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Importance: Approximately 85% of individuals receiving opioid agonist therapy for opioid dependence smoke tobacco. Despite the significant health risks associated with smoking-related diseases, there has been limited evaluation of smoking interventions tailored to this population., Objective: To determine the effectiveness of an intervention combining nicotine replacement with brief behavioral support in reducing cigarette use., Design, Setting, and Participants: This multicenter randomized clinical trial was conducted from April 2022 to October 2023 in 7 specialized opioid agonist therapy clinics in Bergen and Stavanger, Norway. The analyst was blinded to patient groupings. Assessors (study nurses) were not fully blinded to participant allocation. Individuals diagnosed with opioid dependency receiving opioid agonist therapy at participating clinics and smoking at least 1 cigarette per day were eligible for participation. Data analysis was performed from December 2023 through October 2024., Intervention: In addition to standard opioid agonist therapy, participants in the intervention group received a 16-week integrated treatment combining nicotine replacement with brief behavioral support. Participants in the control group received only standard opioid agonist therapy., Main Outcomes and Measures: The primary outcome was at least a 50% reduction in the number of cigarettes smoked, self-reported as cigarette use in the past 7 days at week 16. The analysis followed intention-to-treat principles. Cigarette use was self-reported as per the timeline-follow-back method., Results: Among the 259 participants (mean [SD] age, 48.5 [10.4] years; 80 [30.9%] female), 135 were allocated to the intervention group and 124 to the control group. The odds ratio of at least halving the number of cigarettes smoked was 2.07 (95% CI, 1.14-3.75) in the intervention group compared with the control group., Conclusions and Relevance: Providing integrated nicotine replacement and behavioral support at opioid agonist treatment clinics effectively helped opioid-dependent participants reduce the number of cigarettes smoked., Trial Registration: ClinicalTrials.gov Identifier: NCT05290025.

Background: Persons with opioid use disorders (OUD) and persons with substance use disorders (SUD) who inject substances have a reduced life expectancy of up to 25 years compared with the general population. Chronic liver diseases are a substantial cause of this. Screening strategies based on liver stiffness measurements (LSM) may facilitate early detection, timely intervention, and treatment of liver disease. This study aims to investigate the extent of chronic liver disease measured with transient elastography and the association between LSM and various risk factors, including substance use patterns, hepatitis C virus (HCV) infection, alcohol use, body mass index, age, type 2 diabetes mellitus, and high-density lipoprotein (HDL) cholesterol among people with OUD or with SUD who inject substances., Methods: Data was collected from May 2017 to March 2022 in a cohort of 676 persons from Western Norway. The cohort was recruited from two populations: Persons receiving opioid agonist therapy (OAT) (81% of the sample) or persons with SUD injecting substances but not receiving OAT. All participants were assessed at least once with transient elastography. A linear mixed model was performed to assess the impact of risk factors such as HCV infection, alcohol use, lifestyle-associated factors, and substance use on liver stiffness at baseline and over time. Baseline was defined as the time of the first liver stiffness measurement. The results are presented as coefficients (in kilopascal (kPa)) with 95% confidence intervals (CI)., Results: At baseline, 12% (n = 83) of the study sample had LSM suggestive of advanced chronic liver disease (LSM ≥ 10 kPa). Advanced age (1.0 kPa per 10 years increments, 95% CI: 0.68;1.3), at least weekly alcohol use (1.3, 0.47;2.1), HCV infection (1.2, 0.55;1.9), low HDL cholesterol level (1.4, 0.64;2.2), and higher body mass index (0.25 per increasing unit, 0.17;0.32) were all significantly associated with higher LSM at baseline. Compared with persistent chronic HCV infection, a resolved HCV infection predicted a yearly reduction of LSM (-0.73, -1.3;-0.21) from baseline to the following liver stiffness measurement., Conclusions: More than one-tenth of the participants in this study had LSM suggestive of advanced chronic liver disease. It underscores the need for addressing HCV infection and reducing lifestyle-related liver risk factors, such as metabolic health factors and alcohol consumption, to prevent the advancement of liver fibrosis or cirrhosis in this particular population., (© 2024. The Author(s).)

Background: A considerable inter-individual variability has been reported in the relationship between methadone doses applied and serum concentrations achieved in methadone maintenance treatment. However, the underlying causes for this variability are not fully understood., Objectives: We investigated the influence of genetic, pathophysiological and pharmacological factors on serum methadone concentration-to-dose ratio (CDR) and discussed the clinical implications of the findings., Methods: We used data from two retrospective laboratory databases and a prospective cohort study to investigate the impact on methadone CDR of hepatic cytochrome P450 enzyme system (CYP) genetic polymorphisms, age, sex, concomitant medication, liver fibrosis and body mass index through linear mixed model analyses., Findings: A positive association was found between CDR and the homozygous CYP2B6*6 genotype, concurrent treatment with CYP3A4 inhibitors and body mass index. CDR was lower among women and during concomitant use of CYP inducers. CDR was not associated with age or the degree of liver fibrosis in our investigations., Conclusions: This research work supports the need for individually tailored dosage considering the various factors that influence methadone CDR. The gained knowledge can contribute to reducing the risks associated with the treatment and optimizing the desired outcomes., (© 2023 The Authors. Basic & Clinical Pharmacology & Toxicology published by John Wiley & Sons Ltd on behalf of Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: Substance use disorder is associated with unhealthy lifestyle choices, resulting in adverse social and health consequences. People with opioid use disorder receiving opioid agonist therapy, in particular, have high morbidity and reduced quality of life. Physical activity is recommended as an adjunctive treatment for people with substance use disorder, but there is minimal evidence from randomized controlled trials on the effects of this among people with substance use disorder receiving opioid agonist therapy., Methods: BAReAktiv is a multicentre randomized controlled trial. The study aims to recruit 324 patients receiving opioid agonist therapy (parallel groups randomized 1:1 to integrated exercise intervention or control, superiority trial). A 16-week group-based integrated exercise intervention with workouts twice a week. The exercise program consists of endurance and resistance training. The target group will be patients 18 years and older receiving opioid agonist therapy in outpatient clinics in several centers in Western Norway. The primary outcome of the study is the effect on psychological distress measured by Hopkins' symptom checklist with ten items. Secondary outcome measures include physical functioning assessed with a 4-min step test, activity level, fatigue symptoms, quality of life, and changes in inflammation markers. This study will provide improved knowledge on the effects of an integrated exercise program in opioid agonist therapy., Discussion: Systematically integrating exercise programs for people receiving opioid agonist therapy could lead to a shift towards a stronger focus on health behaviors in outpatient care. Integrating exercise could benefit patient recovery and reduce disease burden. Further scale-up will be considered if the provided exercise program is safe and effective., Trial Registration: ClinicalTrials.gov. NCT05242848. Registered on February 16, 2022., (© 2024. The Author(s).)

Background: The COVID-19 pandemic and other life events may trigger worries and psychological distress. These impacts may lead to unhealthy behaviors, such as tobacco smoking, but the degree of such associations is unclear. The current three-wave longitudinal study examines changes in tobacco smoking in Norway between 2020 and 2022 and their associations with psychological distress as well as health- and economy-related worries., Methods: Data were collected in April 2020 (baseline), January 2021, and January 2022 in Bergen, Norway, from an online longitudinal population-based survey. Smoking tobacco (the outcome variable) was dichotomized based on the responses to the question of whether participants smoked cigarettes or not. Tobacco smoking and its associations with psychological distress were assessed among 24,914 participants (response rate 36%) in a mixed model regression presented with coefficients and 95% confidence intervals (CI), adjusting for COVID-19-related worries, home office/study, occupational situation, age, gender, education, having children below 18 years living at home, living alone, and alcohol consumption., Results: A total of 10% of the study sample were current smokers at baseline. At baseline, smoking tobacco was associated with high levels of psychological distress (absolute difference 13%, 95% CI 10%; 15%), advanced age (50-59 years: 11%, CI 10%; 13%), and hazardous alcohol use (4%, CI 3%; 5%) compared to their counterparts. Higher education (-5%, CI -6%; -4%), working from home (-4%, CI -5%; -4%), and higher physical activity levels (-4%, CI -5%; -3%) were associated with non-smoking. The prevalence of smoking among individuals experiencing severe psychological distress decreased slightly over time (-2% per year, CI -3%; -1%)., Conclusions: Smoking was associated with severe psychological distress, advanced age, and hazardous alcohol use at baseline; non-smoking was associated with high education, working from home, and high physical activity. Nevertheless, the smoking rate among individuals experiencing severe psychological distress slightly decreased over the course of the COVID-19 pandemic., (© 2024. The Author(s).)

Aims: This study evaluates long-term changes in physical activity and its associations with various predictors after a behavior change program at the Norwegian Healthy Life Centers., Background: Physical activity is recommended and is part of public health strategies to prevent noncommunicable diseases., Methods: This longitudinal cohort, based on a controlled randomized trial, studies a population of 116 Healthy Life Center participants in South-Western Norway who wore SenseWear Armbands to measure time spent in moderate to vigorous physical activity and sedentary time based on metabolic equivalents. The measurements were obtained at baseline, immediately post-intervention, and 24 months after baseline. Linear mixed model analyses were performed to assess predictors for change in physical activity and sedentary time., Findings: High physical activity levels at baseline were maintained during the 24-month study period. Young, male participants with good self-rated health, utilizing local PA facilities were most active, and young participants utilizing local facilities were also less sedentary. The participants with higher levels of education were less active initially but caught up with the difference during follow-up. A high degree of controlled regulation, characterized by bad conscience and external pressure, predicted more sedentary behavior and a trend toward being less physically active. Autonomous motivation was associated with less time spent on sedentary behaviors. People with high self-efficacy for physical activity were more sedentary initially but showed a reduction in their sedentary behavior.The study supports the importance of attending local training facilities and adopting motivation for behavioral change that is not based on guilt and external rewards. Interventions aimed at improving physical activity among people at risk for noncommunicable diseases benefit from habitual use of local training facilities, strengthening their self-perceived health and the development of internalized motivation. However, it has not been shown to mitigate social health disparities.

People with substance use disorders (SUD) have a high prevalence of chronic hepatitis C virus (HCV) infection and mental health disorders. We aimed to assess the impact of integrated HCV treatment on psychological distress measured by Hopkins-symptom-checklist-10 (SCL-10). This multi-center randomized controlled trial evaluated psychological distress as a secondary outcome of integrated HCV treatment (INTRO-HCV trial). From 2017 to 2019, 289 participants were randomly assigned to receive either integrated or standard HCV treatment with direct-acting antiviral therapy. Integrated HCV treatment was delivered in eight decentralized outpatient opioid agonist therapy clinics and two community care centers; standard treatment was delivered in internal medicine outpatient clinics at centralized hospitals. Participants in the integrated treatment arm had a sustained virologic response of 93% compared to 73% for those in standard treatment arm. Psychological distress was assessed using SCL-10 prior to initiation of HCV treatment and 12 weeks after treatment completion. The mean SCL-10 score prior to HCV treatment was 2.2 (standard deviation [SD]: 0.7) for patients receiving integrated HCV treatment and 2.2 (SD: 0.8) for those receiving standard HCV treatment. Twelve weeks after the end of treatment, the mean SCL-10 score change was - 0.1 (- 0.3;0.0) in the integrated compared to the standard arm. Psychological distress did not substantially change during the treatment period and was not significantly different between the treatment arms., (© 2024. The Author(s).)

This protocol paper presents an updated statistical analysis plan of the protocol of a randomised controlled trial. The randomised controlled trial investigates the effect of integrating smoking cessation interventions at outpatient opioid agonist therapy (OAT) clinics for persons with opioid dependency receiving OAT medication. The intervention group receives weekly follow-up including a short behavioural intervention and provision of nicotine replacement products. The control group receives standard treatment. The duration of the intervention is 16 weeks and the follow-up was completed by the end of October 2023. The primary outcome is defined as the proportion of participants reducing the number of cigarettes smoked by at least a 50% at week 16 of the intervention period. The primary outcome will be analysed according to intention-to-treat principles. Missing outcome data will be set equal to the baseline values. Development and reporting of the statistical analysis plan follow the Guidelines for the Content of Statistical Analysis Plans in Clinical Trials.Trial registration ClinicalTrials.gov NCT05290025. Registered on 22 March 2022., (© 2024. The Author(s).)

Background and Aims: The INTRO-HCV randomized controlled trial conducted in Norway over 2017-2019 found that integrated treatment, compared with standard-of-care hospital treatment, for hepatitis C virus (HCV) with direct-acting antivirals (DAAs) improved treatment outcomes among people who inject drugs (PWID). We evaluated cost-effectiveness of the INTRO-HCV intervention., Design: A Markov health state transition model of HCV disease progression and treatment with cost-effectiveness analysis from the health-provider perspective. Primary cost, utility, and health outcome data were derived from the trial. Costs and health benefits (quality-adjusted life-years, QALYs) were tracked over 50 years. Probabilistic and univariate sensitivity analyses investigated DAA price reductions and variations in HCV treatment and disease care cost assumptions, using costs from different countries (Norway, United Kingdom, United States, France, Australia)., Setting and Participants: PWID attending community-based drug treatment centers for people with opioid dependence in Norway., Measurements: Incremental cost-effectiveness ratio (ICER) in terms of cost per QALY gained, compared against a conventional (€70 000/QALY) willingness-to-pay threshold for Norway and lower (€20 000/QALY) threshold common among high-income countries., Findings: Integrated treatment resulted in an ICER of €13 300/QALY gained, with 99% and 71% probability of being cost-effective against conventional and lower willingness-to-pay thresholds, respectively. A 30% lower DAA price reduced the ICER to €6 900/QALY gained, with 91% probability of being cost-effective at the lower willingness-to-pay threshold. A 60% and 90% lower DAA price had 36% and >99% probability of being cost-saving, respectively. Sensitivity analyses suggest integrated treatment was cost-effective at the lower willingness-to-pay threshold (>60% probability) across different assumptions on HCV treatment and disease care costs with 30% DAA price reduction, and became cost-saving with 60%-90% price reductions., Conclusions: Integrated hepatitis C virus treatment for people who inject drugs in community settings is likely cost-effective compared with standard-of-care referral pathways in Norway and may be cost-saving in settings with particular characteristics., (© 2023 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

In 2020, the COVID-19 pandemic highlighted obesity's long-term rise. Some of the impacts of the pandemic were increased psychological distress, emotional eating, higher consumption of high-sugar foods and drinks, and a more sedentary lifestyle. This study examined BMI changes over time and their associations with psychological distress and lifestyle changes. This population-based cohort study had 24,968 baseline participants and 15,904 and 9442 one- and two-year follow-ups, respectively. Weight, height, psychological distress, high-sugar foods and drinks, physical activity, and emotional eating were assessed. These factors and BMI were examined at baseline and over time. We used mediation analyses and structural equation modeling to determine how psychological distress affects BMI. The mean BMI was 25.7 kg/m 2 at baseline and 26.2 kg/m 2 at two years. High psychological distress, daily emotional eating, and low physical activity were associated with higher BMI at baseline and higher yearly increases in BMI compared to reference levels. Emotional eating mediated 33% of the psychological distress BMI effect. Overall, BMI increased during the pandemic. Psychological distress during the pandemic was linked to weight gain partly through emotional eating. This association remained strong over time during different stages of the pandemic.

Background: Attention-deficit/hyperactivity disorder (ADHD) symptoms may challenge sufficient treatment of substance use and mental disorders. The literature on the extent of such symptoms among patients receiving opioid agonist therapy (OAT) is scarce. This study examined ADHD symptoms using the ADHD self-report scale (ASRS) and the association between the 'ASRS-memory' and 'ASRS-attention' scores and substance use and sociodemographic characteristics among patients receiving OAT., Methods: We used data from assessment visits of a cohort of patients in Norway. In total, 701 patients were included from May 2017 to March 2022. All patients responded at least once to two ASRS questions assessing memory and attention, respectively. Ordinal regression analyses were performed to investigate whether the two obtained scores were associated with age, sex, frequent substance use, injecting use, housing status, and educational attainment at baseline, i.e., the first assessment, and over time. The results are presented as odds ratios (OR) with 95% confidence intervals (CI). Additionally, a subsample of 225 patients completed an extended interview, including the ASRS-screener and collection of registered mental disorder diagnoses from the medical records. Standard cutoffs were used to define the presence of each ASRS symptom or a positive ASRS-screener ('ASRS-positive')., Results: At baseline, 428 (61%) and 307 (53%) patients scored over the cutoffs on the 'ASRS-memory' and 'ASRS-attention,' respectively. Frequent cannabis use was associated with higher 'ASRS-memory' (OR: 1.7, 95% CI: 1.1-2.6) and 'ASRS-attention' (1.7, 1.1-2.5) scores compared with less or no use at baseline, though reduced score on the 'ASRS-memory' over time (0.7, 0.6-1.0). At baseline, frequent stimulant use (1.8, 1.0-3.2) and low educational attainment (0.1, 0.0-0.8) were associated with higher 'ASRS-memory' scores. In the subsample fulfilling the ASRS-screener, 45% of the patients were 'ASRS-positive,' of whom 13% with a registered ADHD diagnosis., Conclusions: Our findings illustrate a relationship between the ASRS-memory and -attention scores and frequent cannabis and stimulant use. Furthermore, nearly half of the subsample was 'ASRS-positive.' Patients receiving OAT might benefit from being further assessed for ADHD, but improved diagnostic methods are required., (© 2023. The Author(s).)

Introduction: The COVID-19 pandemic and infection control measures caused changes to daily life for most people. Heavy alcohol consumption and physical inactivity are two important behavioral risk factors for noncommunicable diseases worldwide. The COVID-19 pandemic, with its social distancing measures, home office policies, isolation, and quarantine requirements may have an impact on these factors. This three-wave longitudinal study aims to investigate if psychological distress and worries related to health and economy were associated with levels and changes in alcohol consumption and physical activity during the two first years of the COVID-19 pandemic in Norway., Methods: We used data collected in April 2020, January 2021, and January 2022 from an online longitudinal population-based survey. Alcohol consumption and physical activity status were assessed at all three measuring points via the Alcohol Use Disorder Identification Test (AUDIT-C) and the International Physical Activity Questionnaire (IPAQ-SF). COVID-19-related worries, home office/study, occupational situation, age, gender, children below 18 years living at home, and psychological distress (measured with the Symptom Checklist (SCL-10)) were included as independent variables in the model. A mixed model regression was used and presented with coefficients with 95% confidence intervals (CI)., Results: Analysis of data from 25,708 participants demonstrates that participants with substantial symptoms of psychological distress more often reported higher alcohol consumption (1.86 units/week, CI 1.48-2.24) and lower levels of physical activity [-1,043 Metabolic Equivalents of Task (METs) per week, CI -1,257;-828] at baseline. Working/studying from home (0.37 units/week, CI 0.24-0.50) and being male (1.57 units/week, CI 1.45-1.69) were associated with higher alcohol consumption. Working/studying from home (-536 METs/week, CI -609;-463), and being older than 70 years (-503 METs/week, CI -650;-355) were related to lower levels of physical activity. The differences in activity levels between those with the highest and lowest levels of psychological distress reduced over time (239 METs/week, CI 67;412), and similarly the differences in alcohol intake reduced over time among those having and not having children < 18 years (0.10 units/week, CI 0.01-0.19)., Conclusion: These findings highlight the substantial increases in risks related to inactivity and alcohol consumption among those with high levels of psychological distress symptoms, and particularly during the COVID-19 pandemic, and increase the understanding of factors associated with worries and health behavior., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Alpers, Pallesen, Vold, Haug, Lunde, Skogen, Mamen, Mæland and Fadnes.)

Objective: Assess the association between oral and general health related quality of life using oral impacts on daily performances (OIDP) and the quality of life tool EQ-5D-5L from EuroQoL among patients with substance use disorder (SUD) who receive opioid agonist therapy., Method: 609 patients with SUD completed the EQ-5D-5L. A dental sub-study of 167 patients completed OIDP and an oral examination when attending outpatient clinics in Western Norway for their opioid agonist therapy. The merged analytical sample consisted of 165 patients. The association between OIDP and EQ-5D-5L was assessed by Spearman's rho and a linear multiple variable regression analysis. A line graph and a Pen's parade displayed the distributions of OIDP sum scores and EQ-5D-5L index values., Results: Overall mean summary- and index EQ-5D-5L scores were 9.97 (sd 3.25) and 0.69 (sd 0.22). Mean score for OIDP was 9.75 (sd 9.59). Spearman's rho was 0.34 ( p  < .01) between OIDP and EQ-5D-5L summary scores. Linear regression revealed an association adjusted for sex and age of 0.12 (95% CI 0.07-0.17) and a coefficient of determination of 0.1460., Conclusion: This study reveals a strong association between OIDP and EQ-5D-5L reflecting the importance of oral health to general health for patients with SUD. Health care professionals should pay attention to oral health. Effective interventions might improve patients' oral and health related quality of life.

Background: Most people who inject drugs (PWIDs) suffer from severe fatigue, and chronic hepatitis C virus (HCV) infection may play a role in this. However, there is scarce evidence about interventions that alleviate fatigue among PWIDs. The present study investigated the effect of integrated HCV treatment on fatigue in this population compared to the effect of standard HCV treatment, adjusted for sustained virological response of the HCV treatment., Methods: This multi-center, randomized controlled trial evaluated fatigue as a secondary outcome of integrated HCV treatment (the INTRO-HCV trial). From May 2017 to June 2019, 276 participants in Bergen and Stavanger, Norway, were randomly assigned to receive integrated and standard HCV treatment. Integrated treatment was delivered in eight decentralized outpatient opioid agonist therapy clinics and two community care centers; standard treatment was delivered in specialized infectious disease outpatient clinics at referral hospitals. Fatigue was assessed prior to treatment and 12 weeks after treatment using the nine-item Fatigue Severity Scale (FSS-9). We applied a linear mixed model to evaluate the impact of integrated HCV treatment on changes in FSS-9 (ΔFSS-9) sum scores., Results: At baseline, the mean FSS-9 sum score was 46 (standard deviation (SD): 15) for participants on integrated HCV treatment and 41 (SD: 16) for those on standard treatment. Twelve weeks after completed HCV treatment, the mean FSS-9 sum score for participants receiving integrated HCV treatment was 42 (SD: 15) and 40 (SD: 14) for those receiving standard HCV treatment. Integrated HCV treatment did not reduce the FSS-9 scores compared to standard HCV treatment (ΔFSS-9: -3.0, 95% confidence interval (CI): -6.4;0.4)., Conclusions: Fatigue is a common symptom among PWIDs. Integrated HCV treatment is at least equal to standard HCV treatment in improving fatigue., Trial Registration: ClinicalTrials.gov.no NCT03155906, 16/05/2017., (© 2023. The Author(s).)

Psychological distress is linked to unhealthy eating behaviors such as emotional eating and consumption of high-sugar food and drinks. Cross-sectional studies from early in the COVID-19 pandemic showed a high occurrence of worries and psychological distress, and this was associated with emotional eating. Few larger studies have examined how this coping pattern develops over time. This cohort study with 24,968 participants assessed changes over time in emotional eating, consumption of sugary foods as an example of unhealthy food choices, and consumption of fruits and vegetables as an example of healthy food choices. Further, associations between these and psychological distress, worries, and socio-demographic factors were assessed. Data were collected at three time points (April 2020, initially in the COVID-19 pandemic, then one and two years later). Emotional eating and intake of sugary foods and drinks were high at the start of the pandemic, followed by a reduction over time. High psychological distress was strongly associated with higher levels of emotional eating and high-sugar food intake, and lower levels of healthy eating habits. The strength of this association reduced over time. Our findings indicate the high frequency in unhealthy food choices seen early in the COVID-19 pandemic improved over time.

Background: There is limited knowledge on the causes of large variations in serum methadone concentrations and dose requirements., Objectives: We investigated the impact of the degree of liver fibrosis on dose-adjusted steady-state serum methadone concentrations., Methods: We assessed the clinical and laboratory data of 155 Norwegian patients with opioid use disorder undergoing methadone maintenance treatment in outpatient clinics in the period 2016-2020. A possible association between the degree of liver fibrosis and dose-adjusted serum methadone concentration was explored using a linear mixed-model analysis., Results: When adjusted for age, gender, body mass index, and genotypes of CYP2B6 and CYP3A5 , the concentration-to-dose ratio of methadone did not increase among the participants with liver fibrosis (Coefficient: 0.70; 95% CI: -2.16, 3.57; P : 0.631), even among those with advanced cirrhosis (-0.50; -4.59, 3.59; 0.810)., Conclusions: Although no correlation was found between the degree of liver stiffness and dose-adjusted serum methadone concentration, close clinical monitoring should be considered, especially among patients with advanced cirrhosis. Still, serum methadone measurements can be considered a supplement to clinical assessments, taking into account intra-individual variations.

Background: A woman in her twenties was admitted to the psychiatric ward with suspected psychosis. Routine tests revealed a rare and potentially dangerous cause of her symptoms., Case Presentation: The patient had a history of bipolar II disorder, recurrent depressive disorder and hypothyroidism, and presented to the psychiatric emergency department with a one-week history of delusions of persecutory character and increasing insomnia. She had given birth four months prior to admission. Clinical examination was otherwise unremarkable. Bipolar psychosis was considered the most likely diagnosis, and she was started on antipsychotic medication with quetiapine 100 mg × 2. Routine blood tests revealed severe hypothyroidism with thyroid stimulating hormone (TSH) of 151,00 mIU/L and free T4 (fT4) of <3,0 pmol/L (9,5-22,0), and the patient was treated with a high dose of oral levothyroxine. After a few days the patient's psychiatric symptoms resolved completely, and her fT4 increased to 10,8 pmol/L. Upon further questioning, the patient admitted to increasing fatigue and constantly feeling cold over the previous few months, which she attributed to being a parent. She was discharged after a week without any psychiatric symptoms., Interpretation: This case report highlights the importance of a broad somatic differential diagnostic approach to patients with psychosis.

Background: People with substance use disorders generally have unhealthy diets, including limited intake of fruit and vegetables. Evidence shows substantial health benefits from increasing fruit and vegetable consumption on various indicators and possibly also psychological distress. A pilot study has indicated that supplementation with fruit smoothie could be promising also among people receiving opioid agonist therapy for opioid dependence. FruktBAR will compare the efficacy of added fruit smoothie supplementation to people receiving opioid agonist therapy compared to standard treatment without added supplementation., Methods: FruktBAR is a multicentre, randomised controlled trial. The trial will aim to recruit 302 patients receiving opioid agonist therapy. The intervention involves daily supplementation with 250 ml fruit smoothie including a variety of fruits such as apple, pineapple, mango, bananas, orange, blueberries, passion fruit, coconut, lime, and blackcurrant. The main endpoints are 16 weeks after intervention initiation. Participants will be included and followed up during and after the intervention. The target group will be patients with opioid dependence receiving opioid agonist therapy from involved outpatient clinics in Bergen and Stavanger, two of the largest cities in Norway. The main outcome is psychological distress assessed with Hopkins Symptom Checklist (SCL-10) at the end of the intervention period 16 weeks after initiation, and will be compared between the intervention and control arms. Secondary outcome measures are changes in fatigue, physical functioning assessed with a 4-minute step-test, health-related quality of life, biochemical indicators of inflammation, and biochemical indicators of fruit intake., Discussion: This study will inform on the relative advantages or disadvantages of fruit supplementation in addition to the current medically and psychologically oriented treatment of people receiving opioid agonist therapy. If the supplementation is efficacious, it can be considered for further scale-up., Trial Registration: Registered 2022-02-08 in ClinicalTrials.gov , identifier NCT05229770., (© 2022. The Author(s).)

Background: About 85% of patients receiving opioid agonist therapy (OAT) for opioid dependence are smoking tobacco. Although smoke-related pulmonary diseases are significant contributors to morbidity and mortality, few smoking cessation interventions are evaluated within this group, and few OAT patients are offered smoking cessation as an integrated part of their addiction treatment. This study protocol describes an integrated smoking cessation intervention aimed at patients receiving OAT and smoking tobacco., Methods: This is a multicentre, randomised controlled clinical trial that will recruit 266 daily tobacco smoking patients receiving OAT in OAT outpatient clinics in Bergen and Stavanger, Norway. The patients randomised for the intervention arm will be offered smoking cessation therapy consisting of weekly brief behavioural interventions and prescription-free nicotine replacement products. In the control arm, patients will receive standard care without any added interventions related to smoking cessation. The smoking cessation intervention includes psychoeducational techniques with components from motivational interviewing, and nicotine replacement products such as nicotine lozenges, patches, and chewing gum. The duration of the intervention is 16 weeks, with the option of extending it by a further 8 weeks. The main outcomes are measured at 16 weeks after initiation of the intervention, and sustained effects are evaluated 1 year after intervention initiation. The primary outcome is smoking cessation verified by carbon monoxide (CO) levels or at least a 50% reduction in the number of cigarettes smoked. Secondary outcomes are changes in psychological well-being, biochemical inflammation markers, changes in physical health, quality of life, and fatigue., Discussion: Integration of other treatments to standard OAT care improves adherence and completion rates providing another rationale for integrated smoking cessation treatment. Thus, if integrated smoking cessation treatment is superior to standard care, this trial provides important information on further scale-up., Trial Registration: ClinicalTrials.gov NCT05290025. Registered on 22 March 2022., (© 2022. The Author(s).)

Chronic and harmful substance use is associated with a cluster of harms to health, including micronutrient deficiencies. Maintaining adequate levels of vitamin D is important for musculoskeletal and other aspects of health. In this prospective longitudinal cohort study, 666 participants drawn from outpatient opioid agonist therapy (OAT) clinics and community care clinics for substance use disorder in Western Norway were assessed annually for determination of serum 25-hydroxyvitamin D [s-25(OH)D] levels. Fifty-seven percent were deficient at baseline (s-25(OH)D < 50 nmol/l), and 19% were severely deficient (s-25(OH)D < 25 nmol/l). Among those deficient/severely deficient at baseline, 70% remained deficient/severely deficient at the last measurement (mean duration 714 days). Substance use patterns and dosage of opioids for OAT were not associated with vitamin D levels. One exception was found for cannabis, where consumption on a minimum weekly basis was associated with lower levels at baseline (mean difference: -5.2 nmol/l, 95% confidence interval [CI]: -9.1, - 1.3), but without clear time trends (mean change per year: 1.4 nmol/l, CI: - 0.86, 3.7). The high prevalence of sustained vitamin D deficiency in this cohort highlights the need for targeted monitoring and supplementation for this and similar at-risk populations., (© 2022. The Author(s).)

Substance use disorder (SUD) is associated with poor nutrition. Vitamin B9, or folate, is an important micronutrient for health. The aim of this prospective longitudinal cohort study was to assess serum folate levels among people with SUD and to investigate the impact of factors related to substance use severity on folate status. Participants were recruited from outpatient clinics for opioid agonist therapy (OAT) and municipal health-care clinics for SUD in Western Norway. They were assessed annually, including blood sampling for determination of micronutrient status. Overall, 663 participants with a total of 2236 serum folate measurements were included. A linear mixed model was applied, and measures are presented as β-coefficients with 95% confidence interval (CI). Forty-eight percent (CI: 44−51) of the population had low serum folate levels (s-folate < 10 nmol/L), and 23% (CI: 20−26) were deficient (s-folate < 6.8 nmol/L) at baseline. Sixty percent (CI: 53−65) sustained their poor folate status in at least one subsequent assessment. Except for weekly use of cannabis (mean difference in serum folate [nmol/L]: −1.8, CI: −3.3, −0.25) and alcohol (1.9, CI: 0.15, 3.6), weekly use of no other substance class was associated with baseline differences in serum folate when compared to less frequent or no use. Injecting substances was associated with a reduction in serum folate over time (−1.2, CI: −2.3, −0.14), as was higher dosages of OAT medication (−1.1, CI: −2.2, −0.024). Our findings emphasize the need of addressing nutrition among people with severe SUD.

People with severe substance use disorder (SUD) have a higher burden of micronutrient deficiency compared with the general population. The aim of this study was to investigate vitamin B12 status and risk factors of deficiency related to substance use, opioid agonist therapy (OAT), as well as hepatitis C infection and liver fibrosis. In this prospective cohort study, participants were recruited from outpatient OAT and SUD clinics in western Norway, and assessed annually with a clinical interview and exam, including venous blood sampling. Data were collected between March 2016 and June 2020, and a total of 2451 serum vitamin B12 measurements from 672 participants were included. The median serum vitamin B12 concentration was 396 (standard deviation 198) pmol/L at baseline, 22% of the population had suboptimal levels (<300 pmol/L) and 1.2% were deficient at baseline (<175 pmol/L). No clear associations were seen with substance use patterns, but liver disease and younger age were associated with higher vitamin B12 levels. Although the majority of participants had satisfactory vitamin B12 levels, about a fifth had suboptimal levels that might or might not be adequate for metabolic needs. Future studies could investigate potential gains in interventions among patients with suboptimal but non-deficient levels.

Background: Death by suicide in patients enrolled in opioid agonist therapy (OAT) is a major clinical concern. However, little knowledge exists regarding suicide attempts in this patient group. This study presents the lifetime prevalence of suicide attempts and the associations between suicide attempts and clinical and sociodemographic variables such as education, sex, early onset of substance use (< 13 years of age), substance use patterns, and injecting substance use among patients receiving OAT., Methods: We used data from a cohort of OAT patients in Norway obtained from a health assessment of self-reported suicide attempts and sociodemographic and clinical factors. A total of 595 patients receiving OAT were assessed from 2016 to 2020. A binary logistic regression analysis was performed and reported with an unadjusted odds ratio and 95% confidence intervals (OR). The purpose of this assessment was to analyze associations between suicide attempts and substance use patterns as well as the injection of substances during the 30 days leading up to the health assessment. A negative binomial regression analysis with an incidence rate ratio and 95% confidence intervals (IRR) was performed to investigate sex, education, early onset of substance use, and the number of suicide attempts., Results: Forty-one percent of the OAT patients had attempted to die by suicide at least once during their lifetime. An early onset of substance use was strongly associated with the suicide attempts (IRR: 1.7, 1.3-2.2). No significant association was found between suicide attempts and sex (IRR: 1.2, 0.9-1.6) or education (IRR: 0.6, 0.2-2.1). Likewise, no association was identified between suicide attempts and injecting substance use (OR: 0.9, 0.6-1.3), nor using alcohol (OR: 0.9, 0.7-1.3), amphetamines (OR: 1.0, 0.7-1.3), benzodiazepines (OR: 1.0, 0.7-1.4), cannabis (OR: 1.2, 0.9-1.7), cocaine (OR: 1.3, 0.6-3.0), or opioids (OR: 1.4, 0.9-2.0)., Conclusion: The lifetime prevalence of suicide attempts was alarmingly high in the OAT population. An early onset of substance use seemed to be an important risk factor for suicide attempts. There was a non-significant association to more current use of opioids among OAT patients with previous suicide attempts., (© 2022. The Author(s).)

Background: Continuous use of amphetamines, alcohol, benzodiazepines, cannabis, cocaine, or opioids contributes to health impairments, increased morbidity, and overdose deaths among patients with substance use disorders (SUDs). This study evaluates the impact of inpatient detoxification, injecting substance use, age, and gender on substance use over time among patients undergoing outpatient SUD treatment., Methods: We used data from a cohort of SUD patients in Norway obtained from health assessments of self-reported substance use and sociodemographic and clinical factors. A total of 881 substance use measurements, including substances and frequency of use, were assessed for 708 SUD patients in 2016-2020. Of those, 171 patients provided two or more substance use measurements. The total substance use was calculated, creating a substance use severity index (SUSI), ranging from zero (no use) to one (daily use of all substances). We defined baseline as the first substance use measurement when the measurements were listed chronologically. Time was defined as years from baseline. We used a linear mixed model to analyze the SUSI at baseline and over time, and its associations with inpatient detoxification, injecting substance use, gender, and age, presented with coefficients and 95% confidence intervals (CI)., Results: No longitudinal changes in the SUSI were found compared with baseline (change in SUSI (cSUSI): 0.04, 95% CI: - 0.05;0.13, p = 0.397). Likewise, "inpatient detoxification" was not associated with changes in the SUSI compared with "no inpatient detoxification" (cSUSI: 0.00, 95% CI: - 0.04;0.04, p = 0.952). However, injecting substances were associated with a higher SUSI than not injecting substances at baseline (difference in SUSI: 0.19, 95% CI: 0.16;0.21, p = < 0.001), and starting to inject substances was associated with increasing SUSI over time compared with not starting to inject substances (cSUSI: 0.11, 95% CI: 0.07;0.15, p = < 0.001). Gender was not significantly associated with changes in the SUSI (cSUSI: - 0.04, 95% CI: - 0.07;0.00, p = 0.052), while patients over 60 years of age had a lower SUSI than those under the age of 30 at baseline (difference in SUSI: - 0.08, 95% CI: - 0.14;- 0.01, p = 0.018), with no change over time (cSUSI: - 0.05, 95% CI: - 0.16;0.05, p = 0.297)., Conclusion: The present study demonstrates that inpatient detoxification was not associated with substance use changes over time for patients undergoing outpatient SUD treatment. Otherwise, injecting substance use was a particular risk factor for a high level of substance use. Future research needs to evaluate the impact of other treatment approaches on substance use, ideally in randomized controlled trials., (© 2021. The Author(s).)

Background: The standard pathways of testing and treatment for hepatitis C virus (HCV) infection in tertiary healthcare are not easily accessed by people who inject drugs (PWID). The aim of this study was to evaluate the efficacy of integrated treatment of chronic HCV infection among PWID., Methods and Findings: INTRO-HCV is a multicenter, randomized controlled clinical trial. Participants recruited from opioid agonist therapy (OAT) and community care clinics in Norway over 2017 to 2019 were randomly 1:1 assigned to the 2 treatment approaches. Integrated treatment was delivered by multidisciplinary teams at opioid agonist treatment clinics or community care centers (CCCs) for people with substance use disorders. This included on-site testing for HCV, liver fibrosis assessment, counseling, treatment, and posttreatment follow-up. Standard treatment was delivered in hospital outpatient clinics. Oral direct-acting antiviral (DAA) medications were administered in both arms. The study was not completely blinded. The primary outcomes were time-to-treatment initiation and sustained virologic response (SVR), defined as undetectable HCV RNA 12 weeks after treatment completion, analyzed with intention to treat, and presented as hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals. Among 298 included participants, 150 were randomized to standard treatment, of which 116/150 (77%) initiated treatment, with 108/150 (72%) initiating within 1 year of referral. Among those 148 randomized to integrated care, 145/148 (98%) initiated treatment, with 141/148 (95%) initiating within 1 year of referral. The HR for the time to initiating treatment in the integrated arm was 2.2 (1.7 to 2.9) compared to standard treatment. SVR was confirmed in 123 (85% of initiated/83% of all) for integrated treatment compared to 96 (83% of initiated/64% of all) for the standard treatment (OR among treated: 1.5 [0.8 to 2.9], among all: 2.8 [1.6 to 4.8]). No severe adverse events were linked to the treatment., Conclusions: Integrated treatment for HCV in PWID was superior to standard treatment in terms of time-to-treatment initiation, and subsequently, more people achieved SVR. Among those who initiated treatment, the SVR rates were comparable. Scaling up of integrated treatment models could be an important tool for elimination of HCV., Trial Registration: ClinicalTrials.gov.no NCT03155906., Competing Interests: The authors LTF, CFA, JHV, SS, CO, FC, EML, KAJ, have declared that no competing interests exist. We have read the journal’s policy and these authors of this manuscript have the following competing interests: AL has received lecture and advisory fees from Gilead, GSK and MSD. OJL has received project grants from AbbVie, Gilead and MSD. OD has received research grants from and been in advisory board for MSD, Abbvie and Gilead. PV has received an unrestricted research grant off Gilead. HM has received lecture and advisory fees from Gilead, Abbvie and MSD.

Background: There is little evidence-based guidance on how to optimize methadone dosages among patients with opioid addiction undergoing methadone maintenance treatment (MMT). This study aims to investigate whether self-perceived opioid withdrawal symptoms, adverse effects, and self-reported substance use in patients on MMT are related to serum methadone concentrations and the role that these variables could play in clinical decisions on dose adjustments., Methods: This naturalistic prospective cohort study included clinical and laboratory measurements from 83 patients undergoing MMT in outpatient clinics in Bergen, Norway, from May 2017 to January 2020. Information on age, gender, methadone daily doses and serum concentrations, subjective opioid withdrawal symptoms using 16 items Subjective Opioid Withdrawal Scale (SOWS) questionnaire, self-reported adverse effects, and substance use was obtained. Linear mixed modelling was used for analyzing the data., Results: The mean age of the participants was 45 years, and 33% were women. Almost half reported mild to moderate subjective opioid withdrawal symptoms, and all had experienced at least one subjective adverse effect. The use of at least one substance was reported by 88% of the participants. Serum concentration-to-dose ratios were lower among those who had reported subjective opioid withdrawal symptoms (p) = 0.039). The total SOWS score (p < 0.001); the specific subjective withdrawal symptoms of anxiety (p = 0.004), bone and muscle aches (p = 0.003), restlessness (p = 0.017), and (slightly) shaking (p = 0.046), also use of heroin (p = 0.015) and alcohol (p = 0.011) were associated with lower methadone concentrations. Cannabis use was slightly related to higher methadone concentrations (p = 0.049)., Conclusions: The findings suggest that the patient's self-perceived symptoms and current clinical condition are related to the serum concentrations of methadone. This interpretation supports dose adjustments based on patient-reported symptoms. In some aberrant cases, measurement of serum concentrations together with other individual assessments may be considered to support the clinical decision.

Background: Little attention has been paid to customising fatigue questionnaires for patients with Substance Use Disorders (SUDs). The present study aims to validate and shorten the nine-item Fatigue Severity Scale (FSS-9) and Visual Analogue Fatigue Scale (VAFS) for use with this population., Methods: We used data from a nested cohort with annual health assessments with responses on the FSS-9 and VAFS. During the period 2016-2020, 917 health assessments were collected from 655 patients with SUD in Bergen and Stavanger, Norway. A total of 225 patients answered the health assessment at least twice. We defined baseline as the first annual health assessment when the health assessments were sorted chronologically per patient. We checked for internal consistency, and we used longitudinal confirmatory factor analysis (CFA) and linear mixed model (LMM) analysis to validate and shorten the FSS-9 and VAFS., Results: The internal consistency of the FSS-9 was excellent with a Cronbach's α of 0.94 at baseline and 0.93 at the second annual health assessment. When shortening the FSS-9 to a three-item FSS (FSS-3, items 5-7), the Cronbach's α was 0.87 at baseline and 0.84 at the second health assessment. The internal consistency was not affected when the VAFS was added to the FSS-3 and the FSS-9. The longitudinal CFA model showed a well-fitting model for the FSS-3 (χ 2  = 13.33, degree of freedom = 8, P = 0.101). The LMM analysis showed equal linear changes at the individual level for the FSS-3 (slope: 0.00, P > 0.05) and FSS-9 (slope: 0.01, P > 0.05) between the health assessments., Conclusion: The FSS-9 could be shortened to the FSS-3 with high validity and reliability for patients with SUDs and the addition of VAFS did not provide much added variability.

Background: There is high co-occurrence of substance use disorders (SUD) and mental health disorders. We aimed to assess impact of substance use patterns and sociodemographic factors on mental health distress using the ten-item Hopkins Symptom Checklist (SCL-10) over time., Methods: Nested prospective cohort study of 707 participants with severe SUD across nine opioid-agonist-therapy outpatient clinics and low-threshold municipality clinics in Norway, during 2017-2020. Descriptive statistics were derived at baseline and reported by means and standard deviation (SD). A linear mixed model analysis was used to assess the impact of substance use patterns and sociodemographic factors on SCL-10 sum score with beta coefficients with 95% confidence intervals (CI)., Results: Mean (SD) SCL-10 score was 2.2 (0.8) at baseline with large variations across patients. We observed more symptoms of mental health disorders among people with frequent use of benzodiazepines (beta 3.6, CI:2.4;4.8), cannabis (1.3, CI:0.2;2.5), opioids (2.7, CI:1.1;4.2), and less symptoms among people using frequent stimulant use (- 2.7, CI:-4.1;-1.4) compared to no or less frequent use. Females (1.8, CI:0.7;3.0) and participants with debt worries (2.2, CI:1.1;3.3) and unstable living conditions (1.7, CI:0.0;3.3) had also higher burden of mental health symptoms. There were large individual variations in SCL-10 score from baseline to follow-up, but no consistent time trends indicating change over time for the whole group. 65% of the cohort had a mean score > 1.85, the standard reference score., Conclusions: People with SUD have a considerable burden of mental health symptoms. We found no association between substance use patterns and change in mental health symptoms over time. This could suggest that the differences observed were indicating flattening of effects or self-medication to a larger degree than medication-related decline in mental health. This call for better individualized mental health assessment and patient care.

Background: The impact of clinical and sociodemographic factors on fatigue remains unknown among patients with substance use disorders (SUD). This study aims to evaluate fatigue among patients with SUD using a nine-item fatigue severity scale (FSS-9) and identify the impact that clinical and sociodemographic factors - such as injecting substance use, chronic infectious diseases, liver fibrosis, opioid agonist therapy (OAT), debt difficulties, and housing situation - have on fatigue., Methods: We used data from a cohort of patients with SUD in Norway with annual health assessments surveying FSS-9 and some clinical and sociodemographic factors. A total of 915 FSS-9 measurements were collected from 654 patients during the period 2016-2020. We defined baseline as the first annual health assessment when the health assessments were listed chronologically. Time was defined as years from baseline. We used a linear mixed model to analyse whether the clinical and sociodemographic factors affected the FSS-9 sum score, presented with beta coefficients (β) with 95% confidence intervals (CI)., Results: The mean sum score of the FSS-9 was 43 (standard deviation: 16) at baseline. Females compared with males (adjusted mean difference of FSS-9 sum score: 4.1, 95% CI: 1.3-7.0), having debt difficulties compared with having no debt difficulties (2.9;0.4-5.3), and frequent use of benzodiazepines (5.7;3.0-8.4) or amphetamines (-5.0;-8.0- -2.0) compared to less frequent or no use of these substances changed the FSS-9 baseline sum score. The other clinical and sociodemographic factors did not predict any clinically relevant change in the FSS-9 sum score from baseline to the following health assessments., Conclusion: Patients with SUD suffer from high levels of fatigue. Female patients, patients with debt difficulties, and those with extensive use of benzodiazepines are at particular risk of being fatigued. This should be taken into consideration when planning health services.

Background: Opioid dependence carries the highest disease burden of all illicit drugs. Opioid agonist therapy (OAT) is an evidence-based medical intervention that reduces morbidity and mortality. There is limited knowledge on the health-related quality of life (HRQoL) of long-term patients in OAT. This study measures HRQoL and self-perceived health of long-term patients on OAT, compares the scores to a Norwegian reference population, and assesses changes in these scores at 1-year follow up., Methods: We conducted a nested prospective cohort study among nine OAT outpatient clinics in Norway. 609 OAT patients were included, 245 (40%) followed-up one year later. Data on patient characteristics, HRQoL, and self-perceived health was collected. HRQoL was assessed with the EQ-5D-5L, which measures five dimensions (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) on a five-point Likert scale (from "no problems" to "extreme problems"). An UK value set was applied to calculate index values (from 0 to 1) for the EQ-5D-5L and compare them to a Norwegian reference population. Self-perceived health was measured with EQ-VAS (from 0 to 100)., Results: Mean (standard deviation (SD)) EQ-5D-5L index value at baseline was 0.699 (0.250) and EQ-VAS 57 (22) compared to 0.848 (0.200) and 80(19) for the Norwegian reference population. There were large variations in EQ-5D-5L index values, where 43% had > 0.8 and 5% had < 0.2 at baseline. The lowest EQ-5D-5L index values were observed for female patients, age groups older than 40 years and for methadone users. At follow-up, improvements in HRQoL were observed across almost all dimensions and found significant for mobility and pain/discomfort. Mean (SD) overall index value and EQ-VAS at follow up were 0.729 (0.237) and 59 (22) respectively., Conclusion: The average HRQoL and self-perceived health of OAT patients is significantly lower than that of the general population, and lower than what has been found among other severe somatic and psychiatric conditions. Around 34% had very good HRQoL, higher than average Norwegian values, and around 5% had extremely poor HRQoL.

Objectives: We aimed to calculate cumulative hepatitis C virus (HCV) treatment coverage among individuals enrolled in opioid agonist therapy (OAT) in Norway between 2013 and 2017 and to document the treatment transition to direct-acting antiviral (DAA) agents. Moreover, we aimed to describe adherence to DAAs in the same cohort., Design: Prospective cohort, registry data., Setting: Specialist healthcare service (secondary) PARTICIPANTS AND OUTCOMES: This observational study was based on data from The Norwegian Prescription Database. We studied dispensed OAT and HCV treatment annually to calculate the cumulative frequency, and employed secondary sources to calculate prevalence, incidence and HCV treatment coverage from 2013 to 2017, among the OAT population. Factors associated with adherence to DAAs were identified a priori and subject to logistic regression., Results: 10 371 individuals were identified with dispensed OAT, 1475 individuals of these were identified with dispensed HCV treatment. Annual HCV treatment coverage increased from 3.5% (95% CI: 3.2 to 4.4) in 2013 to 17% (95% CI: 17 to 20) in 2017, giving a cumulative HCV coverage among OAT patients in Norway of 38.5%. A complete shift to interferon-free treatment regimens occurred, where DAAs accounting for 32% of HCV treatments in 2013 and 99% in 2017. About two-thirds of OAT patients were considered adherent to their DAA regimens across all genotypes. High level of OAT continuity was associated with improved adherence to DAAs (adjusted OR 1.4, 95% CI: 1 to 2, p=0.035)., Conclusions: A large increase in HCV treatment coverage attributed by a complete shift to interferon-free regimens among the Norwegian OAT population has been demonstrated. However, treatment coverage is inadmissibly too low and a further substantial scale-up in HCV treatment is required to reach the universal targets of controlling and eliminating the HCV endemic., Competing Interests: Competing interests: IO is employed at the Centre for Pharmacoepidemiology, Karolinska Institutet, which receives grants from several entities (pharmaceutical companies, regulatory authorities and contract research organisations) for performance of drug safety and drug utilisation studies, unrelated to this work. None of the other authors have competing interests., (© 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.)

Objectives: To compare the use of benzodiazepines, z-hypnotics, gabapentinoids, opioids and centrally acting stimulants (CAS) among patients who had received opioid agonist therapy (OAT) in Norway and Sweden during the period 2015 - 2017., Design: A register-based prospective cohort study using information about dispensed drugs from the Norwegian Prescription Database and Swedish Prescribed Drug Register., Setting: Patients who were dispensed OAT opioids from pharmacies., Participants: A total of 7176 Norwegian and 3591 Swedish patients on OAT were included., Outcome Measures: The number and frequency of potentially addictive drugs dispensed were calculated for the two countries. The mean daily doses of dispensed benzodiazepines and z-hypnotics were summarised by calculating benzodiazepines in diazepam equivalents and z-hypnotics in zopiclone equivalents., Results: In 2017, 46% of patients in Norway, and 15% in Sweden, were dispensed a benzodiazepine. Moreover, 14% in Norway and 26% in Sweden received z-hypnotics. Gabapentinoids were dispensed to 10% of patients in Norway and 19% of patients in Sweden. In Norway, 6% and 12% of the patients received strong and weak non-OAT opioids, respectively, whereas in Sweden 10% were dispensed strong non-OAT opioids and 5% weak non-OAT opioids . CAS were dispensed to 4% in Norway and 18% in Sweden. The mean daily doses of benzodiazepines were 16 and 17 mg diazepam equivalents in Norway and Sweden, respectively. For z-hypnotics, the mean daily dose was 8 mg zopiclone equivalents in both countries. 'Benzodiazepines and z-hypnotics' was the most dispensed drug combination in 2017. Similar results were found in 2015 and 2016., Conclusions: Nearly half of those patients who were dispensed an OAT opioid in Norway and Sweden were dispensed potentially addictive drugs. The differences identified between Norway and Sweden might be related to differences in eligibility guidelines and restrictions with respect to OAT., Competing Interests: Competing interests: IO and JR are employed at the Centre for Pharmacoepidemiology, Karolinska Institute, which receives grants from several entities (pharmaceutical companies, regulatory authorities and contract research organisations) for performance of drug safety and drug utilisation studies, unrelated to this work., (© 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.)

Background: Dispensations of opioid analgesics to patients on opioid agonist therapy (OAT) may increase the risk of overdoses. The current study's objectives are to investigate the dispensation rates and mean daily doses of dispensed opioid analgesics among patients who received OAT opioids in Norway during 2013-2017 and evaluate whether discontinuing OAT opioids affects the dispensed dose of opioid analgesics., Methods: Information on opioids was collected from the Norwegian Prescription Database. Dispensation rates were calculated by dividing the number of patients who were dispensed at least one opioid analgesic by the number of patients who were dispensed an OAT opioid. We calculated the mean daily dose of opioid analgesics in oral morphine equivalents. The OAT opioid dose was defined as a ratio between the dispensed doses divided by the mean recommended dose. We used logistic regression to estimate the association between the dispensation of an opioid analgesic, a dose of OAT opioids, having chronic pain, and being on palliative care., Results: A total of 10,371 patients were dispensed at least one OAT opioid during the study period. In 2017, 18% were dispensed an opioid analgesic with a mean daily dose of 29 mg of oral morphine equivalents. Being dispensed an opioid analgesic was associated with having chronic pain (adjusted odds ratio (aOR): 3.6, 95% confidence interval: 3.2-4.2), being on palliative care (aOR: 6.1, 4.7-7.9), and receiving an OAT opioid dose below half of the recommended OAT dose (aOR: 1.7, 1.4-2.0). Similar results were seen in 2013-2016. The discontinuation of OAT opioids could increase the dose of dispensed opioid analgesics., Conclusion: Reducing the dispensation of opioid analgesics can be achieved by increasing the OAT opioid dose for patients on a low OAT dose, and by extending the period needed to taper off the OAT opioid dose at discontinuation.

Background: Treatment with direct-acting antiviral agents (DAAs) offers an opportunity to eliminate hepatitis C virus (HCV) endemic among people who inject drugs (PWID) and people enrolled in opioid agonist therapy (OAT) programs. The objective of this study was to estimate and to compare HCV treatment uptake after the introduction of DAAs among patients receiving OAT in Sweden and Norway. We also aimed to evaluate predictors of DAAs treatment among OAT patients in both countries., Methods: This observational study was conducted with data from The Swedish Prescribed Drug Register and The Norwegian Prescription Database. We studied dispensed medications to calculate HCV treatment among OAT patients from 2014 to 2017 in Sweden and Norway. HCV prevalence was estimated from primary and secondary sources. Dispensations of medicines from different therapeutic areas, which served as proxy for co-morbidities in 2017, were conditionally adjusted for age, gender, and OAT medications. Logistic regression was used to evaluate these parameters., Results: In total 3529 individuals were identified with dispensed OAT in the Swedish cohort and 7739 individuals in the Norwegian cohort. HCV treatment was utilized by 407 persons in Sweden and 920 in Norway during the study period. Annual HCV and DAA treatment uptake increased in both countries. The estimated cumulative HCV treatment uptake at the end of 2017 was 31% in Norway and 28% in Sweden. DAA treatment was associated with increased age (aOR 1.8; 95% CI 1.0-3.2) and the dispensation of drugs used for diabetes (aOR 3.2; 95% CI 1.8-5.7) in Sweden. In Norway, lipid modifying agents and antibacterials were associated with decreased odds (aOR 0.4; 95%CI 0.2-0.9, aOR 0.8; 95%CI 0.6-1.0)., Conclusions: An increase in DAA treatment and HCV treatment uptake was observed among Swedish and Norwegian OAT patients whilst introducing new direct-acting antiviral treatment regimens. However, more than two thirds of the OAT population in Norway and Sweden were untreated at the beginning of 2018. A further scale-up is crucial in order to control and eliminate the HCV endemic among OAT patients.

Background: Dispensations of benzodiazepines, z-hypnotics, and gabapentinoids to patients on opioid agonist therapy (OAT) are common and have pros and cons. The objectives of the current study are to define the dispensation rates of these potentially addictive drugs, and whether the number and the mean daily doses of dispensed OAT opioids and discontinuing OAT, are associated with being dispensed benzodiazepines, z-hypnotics and gabapentinoids among patients on OAT in Norway in the period 2013 to 2017., Methods: Information about all dispensed opioids, benzodiazepines, z-hypnotics and gabapentinoids were recorded from the Norwegian Prescription Database (NorPD). A total of 10,371 OAT patients were included in the study period. The dispensation rates were defined as the number of patients who were dispensed at least one of the potentially addictive drugs divided among the number of patients who have dispensed an OAT opioid per calendar year. Mean daily doses were calculated, and for benzodiazepines and z-hypnotics, stated in diazepam equivalents. The association between dispensed potentially addictive drugs, and the number and the type of dispensed OAT opioids were calculated by using logistic regression models., Results: Half of the OAT patients received at least one dispensation of a benzodiazepine or z-hypnotic, and 11% were dispensed at least a gabapentinoid in 2017. For dispensed benzodiazepines or z-hypnotics, the mean daily dose was reduced from 21 mg (95% confidence interval (CI): 20-23) diazepam equivalents in 2013 to 17 mg (95% CI: 16-17) in 2017. The mean daily dose of pregabalin increased from 365 mg (95% CI: 309-421) in 2013 to 386 mg (95% CI: 349-423) in 2017. Being dispensed a gabapentinoid (adjusted odds ratio (aOR) = 2.5, 95% CI: 2.1-3.0) or a non-OAT opioid (aOR = 3.0, 95% CI: 2.6-3.5) was associated with being dispensed a benzodiazepine or z-hypnotic. Discontinuing OAT did not affect the number of dispensations and the doses of potentially addictive drugs., Conclusion: The dispensation rates of potentially addictive drugs are high in the OAT population. Treatment indications, as well as requirements for prescription authority, need to be debated and made explicit. Randomized controlled trials evaluating the benefits and risks of such co-prescription are required.

Background: It is estimated that up to a third of patients on opioid agonist therapy (OAT) have attention deficit hyperactivity disorder (ADHD). Treatment by ADHD medication, including a centrally acting stimulant (CAS) or atomoxetine is one of the essential approaches. This study evaluates the use of dispensed ADHD medications in the Norwegian OAT population in the period from 2015 to 2017. Types and doses of ADHD medications, co-dispensations of other potentially addictive drugs like benzodiazepines, z-hypnotics, gabapentinoids, and non-OAT opioids, as well as direct-acting antivirals (DAA) against hepatitis C infection, are investigated., Methods: Information about all dispensed ADHD medication, OAT opioids, and the defined potentially addictive drugs were recorded from the Norwegian Prescription Database. Dispensation rates, the types, and the doses of dispensed ADHD medications were estimated by summarizing the number of dispensations, and the dispensed doses. Logistic regression analyses were employed to assess the associations between ADHD medication, and OAT opioid use, and dispensations of other potentially addictive drugs and DAAs against hepatitis C infection., Results: A total of 9235 OAT patients were included. The proportion of patients who were dispensed ADHD medication increased from 3.5 to 4.6% throughout the study period. The three most dispensed CAS were short- and intermediate-acting methylphenidate (55%), lisdexamphetamine (24%), and dexamphetamine (17%) in 2017. Buprenorphine, rather than methadone, as OAT opioid (adjusted odds ratio: 1.6, CI: 1.2-2.1) was associated with being dispensed ADHD medication. Among patients who received CAS and OAT opioids each calendar year, the dispensed doses of methylphenidate increased from 63 mg/day in 2015 to 76 mg/day in 2017 (p = 0.01). Sixty percent of patients receiving ADHD medications were also dispensed other addictive drugs concomitantly in 2017. Similar results were found in 2015 and 2016., Conclusion: Co-prescription of ADHD medications was low among patients on OAT in Norway, considering a high prevalence of ADHD in this patient group. On the other hand, concurrent dispensations of multiple addictive drugs were common in this population. Understanding the underlying reasons for such prescribing is essential, and research on how to optimize ADHD medication of patients with ADHD receiving OAT is needed.

Background: A large proportion of people who inject drugs (PWID) living with hepatitis C virus (HCV) infection have not been treated. It is unknown whether inclusion of HCV diagnostics and treatment into integrated substance use disorder treatment and care clinics will improve uptake and outcome of HCV treatment in PWID. The aim is to assess the efficacy of integrating HCV treatment to PWID and this paper will present the protocol for an ongoing trial., Methods: INTRO-HCV is a multicentre, randomised controlled clinical trial that will compare the efficacy of integrated treatment of HCV in PWID with the current standard treatment. Integrated treatment includes testing for HCV, assessing liver fibrosis with transient elastography, counselling, treatment delivery, follow-up and evaluation provided by integrated substance use disorder treatment and care clinics. Most of these clinics for PWID provide opioid agonist therapy while some clinics provide low-threshold care without opioid agonist therapy. Standard care involves referral to further diagnostics, treatment and treatment follow-up given in a hospital outpatient clinic with equivalent medications. The differences between the delivery platforms in the two trial arms involve use of a drop-in approach rather than specific appointment times, no need for additional travelling, less blood samples taken during treatment, and treatment given from already known clinicians. The trial will recruit approximately 200 HCV infected individuals in Bergen and Stavanger, Norway. The primary outcomes are time to treatment initiation and sustained virologic response, defined as undetectable HCV RNA 12 weeks after end of treatment. Secondary outcomes are cost-effectiveness, treatment adherence, changes in quality of life, fatigue and psychological well-being, changes in drug use, infection related risk behaviour, and risk of reinfection. The target group is PWID with HCV diagnosed receiving treatment and care within clinics for PWID., Discussion: This study will inform on the effects of an integrated treatment program for HCV in clinics for PWID compared to standard care aiming to increase access to treatment and improving treatment adherence. If the integrated treatment model is found to be safe and efficacious, it can be considered for further scale-up., Trial Registration: ClinicalTrials.gov.no. NCT03155906.

Background: Various integrated care models have been used to improve treatment completion of medications for chronic hepatitis B virus (HBV), chronic hepatitis C virus (HCV), Mycobacterium tuberculosis (TB), and Human immunodeficiency virus (HIV) among people with substance use disorders (SUD). We have conducted a systematic review to evaluate whether integrated models have impacts of the treatment of infectious diseases among marginalized people with SUD., Methods: We searched MEDLINE/PubMed (1946 to 2018, on July 26, 2018) and Embase (from 1974 to 2018, on July 26, 2018) for randomized controlled trials (RCTs) and cohort studies evaluating diverse integrated models' effects on sustained virological response (SVR), HIV suppression, HBV curation or suppression, completion of TB treatment regimen among people with SUD. The included studies were assessed qualitatively., Results: Altogether, 1640 studies, and references to 1135 related reviews and RCTs were considered, and only seven RCTs and three cohort studies fulfilled the inclusion criteria. We identified nine integrated care models. Two studies, one RCT and one cohort study, showed a significant effect of their integrated models. The RCT evaluated psychosocial treatment, opioid agonist treatment (OAT) and directly observed TB treatment, and found a significant increase in TB treatment completions among intervention group compared to control group (60% versus 13%, p < 0.01). The cohort study including OAT and TB treatments had an effect on TB treatment completion in hospitalized patients (89% versus 73%, p = 0.03). Eight out of ten studies showed no significant effects of their integrated care models on defined outcomes. One of which having included 363 participants in a RCT showed no effect on SVR compared to the control group when the results adjusted for active substance use and alcohol dependence in a post-hoc analysis (11% versus 7%, p = 0.49)., Conclusions: The findings indicate uncertainty on the effects of integrated care models' on treatment for severe infectious diseases among people with SUD. Some studies point toward that integrated models could improve care of people with SUD, yet high-quality studies and preferably, sufficiently sized clinical trials are needed to conclude on the degree of impact.