Increased cancer incidence and mortality among people with opioid use-related disorders: A nation-wide cohort study.

BACKGROUND AND AIMS: Studies on cancer incidence and mortality among people with opioid use-related disorders are lacking. We aimed to measure cancer-specific incidence, mortality and survival among people diagnosed with opioid use-related disorders in Norway during 2010-18. DESIGN AND SETTING: This was a cohort study conducted in Norway during 2010-18. PARTICIPANTS: Individuals (n = 20 710) diagnosed with opioid use-related disorders. MEASUREMENTS: We conducted a cohort study utilizing a data-linkage of national health and population registers. Information on opioid use-related disorders was extracted from specialized healthcare, malignancies from the Cancer Registry of Norway and deaths from Cause of Death Registry. Cancer incidence and mortality were compared with the general population by calculating sex-specific age-standardized incidence (SIR) and mortality (SMR) ratios. One-year survival rates were computed. FINDINGS: Compared with the general population, people with opioid use-related disorders were at an increased risk of developing cancer overall [SIR = 1.2, 95% confidence interval (CI) = 1.1-1.3] with a higher than twofold cancer mortality rate (SMR = 2.3, 95% CI = 2.0-2.7). Excess risk was observed for liver (12.6, 95% CI = 9.1-17.0), larynx (4.7, 95% CI = 1.7-10.2), lung (3.5, 95% CI = 2.8-4.3) and pancreas cancer (2.6, 95% CI = 1.6-4.0), whereas reduced risk was found for melanoma (0.5, 95% CI = 0.3-0.9), breast (0.6, 95% CI = 0.4-0.9) and prostate cancers (0.3, 95% CI = 0.1-0.4). Site-specific SMRs were significantly elevated for liver (12.3, 95% CI = 8.5-17.2), lung (3.9, 95% CI = 3.0-5.0), pancreas (3.0, 95% CI = 1.7-4.8) and colon cancers (1.9, 95% CI = 1.1-3.1). The average 1-year survival rate after a cancer diagnosis was low in liver, pancreas and colon cancer, ranging from 10 to 15% less than that of the general population. CONCLUSIONS: In Norway, cancer incidence and cancer-related mortality appear to be elevated among individuals with opioid use-related disorders.

Exploring dual diagnosis in opioid agonist treatment patients: a registry-linkage study in Czechia and Norway.

BACKGROUND: Knowledge of co-occurring mental disorders (termed 'dual diagnosis') among patients receiving opioid agonist treatment (OAT) is scarce. This study aimed (1) to estimate the prevalence and structure of dual diagnoses in two national cohorts of OAT patients and (2) to compare mental disorders between OAT patients and the general populations stratified on sex and standardized by age. METHODS: A registry-linkage study of OAT patients from Czechia (N = 4,280) and Norway (N = 11,389) during 2010-2019 was conducted. Data on mental disorders (F00-F99; ICD-10) recorded in nationwide health registers were linked to the individuals registered in OAT. Dual diagnoses were defined as any mental disorder excluding substance use disorders (SUDs, F10-F19; ICD-10). Sex-specific age-standardized morbidity ratios (SMR) were calculated for 2019 to compare OAT patients and the general populations. RESULTS: The prevalence of dual diagnosis was 57.3% for Czechia and 78.3% for Norway. In Czechia, anxiety (31.1%) and personality disorders (25.7%) were the most prevalent, whereas anxiety (33.8%) and depression (20.8%) were the most prevalent in Norway. Large country-specific variations were observed, e.g., in ADHD (0.5% in Czechia, 15.8% in Norway), implying differences in screening and diagnostic practices. The SMR estimates for any mental disorders were 3.1 (females) and 5.1 (males) in Czechia and 5.6 (females) and 8.2 (males) in Norway. OAT females had a significantly higher prevalence of co-occurring mental disorders, whereas SMRs were higher in OAT males. In addition to opioid use disorder (OUD), other substance use disorders (SUDs) were frequently recorded in both countries. CONCLUSIONS: Results indicate an excess of mental health problems in OAT patients compared to the general population of the same sex and age in both countries, requiring appropriate clinical attention. Country-specific differences may stem from variations in diagnostics and care, reporting to registers, OAT provision, or substance use patterns.

Treatment patterns of antidepressants in children and adolescents in Scandinavia.

The aim of this study was to examine variations in use of antidepressants among children and adolescents in the three Scandinavian countries (Sweden, Norway, and Denmark). We identified new users of antidepressants (5-17 years) during 2007-2018 and described the annual incidence rate, treatment duration, concomitant psychotropic drug use, and the clinical setting of the prescribing physician (in Sweden and Denmark). Incident use of antidepressants increased by a factor 1.9 in Sweden, 1.3 in Norway and decreased by a factor 0.6 in Denmark during the study period. In Sweden, 58% of antidepressant users were covered by a prescription 12 months after initiation compared to 40% in Norway and 49% in Denmark. Also, 34% of Swedish antidepressant users were in continuous treatment after 12 months compared to 26% in Norway and 31% in Denmark. Concomitant use of other psychotropics was more common in Sweden (57%) than in Norway (37%) and Denmark (27%). During 2007-2018, clinicians from psychiatry settings initiated 75% of antidepressant treatments in Sweden, while this was the case for 50% of prescriptions in Denmark, although the proportion increased over time. The number of new antidepressant users is high and still rising in Sweden compared to Norway and Denmark. Swedish antidepressant users are more likely to use other psychotropics and to be covered by an antidepressant prescription after one year. Most antidepressants in Sweden are prescribed by physicians within psychiatric settings suggesting that they are based on specialized psychiatric evaluation.

Morbidity among Adolescent Hypnotic Drug Users in Norway: An Observational Population-Based Study.

We have previously shown that the use of hypnotic drugs increased among young Scandinavians during 2012-2018. This study aimed to explore psychiatric and somatic morbidity among adolescent hypnotic drug users in a cohort study of 13-17-year-old individuals during 2008-2018 in Norway. Data sources were (i) prescription data from the Norwegian Prescription Database linked to specialist health care diagnoses from the Norwegian Patient Registry and (ii) sleep disorder diagnoses from the Primary Health Care Database. Hypnotic drugs were defined as the sedative antihistamine alimemazine and the ATC group "Hypnotics and Sedatives" (N05C), excluding midazolam. In 2017, 2519 girls (16.5/1000) and 1718 boys (10.7/1000) were incident (new) users of hypnotic drugs. Most of these new users (82% of girls, 77% of boys) were referred to secondary health care, where the most frequent diagnoses were mental and behavioral disorders (51.8% of girls, 46.2% of boys), while only 3.2% received a specific sleep disorder diagnosis. The most common mental and behavioral disorders were "Neurotic stress-related disorders" among girls (27.4%) and "Behavioral and emotional disorders" among boys (23.6%). In conclusion, the trend of increasing hypnotic drug use among adolescents reflects the initiation of hypnotic drugs in a subgroup of the population with a higher disease burden, mainly due to psychiatric disorders, than the general population.

Patterns of filled prescriptions and the association with risk of drug-induced death. A population-based nested case-control register study.

PURPOSE: Opioid analgesics (OA) and other pharmaceuticals have been associated with drug-induced deaths. However, there is a lack of knowledge regarding patterns of use of these pharmaceuticals in the population and regarding such associations. We identify and describe subgroups of people with different patterns of filled prescriptions of OA and other relevant pharmaceuticals and examine associations with drug-induced deaths. In addition, we estimate the proportion of drug-induced deaths with a filled OA prescription and OA as cause of death. METHODS: A Norwegian population-based nested case-control register study with cases (drug-induced deaths 2010-2018, N = 2388) and population controls matched for age, gender and year of inclusion (N = 21 465). Patterns of filled prescriptions for opioid analgesics (OA), benzodiazepines and benzodiazepine-related drugs, gabapentinoids, ADHD medication and antidepressants/antipsychotics were explored by k-means cluster analysis. Associations with drug-induced deaths were estimated by conditional logistic regression adjusted for sociodemographic characteristics. Overlap of filled OA prescriptions and OA as cause of death was estimated. RESULTS: Five clusters were identified: 'few prescriptions', 'weak OA', 'ADHD medication', 'sedative/psychiatric morbidity' and 'strong OA'. The 'strong OA' cluster had higher socioeconomic status compared to the other groupings. The risk of drug-induced death was also highest in this cluster (OR = 35.5; CI 25.6-49.3) and, for 68% (CI 64-73) of cases, filled prescriptions for OA was indicated as the underlying cause of death. CONCLUSIONS: The cluster analysis identified a subgroup with filled prescriptions of OA and other pharmaceuticals and a higher socioeconomic status than other subgroups. This subgroup had a high risk of drug-induced death that needs to be addressed.

Psykiske lidelser og plager ved vedvarende opioidbruk for langvarige ikke-kreftrelaterte smerter ­ en registerstudie.

Background: Knowledge of mental disorders among patients with persistent opioid use for the treatment of chronic non-cancer pain is essential, as mental disorders and symptoms can exacerbate or perpetuate pain and impact on the ability of patients to manage their illness. We have studied the prevalence of mental disorders and symptoms, including substance use disorders, in patients with persistent opioid use in 2019. Material and method: Persons ≥ 18 years with persistent opioid use and persons ≥ 18 years with at least one registered mental disorder in the specialist healthcare service in 2019 were included. Data were retrieved from national health registries in Norway. Patients who received opioids reimbursed for the treatment of chronic pain were compared with those who received opioids without reimbursement. Results: The prevalence of mental disorders and symptoms was 34 % among 14 403 persons who received reimbursed opioids, and 42 % among 38 001 persons who received opioids without reimbursement. This is equivalent to a two to threefold increase in prevalence compared to the general population. There was a particularly higher prevalence of anxiety disorders and substance use disorders. The prevalence of mental disorders and symptoms was highest in the age group 18-44 years (49-55 %). Interpretation: Among patients with persistent opioid use, a large proportion had mental disorders and symptoms, which are known risk factors for developing problematic opioid use and opioid use disorder.

Recognition and management of children and adolescents with conduct disorder: a real-world data study from four western countries.

BACKGROUND: Conduct disorders (CD) are among the most frequent psychiatric disorders in children and adolescents, with an estimated worldwide prevalence in the community of 2-4%. Evidence-based psychological outpatient treatment leads to significant improvement in about two-thirds of cases. However, there seems to be considerable variation in rates of CD diagnoses and implementation of evidence-based interventions between nations. The aim of this study was to compare administrative prevalence and treatment patterns for CD in children and adolescents seen in health care systems across four Western countries (Denmark, Germany, Norway, and the USA). METHODS: Cross-sectional observational study using healthcare data to identify children and adolescents (aged 0-19 years) with an ICD-10 code for CD within the calendar year 2018. Within each country's study population, the prevalence of CD, psychiatric comorbidity, psychopharmacological treatment, and psychiatric hospitalisation was calculated. RESULTS: The prevalence of diagnosed CD differed 31-fold between countries: 0.1% (Denmark), 0.3% (Norway), 1.1% (USA) and 3.1% (Germany), with a male/female ratio of 2.0-2.5:1. The rate of psychiatric comorbidity ranged from 69.7 to 86.1%, with attention-deficit/hyperactivity disorder being most common. Between 4.0% (Germany) and 12.2% (USA) of youths with a CD diagnosis were prescribed antipsychotic medication, and 1.2% (Norway) to 12.5% (Germany) underwent psychiatric hospitalisation. CONCLUSION: Recognition and characteristics of youths diagnosed with CD varied greatly by country. In some countries, the administrative prevalence of diagnosed CD was markedly lower than the average estimated worldwide prevalence. This variation might reflect country-specific differences in CD prevalence, referral thresholds for mental health care, diagnostic tradition, and international variation in service organisation, CD recognition, and availability of treatment offers for youths with CD. The rather high rates of antipsychotic prescription and hospitalisation in some countries are remarkable, due to the lack of evidence for these therapeutic approaches. These findings stress the need of prioritising evidence-based treatment options in CD. Future research should focus on possible reasons for inter-country variation in recognition and management of CD, and also address possible differences in patient-level outcomes.

Fatal drug overdoses in individuals treated pharmacologically for chronic pain: a nationwide register-based study.

INTRODUCTION: Chronic pain patients may be at an increased risk for drug overdoses as a result of comorbid psychiatric disorders and treatment with risk-increasing prescription medications, such as opioids. We aimed to characterise fatal drug overdoses and investigate factors associated with the deaths among individuals who had been treated pharmacologically for chronic pain. METHODS: We included all individuals who received analgesics reimbursed for chronic pain in Norway during 2010-9 (n=569 047). Among this population, we identified all individuals with drug overdoses as cause of death (cases). Extracting data from national registries on diagnoses, filled prescriptions, and socioeconomic variables, we used a nested case-control design to compare the cases with age- and sex-matched controls from the study population. RESULTS: Overall, 623 (0.11%) individuals in the study population died of an overdose. Most, 66.8%, had overdosed accidentally, and 61.9% as a result of pharmaceutically available opioids. Compared with the controls (n=62 245), overdoses overall were associated strongly with substance use disorders (adjusted odds ratio 7.78 [95% confidence interval 6.20-9.77]), use of combinations of opioids, benzodiazepines and related drugs and gabapentinoids (4.60 [3.62-5.85]), previous poisoning with pharmaceuticals (2.78 [2.20-3.51]), and with living alone the last year of life (2.11 [1.75-2.54]). Intentional overdoses had a stronger association with previous poisonings with pharmaceuticals whereas accidental overdoses were strongly associated with substance use disorders. CONCLUSIONS: This study shows the need for better identification of overdose and suicide risk in individuals treated for chronic pain. Extra caution is needed when treating complex comorbid disorders, especially with overdose risk-increasing medications.

Childhood trauma and the use of opioids and other prescription analgesics in adolescence and young adulthood: The HUNT Study.

ABSTRACT: Opioid and nonopioid analgesics are commonly prescribed to young people to alleviate pain. Even short-term prescriptions increase the risk of persistent use and future misuse of potent analgesics, such as opioids. Childhood trauma exposure has been found to be related to pain conditions and to using more prescription analgesics. This large, prospective cohort study aimed to investigate the association of a broad range of childhood trauma exposures with prescription rates for opioid and nonopioid analgesics in adolescence and young adulthood. Self-reported data on childhood trauma exposures from adolescents (aged 13-19 years) who participated in the Young-HUNT3 Study (2006-2008, n = 8199) were linked to data from the Norwegian Prescription Database (NorPD, 2004-2021). We found that exposure to childhood trauma was consistently associated with higher prescription rates for opioids throughout adolescence and young adulthood. The highest incidence rate ratio (IRR) in adolescence was observed for sexual abuse (IRR 1.63, confidence interval [CI] 1.19-2.23). In young adulthood, the highest IRR was observed for physical violence (2.66, CI 2.27-3.12). The same overall pattern was observed for nonopioid analgesics. The more frequent prescriptions of opioid and nonopioid analgesics to participants exposed to childhood trauma suggests a higher symptom load of pain causing them to seek professional help with pain relief. Receiving potent analgesics is not without risk, and the likelihood of misuse may be elevated among trauma-exposed individuals. A trauma-informed approach to pain could be vital for guiding clinicians to the most effective and least harmful treatment for each patient.

Large variations in all-cause and overdose mortality among >13,000 patients in and out of opioid maintenance treatment in different settings: a comparative registry linkage study.

Background: Opioid maintenance treatment (OMT) has the potential to reduce mortality rates substantially. We aimed to compare all-cause and overdose mortality among OMT patients while in or out of OMT in two different countries with different approaches to OMT. Methods: Two nation-wide, registry-based cohorts were linked by using similar analytical strategies. These included 3,637 male and 1,580 female patients enrolled in OMT in Czechia (years 2000-2019), and 6,387 male and 2,078 female patients enrolled in OMT in Denmark (years 2007-2018). The direct standardization method using the European (EU-27 plus EFTA 2011-2030) Standard was employed to calculate age-standardized rate to weight for age. All-cause and overdose crude mortality rates (CMR) as number of deaths per 1,000 person years (PY) in and out of OMT were calculated for all patients. CMRs were stratified by sex and OMT medication modality (methadone, buprenorphine, and buprenorphine with naloxone). Results: Age-standardized rate for OMT patients in Czechia and Denmark was 9.7/1,000 PY and 29.8/1,000 PY, respectively. In Czechia, the all-cause CMR was 4.3/1,000 PY in treatment and 10.8/1,000 PY out of treatment. The overdose CMR was 0.5/1,000 PY in treatment and 1.2/1,000 PY out of treatment. In Denmark, the all-cause CMR was 26.6/1,000 PY in treatment and 28.2/1,000 PY out of treatment and the overdose CMR was 7.3/1,000 PY in treatment and 7.0/1,000 PY out of treatment. Conclusion: Country-specific differences in mortality while in and out of OMT in Czechia and Denmark may be partly explained by different patient characteristics and treatment systems in the two countries. The findings contribute to the public health debate about OMT management and may be of interest to practitioners, policy and decision makers when balancing the safety and accessibility of OMT.

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

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

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

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

Opioid prescriptions among Sami and non-Sami with chronic pain: The SAMINOR 2 Questionnaire Survey and the Norwegian Prescription Database.

This study is the first to investigate the prevalence of filled opioid prescriptions among indigenous Sami people with self-reported chronic musculoskeletal pain (CMSP) and compare it with that of non-Sami living in the same area. Baseline data from the SAMINOR 2 Questionnaire Survey (2012) was linked prospectively to the Norwegian Prescription Database. Information on filled opioid prescriptions during 2012-2019 was collected for 4767 persons who reported CMSP in SAMINOR 2. Gender-stratified chi-square tests, two-sample t-tests, Kruskal - Wallis tests, and multinomial logistic regression was applied. Two out of three CMSP respondents received no or only one prescription of opioids during 2012-2019. In each year, 80% of women received no opioids, 7-10% received one prescription of ≤ 180 defined daily doses (DDD), 8-9% received in total ≤ 180 DDD in two or more prescriptions, and 2-3% received > 180 DDD of opioids. Among men, 81-83% received no opioids, 8-11% received one prescription with ≤ 180 DDD, 5-9% received ≤ 180 DDD in two or more prescriptions, and 1-2% received > 180 DDD of opioids in a single year. There were no overall ethnic differences, which indicates a similar prescription policy for opioids for Sami and non-Sami with CMSP.

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

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

Persistent Use of Prescription Opioids Before and After Lumbar Spine Surgery: Observational Study With Prospectively Collected Data From Two Norwegian National Registries.

STUDY DESIGN: Prospective pharmacoepidemiologic study. OBJECTIVE: To investigate clinical and sociodemographic factors associated with persistent opioid use in the years following spine surgery among patients with persistent opioid use preceding lumbar spine surgery. SUMMARY OF BACKGROUND DATA: It is unknown whether successful spine surgery leads to a cessation of preoperative persistent opioid use. MATERIALS AND METHODS: Data from the Norwegian Registry for Spine Surgery and the Norwegian Prescription Database were linked for patients operated for degenerative lumbar spine disorders between 2007 and 2017. The primary outcome measure was persistent opioid use in the second year after surgery. Functional disability was measured with the Oswestry Disability Index (ODI). Factors associated with persistent opioid use in the year before, and two years following, surgery were identified using multivariable logistic regression analysis. The variables included in the analysis were selected based on their demonstrated role in prior studies. RESULTS: The prevalence of persistent opioid use was 8.7% in the year before surgery. Approximately two-thirds of patients also met the criteria for persistent opioid use the second year after surgery. Among patients who did not meet the criteria for persistent opioid use the year before surgery, 991 (3.3%) patients developed persistent opioid use in the second year following surgery. The strongest association was exhibited by high doses of benzodiazepines in the year preceding surgery (OR 1.7, 95% CI 1.26 to 2.19, P <0.001). Among patients without persistent opioid use, the most influential factor associated with new-onset persistent opioid use in the second year after surgery was the use of high doses of benzodiazepines (OR 1.8, 95% CI 1.26 to 2.44, P <0.001), high doses of z -hypnotics (OR 2.6, 95% CI 2.10 to 3.23, P <0.001) and previous surgery at the same lumbar level (OR 1.37, 95% CI 1.11 to 1.68, P =0.003). CONCLUSION: A substantial proportion of patients reported sustained opioid use after surgery. Patients with persistent opioid use before surgery should be supported to taper off opioid treatment. Special efforts appear to be required to taper off opioid use in patients using high doses of benzodiazepines. LEVEL OF EVIDENCE: 2; Prospective observational study.

Prenatal opioid exposure and risk of asthma in childhood: a population-based study from Denmark, Norway, and Sweden.

Background: Opioids may modulate the immune function through opioid receptors on immune cells. Long-term consequences of prenatal opioid exposure on the immune system, such as childhood asthma, are unknown. Objectives: To investigate whether prenatal opioid exposure is associated with the risk of childhood asthma. Methods: Cohort study using linked nationwide registers in Denmark (1996-2015), Norway (2005-2015), and Sweden (2006-2013). Children born by mothers who were chronic opioid analgesics users before pregnancy (n = 14,764) or who were receiving opioid maintenance therapy (OMT) before or during pregnancy (n = 1,595) were identified based on information from each of the medical birth registers and prescription registers. Long-term opioid analgesics exposed children were compared to short-term exposed or unexposed, whereas OMT exposed children were compared to OMT unexposed. Asthma among children ≥1 years of age was defined as two or more filled prescriptions of antiasthmatic medication within 365 days, or a diagnosis of asthma. Hazard ratios (HRs) were calculated using Cox proportional hazards regression with attained age as the time scale. Inverse probability of treatment weights based on propensity scores were applied to adjust for measured confounders. Individual level data from Norway and Sweden were pooled, whereas individual level data from Denmark were analyzed separately. For the opioid analgesics comparisons, adjusted HRs (aHR) from the combined Norwegian/Swedish data and the Danish data were pooled in a fixed-effects meta-analysis. Results: For the opioid analgesics cohort, no increased risk of asthma was observed in long-term exposed children neither compared with unexposed [aHR = 0.99 (95% CI 0.87-1.12)], nor compared with short-term exposed [aHR = 0.97 (0.86-1.10)]. No increased risk of asthma was observed in OMT exposed compared with OMT unexposed children [Norway/Sweden: aHR = 1.07 (0.60-1.92), Denmark: aHR = 1.25 (0.87-1.81)]. Results from sensitivity analyses, where potential misclassification of the outcome and misclassification of OMT exposure were assessed, as well as starting follow-up at 6 years of age, showed that the estimates of association were generally robust. Conclusion: We found no association between prenatal exposure to opioids and risk of childhood asthma. Results were consistent across two different opioid exposure groups with different confounder distributions.

Can academic detailing reduce opioid prescriptions in chronic non-cancer pain?

BACKGROUND: One measure to support optimal opioid prescription is academic detailing (AD) with one-to-one visits by trained professionals (academic detailers) to general practitioners (GPs). OBJECTIVE: To investigate the usefulness of AD visits on GPs' opioid prescribing patterns in Norway, and academic detailers' experiences with AD visits to GPs on opioid prescription. METHODS: Design: A quantitative registry study on opioid prescriptions and a qualitative focus group interview study with academic detailers. PARTICIPANTS: For the registry study, municipalities where more than 75% of the GPs had received an AD visit were considered intervention municipalities, whereas in the non-intervention municipalities no GPs had received AD-visits. In the focus groups, academic detailers who had conducted three or more AD-visits were invited to participate. INTERVENTION: A campaign on opioid prescription with AD visits using a brochure with key messages based on the national guideline for treatment of chronic non-cancer pain and updated evidence on the potential benefits and risks of prescribing opioids. The AD visits in the campaign were planned for 20-25 min in a one-to-one setting in the GP's office. MAIN MEASURES: The Norwegian Prescription Database (NorPD) was utilized for registry data. Data on amount of drugs dispensed are recoded as Defined Daily Doses (DDDs). RESULTS: Compared to non-intervention, the intervention resulted in a decrease in the number of prevalent and incident users of opioids and incident users of reimbursed opioids for chronic non-cancer pain in municipalities in Central Norway. The results from the focus group interviews were categorized into the themes: "To get in position", "Adjusting messages", "What did the GPs struggle with, in relation to opioid prescription?" and "Did we reach the right recipients with the visits?". CONCLUSIONS: In Central Norway, the intervention resulted in a desired effect on number of opioid users. According to the academic detailers, the GPs' length of working experience and familiarity with the topic gave different presumptions for making use of the information presented in the AD-visits.

Morbidity through 3 Years of Age in Children of Women Using Methamphetamine during Pregnancy: A National Registry Study.

BACKGROUND: There is a lack of studies on methamphetamine (MA) exposure and morbidity in children beyond the perinatal period. OBJECTIVES: We compared morbidity in children (0-3 years) with prenatal MA exposure to opioid-exposed and to non-exposed children. METHODS: We used data from a Czech nationwide, registry-based cohort study (2000-2014). Children, who reached 3 years of age, of mothers hospitalized with (i) MA use disorder during pregnancy (MA; n = 194), (ii) opioid use disorder during pregnancy (opioids; n = 166), and (iii) general population (GP; n = 1,294,349) with no recorded history of substance use disorder (SUD). Information on inpatient contacts, length of stay, and diagnoses (International Statistical Classification of Diseases and Related Health Problems 10th Revision [ICD-10]) were assessed. Crude and adjusted odds ratios (aOR), 95% confidence interval (CI) for the risk of hospitalization, and for getting diagnosis from the ICD-10 diagnosis chapters were calculated using binary logistic regression. A stratified analysis on hospitalizations with SUD of mothers was performed. RESULTS: No significant differences were found in the measures of hospitalization between the MA and opioid groups. Children prenatally exposed to MA and opioids had higher numbers of hospitalizations and diagnoses and longer stays in hospital than children in the GP. Increased risks of certain infectious and parasitic diseases were found in both MA (aOR = 1.6; CI: 1.1-2.3) and opioid (aOR = 1.9; 1.3-2.8) groups as compared to the GP group. The most pronounced difference in stratified analysis on maternal hospitalizations related to SUD after birth was observed for injury, poisoning, and certain other consequences of external causes in the strata of the MA group who had hospitalized mothers (aOR 6.3, 1.6-24.6) compared to the strata without maternal hospitalizations (aOR 1.4, 0.9-2.3). CONCLUSION: This study suggests that children born to mothers using MA during pregnancy have similar morbidity during the first 3 years of life but higher than the GP. The excess of risk was primarily due to infections and injuries in the MA group.

Utilization of antidepressants, anxiolytics, and hypnotics during the COVID-19 pandemic in Scandinavia.

OBJECTIVE: To study patterns of antidepressant, anxiolytic, and hypnotic drug utilization in Denmark, Norway, and Sweden during the first year of the COVID-19 pandemic. METHODS: The monthly observed number of prescription fills of antidepressants, benzodiazepines and benzodiazepine-related hypnotics (BZ), and other anxiolytics and hypnotics (OAH) per population in 2020 were compared with predicted numbers based on analysis of covariance of prescription fills during 2015-2019. RESULTS: In March 2020, there was an increased number of prescription fills for antidepressants, anxiolytics, and hypnotics in youths and adults aged 20-59 years in Denmark, Norway, and Sweden. Antidepressant prescription fills increased between 13.5 % and 31.3 % at the end of 2020 in all age groups in Denmark and 17.4 % in youths in Norway. BZ drug prescription fills increased by 20.8 % at the end of 2020 in the 20-59 year age group in Denmark and decreased by 16.7 % in youths in Sweden. A general increase of prescription fills of OAH at the end of 2020 was observed in all countries (range 24.0-80.0 % in Denmark, 11.5-30.8 % in Norway, and 9.1-12.1 % in Sweden). Increases of prescription fills of OAH occurred earlier in Denmark. LIMITATIONS: Aggregated data with lack of information on indications. CONCLUSIONS: Peaks of utilization of antidepressants, anxiolytics, and hypnotics observed in March 2020 may reflect medication stock piling. Increased antidepressant drug utilization in Denmark and in Norwegian youths together with the general increase in OAH utilization in the Scandinavian countries in late 2020 may indicate an increase of symptoms of depression and anxiety, as well as disturbed sleep.

Use of benzodiazepines and benzodiazepine-related drugs in the Nordic countries between 2000 and 2020.

Use of benzodiazepines (BZ) and related drugs is subject to considerable debate due to problems with dependency and adverse events. We aimed to describe and compare their use across the Nordic countries. Data on the use of clonazepam, BZ-sedatives, BZ-hypnotics, and benzodiazepine-related drugs (BZRD) in adults (≥20 years) were obtained from nationwide registers in Denmark, Finland, Iceland, Norway, and Sweden, 2000-2020. Main measures were therapeutic intensity (TI:DDD/1000 inhabitants [inhab.]/day) and annual prevalence (users/1000 inhab./year). Overall, TI of BZ and related drugs decreased in all Nordic countries from 2004 to 2020. However, there were considerable differences between countries in TI. In 2020, the TI of BZ and related drugs ranged from 17 DDD/1000 inhab./day in Denmark to 93 DDD/1000 inhab./day in Iceland. BZRD accounted for 55-78% of BZ use in 2020, followed by BZ sedatives at 20-44%, BZ-hypnotics at <1-5%, and clonazepam at <1-2%. Annual prevalence of BZ use increased with age in all countries, and the highest annual prevalence was observed among people ≥80 years. Overall, the use of BZ and related drugs has decreased in all Nordic countries from 2004 to 2020, however, with considerable differences in their use between countries. The highest prevalence was observed among the oldest age groups-despite warnings against their use in this population.