in this country and elsewhere. DESIGN AND METHODS: Key stakeholders with principal responsibility for identified THN programs operating in Australia provided descriptions of program development, implementation and characteristics. Short summaries of known THN programs from each jurisdiction are provided along with a table detailing program characteristics and outcomes. RESULTS: Data collected across current Australian THN programs suggest that to date over 2500 Australians at risk of overdose have been trained and provided naloxone. Evaluation data from four programs recorded 146 overdose reversals involving naloxone that was given by THN participants. DISCUSSION AND CONCLUSIONS: Peer drug user groups currently play a central role in the development, delivery and scale-up of THN in Australia. Health professionals who work with people who use illicit opioids are increasingly taking part as alcohol and other drug-related health agencies have recognised the opportunity for THN provision through interactions with their clients. Australia has made rapid progress in removing regulatory barriers to naloxone since the initiation of the first THN program in 2012. However, logistical and economic barriers remain and further work is needed to expand access to this life-saving medication.

Does training people to administer take-home naloxone increase their knowledge? Evidence from Australian programs.

INTRODUCTION AND AIMS: Take-home naloxone (THN) programs have been operating in Australia since 2012 in a variety of settings. We examine whether THN programs were effective in increasing knowledge about opioid overdose and appropriate responses in program participants. DESIGN AND METHODS: Data were obtained from pre- and post-training questionnaires administered as part of the early evaluations of THN naloxone programs operated in Sydney (n = 67), Melbourne (n = 280), Perth (n = 153) and Canberra (n = 183). Pooled data from comparable items, analysed in the domains specified in previously-developed evaluation scales, were compared using repeated-measures analysis of variance and random effects logistic regression. Results pre- and post-training were compared as well as results across sites. RESULTS: High levels of knowledge about overdose risks and signs and appropriate actions to take were observed at baseline and this generally improved over time. No substantial differences were identified across cities. Knowledge also increased with participant age but the improvements over time were similar in each age group. There were small differences by participant gender with knowledge generally higher among females. DISCUSSION AND CONCLUSIONS: THN programs are effective in improving knowledge related to overdose response. Major improvements in knowledge were limited to overdose recognition and effect of naloxone suggesting that education may best be focused on overdose signs and the use of naloxone among populations accessed through these programs. A focus on younger people also appears warranted. Further work is needed to understand the impact of training and knowledge on actual behaviours around overdose events.

Findings and lessons learnt from implementing Australia's first health service based take-home naloxone program.

INTRODUCTION AND AIMS: Opioid overdose prevention programs providing take-home naloxone have been expanding internationally. This paper summarises findings and lessons learnt from the Overdose Prevention and Emergency Naloxone Project which is the first take-home naloxone program in Australia implemented in a health care setting. METHODS: The Project intervention provided education and take-home naloxone to opioid-using clients at Kirketon Road Centre and The Langton Centre in Sydney. The evaluation study examined uptake and acceptability of the intervention; participants' knowledge and attitudes regarding overdose and participants' experience in opioid overdose situations six months after the intervention. Participants completed baseline, post-training and follow-up questionnaires regarding overdose prevention and management which were analysed using repeated measures analysis of variance. RESULTS: Eighty-three people participated in the intervention, with 35 (42%) completing follow-up interviews-51% reporting using naloxone with 30 overdoses successfully reversed. There were significant improvements in knowledge and attitudes immediately following training with much retained at follow-up, particularly regarding feeling informed enough (97%) and confident to inject naloxone (100%). DISCUSSION: Take-home naloxone programs can be successfully implemented in Australian health settings. Barriers to uptake, such as lengthy processes and misperceptions around interest in overdose prevention, should be addressed in future program implementation.

Delivering direct acting antiviral therapy for hepatitis C to highly marginalised and current drug injecting populations in a targeted primary health care setting.

BACKGROUND: The Kirketon Road Centre (KRC) is a community-based public health facility in Sydney, Australia, that provides healthcare to people who inject drugs (PWID), including hepatitis C virus (HCV) treatment. From March 2016, the Australian Government has provided access to direct-acting antivirals (DAA) for adults with chronic HCV, without liver disease stage or drug and alcohol use restrictions. The aim of this study was to report DAA treatment outcomes among highly marginalised PWID treated at KRC. METHODS: All individuals initiating DAA treatment at KRC and due for sustained virological response (SVR12) testing by end 2016 were included. Demographic, drug use behaviour, clinical parameters, adherence support and HCV treatment outcomes, including SVR12 were recorded. Factors associated with SVR12, loss-to-follow-up (LTFU) and delayed SVR12 testing (>SVR16) were assessed by multivariate analysis. SVR12 was assessed by intention-to-treat (ITT) and modified ITT, the latter excluding individuals with an end-of-treatment response (ETR) but no SVR12 assessment, or who postponed their SVR12 date due to treatment interruption. RESULTS: A total of 72 individuals commencing DAAs were included, of whom 67% were male, 30% homeless, and 32% Aboriginal. All had a lifetime history of injecting drug use, with 75% having injected within the last six months, and 44% injecting at least weekly; 25% were also enrolled in opioid substitution therapy. Twenty-five (35%) individuals elected to receive an enhanced adherence-support package. Fifty-nine of 72 (82%) individuals due for SVR12 attended for testing, of whom 59/59 (100%) achieved SVR, providing an ITT SVR of 82%. A further six individuals had undetectable HCV RNA at ETR, but no SVR12 assessment, and one interrupted treatment, providing a mITT SVR of 91%. Homelessness was associated with delayed SVR12 testing (OR 24.9 95%CI 2.9-212.8, p=0.003). There was no association between LTFU and frequency of drug injection, last drug injected, or planned treatment duration. CONCLUSION: This study confirms that PWID can be successfully treated for HCV in a real-world setting using an integrated primary health care model. It also demonstrates feasibility to upscale DAA therapy in high-risk PWID populations, with potential individual and population-level public health benefits. Enhanced efforts are required to optimise post-treatment follow-up.

Treating Addictions: Harm Reduction in Clinical Care and Prevention.

This paper examines the role of clinical practitioners and clinical researchers internationally in establishing the utility of harm-reduction approaches to substance use. It thus illustrates the potential for clinicians to play a pivotal role in health promoting structural interventions based on harm-reduction goals and public health models. Popular media images of drug use as uniformly damaging, and abstinence as the only acceptable goal of treatment, threaten to distort clinical care away from a basis in evidence, which shows that some ways of using drugs are far more harmful than others and that punitive approaches and insistence on total abstinence as the only goal of treatment often increases the harms of drug use rather than reducing drug use. Therefore the leadership and scientific authority of clinicians who understand the health impact of harm-reduction strategies is needed. Through a review of harm-reduction interventions in Canada, the United Kingdom, the United States, Australia, Switzerland, and the Netherlands, we identify three ways that clinicians have helped to achieve a paradigm shift from punitive approaches to harm-reduction principles in clinical care and in drug policy: (1) through clinical research to provide data establishing the effectiveness and feasibility of harm-reduction approaches, (2) by developing innovative clinical programmes that employ harm reduction, and thereby (3) changing the standard of care to include routine use of these evidence-based (but often misunderstood) approaches in their practices. We argue that through promotion of harm-reduction goals and methods, clinicians have unique opportunities to improve the health outcomes of vulnerable populations.

Reducing injecting-related injury and diseases in people who inject drugs: Results from a clinician-led brief intervention.

BACKGROUND: The burden of disease associated with injecting-related injury and diseases (IRIDs) is significant among people who inject drugs (PWID). OBJECTIVE: The aim of this study was to evaluate a clinician-led brief intervention involving safer injecting messages and demonstration of safer injecting techniques at the time of venepuncture for serological testing. METHODS: We conducted a before and after evaluation study. History of IRIDs and injecting-related risk behaviours were assessed and compared at baseline and follow-up. RESULTS: Fifty-eight participants completed the pre-intervention and post-intervention evaluation surveys. Compared to baseline, at follow-up fewer participants reported not cleaning their hands prior to injecting (16% cf 31%; P = 0.039); more reported applying a tourniquet correctly (38% cf 24%; P = 0.008), never missing a vein (56% cf 31%; P = 0.007), and applying pressure for at least one to two minutes after injecting (33% cf 13%; P = 0.035). DISCUSSION: The intervention was found to be feasible, justifying its inclusion into routine clinical care. We recommend that other health services targeting PWID implement similar interventions.

Development of immunity following financial incentives for hepatitis B vaccination among people who inject drugs: A randomized controlled trial.

BACKGROUND: People who inject drugs (PWID) are at risk of hepatitis B virus (HBV) but have low rates of vaccination completion. The provision of modest financial incentives increases vaccination schedule completion, but their association with serological protection has yet to be determined. OBJECTIVE: To investigate factors associated with vaccine-induced immunity among a sample of PWID randomly allocated to receive AUD$30 cash following receipt of doses two and three ('incentive condition') or standard care ('control condition') using an accelerated 3-dose (0,7,21 days) HBV vaccination schedule. STUDY DESIGN: A randomised controlled trial among PWID attending two inner-city health services and a field site in Sydney, Australia, assessing vaccine-induced immunity measured by hepatitis B surface antibodies (HBsAb ≥ 10 mIU/ml) at 12 weeks. The cost of the financial incentives and the provision of the vaccine program are also reported. RESULTS: Just over three-quarters of participants - 107/139 (77%)--completed the vaccination schedule and 79/139 (57%) were HBsAb ≥ 10 mIU/ml at 12 weeks. Vaccine series completion was the only variable significantly associated with vaccine-induced immunity in univariate analysis (62% vs 41%, p<0.035) but was not significant in multivariate analysis. There was no statistically discernible association between group allocation and series completion (62% vs 53%). The mean costs were AUD$150.5, (95% confidence interval [CI]: 142.7-158.3) and AUD$76.9 (95% CI: 72.6-81.3) for the intervention and control groups respectively. CONCLUSION: Despite increasing HBV vaccination completion, provision of financial incentives was not associated with enhanced serological protection. Further research into factors which affect response rates and the optimal vaccination regimen and incentive schemes for this population are needed.

Injecting risk behaviours following treatment for hepatitis C virus infection among people who inject drugs: The Australian Trial in Acute Hepatitis C.

BACKGROUND: A barrier to hepatitis C virus (HCV) treatment among people who inject drugs (PWID) has been a concern that interferon-based HCV treatment may increase injecting risk behaviours. This study evaluated recent (past month) injecting risk behaviours during follow-up among PWID that did and did not receive HCV treatment. METHODS: The Australian Trial in Acute Hepatitis C (ATAHC) was a prospective study of natural history and treatment of recent HCV infection. Analyses were performed using generalized estimating equations. RESULTS: Among 124 participants with a history of injecting drug use (median age 32 years), 69% were male, and 68% were treated for HCV infection. HCV treatment was not associated with an increase in recent injecting drug use (adjusted odds ratio (aOR) 1.06, 95% CI 0.93, 1.21) or recent used needle and syringe borrowing during follow-up (aOR 0.99, 95% CI 0.89, 1.08). HCV treatment was associated with a decrease in recent ancillary injecting equipment sharing during follow-up (aOR 0.85, 95% CI 0.74, 0.99). Further, among treated participants who remained in follow-up (n=24), ancillary injecting equipment sharing significantly decreased from 54% at enrolment to 17% during follow-up (P=0.012). CONCLUSIONS: HCV treatment was not associated with drug use or used needle and syringe borrowing during follow-up, but was associated with decreased ancillary injecting equipment sharing during follow-up. Programs to enhance HCV assessment and treatment among PWID should be expanded, given that HCV treatment does not lead to increases in injecting risk behaviours and has previously been demonstrated to be safe and effective among PWID.

Performance and image enhancing drug injectors' access to needle syringe programs: Responding to a public policy dilemma.

BACKGROUND: The number of people who inject performance and image enhancing drugs (PIEDs) attending Australian needle syringe programs (NSPs) has increased recently with cost and capacity implications for this already stretched public health program. The need to prioritise populations' NSP access poses dilemmas for a program that has always sought to minimise entry barriers. METHODS: To assess their injecting-related risk of HIV and HCV, the Kirketon Road Centre (KRC) surveyed PIEDs injectors attending its two NSPs in inner Sydney in late 2013. Demographic, injecting risk, HIV and HCV testing, and NSP access data were analysed and then compared with similar data collected in the Australian Needle Syringe Program Survey (ANSPS) and the NSW NSP Enhanced Data Collection (NNEDC) survey conducted in the state of NSW in the same time period. RESULTS: PIEDs injectors surveyed (n=103) were predominantly male (99%) and only one reported ever receptive needle syringe sharing any injecting equipment. KRC participants were similar to the other survey populations in having rarely ever injected intravenously (6%); being tested for HIV and HCV in the last year (44% and 32% respectively), and reporting low rates of HCV (0%). But they were much more likely to be gay or bisexual (42% vs 2% and 4% in the NSW surveys, p<0.001). Compared to their heterosexual counterparts at KRC, this subgroup was older (35 vs 31 years, p=0.011), and more likely to: have been injecting for <3 years (70% vs 44%, p=0.025); to have ever been tested for HIV (88% vs 46%, p<0.001); to have been tested for HIV and HCV in the last year (72% vs 24%, p<0.001 and 51% vs 19%, p=0.001 respectively); and to report being HIV positive (9% vs 0%, p<0.001). CONCLUSIONS: PIEDs injectors with no other risk factors were at low risk of HIV and HCV, informing KRC's more targeted approach to their health needs. This included providing PIEDs-focused health information and promoting more frequent BBI testing, while encouraging injecting equipment access through other legal sources. This is a case study of how evidence can help resolve public policy dilemmas at the local level, thereby ensuring that scarce public health resources continue to be directed towards those people who inject drugs most at risk of BBIs.

Surveillance of injecting-related injury and diseases in people who inject drugs attending a targeted primary health care facility in Sydney's Kings Cross.

OBJECTIVE: This study examined the prevalence of injecting-related injuries and diseases (IRIDs) and associated risk factors among people who inject drugs (PWID) attending a primary health care facility in Sydney's Kings Cross. METHODS: We calculated prevalence of a wide range of IRIDs utilising data reported by 702 PWID who completed a clinician-administered survey at their first visit. Multivariable logistic regressions identified factors independently associated with at least one episode of: i) cutaneous and ii) non-cutaneous IRIDs. RESULTS: Lifetime prevalence of cutaneous IRIDs was 23%. Forty-two per cent of PWID with a history of abscess attended hospital at their most recent episode. Female gender, lifetime receptive syringe sharing (RSS), injecting while in custody, and ever injecting in places other than the arm were independently associated with reporting at least one episode of cutaneous IRIDs. Ever injecting in sites other than the arm, injecting for five or more years and lifetime history of RSS were independently associated with at least one episode of non-cutaneous IRIDs. CONCLUSIONS: IRIDs are a substantial health issue for PWID. Their ongoing surveillance is warranted particularly in primary care settings targeting PWID to inform prevention and early management, thus reducing complications that may require hospital admission.

A randomised controlled trial of financial incentives to increase hepatitis B vaccination completion among people who inject drugs in Australia.

OBJECTIVE: This study aimed to investigate the efficacy of modest financial incentives in increasing completion of an accelerated 3-dose hepatitis B virus (HBV) vaccination schedule (0, 7, 21days) among people who inject drugs (PWID). METHODS: Randomised controlled trial. Participants were randomly allocated to receive $30 Australian Dollars cash following receipt of vaccine doses two and three ('incentive condition'), or standard care ('control condition'). Serologically confirmed HBV-susceptible PWID. Two inner-city health services and a field study site in Sydney, Australia. The primary outcome was completion of the vaccination series. Additional assessments included self-reported demographic, drug use and treatment, and risk-taking histories. RESULTS: Compared to the control condition, significantly more participants in the incentive condition received all three vaccine doses, under intention-to-treat analyses (n=139; 87% versus 66%; p=.004); and within the specified window periods under per protocol analyses (n=107 received three vaccine doses; 92% versus 67%; p=.001). Multivariate analysis indicated that the incentive condition and longer injecting histories significantly increased the likelihood of series completion. Aboriginal/Torres Strait Islanders were significantly less likely to complete the series. CONCLUSIONS: Modest financial incentives, per-dose, increased adherence to the accelerated HBV vaccination schedule among PWID. Results have implications for increasing HBV and, potentially, other vaccine-preventable infections, among PWID.

Correlates of susceptibility to hepatitis B among people who inject drugs in Sydney, Australia.

Despite a safe, effective vaccine, hepatitis B virus (HBV) vaccination coverage remains low among people who inject drugs (PWID). Characteristics of participants screened for a trial investigating the efficacy of financial incentives in increasing vaccination completion among PWID were examined to inform targeting of vaccination programs. Recruitment occurred at two health services in inner-city Sydney that target PWID. HBV status was confirmed via serological testing, and questionnaires elicited demographic, drug use, and HBV risk data. Multinomial logistic regression was utilized to determine variables independently associated with HBV status. Of 172 participants, 64% were susceptible, 17% exposed (HBV core antibody-positive), and 19% demonstrated evidence of prior vaccination (HBV surface antibody ≥ 10 mIU/ml). Compared with exposed participants, susceptible participants were significantly more likely to be aged less than 35 years and significantly less likely to be receiving current opioid substitution therapy (OST) and to test hepatitis C antibody-positive. In comparison to vaccinated participants, susceptible participants were significantly more likely to be male and significantly less likely to report daily or more frequent injecting, current OST, and prior awareness of HBV vaccine. HBV vaccination uptake could potentially be increased by targeting younger, less frequent injectors, particularly young men. In addition to expanding vaccination through OST, targeting "at risk" youth who are likely to have missed adolescent catch-up programs may be an important strategy to increase coverage. The lack of an association between incarceration and vaccination also suggests increasing vaccination uptake and completion in adult and juvenile correctional facilities may also be important.

The reliability of sensitive information provided by injecting drug users in a clinical setting: clinician-administered versus audio computer-assisted self-interviewing (ACASI).

Research with injecting drug users (IDUs) suggests greater willingness to report sensitive and stigmatised behaviour via audio computer-assisted self-interviewing (ACASI) methods than during face-to-face interviews (FFIs); however, previous studies were limited in verifying this within the same individuals at the same time point. This study examines the relative willingness of IDUs to report sensitive information via ACASI and during a face-to-face clinical assessment administered in health services for IDUs. During recruitment for a randomised controlled trial undertaken at two IDU-targeted health services, assessments were undertaken as per clinical protocols, followed by referral of eligible clients to the trial, in which baseline self-report data were collected via ACASI. Five questions about sensitive injecting and sexual risk behaviours were administered to participants during both clinical interviews and baseline research data collection. "Percentage agreement" determined the magnitude of concordance/discordance in responses across interview methods, while tests appropriate to data format assessed the statistical significance of this variation. Results for all five variables suggest that, relative to ACASI, FFI elicited responses that may be perceived as more socially desirable. Discordance was statistically significant for four of the five variables examined. Participants who reported a history of sex work were more likely to provide discordant responses to at least one socially sensitive item. In health services for IDUs, information collection via ACASI may elicit more reliable and valid responses than FFI. Adoption of a universal precautionary approach to complement individually tailored assessment of and advice regarding health risk behaviours for IDUs may address this issue.

Effect of pegylated interferon-α-2a treatment on mental health during recent hepatitis C virus infection.

BACKGROUND AND AIM: Pegylated interferon (PEG-IFN) treatment for hepatitis C virus (HCV) infection has neuropsychiatric side effects. Data on the effect of HCV treatment on mental health among injecting drug users (IDUs) are limited. We assessed mental health during treatment of recently acquired HCV, within a predominantly IDU population. METHODS: Participants with HCV received PEG-IFN-α-2a (180 µg/week) for 24 weeks; HCV/HIV received PEG-IFN with ribavirin. Depression was assessed using the Mini-International Neuropsychiatric Interview (MINI). Logistic regression was used to identify factors associated with depression at enrolment and during treatment. Also, the effect of depression prior to and during treatment on sustained virological response (SVR) was assessed. RESULTS: Of 163 participants, 111 received treatment (HCV, n = 74; HCV/HIV, n = 37), with 76% ever reporting IDU. At enrolment, 16% had depression (n = 25). In adjusted analysis, depression at enrolment occurred less often in participants full-/part-time employed (adjusted odds ratio [AOR] 0.23; 95% confidence interval [CI]: 0.06, 0.82, P = 0.023) and more often in recent IDUs (AOR 3.04; 95% CI: 1.19, 7.72, P = 0.019). During treatment, 35% (n = 31) developed new-onset depression. In adjusted analysis, poorer social functioning (higher score) was associated with new-onset depression (score ≤ 9 vs score ≥ 17; OR 5.69; 95% CI: 1.61, 20.14, P = 0.007). SVR was similar among participants with and without depression at enrolment (60% vs 61%, P = 0.951) and in those with and without new-onset depression (74% vs 63%, P = 0.293). CONCLUSIONS: Although depression at enrolment and during treatment was common among participants with recent HCV, neither influenced SVR. Participants with poor social functioning may be most at risk of developing depression during HCV therapy.