Effect of integrated hepatitis C virus treatment on psychological distress in people with substance use disorders.

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.

Cost-effectiveness of integrated treatment for hepatitis C virus (HCV) among people who inject drugs in Norway: An economic evaluation of the INTRO-HCV trial.

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.

The efficacy of integrated hepatitis C virus treatment in relieving fatigue in people who inject drugs: a randomized controlled trial.

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.

Impact of liver fibrosis and clinical characteristics on dose-adjusted serum methadone concentrations.

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.

Association between oral and general health related quality of life among Norwegian patients with substance use disorders in opioid agonist therapy.

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.

Vitamin D status and associations with substance use patterns among people with severe substance use disorders in Western Norway.

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.

Folate Status as a Nutritional Indicator among People with Substance Use Disorder; A Prospective Cohort Study in Norway.

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 ß-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.

Vitamin B12 Levels, Substance Use Patterns and Clinical Characteristics among People with Severe Substance Use Disorders: A Cohort Study from Western Norway.

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.

Prevalence and correlates of suicide attempts in high-risk populations: a cross-sectional study among patients receiving opioid agonist therapy in Norway.

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.

Changes in substance use during outpatient treatment for substance use disorders: a prospective Norwegian cohort study from 2016 to 2020.

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.

Integrated treatment of hepatitis C virus infection among people who inject drugs: A multicenter randomized controlled trial (INTRO-HCV).

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.

Subjective symptoms and serum methadone concentrations: what should guide dose adjustments in methadone maintenance treatment? A naturalistic cohort study from Norway.

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.

Validation of a three-item Fatigue Severity Scale for patients with substance use disorder: a cohort study from Norway for the period 2016-2020.

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 (χ2 = 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.

Substance use and symptoms of mental health disorders: a prospective cohort of patients with severe substance use disorders in Norway.

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.

Impact of clinical and sociodemographic factors on fatigue among patients with substance use disorder: a cohort study from Norway for the period 2016-2020.

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 (ß) 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.

Health-related quality of life of long-term patients receiving opioid agonist therapy: a nested prospective cohort study in Norway.

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.

On the path towards universal coverage of hepatitis C treatment among people receiving opioid agonist therapy (OAT) in Norway: a prospective cohort study from 2013 to 2017.

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.

Potentially addictive drugs dispensing to patients receiving opioid agonist therapy: a register-based prospective cohort study in Norway and Sweden from 2015 to 2017.

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.

Uptake and predictors of direct-acting antiviral treatment for hepatitis C among people receiving opioid agonist therapy in Sweden and Norway: a drug utilization study from 2014 to 2017.

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.

Too much or too little opioids to patients receiving opioid agonist therapy in Norway (2013-2017): a prospective cohort study.

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.