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.

Real-world effectiveness of antidepressants, antipsychotics and their combinations in the maintenance treatment of psychotic depression. Evidence from within-subject analyses of two nationwide cohorts.

Psychotic depression (PD) is a severe mental disorder leading to functional disability and high risk of suicide, but very little is known about the comparative effectiveness of medications used in its maintenance treatment. The objective of this study was to investigate the comparative effectiveness of specific antipsychotics and antidepressants, and their combinations, on the risk of psychiatric hospitalization among persons with PD in routine care. Persons aged 16-65 years with a first-time diagnosis of PD were identified from Finnish (years 2000-2018) and Swedish (years 2006-2021) nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. The main exposures were specific antipsychotics and antidepressants, and the main outcome measure was psychiatric hospitalization as a marker of severe relapse. The risk of hospitalization associated with periods of use vs. non-use of medications (expressed as adjusted hazard ratio, aHR) was assessed by a within-individual design, using each individual as his/her own control, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately, and then combined using a fixed-effect meta-analysis. The Finnish cohort included 19,330 persons (mean age: 39.8±14.7 years; 57.9% women) and the Swedish cohort 13,684 persons (mean age: 41.3±14.0 years; 53.5% women). Individual antidepressants associated with a decreased risk of relapse vs. non-use of antidepressants were bupropion (aHR=0.73, 95% CI: 0.63-0.85), vortioxetine (aHR=0.78, 95% CI: 0.63-0.96) and venlafaxine (aHR=0.92, 95% CI: 0.86-0.98). Any long-acting injectable antipsychotic (LAI) (aHR=0.60, 95% CI: 0.45-0.80) and clozapine (aHR=0.72, 95% CI: 0.57-0.91) were associated with a decreased risk of relapse vs. non-use of antipsychotics. Among monotherapies, only vortioxetine (aHR=0.67, 95% CI: 0.47-0.95) and bupropion (aHR=0.71, 95% CI: 0.56-0.89) were associated with a significantly decreased risk of relapse vs. non-use of both antidepressants and antipsychotics. In an exploratory analysis of antidepressant-antipsychotic combinations, a decreased relapse risk was found for amitriptyline-olanzapine (aHR=0.45, 95% CI: 0.28-0.71), sertraline-quetiapine (aHR=0.79, 95% CI: 0.67-0.93) and venlafaxine-quetiapine (aHR=0.82, 95% CI: 0.73-0.91) vs. non-use of antidepressants and antipsychotics. Benzodiazepines and related drugs (aHR=1.29, 95% CI: 1.24-1.34) and mirtazapine (aHR=1.17, 95% CI: 1.07-1.29) were associated with an increased risk of relapse. These data indicate that, in the maintenance treatment of PD, bupropion, vortioxetine, venlafaxine, any LAI, clozapine, and only few specific antidepressant-antipsychotic combinations are associated with a decreased risk of relapse. These findings challenge the current recommendation by treatment guidelines to combine an antipsychotic with an antidepressant (without further specification) as standard treatment in PD.

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.

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.

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.

Cohort Description: Preventing an Opioid Epidemic in Norway - Focusing on Treatment of Chronic Pain (POINT) - A National Registry-Based Study.

Aim: The POINT project aims to provide evidence to optimise chronic pain management, prevent adverse consequences of opioids, and improve chronic pain patients' pain relief, functional capacity, and quality of life. We describe the outline of the project and its work packages. More specifically, we describe a cohort of persons with chronic pain and a cohort of long-term opioid users identified from a national registry linkage. Data Sources: The project utilises data from nationwide healthcare and population registers in Norway. Using the Norwegian Prescription Database, we identified a cohort of persons who have been dispensed drugs reimbursed for chronic pain and a cohort of persons who used opioids long term from 2010 to 2019. Data from the Norwegian Registry for Primary Health Care and the Norwegian Patient Registry (2008-2019), Cancer Registry (1990-2018) Cause of Death Registry (2010-2019) and demographic and socioeconomic registers from Statistics Norway (2010-2019) were linked to the cohorts. Study Population: There were 568,869 participants with chronic pain. Sixty-three percent of the cohort was women, and the mean age was 57.1 years. There were 336,712 long-term opioid users (58.6% women; 60.9 years). In chronic pain and long-term opioid user cohorts, the most frequent musculoskeletal diagnosis was back pain diagnosed in primary care (27.6% and 30.7%). Psychiatric diagnoses were also common. Main Variables: Upcoming studies will utilise psychiatric and somatic diagnoses from the patient registers, drug use from the prescription register, causes of death, demographics, and socioeconomic status (eg, education, income, workability, immigrant status) as exposures or outcomes. Conclusion and Future Plans: The two cohorts have numerous pain-related diagnoses, especially in the musculoskeletal system, and noticeably frequent somatic and psychiatric morbidity. The POINT project also includes later work packages that explore prescriber and patient perspectives around safe and effective treatment of chronic pain.

Individuals Dying of Overdoses Related to Pharmaceutical Opioids Differ from Individuals Dying of Overdoses Related to Other Substances: A Population-Based Register Study.

BACKGROUND: Pharmaceutical opioid (PO) overdose deaths have increased in many Western countries. There are indications that those dying from a PO overdose differ from those dying from other types of overdoses. These differences might pose a challenge as the majority of current preventive measures are tailored toward those with the characteristics of "conventional" overdose deaths. OBJECTIVE: We investigated differences in the characteristics of persons who died from PO overdoses compared to all other overdoses. MATERIAL AND METHODS: Using the Norwegian Cause of Death Registry, we retrieved information on overdoses classified according to ICD-10 and identified PO overdoses (T40.2; T40.4) and all other overdoses (T40.X; T43.6) in 2010-2019. By linking data from nationwide registers, we analyzed data on opioid dispensations and the history of mental and behavioral disorders. 1,224 persons were registered with PO overdoses and 1,432 persons with other overdoses. RESULTS: Persons in the PO overdose group were older and were more frequently women (35.0% vs. 20.5%) than persons with other overdoses. They had a higher prevalence of chronic pain (35.8% vs. 13.2%), history of cancer (8.1% vs. 1.8%), filled prescriptions of analgetic opioids more frequently the month before death (38.8% vs. 12.0%), and used threefold higher doses of prescribed opioids compared to individuals in all other overdose group (66 vs. 26 oral morphine equivalents/day). In the PO overdose group, oxycodone and fentanyl were more frequently dispensed, while codeine was more frequently dispensed in the other overdose groups. A lower proportion of those in the PO overdose group had recorded diagnoses of substance use disorders, schizophrenia, and hyperkinetic disorder compared to the other overdose groups. CONCLUSION: Persons dying from overdoses on POs often differ from the population targeted by existing prevention strategies, as they are more frequently older women with chronic pain and using high doses of prescription opioids.

Describing long-term opioid use utilizing Nordic prescription registers-A Norwegian example.

Previous studies have defined long-term opioid use in varying ways, decreasing comparability, reproducibility and clinical applicability of the research. Based on recommendations from recent systematic reviews, we aimed to develop a methodology to estimate the prevalence of use persisting more than three months utilizing one of the Nordic prescription registers. We used the Norwegian Prescription Register (NorPD) to extract data on all opioid dispensations between 1 January 2004 and 31 October 2019. New users of opioids (washout 365 days) were defined as long-term users if they fulfilled two criteria: (1) they had ≥2 dispensations of opioids, 91-180 days apart; (2) days 0-90 included ≥90 dispensed administration units (e.g., tablets) of opioids. Overall, there were 2,543,224 new users of opioids during the study period. Of these, 354,666 (13.9%) fulfilled the criteria for long-term opioid use at least once. Compared with those who did not fulfil the criteria (short-term users), long-term users were older, more likely women and used tramadol, oxycodone and buprenorphine more frequently as their first opioid. In conclusion, we found that 1/7 of opioid users continued use longer than 3 months. Future outcome research should identify the clinically most important dose requirements for long-term opioid use criteria.

Filled prescriptions for opioids among children and adolescents - A nationwide study from 2010 to 2018.

BACKGROUND: Prescribing opioids for children and adolescents should be reserved for advanced life-limiting diseases and moderate-to-severe acute pain. Pediatric codeine use is discouraged by several authorities, but the effects of these recommendations are not fully known. We investigated opioid utilization trends among 0-18-year-olds and characterized those who filled ≥1 opioid prescriptions, with emphasis on those who did so >3 times within a year. METHODS: The prevalence of filled opioid prescriptions among 0-18-year-old Norwegians in 2010-2018 (N = 77,942) was measured from nationwide healthcare registries. Characteristics, healthcare utilization, and other drug use of those who newly filled 1, 2-3, or >3 opioid prescriptions in 2011-2014 were compared to 2015-2018, excluding persons with cancer. RESULTS: From 2010 to 2018, the prevalence of opioid use decreased from 9.0 to 7.0 per 1000 persons. The largest decrease was among children <12 years, from 4.1 to 0.4 per 1000 persons, mainly due to decreasing codeine use. The proportion of those who filled >3 opioid prescriptions was 2.1% in 2011-2014 and 3.1% in 2015-2018. Those with >3 dispensations had a median of 4 contacts/year with secondary healthcare (interquartile range 2-7); the most frequent diagnoses indicated post-surgery follow-up. Most commonly dispensed other drugs were non-steroidal anti-inflammatory drugs. CONCLUSIONS: Opioid dispensations for the young have declined in recent years. Multiple opioid dispensations were rare and associated with frequent healthcare utilization. Reducing codeine is in line with recommendations, but the effects of decreased opioid use on the quality of pain management remain unknown.

Medication Management in Frail Older People: Consensus Principles for Clinical Practice, Research, and Education.

Frailty is a geriatric condition associated with increased vulnerability to adverse drug events and medication-related harm. Existing clinical practice guidelines rarely provide medication management recommendations specific to frail older people. This report presents international consensus principles, generated by the Optimizing Geriatric Pharmacotherapy through Pharmacoepidemiology Network, related to medication management in frail older people. This consensus comprises 7 principles for clinical practice, 6 principles for research, and 4 principles for education. Principles for clinical practice include (1) perform medication reconciliation and maintain an up-to-date medication list; (2) assess and plan based on individual's capacity to self-manage medications; (3) ensure appropriate prescribing and deprescribing; (4) simplify medication regimens when appropriate to reduce unnecessary burden; (5) be alert to the contribution of medications to geriatric syndromes; (6) regularly review medication regimens to align with changing goals of care; and (7) facilitate multidisciplinary communication among patients, caregivers, and healthcare teams. Principles for research include (1) include frail older people in randomized controlled trials; (2) consider frailty status as an effect modifier; (3) ensure collection and reporting of outcome measures important in frailty; (4) assess impact of frailty on pharmacokinetics and pharmacodynamics; (5) encourage frailty research in under-researched settings; and (6) utilize routinely collected linked health data. Principles for education include (1) provide undergraduate and postgraduate education on frailty; (2) minimize low-value care related to medication management; (3) improve health and medication literacy; and (4) incorporate evidence in relation to frailty into clinical practice guidelines. These principles for clinical practice, research and education highlight different considerations for optimizing medication management in frail older people. These principles can be used in conjunction with existing best practice guidelines to help achieve optimal health outcomes for this vulnerable population. Implementation of the principles will require multidisciplinary collaboration between healthcare professionals, researchers, educators, organizational leaders, and policymakers.

Medication Use and Health Care Utilization After a Cost-sharing Increase in Schizophrenia: A Nationwide Analysis.

BACKGROUND: Increases in prescription drug cost-sharing may decrease adherence to treatment among persons with schizophrenia and lead to discontinuation of use and an increased risk of hospitalization. OBJECTIVE: The objective of this study was to investigate the impact of new deductible and increased drug copayments implemented on antipsychotic and other drug purchases and on rates of hospitalizations and primary care contacts among persons with schizophrenia in Finland. RESEARCH DESIGN: Interrupted time series analysis. SUBJECTS: All persons with schizophrenia in Finland who were alive at the beginning of 2015 (N=41,017). MEASURES: We measured the rates of antipsychotic, other psychotropic and cardiometabolic drug purchasers, hospitalizations, and primary care contacts during 2015 and 2016 with data collected from several nationwide health care registers. RESULTS: During 2016, the proportion of antipsychotic purchasers decreased by -0.26 percentage points per month [95% confidence interval (CI): -0.47 to -0.05] compared with 2015. The trend of other psychotropic purchasers decreased to -0.13 percentage points per month in 2016 (95% CI: -0.22 to -0.04) compared with 2015 and cardiometabolic drug purchases to -0.17 percentage points per month (95% CI: -0.29 to -0.05) compared with 2015. The decreasing trend of psychiatric hospitalizations in 2015 halted in 2016. There were no other significant differences in health care utilization. CONCLUSIONS: In our nationwide time-series analysis, we observed decreases in the slopes of antipsychotic and other drug purchases of persons with schizophrenia after prescription drug cost-sharing increase implementation on January 1, 2016. Policymakers need to be aware of the unintended consequences of increasing cost-sharing among people with severe mental disorders.

Opioid Use After Hospital Care due to Hip Fracture Among Community-Dwelling Persons With and Without Alzheimer's Disease.

BACKGROUND: Hip fractures are common among persons with Alzheimer's disease (AD), but problems in pain assessment may lead to insufficient analgesia after hospitalization. OBJECTIVE: We investigated the prevalence of opioid use in the 6 months after discharge from hospital care due to hip fracture among community-dwellers with and without AD. SETTING AND METHOD: The Medication use and Alzheimer's disease (MEDALZ) cohort was used for this study, consisting of all community-dwelling persons newly diagnosed with AD during 2005-2011 in Finland and their comparison persons without AD matched on age, sex, and region of residence at the time of AD diagnosis. Data were collected from nationwide healthcare registers. MAIN OUTCOME MEASURES: We investigated opioid use versus non-use in persons with and without AD in the 6 months after discharge from hospital care due to hip fracture. RESULTS: Altogether 2342 persons with AD and 1615 persons without AD, discharged to community settings within ≤ 120 days after a hip fracture, were included. A higher percentage of persons with AD used opioids compared to those without AD, 39.5% [95% confidence interval (CI) 37.5-41.5] versus 31.2% (95% CI 28.9-33.5). Persons with AD used more frequently strong opioids during the first 3 months and buprenorphine during the 6-month period, and used weak opioids less frequently after the first month after discharge compared to those without AD. CONCLUSIONS: Frequent opioid use after hospital care due to hip fracture may indicate increased attention to pain among persons with AD. Nevertheless, the benefits and harms of opioid use should be evaluated regularly in community-dwelling older persons.

Hospital-Treated Pneumonia Associated with Opioid Use Among Community Dwellers with Alzheimer's Disease.

BACKGROUND: Pneumonia is a common cause for hospitalization and excess mortality among persons with Alzheimer's disease (AD), but little research exists evaluating drug use as its risk factor. OBJECTIVE: We investigated the association between opioid use and hospital-treated pneumonia among community dwellers with AD. METHODS: This study was part of the Medication use and Alzheimer's Disease (MEDALZ) cohort. We included all community dwellers newly diagnosed with AD during 2010-2011 in Finland with incident prescription opioid use (n = 5,623) and age-, sex-, and time since AD diagnosis-matched nonusers (n = 5,623). Opioid use data, modelled from pharmacy dispensing data, and hospital-treated pneumonia were retrieved from nationwide registers. Patients with active cancer treatment were excluded. Hazard models compared opioid users to nonusers, adjusting for comorbidities, socioeconomic position. and other drug use. RESULTS: Incident opioid use was associated with an increased risk of hospital-treated pneumonia compared to nonuse (adjusted HR, aHR 1.34, 95% CI 1.14-1.57). Highest risk was observed during the first two months of use (aHR 2.58, 95% CI 1.87-3.55). Compared to weak opioids, buprenorphine was not associated with a higher risk of pneumonia (aHR 1.20, 95% CI 0.83-1.76), but strong opioids were (aHR 1.84, 95% CI 1.15-2.97). The risk was higher for those using ≥50 morphine milligram equivalents (MME)/day (aHR 2.03, 95% CI 1.24-3.31), compared to using <50 MME/day. CONCLUSIONS: Opioid use was associated with a risk of hospital-treated pneumonia in a dose-dependent manner among persons with AD. Risk-minimization strategies should be considered if opioid therapy is needed.

Concomitant use of benzodiazepines and opioids in community-dwelling older people with or without Alzheimer's disease-A nationwide register-based study in Finland.

OBJECTIVE: The study aims to determine the prevalence of concomitant use of benzodiazepines and opioids among community-dwelling older people with or without Alzheimer's disease (AD). An additional aim was to describe the factors associated with prolonged concomitant use, and the most commonly used combinations of these drugs. METHODS: This study utilized data from the register-based Medication Use and Alzheimer's disease (MEDALZ) study, including all community-dwelling residents of Finland who received a clinically verified AD diagnosis between 2005 and 2011 (n = 70 718) and their matched comparison persons without AD. After exclusion of individuals who were hospitalized throughout the follow-up, 69 353 persons with and 69 353 without AD were included in this study. RESULTS: Benzodiazepines and related drugs (BZDRs) were used by 28 475 (41.1%) of those with and 24 506 (35.3%) of those without AD. Prolonged (greater than or equal to 90 days) concomitant use of BZDRs and opioids was more common among BZDR users without AD (N = 3936; 16.1%) than among those with AD (N = 2963; 10.4%). A shorter duration of concomitant use (1-89 days) revealed similar results, N = 3821; 15.6% and N = 3008; 10.6%, respectively. Prolonged concomitant use of BZDRs and opioids was associated with female sex, low socioeconomic position, most of the common comorbidities and history of substance abuse or long-term benzodiazepine use. The most commonly used combinations were Z-drug (31.7%) or benzodiazepine (29.9%) with a weak opioid. CONCLUSIONS: Despite the recommendations and risks, the prevalence of concomitant BZDR and opioid use was common in older persons with or without AD. It is important to develop strategies to reduce unnecessary concomitant use of these drugs.

Incident opioid use and risk of hip fracture among persons with Alzheimer disease: a nationwide matched cohort study.

The objective of this study was to investigate whether incident opioid use is associated with an increased risk of hip fractures among community-dwelling persons with Alzheimer disease (AD) and to assess the association in terms of duration of use and opioid strength. Among community-dwelling persons with AD diagnosed in 2010 to 2011 (N = 23,100), a matched cohort study comparing incident opioid users (N = 4750) with opioid nonusers (N = 4750) was constructed. Matching was based on age, sex, and time since AD diagnosis at opioid initiation. Data on drug use and hip fractures were retrieved from nationwide registers. Incident opioid users were identified with a 1-year washout. Cox proportional hazard models compared the risk of hip fracture between opioid use and nonuse, and were weighted with inverse probability of treatment (IPT), based on a propensity score. Age-adjusted incidence rate of hip fractures was 3.47 (95% confidence interval [CI] 2.62-4.33) during opioid use and 1.94 (95% CI 1.65-2.22) during nonuse. Opioid use was associated with an increased risk of hip fracture (IPT-weighted hazard ratio [HR] 1.96, 95% CI 1.27-3.02). The risk was observed during the first 2 months of use (IPT-weighted HR 2.37, 1.04-5.41) and attenuated after that. The results suggest an increase in the risk of hip fracture by increasing opioid strength; weak opioids IPT-weighted HR 1.75 (0.91-3.35), buprenorphine IPT-weighted HR 2.10 (1.41-3.13), and strong opioids IPT-weighted HR 2.89 (1.32-6.32). Further research is needed to find out whether the risk of injurious falls is avoidable by slow titration of opioid doses in the beginning of treatment.

Impact of opioid initiation on antipsychotic and benzodiazepine and related drug use among persons with Alzheimer's disease.

ABSTRACTBackground:We analyzed the impact of opioid initiation on the prevalence of antipsychotic and benzodiazepine and related drug (BZDR) use among community-dwelling persons with Alzheimer's disease (AD). METHODS: We utilized the register-based Medication use and Alzheimer's disease (MEDALZ) cohort for this study. We included all community-dwelling persons diagnosed with AD during 2010-2011 in Finland initiating opioid use (n = 3,327) and a matched cohort of persons not initiating opioids (n = 3,325). Interrupted time series analyses were conducted to compare the prevalence of antipsychotic and BZDR use in 30-day periods within six months before opioid initiation to 30-day periods six months later. RESULTS: Before opioid initiation, prevalence of antipsychotic use among opioid initiators was 13.3%, 18.3% at opioid initiation, and 17.3% six months later. Prevalences of BZDR use were 27.1% six months prior, 28.9% at opioid initiation, and 26.9% six months later. After opioid initiation, antipsychotic and BZDR use declined by 0.3 percentage points (pps, 95% confidence interval 0.1-0.5) and 0.4 pps (0.2-0.7) per month, respectively, until the end of the follow-up. Compared to persons not initiating opioid use, opioid initiation immediately resulted in an increase in prevalence of 1.9 pps (0.9-2.8) for antipsychotics and of 1.6 pps (0.9-2.2) for BZDR use. However, in total there was a comparative decrease of 0.5 pps (0.3-0.8) per month for antipsychotics and of 0.4 pps (0.2-0.6) for BZDR use until the end of the follow-up. CONCLUSION: Our results suggest that opioid initiation may reduce antipsychotic and BZDR use among persons with AD.

Is Alzheimer's Disease Associated with Previous Opioid Use?

Objective: We investigated whether opioid use, duration of use, and cumulative dose are associated with an increased risk of Alzheimer's disease (AD). Methods: A Finnish nationwide nested case-control study, MEDALZ, included 70,718 individuals with AD and up to four age-, sex-, and region of residence-matched comparison individuals. The cohort included all Finnish persons with a clinically verified AD diagnosis during 2005 to 2011; the mean age was 80 years (SD = 7 years), and 65% were women. Register-based data on opioid purchases (excluding codeine) were modeled into drug use periods using the PRE2DUP method. Cumulative opioid doses were transformed to total standardized doses (TSDs). We utilized a three-year time window between exposure (opioid use) and outcome (AD) to avoid reverse causality. Analyses were adjusted for comorbid conditions and drug use. Results: Opioid use was not associated with an increased risk of AD (adjusted odds ratio [OR] = 1.00, 95% confidence interval [CI] = 0.98-1.03). Neither longer duration of use (cumulative use for >365 days: adjusted OR = 1.02, 95% CI = 0.96-1.08) nor high cumulative doses (>90 TSDs: adjusted OR = 1.02, 95% CI = 0.98-1.07) of opioids was associated with risk of AD. Conclusions: Although opioid use was not associated with an increased risk of AD, further studies should be performed to assess the safety of long-term opioid use in terms of other cognitive effects.

Long-term use of opioids for nonmalignant pain among community-dwelling persons with and without Alzheimer disease in Finland: a nationwide register-based study.

Persons with Alzheimer disease (AD) commonly present with chronic nonmalignant pain, but long-term use of opioids among this population has not been studied previously. Our aim was to investigate the prevalence of long-term (≥180 days) use of opioids for nonmalignant pain and associated factors among community-dwelling persons with AD and to compare the prevalence with a matched cohort without AD. The Medication use and Alzheimer's disease (MEDALZ) cohort was used for this study, comprising all community-dwelling persons diagnosed with AD in Finland during 2005 to 2011 and their matched comparison persons without AD. After exclusion of persons with active cancer treatment, 62,074 persons with and 62,074 persons without AD were included in this study. Data were collected from nationwide registers. Opioids were used by 13,111 persons with and by 16,659 without AD. Overall long-term opioid use was more common among persons without AD (8.7%) than among persons with AD (7.2%, P < 0.0001). However, among opioid users, prevalence of long-term opioid use was slightly higher among persons with AD than among those without AD (34.2% vs 32.3%, respectively, P = 0.0004). Long-term use of transdermal opioids was more than 2-fold among opioid users with AD (13.2%) compared with users without AD (5.5%). Factors associated with long-term opioid use included AD, age ≥80 years, female sex, rheumatoid arthritis, osteoporosis, low socioeconomic position, history of substance abuse, and long-term benzodiazepine use. Prevalence of long-term opioid use was somewhat similar among both groups. Among persons with AD, long-term opioid use was strongly associated with transdermal opioids.