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


Academic year: 2022

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





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Concomitant use of benzodiazepines and opioids in community-dwelling older people with or without

Alzheimer's disease - A nationwide register-based study in Finland

Karttunen, Niina


Tieteelliset aikakauslehtiartikkelit

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

A Short running title; Concomitant use of benzodiazepines and opioids Authors;

Niina Karttunen, PhD (Pharm) 1,2; Heidi Taipale, PhD (Pharm) 1,2,3; Aleksi Hamina, MSc (Pharm) 1,2; Antti Tanskanen, Phil Lic3,4,5; Jari Tiihonen, MD, PhD3,4,6; Anna-Maija Tolppanen, PhD2,7; Sirpa Hartikainen, MD, PhD1,2,7

1Kuopio Research Centre of Geriatric Care, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland

2School of Pharmacy, University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland

3Department of Clinical Neuroscience, Karolinska Institutet, Tomtebodavägen 18A, 5th floor, 171 77 Stockholm, Sweden

4Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Kuopio, Finland

5Impact Assessment Unit, National Institute for Health and Welfare, PO Box 30, FI-00271 Helsinki, Finland

6Center for Psychiatry Research, Stockholm City Council, Stockholm, Sweden.

7Research Centre for Comparative Effectiveness and Patient Safety (RECEPS), University of Eastern Finland, PO Box 1627, 70211 Kuopio, Finland

Corresponding author;

Niina Karttunen, PhD (Pharm)

Kuopio Research Centre of Geriatric Care University of Eastern Finland, PO Box 1627 70211 Kuopio, Finland

Tel: + 358503831882; E-mail: niina.karttunen@uef.fi

The word count of the body text: 3417



Objective: 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 (≥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.

Keywords; Benzodiazepines, opioids, older people, Alzheimer’s disease



- The combined use of BZDRs and opioids has been associated with serious risks in older persons, especially in frail individuals with Alzheimer’s disease (AD).

- 21% of BZDR users with AD and 32% of those without AD were concomitant BZDR and opioid users. Half of them were inappropriately prolonged (>90 days) concomitant users irrespective of their AD status.

- BZDR users with AD were prescribed more commonly stronger opioids than those without AD.

- It is important to develop strategies which could reduce the unnecessary co-use of these drugs, as their benefits rarely outweigh their risks in older persons.



Benzodiazepines and related drugs (BZDRs) are widely used in older patients, especially for the treatment of rather common symptoms such as anxiety and insomnia1-3. The use of BZDRs in older people is problematic because they are associated with several risks, such as sedation, dependence, falls and fractures4. In general, BZDRs are approved for short-term use (<2–4 weeks) and not recommended for long-term use5. In older people, even short-term use of BZDRs poses risks due to sedation and falls resulting in fractures6,7. The American Geriatrics Society (AGS) Beers Criteria include a strong recommendation to avoid the use of BZDRs in older patients8. Despite these recommendations, 28–38% of community-dwelling older people use BZDRs at least occasionally, and the prevalence is usually higher among persons with Alzheimer’s disease (AD) or dementia3,9-11. In fact, it has been estimated that 30% of community-dwelling older patients with AD and 26% of those without AD are long-term users of BZDRs3. The difference probably is attributable to some behavioral and psychological symptoms of dementia (BPSD), e.g. restlessness, anxiety, depression and sleep changes, which are extremely prevalent in AD patients12. However, non-pharmacological approaches and anti-dementia drugs are recommended as the first-line treatment of these symptoms13.

The concomitant use of BZDRs with opioid analgesics seems to be rising14,15, which further increases the prevalence of adverse events. Both of these drug groups cause sedation and dizziness that predispose older people to falls and fractures 16,17. Thus, vulnerable individuals with AD have a higher risk of hip fracture and related adverse health outcomes, such as institutionalization and mortality, than their counterparts without AD 17,18. The concomitant use of BZDRs with opioid analgesics results in greater respiratory depression than with either drug alone 19. This may increase the risk of sedation related aspiration and pneumonia, that has been associated with both BZDR and opioid use separately

20,21. There are some studies suggesting that these drug groups may even be associated with the development of dementia or AD 22,23, but also conflicting results have been published 24,25. In addition, emergency department visits and drug overdose deaths involving both benzodiazepines and opioids


have increased in all age groups in the U.S. during 2004–2011 26. There are clear clinical guidelines and consensus statements on drug therapy in older patients, which advise against co-prescribing drugs that act on the central nervous system 8. The concomitant use of BZDRs and opioids in an older population, in which this combination is generally contraindicated, represents a public health issue that is associated with several risks.

However, there is a limited literature investigating the concomitant benzodiazepine and opioid use, especially in vulnerable older persons and AD patients. Existing studies have concentrated on younger populations 15,27, non-medical use of this drug combination 26 and patients with chronic non-cancer pain 28-30 or post-traumatic stress disorder 14. Variations in the definition of concomitancy have ranged from one day of overlap to >90 consecutive days during one year, which complicates any comparison between these studies. The objective of the present study was to determine the prevalence of concomitant BZDR and opioid use among community-dwelling older people with or without AD. In addition, our aim was to describe the factors associated with concomitant use, and the most commonly used combinations of BZDRs and opioids.


Data sources and ethical considerations

This study was a part of the Medication use and Alzheimer’s disease (MEDALZ) study that has been previously described in detail 31. The MEDALZ cohort includes all community-dwelling Finnish citizens newly diagnosed with AD during 2005–2011 (N=70,718). One comparison person without AD was matched to each AD case based on age, sex and region of residence at the date of AD diagnosis (the index date). The data evaluated in the MEDALZ study was collected from several nationwide health care registers: Special Reimbursement Register (1972–2012), Prescription Register (1995–2012) and Hospital Discharge Register (1972–2012). Socioeconomic data was obtained from Statistics Finland.

Data of the registers were routinely collected and de-identified (i.e. personal identification numbers were replaced by research identification tags, enabling the data linkage) before they were submitted


to the research team. Thus, according to Finnish legislation, additional ethics committee approval or informed consent was not required.

AD diagnoses

Individuals with AD were identified from the Special Reimbursement Register that is maintained by the Social Insurance Institution (SII). The register consists of data on entitlement to special reimbursements of drugs prescribed for chronic illnesses. A special reimbursement for AD is granted if the predefined diagnostic protocol and criteria are fulfilled. AD diagnoses are made according to NINCDS-ADRDA32 and DSM-IV33 criteria. The diagnostic protocol includes computer tomography or magnetic resonance imaging scan and confirmation of the diagnosis by a neurologist or a geriatrician.

The use of BZDRs and opioids

The use of BZDRs and opioids was determined from the Prescription register that includes information on purchases of reimbursed prescription drugs. In Finland, BZDRs and opioids are available only on prescription and they are widely reimbursed. However, some small BZDR packages of 10–30 tablets and some codeine combination products were not consistently reimbursed during the follow-up period of this study. Drugs used in hospital and public nursing homes are not recorded in the Prescription register and thus, our study focuses on community-dwelling individuals. In 2010, the proportion of older Finns who lived in public nursing home or in long-term hospital care was less than 5%34. In the Prescription register, drugs are classified according to the Anatomical Therapeutic Chemical -classification system (ATC)35. The BZDRs included benzodiazepines (ATC codes N05BA, N05CD) and related drugs (so-called Z-hypnotics, code N05CF). These two drug groups were combined because previous studies suggest that Z-drugs are no safer than benzodiazepines with respect to falls

36,37, hip fractures38 or cognitive adverse events39.

Opioids (N02A) included weak opioids (codeine, N02AA59 and tramadol, N02AX02), partial opioid agonists (buprenorphine, N02AE01) and strong opioids (morphine, N02AA01; hydromorphone


N02AA03; oxycodone, N02AA05; fentanyl, N02AB03; dextropropoxyphene, N02AC04 and pentazocine, N02AD01). Drug use periods (when continuous drug use started and ended) were modelled by PRE2DUP 40, 41, which is a mathematical modelling method based on individual purchase histories and which calculates sliding averages of the daily dose (in Defined Daily Doses). Individual purchases were combined to the same drug use period if the purchased amount of drug was enough to last to the next purchase with the calculated personal daily dose, taking into account the regularity of purchases, stockpiling, and hospitalizations.

BZDR use was defined as “use of any BZDR” by combining overlapping use periods of different drug substances meaning that the individual was allowed to change from one BZDR to another as long as there were no breaks in drug availability. Long-term use of BZDRs was defined as ≥180 days of continuous use of any BZDR, similarly to previous studies 42-44. Prolonged concomitant BZDR and opioid use was defined as overlapping BZDR and opioid use for ≥ 90 days, because it typically included two or more purchases of BZDRs and opioids.


Data on comorbidities were collected from the Special Reimbursement, Prescription, and Hospital Discharge registers. Asthma or chronic obstructive pulmonary disease, cardiovascular disease, diabetes (types 1 and 2), rheumatoid arthritis and other connective tissue diseases before the index date were extracted from the Special Reimbursement Register. Combined covariate “cardiovascular disease” included chronic heart failure, arterial hypertension, coronary artery disease and chronic arrhythmias (one or more of these conditions diagnosed ever before the start of the follow-up). Data on the history of bisphosphonate use (M05BA, M05BB) was collected from Prescription register and it was considered to represent osteoporosis. The Hospital Discharge register was utilized to gather information of the following comorbidities; a history of hip fracture (included ICD-10 codes S72.0, S72.1, and S72.2 and corresponding ICD-8 and ICD-9 codes), schizophrenia (schizophrenia, schizotypal, or delusional disorders F20–29), depression or bipolar disorder (F30–34, F38–39) and substance abuse


(hospitalization due to alcohol or narcotic use or alcoholic pancreatitis). The covariate “active cancer”

comprised hospitalization due to cancer or antineoplastic drug use during a 1-year period before the start of the follow-up. Antineoplastic drugs included antineoplastic agents (L01), endocrine therapy (L02), colony stimulating factors (L03AA), interferon-α natural (L03AB01), interferon-α-2a (L03AB04), interferon-α-2b (L03AB05), interleukins (L03AC), other immunostimulants (L03AX) excluding glatiramer acetate (L03AX13), sirolimus (L04AA10), everolimus (L04AA18), alentuzumab (L04AA34), thalidomide (L04AX02), methotrexate (L04AX03) and (L01BA01) excluding persons with a special reimbursement for rheumatoid arthritis. Study persons who had used BZDRs ≥365 days before the AD diagnosis or the index date were included in the “history of long-term BZDR use” group.

Socioeconomic position

Socioeconomic position was categorized into four classes (high, medium, low, and unknown) that were based on classification by Statistics Finland. Socioeconomic position was defined as the highest position recorded for study persons when they were 45–55 years old. The highest class included entrepreneurs and higher clerical workers, the medium class included lower clerical workers and employees, and the lowest class included unemployed, retirees and students. Persons with unknown socioeconomic class and those with missing data at Statistics Finland (1.2% of the cohort) were combined into a class designated as “unknown”.

Statistical analyses

Percentages with P-values were determined by cross-tabulation analyses with Chi-square tests to describe the study population’s characteristics according to AD status and concomitant use of BZDRs with opioids. Medians with interquartile rates (IQRs) were used to define the duration of follow-up time and drug use. Logistic regression modelling was used to determine crude and adjusted odds ratios (ORs) with 95% confidence intervals (95%CI) for the association between demographic parameters, health characteristics and concomitant use of BZDRs and opioids (≥90 days). The following factors were included in the adjusted models; age, sex, socioeconomic position,


cardiovascular disease, diabetes, asthma or COPD, rheumatoid arthritis, history of hip fracture, osteoporosis, cancer, schizophrenia, depression or bipolar disorder, history of substance abuse and history of long-term BZDR use. The comparison group consisted of those individuals who did not have prolonged concomitant use of BZDRs and opioids (BZDR-only users and those with shorter concomitant use). All statistical analyses were carried out using SAS statistical software, version 9.4 (SAS Institute Inc., Cary, North Carolina, USA) and P-values <0.05 were considered statistically significant.


Study population and concomitant use

The current study included 69,353 individuals with and 69,353 persons without Alzheimer’s disease (AD) (Figure 1). In both groups, the mean age was 80.0 (SD 7.1) and 65.1% were women. BZDRs were being used by 24,506 (35.3%) of persons without AD and 28,475 (41.1%) of those with AD (P < 0.001).

When restricted to the BZDR users, then individuals without AD were more likely to be prescribed opioids (N=7757, 31.6%) than those with AD (N=5971, 21.0%). Prolonged concomitant use of BZDRs and opioids (≥ 90 days) was more common among BZDR users without AD (N=3936, 16.1%) than among those with AD (N=2963, 10.4%). If the duration of concomitant use was reduced (1-89 days) then similar results were nonetheless obtained (N=3008, 15.6% and N=2963, 10.4%, respectively).

The median length of the concomitant BZDR and opioid use was 224 days (IQR 124-519) in persons without AD and 202 days (IQR 123-406) in those with AD (P < 0.001). The length of the follow-up time was significantly shorter for individuals with AD than those without AD due to their higher mortality (26.1% vs. 20.7%) and their transfer into long-term institutional care (21.2% vs. 7.2%). The median duration of the follow-up time was 1095 days (IQR 637-1698) for individuals with AD and 1370 days (IQR 781-2010) for those without AD (P<0.001).


Concomitant BZDR and opioid users with or without AD were more often aged over 80 years, women, had a low socioeconomic position, had cardiovascular disease, diabetes, asthma or COPD, rheumatoid arthritis, osteoporosis, active cancer, depression or bipolar disease, a history of hip fracture, substance abuse and long-term BZDR use (Table 1).

Associated factors

In both unadjusted and adjusted logistic regression models, Alzheimer’s disease was inversely associated with prolonged concomitant BZDR and opioid use (adjusted OR 0.63, 95% CI 0.60–0.66) as compared to BZDR use without prolonged concomitant opioid use (Table 2). Female sex, low socioeconomic position and all comorbidities except schizophrenia were associated with concomitant BZDR and opioid use in all BZDR users. Similar results were seen in BZDR users with or without AD, however, in individuals diagnosed with AD, it was found that diabetes and depression or bipolar disorder were not associated with concomitant BZDR and opioid use in the adjusted model.

Drug combinations

The most commonly used drug combinations were a z-drug with a weak opioid (31.7%) and a benzodiazepine with a weak opioid (29.9%) (Figure 2). However, individuals with AD more often were prescribed a benzodiazepine with a weak opioid (27.6%) rather than a z-drug with a weak opioid (24.8%). Furthermore, combinations including buprenorphine or strong opioid were more common among persons with AD than among those without AD.


As far as we are aware, this is the first study which has investigated the concomitant use of BZDRs and opioids and associated factors among community-dwelling older persons with AD and their comparison persons. The prevalence and duration of concomitant BZDR and opioid use were higher among persons without AD than among those with AD, although BZDR use was more common in the AD group. The lower prevalence of opioid use among those with AD may reflect the difficulty of pain


assessment and treatment in this patient group. Earlier studies have revealed that individuals with AD or dementia are less likely to be prescribed analgesic medications than those without AD or dementia

45,46. On the other hand, the lower prevalence of opioid use may indicate the clinical reality of the benefits of reducing sedative ADRs in vulnerable persons with AD. Specific reasons for this difference will require further study.

One particularly concerning finding was that half of the BZDR and opioid users were inappropriately prolonged concomitant users, irrespective of their AD status. Prolonged concomitant use of these drugs is a cause for concern, because both drug groups are associated with serious adverse events such as fall-related fractures16,17. Both BZDRs and opioids affect negatively cognition and perception, which is particularly harmful for those suffering from AD 47,48. Therefore, to avoid medication-related hazards, prolonged concomitant use should be avoided and if necessary, it should be carefully monitored and terminated as soon as possible. Current evidence suggests that interventions to stop using BZDRs among older people often lead to the successful discontinuation of these drugs49.

Associated factors

In the adjusted analysis, older age (≥ 80 years) was inversely associated with prolonged concomitant use of BZDRs and opioids. This may indicate a more careful consideration of potential risks of concomitant use among the oldest persons. Women were more likely to be prolonged concomitant BZDR and opioid users than men, which is in line with previous studies which have evaluated the general population and patients with chronic non-malignant pain 15,27,29,30. One explanation is that pain and mental health conditions are more common among women than men50,51. In addition, men tend to postpone health care consultations for pain and mental disorders longer than women52,53. A low socioeconomic position was associated with prolonged concomitant BZDR and opioid use in persons with and without AD. Individuals with a higher education have a lower risk for developing AD54 and on the other hand, low education has been associated with musculoskeletal conditions and pain which may explain the difference in drug use 55,56 .


Asthma and COPD were associated with prolonged concomitant BZDR and opioid use, which is a cause of concern, since both of these drug groups potentially reduce respiratory function and cause sedation-related aspiration. It has been reported recently, that the risk of pneumonia is associated with both BZDR and opioid use separately 20,21. A second somewhat alarming finding was that the presence of osteoporosis and a history of hip fracture were associated with prolonged concomitant BZDR and opioid use. Individuals suffering from these conditions may be particularly vulnerable to falls and fractures, which are known risks of both drug groups16,17.

Prolonged concomitant use of BZDR and opioids was associated with a history of substance abuse and previous long-term BZDR use. The odds were slightly higher among individuals without AD than in AD patients. Our result is consistent with an earlier study showing that benzodiazepines and opioids are often co-used for more than seven days among individuals with a substance use disorder 57. Furthermore, a history of long-term BZDR use has been associated with long-term opioid use and chronic opioid use is more common in individuals without AD than among those with AD 45. The risk of prescription drug misuse and unintentional overdose may be higher among individuals with a history of previous substance abuse or long-term BZDR use. Thus, prescribing these drugs in the presence of previous substance use disorder or chronic BZDR use should be considered with care and co-use should be monitored regularly.

Drug combinations

The most commonly used drug combinations among persons with AD were somewhat different than among those without AD. Individuals with AD were most commonly using benzodiazepines with weak opioids while those without AD were more likely to have been prescribed a Z-drug with weak opioid.

This may reflect the broader use profile of benzodiazepines, since they are also provided to treat acute agitation or agitation associated with anxiety in dementia patients 12. BZDR users with AD were prescribed more commonly stronger opioids than those without AD. Individuals with AD may be more vulnerable and frail than those without AD, and the dosing of drugs may be challenging due to their


impaired cognition. It has been previously reported that transdermal opioids are more commonly used in individuals with AD than those without AD 45. In Finland, only buprenorphine and fentanyl are available as transdermal formulations and this partly explains the trend. However, the use of strong opioids should be limited to situations where alternative drugs provide insufficient pain control. Thus, it is important to develop also mild analgesic drug products that can be easily and safely administered to older people with impaired cognition.

Strengths and limitations

The major strength of the current study is its extensive cohort of real-life drug users. The registers utilized in this study were nationwide and comprised all community-dwelling persons who received a clinically verified diagnosis of AD and their matched comparison persons. These registers are well suited for epidemiological drug utilization studies with good coverage and validity 58. In contrast to prescription-based data, data on dispensed drugs and the PRE2DUP modelling method provide a detailed estimation of the actual drug exposure and take individual variation of doses into account 40. Thus, the concomitant BZDR and opioid use represented actual co-use of these drugs. The diagnosis of AD can be considered as reliable due to the explicit diagnostic criteria, but unfortunately, the register data did not provide information on either the progression or severity of AD symptoms. The prescription register does not include over-the-counter medicines or medication used in hospitals or nursing homes. However, in Finland BZDRs and opioids are available only with prescription and to minimize the effect of institutional care, we excluded those patients who were hospitalized throughout the follow-up. Information on purchases of certain small packages of BZDRs and opioids was missing, because only reimbursed drug purchases are recorded in the Prescription Register and thus, the BZDR and opioid use may have been slightly underestimated. This study included also data on health service use due to substance abuse, which can be considered as a strength, because substance abuse is often associated with the use of BZDRs and opioids 57. However, it is likely that only the most severe cases are registered in the data, and those substance abusers with fewer


problems are not captured. The fact that we could not recognize the clinical context behind concomitant use of BZDRs and opioids is a limitation. Concomitant use may be appropriate in some individuals, for example in those suffering from persistent pain due to cancer. Finally, our study included only community-dwelling older people living in Finland and thus, the results of the study may not be generalizable to other older persons living in different settings or parts of the world.


In conclusion, the concomitant use of BZDRs and opioids was common in community-dwelling older individuals either with or without AD. The result raises concerns about inappropriate prescribing, because the combined use of BZDRs and opioids has been associated with serious risks in older persons, especially in frail individuals with AD. It is important to develop strategies which could reduce the unnecessary co-use of these drugs, as their benefits rarely outweigh their risks in older persons.

Conflicts of interest

JT has served as a consultant to EMA (European Medicines Agency) and Fimea (Finnish Medicines Agency). He has received lecture fees from Eli Lilly, Janssen-Cilag, Lundbeck, and Otsuka; and grant from Stanley Foundation and Sigrid Jusélius Foundation. HT, JT and AT have participated in research projects funded by Janssen and Eli Lilly with grants paid to the institution where they were employed.

AT is a member of Janssen advisory board. Other authors declare no conflicts of interest.



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Table 1. Characteristics of BZDR users and concomitant opioid users with or without Alzheimer’s disease (AD). BZDR users n=52,984.

BZDR users with AD

N=28475 BZDR users without AD

N=24509 BZDR only

n= 22 504 (79%)

Concomitant opioid 1-89d n= 3008 (10.6%)

Concomitant opioid ≥90d n= 2963 (10%)

P BZDR only

n= 16 752 (68%)

Concomitant opioid 1-89d n=3821 (15.6%)

Concomitant opioid ≥90d n= 3936 (16%)


Age ≥ 80 years 12395 (55.1) 1737 (57.8) 1701 (57.4) 0.0025 10 065 (60.1) 2246 (58.8) 2454 (62.4) 0.0044 Female sex 15 038 (66.8) 2101 (69.9) 2198 (74.2) <.0001 11 872 (70.9) 2769 (72.5) 2992 (76.0) <.0001 Socioeconomic position

High Medium Low Unknown

7707 (34.3) 12 879 (57.2) 1662 (7.4) 256 (1.1)

918 (30.5) 1782 (59.2) 266 (8.8) 42 (1.4)

921 (31.1) 1713 (57.8) 298 (10.1) 31 (1.1)


6084 (36.3) 9359 (55.9) 1112 (6.6) 197 (1.2)

1317 (34.5) 2184 (57.2) 268 (7.0) 52 (1.4)

1348 (34.3) 2194 (34.3) 346 (8.8) 48 (1.2)


Cardiovascular disease 11 904 (52.9) 1764 (58.6) 1814 (61.2) <.0001 9313 (55.6) 2327 (60.9) 2512 (63.8) <.0001

Diabetes 2837 (12.6) 425 (14.1) 435 (14.7) 0.0010 1818 (10.9) 483 (12.6) 562 (14.3) <.0001

Asthma/COPD 2048 (9.1) 353 (11.7) 386 (13.0) <.0001 1598 (9.5) 511 (13.4) 556 (14.1) <.0001

Rheumatoid arthritis 959 (4.3) 170 (5.7) 204 (6.9) <.0001 712 (4.3) 231 (6.1) 295 (7.5) <.0001 History of hip fracture 1121 (5.0) 195 (6.5) 237 (8.0) <.0001 664 (4.0) 167 (4.4) 249 (6.3) <.0001 Osteoporosis 3240 (14.4) 653 (21.7) 762 (25.7) <.0001 2296 (13.7) 747 (19.6) 975 (24.8) <.0001

Active cancer 961 (4.3) 295 (9.8) 222 (7.5) <.0001 879 (5.3) 442 (11.6) 396 (10.1) <.0001

Schizophrenia 471 (2.1) 52 (1.7) 50 (1.7) 0.1691 305 (1.8) 36 (0.9) 77 (2.0) 0.0003

Depression or bipolar disorder 1179 (5.2) 171 (5.7) 203 (6.9) 0.0011 783 (4.7) 177 (4.6) 287 (7.3) <.0001 History of substance abuse 811 (3.6) 131 (4.4) 142 (4.8) 0.0016 415 (2.5) 100 (2.6) 144 (3.7) 0.0002 History of long-term BZDR use 10 774 (47.9) 1631 (54.2) 1965 (66.3) <.0001 8609 (51.4) 2102 (55.0) 2957 (75.1) <.0001


Table 2 Factors associated with prolonged (≥90 days) concomitant BZDR and opioid use among persons with or without Alzheimer’s disease (AD).

All BZDR users N=52,984

BZDR users with AD N=28,475

BZDR users without AD N=24,509

Unadjusted OR

(95% CI) Adjusted OR

(95% CI) Unadjusted OR

(95% CI) Adjusted OR

(95% CI) Unadjusted OR

(95% CI) Adjusted OR (95% CI)

AD 0.61 (0.58-0.64) 0.63 (0.60-0.66) - - - -

Age ≥ 80 years 1.13 (1.07-1.18) 0.92 (0.87-0.97) 1.09 (1.01-1.17) 0.91 (0.84-0.99) 1.11 (1.04-1.19) 0.92 (0.86-0.99) Female sex 1.37 (1.29-1.45) 1.20 (1.13-1.28) 1.40 (1.29-1.53) 1.25 (1.14-1.37) 1.28 (1.19-1.39) 1.17 (1.07-1.28) Socioeconomic position

High Medium Low Unknown


1.05 (1.0-1.11) 1.38 (1.25-1.51) 1.02 (0.80-1.30)


1.06 (1.00-1.12) 1.27 (1.15-1.41) 1.18 (0.92-1.51)


1.09 (1.01-1.19) 1.45 (1.26-1.67) 0.97 (0.67-1.42)


1.07 (0.98-1.16) 1.34 (1.16-1.55) 1.01 (0.75-1.61)


1.04 (0.97-1.12) 1.38 (1.21-1.57) 1.06 (0.77-1.45)


1.05 (0.97-1.13) 1.22 (1.06-1.40) 1.24 (0.90-1.71) Comorbidities

Cardiovascular disease Diabetes

Asthma/COPD Rheumatoid arthritis History of hip fracture Osteoporosis

Depression or bipolar disorder Schizophrenia

History of substance abuse Active cancer

1.38 (1.31-1.45) 1.23 (1.14-1.32) 1.46 (1.35-1.57) 1.66 (1.50-1.83) 1.55 (1.40-1.72) 1.90 (1.79-2.02) 1.45 (1.31-1.60) 0.98 (0.81-1.19) 1.33 (1.16-1.51) 1.66 (1.52-1.82)

1.27 (1.20-1.34) 1.17 (1.08-1.26) 1.28 (1.18-1.38) 1.39 (1.25-1.54) 1.27 (1.14-1.41) 1.63 (1.53-1.74) 1.13 (1.02-1.26) 0.78 (0.64-0.95) 1.32 (1.16-1.52) 1.78 (1.62-1.96)

1.37 (1.27-1.48) 1.17 (1.05-1.31) 1.44 (1.29-1.62) 1.60 (1.37-1.86) 1.60 (1.38-1.85) 1.92 (1.76-2.10) 1.32 (1.13-1.53) 0.82 (0.61-1.10) 1.31 (1.10-1.57) 1.56 (1.35-1.81)

1.28 (1.18-1.38) 1.10 (0.99-1.23) 1.26 (1.12-1.42) 1.33 (1.13-1.56) 1.29 (1.11-1.50) 1.62 (1.47-1.78) 1.04 (0.89-1.22) 0.67 (0.49-0.90) 1.30 (1.07-1.57) 1.67 (1.44-1.95)

1.35 (1.26-1.45) 1.32 (1.20-1.46) 1.44 (1.30-1.59) 1.69 (1.47-1.93) 1.60 (1.39-1.86) 1.90 (1.75-2.06) 1.61 (1.40-1.84) 1.18 (0.92-1.52) 1.48 (1.23-1.79) 1.63 (1.45-1.83)

1.27 (1.18-1.37) 1.23 (1.11-1.37) 1.30 (1.17-1.45) 1.45 (1.26-1.67) 1.25 (1.07-1.45) 1.65 (1.51-1.81) 1.22 (1.06-1.41) 0.90 (0.69-1.17) 1.36 (1.11-1.66) 1.88 (1.66-2.12) History of long-term BZDR use 2.47 (2.34-2.61) 2.24 (2.11-2.37) 2.08 (1.92-2.25) 1.89 (1.74-2.05) 2.78 (2.57-3.00) 2.61 (2.41-2.83)


Figure 1. Flow chart of the study population. AD=Alzheimer’s disease, BZDR=Benzodiazepines and related drugs

Figure 2. The most commonly used drug combinations among prolonged concomitant users with or without Alzheimer’s disease (AD). BZD=Benzodiazepine



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