Evaluation of heroin-assisted treatment in Norway: protocol for a mixed methods study.

BACKGROUND: Opioid agonist treatment (OAT) for patients with opioid use disorder (OUD) has a convincing evidence base, although variable retention rates suggest that it may not be beneficial for all. One of the options to include more patients is the introduction of heroin-assisted treatment (HAT), which involves the prescribing of pharmaceutical heroin in a clinical supervised setting. Clinical trials suggest that HAT positively affects illicit drug use, criminal behavior, quality of life, and health. The results are less clear for longer-term outcomes such as mortality, level of function and social integration. This protocol describes a longitudinal evaluation of the introduction of HAT into the OAT services in Norway over a 5-year period. The main aim of the project is to study the individual, organizational and societal effects of implementing HAT in the specialized healthcare services for OUD. METHODS: The project adopts a multidisciplinary approach, where the primary cohort for analysis will consist of approximately 250 patients in Norway, observed during the period of 2022-2026. Cohorts for comparative analysis will include all HAT-patients in Denmark from 2010 to 2022 (N = 500) and all Norwegian patients in conventional OAT (N = 8300). Data comes from individual in-depth and semi-structured interviews, self-report questionnaires, clinical records, and national registries, collected at several time points throughout patients' courses of treatment. Qualitative analyses will use a flexible inductive thematic approach. Quantitative analyses will employ a wide array of methods including bi-variate parametric and non-parametric tests, and various forms of multivariate modeling. DISCUSSION: The project's primary strength lies in its comprehensive and longitudinal approach. It has the potential to reveal new insights on whether pharmaceutical heroin should be an integral part of integrated conventional OAT services to individually tailor treatments for patients with OUD. This could affect considerations about drug treatment even beyond HAT-specific topics, where an expanded understanding of why some do not succeed with conventional OAT will strengthen the knowledge base for drug treatment in general. Results will be disseminated to the scientific community, clinicians, and policy makers. TRIAL REGISTRATION: The study was approved by the Norwegian Regional Committee for Medical and Health Research Ethics (REK), ref.nr.:195733.

Mortality risk and causes of death among people who use opioids in a take-home naloxone cohort.

BACKGROUND: People who use opioids (PWUO) have an excess mortality from a range of causes. The cumulative effect of behavioral, social, and health risk factors complicates the interpretation of the effects of suitable interventions. This study explores mortality causes among a cohort of PWUO in the take-home naloxone (THN) program. METHODS: This was a prospective cohort study of PWUO who received THN between 2015 and 2023. Participant data was linked with death registry data. Crude mortality rates and standardized mortality ratios (SMRs) were calculated for all causes, internal causes, and accidental opioid overdoses (AOOs). In addition to age and gender, risk factors like main route of administration, polydrug use, self-experienced overdoses, and using while alone were fitted in a Cox Regression model to explore factors associated with mortality. RESULTS: The 2194 participants had a considerably higher mortality ratio for all causes investigated when compared to the general population (SMR=10.9, 95 % CI = 9.3,12.6). AOOs were the most prevalent cause of death (49 %). Those who reported frequent opioid use while alone had an elevated risk of dying of 2.6 (95 % CI = 1.1,6.4) compared to those who never used while alone. CONCLUSIONS: Frequent opioid use while alone was associated with elevated mortality risk, supporting the importance of overdose prevention education with naloxone distribution, and additional efforts to improve environmental and social areas for safer drug-use practices among PWUO. The variety of mortality causes found in this study illustrates the need for multifaceted and targeted interventions for people at risk of overdosing.

Who receives heroin-assisted treatment? A comparison of patients receiving opioid maintenance treatment in Denmark.

BACKGROUND: Since 2010, heroin-assisted treatment (HAT) has been one of the treatment options available to people with opioid use disorder (OUD) in Denmark. This study aimed to characterize HAT patients at treatment start and compare their individual characteristics to those of patients entering traditional opioid maintenance treatment (OMT) with methadone or buprenorphine during the same period. METHODS: Patients who initiated HAT or OMT with methadone or buprenorphine in Denmark from 2010 to 2018 were included (n=6798). Multiple national registers were linked to compare treatment groups in terms of socio-demographic variables, previous OUD treatment episodes, hospital-based care, and criminal conviction history. RESULTS: Nearly all HAT patients had a history of methadone treatment (91%) and half had residential treatment experience (48%). In the year previous to admission, HAT patients recorded the highest percentages of non-fatal overdoses (12%) and chronic hepatitis C diagnoses (16%), and the lowest percentages of psychiatric disorders (11%) compared to traditional OMT patients. Criminal convictions were also common: 39% of the HAT group had committed a property crime and 18% a drug-related crime the year before HAT entry. During the study period, an overall reduction in OMT enrollments for each year was recorded. The HAT proportion to the total remained fairly stable (4%-10%), while the buprenorphine proportion increased. CONCLUSIONS: In Denmark, OMT patients exhibited numerous vulnerabilities at treatment start, and among the patient groups, HAT patients were the most burdened. HAT seems to reach the target group and adhere to formulated eligibility criteria.

Prescription high-risk polysubstance use among opioid maintenance treatment patients.

BACKGROUND: Among individuals receiving buprenorphine or methadone as opioid maintenance treatment (OMT), concomitant use of other central nervous system depressants, including prescription drugs, can increase risk of overdose. We aimed to 1) determine the prevalence of use of high-risk prescription drugs (opioid analgesics, benzodiazepines, benzodiazepine-related drugs, and gabapentinoids) among OMT patients, 2) calculate its associations with different mental health and pain-related diagnoses, and 3) compare prevalence of concomitant use with the general population. METHODS: A national sample comprising all individuals filling at least one prescription of OMT drugs in Norway in 2019 was formed. Healthcare registry data were linked to investigate high-risk prescription drug use and different diagnoses. We calculated one-year prevalence of use, amount dispensed in defined daily doses (DDDs), and the number of prescribers for the different high-risk prescription drugs. Logistic regression was used to determine associations (adjusted odds ratios; aOR, 95% confidence intervals (CIs)) between diagnoses and use. Prevalence of use was calculated both in the OMT patient sample and the general population. RESULTS: Among the OMT patient sample (n=7,299), 47.6% (n=3,476) filled prescriptions for benzodiazepines. For each high-risk prescription drug group, there was a median of 1-2 prescribers. Musculoskeletal diagnoses were the strongest factor for concomitant high-risk prescription drug use for both males (aOR 3.23, CI: 2.72-3.85) and females (aOR 3.07, CI: 2.42- 3.90). The 1-year prevalence of benzodiazepine use was 11.4 times higher for males and 7.1 times higher for females in OMT than the general population. The amount in DDDs was higher for every drug for OMT patients than the general population, particularly for benzodiazepines. CONCLUSIONS: OMT patients frequently filled prescriptions for high-risk drugs, and in higher dosages than the general population. However, we found little evidence of 'doctor shopping.' Given that these prescription drugs carry overdose risk, particularly when combined with OMT drugs, our findings emphasize the continued need for education and caution to both prescribers and patients on their concomitant use with OMT.

A study protocol for a European, mixed methods, prospective, cohort study of the effectiveness of naloxone administration by community members, in reversing opioid overdose: NalPORS.

BACKGROUND: Worldwide, opioid use causes more than 100,000 overdose deaths annually. Naloxone has proven efficacy in reversing opioid overdoses and is approved as an emergency antidote to opioid overdose. Take home naloxone (THN) programmes have been introduced to provide 'community members', who are likely to observe opioid overdoses, with naloxone kits and train them to recognise an overdose and administer naloxone. The acceptability and feasibility of THN programmes has been demonstrated, but the real-life effectiveness of naloxone administration by community members is not known. In recent years, the approval of several concentrated naloxone nasal-spray formulations (in addition to injectable formulations, eg.prenoxad) potentially increases acceptability and scope for wider provision. This study aims to determine the effectiveness of THN (all formulations) in real-world conditions. METHODS: A European, multi-country, prospective cohort study, to assess the use of THN by community members to reverse opioid overdoses in a six-month, follow-up period. Participants provided with THN from participating harm reduction and drug treatment sites will be recruited to the study and followed-up for six months. We are particularly interested in the experiences of community members who have been provided with THN and have witnessed an opioid overdose. All participants who witness an opioid overdose during the six-month period (target approx. 600) will be asked to take part in a structured interview about this event. Of these, 60 will be invited to participate in a qualitative interview. A Post Authorisation Efficacy Study (PAES) for the concentrated nasal naloxone, Nyxoid, has been integrated into the study design. DISCUSSION: There are many challenges involved in evaluating the real-life effectiveness of THN. It is not possible to use a randomised trial design, recruitment of community members provided with THN will depend upon recruitment sites distributing THN kits, and the type of THN received by participants will depend on regulations and on local clinical and policy decision-makers. Following up this population, some of whom may be itinerant, over the 6-month study period will be challenging, but we plan to maintain contact with participants through regular text message reminders and staff contact. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05072249. Date of Registration: 8.10.2021.

Gender differences in physical morbidity in opioid agonist treatment patients: population-based cohort studies from the Czech Republic and Norway.

BACKGROUND: Physical diseases represent a significant burden for opioid agonist treatment (OAT) patients. This study described physical morbidity in two national cohorts of OAT patients focusing on gender differences. METHODS: This population-based cohort study linking multiple health registers investigated physical diseases (ICD-10) in patients receiving OAT in the Czech Republic (N = 4,280) and Norway (N = 11,389) during 2010-2019. Gender-stratified analysis was performed. RESULTS: Overall, we found a large burden of physical morbidity across gender groups in OAT patients. In the Czech Republic and Norway, women in OAT had a significantly higher prevalence of physical diseases across most diagnostic chapters, notably genitourinary diseases and neoplasms. Injuries/external causes and infectious/parasitic diseases were among the most common diseases in both women and men. Viral hepatitis accounted for over half of infectious morbidity in women and men in both cohorts. CONCLUSIONS: Our findings support the need for early screening, detection, and treatment of diseases and conditions across organ systems and the integration of health promotion activities to reduce physical morbidity in OAT patients. The gender differences underline the need for a tailored approach to address specific medical conditions.

Cause-Specific Mortality among Patients in Treatment for Opioid Use Disorder in Multiple Settings: A Prospective Comparative Cohort Study.

INTRODUCTION: Among people receiving current or previous opioid maintenance treatment (OMT), the leading cause of premature death is an opioid overdose. However, other causes of mortality remain high in this group. An understanding of causes of deaths across multiple settings can be useful in informing more comprehensive prevention responses. The aim of this study was to describe all non-overdose causes of death in three national cohorts (Czechia, Denmark, and Norway) among OMT patients and to explore associations of non-overdose mortality with age and gender. METHODS: This prospective comparative cohort study used national mortality registry databases for OMT patients from Czechia (2000-2019), Denmark (2000-2018), and Norway (2010-2019). Crude mortality rates and age-standardized mortality rates (ASMRs) were calculated as deaths per 1,000 person years for cause-specific mortality. RESULTS: In total, 29,486 patients were included, with 5,322 deaths recorded (18%). We found variations in causes of death among the cohorts and within gender and age groups. The leading non-overdose causes of death were accidents in Czechia and Denmark, and neoplasms in Norway. Cardiovascular deaths were highest in Czechia, particularly for women in OMT (ASMR 3.59 vs. 1.24 in Norway and 1.87 in Denmark). CONCLUSION: This study found high rates of preventable death among both genders and all age groups. Different demographic structures, variations in risk exposure, as well as variations in coding practices can explain the differences. The findings support increased efforts towards screening and preventative health initiatives among OMT patients specific to the demographic characteristics in different settings.

Pills and the damage done: the opioid epidemic as man-made crisis.

The prescription opioid epidemic has slowly evolved over the past quarter century with increasingly detrimental consequences for public health. Man-made crises are often unforeseen and characterized by a situation without natural causes where - because of human intent, error, negligence, or the failure of manmade systems - the level of needs in the population exceeds available resources to counter the problem. This paper presents the prescription opioid epidemic as a man-made crisis and explores the public health impact of opioid manufacturers and other industries producing commodities with addictive potential as a shared vulnerability among countries. We examine this concept within the framework of the commercial determinants of health. We address three key aspects of the commercial determinants of health: (1) Cross-industry mechanisms, (2) policy inertia, and (3) the role of industry in science. Within cross-industry mechanisms, we explore parallels between prescription opioid epidemic and unhealthy commodity industries in terms of marketing, corporate use of misinformation, and diversionary tactics. Next, we examine how policy inertia has dominated the slow response to this man-made crisis. Lastly, we discuss how results from clinical trials are used as a key marketing strategy for drugs. The origins of the prescription opioid epidemic may be traced to innovations in drug development with the promise of improved pain management. However, through multiple factors, including fraudulent marketing from pharmaceutical industry and policy inertia, the resulting crisis represents a multi-system failure of regulation exploited by corporate greed.

Risks and overdose responses: Participant characteristics from the first seven years of a national take-home naloxone program.

BACKGROUND: In 2014, the Norwegian government funded a large-scale take-home naloxone (THN) program to address high overdose mortality rates. The aims of this study are to describe characteristics among persons trained to receive THN, describe actions taken following THN use at an overdose event and to explore factors associated with naloxone use. METHODS: This was a prospective cohort study of individuals who received THN from 2014 to 2021. Descriptive characteristics were collected at initial training. When returning for refill, participants reported on their previous naloxone use. In a multivariable logistic regression model exploring associations with naloxone use: gender, age, opioid use history, concomitant drug use, injecting, history of experienced or witnessed overdose were included. RESULTS: In total, 3527 individuals were included in this study. There were 958 individuals who returned for refills 2303 times. Most participants were male (63.6%), with a history of opioid use (77.5%). Those who reported naloxone use were more likely to have a history of opioid use (aOR= 4.1; 95% CI=2.77,6.1), were younger (aOR=0.98; 95% CI=0.97,0.99) and had witnessed overdoses (aOR=3.3; 95% CI=1.98,5.34). Among current opioid users, the odds were higher for injectors (aOR=1.57; 95% CI=1.18,2.1). Naloxone use was reported 1282 times. Additional actions such as waking the person and calling the ambulance were frequently reported. Survival was reported in almost all cases (94%). CONCLUSION: People who use drugs are a suitable target group for THN-programs, as they seem to be willing and capable to reverse overdoses effectively. Given their personal risk factors for overdosing, recipients will likely also benefit from overdose prevention education.

A rapid assessment of take-home naloxone provision during COVID-19 in Europe.

BACKGROUND: In March 2020, the World Health Organization declared COVID-19 a global pandemic. In the following weeks, most European countries implemented national lockdowns to mitigate viral spread. Services for people who use drugs had to quickly revise their operating procedures to rearrange service provision while adhering to lockdown requirements. Given the scarcity of literature published on overdose prevention during COVID-19 in Europe, we aimed to examine how these changes to service provision affected take-home naloxone (THN) programmes and naloxone availability across Europe. METHODS: Between November 2020 and January 2021, we conducted a rapid assessment with country experts from European countries that provide THN. We sent country experts a template to report monthly THN distribution data (January 1, 2019-October 31, 2020) and a structured 6-item survey for completion. RESULTS: Responses were received from 14 of the 15 European countries with THN provision of which 11 participated in the rapid assessment: Austria, Denmark, England, Estonia, Lithuania, Northern Ireland, Norway, Scotland, Spain (Catalonia only), Sweden, and Wales. All reported reduced organisational capacity during COVID-19, and some put into place a range of novel approaches to manage the restrictions on face-to-face service provision. In six countries, the introduction of programme innovation occurred alongside the publication of government guidelines recommending increased THN provision during COVID-19. Eight of the eleven participating countries managed to maintain 2019-level monthly THN distribution rates or even increase provision during the pandemic. CONCLUSION: Through programme innovation supported by public guidelines, many European THN programmes managed to ensure stable or even increased THN provision during the pandemic, despite social distancing and stay-at-home orders affecting client mobility.

Who is using take-home naloxone? An examination of supersavers.

BACKGROUND: As the opioid overdose crisis persists and take-home naloxone (THN) programmes expand, it is important that the intervention is targeted towards those most likely to use it. We examined THN program participants to 1) describe those that return for refills, specifically those that reported multiple use (supersavers), and 2) to examine what rescuer characteristics were associated with higher rates of THN use. METHODS: This study included a cohort of consenting THN recipients from June 2014-June 2021 who completed initial and refill questionnaires from a widespread program in Norway. Age, gender, number of witnessed and experienced overdoses were assessed for associations with higher reported rates of THN use. 'Supersavers' reported 3 or more THN uses. RESULTS: A total of 1054 participants returned for a THN refill during the study period. Of these, 558 reported their last THN to have been used on an overdose. Supersavers (those that reported 3 or more THN uses) were younger, primarily reported current opioid use, and had witnessed higher rates of overdoses at the time of initial training when compared to non-supersavers (those that reported 0-2 THN uses). CONCLUSIONS: THN programs should continue to emphasize and prioritize THN for people actively using drugs, particularly those who have witnessed overdoses previously.

Staff preferences towards electronic data collection from a national take-home naloxone program: a cross-sectional study.

BACKGROUND: During the scaling-up of a national Norwegian take-home naloxone (THN) program, data collection methods shifted from paper-based to electronic. The aim of this study was to explore staff preferences towards the shift in data collection. METHODS: In January-February 2020, a survey was sent out via email to personnel involved with the THN program (n = 200). The survey included 17 questions, and covered staff demographics, experiences distributing THN, preferences towards data collection (both paper and electronically), and an open response section. Descriptive statistics were performed for the survey results. The open response section was recorded from each questionnaire and was coded into major themes by the authors. RESULTS: In total, 122 staff completed the survey. Of these, 62% had experience with both electronic and paper-based forms, and there was a near unanimous preference towards electronic data collection over paper-based forms. From the free-text responses, staff found the electronic form to be a useful tool for conversation and overdose prevention education, and that the electronic form was easier to manage than the paper forms. CONCLUSION: The shift towards electronic data collection was necessary for the feasibility of the Norwegian national THN program. This study found that staff not only tolerated the shift, but in most cases preferred this organizational change.

Rethinking 'carriage' of take-home naloxone.

Take-home naloxone (THN) provision to people who use drugs, their family/friends, and non-medical personnel is considered a public health strategy to improve community-based naloxone access and reduce the time to antidote treatment for opioid overdose in order to prevent fatal outcome. THN programs typically report up to three performance indicators: the volume of THN kits distributed, the rate of requests for re-supply of THN kits (e.g., following naloxone use for overdose reversal), and - increasingly - THN "carriage". In this Research Methods piece, we discuss the current shortcomings in the latter measurement of THN carriage from a mixed-methods perspective and describe possible implications for public health related research and improved data analyses. We present an argument for the need to improve research methods in the case of THN "carriage" and propose a multidimensional measurement structure that takes into account: 1) the location of the THN kit relative to its owner, 2) the owner's immediate access to the kit in an emergency, 3) the type of THN device, and 4) the purpose of THN ownership (i.e., for use in self or known/unknown other/s).