Open access Original research

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Risk of long-­term benzodiazepine and Z-­
drug use following the first prescription
among community-­dwelling adults with
anxiety/mood and sleep disorders: a
retrospective cohort study
Jaden Brandt,1 Donica Janzen,1 Silvia Alessi-­Severini,1 Alexander Singer,2
Dan Chateau,3 Murray Enns,4 Christine Leong ‍ ‍1,4

To cite: Brandt J, Janzen D, ABSTRACT

Alessi-­Severini S, et al. Risk Strengths and limitations of this study
Objective To measure the incidence of long-­term
of long-­term benzodiazepine benzodiazepine receptor agonist (BZRA) use among
and Z-­drug use following ►► This study used administrative data from the
individuals with anxiety, mood and/or sleep disorders. To
the first prescription among Manitoba Centre for Health Policy, which is one of
identify factors associated with long-­term use following
community-d­ welling adults the most comprehensive datasets in North America
with anxiety/mood and sleep the first prescription.
containing >140 deidentified linked datasets on
disorders: a retrospective Methods This was a population-­based retrospective
healthcare, education, social/families, justice and
cohort study. BMJ Open cohort study using administrative databases in Manitoba,
registries for all residents of Manitoba (population of
2021;11:e046916. doi:10.1136/ Canada. Individuals with anxiety/mood or sleep disorder
1.4 million people) not restricted by age or income.
bmjopen-2020-046916 who received their first BZRA between 1 April 2001 and 31
►► All diagnoses are identified through physician claims
March 2015 were included. Long-­term use was defined
►► Prepublication history and data or hospitalisations, which are dependent on
additional supplemental material as ≥180 days. Logistic regression modelling was used to
people seeking treatment and may be prone to some
for this paper are available examine predictors of long-­term use.
misclassification. Drug information is also based on
online. To view these files, Results Among 206 933 individuals included, long-­term
dispensing records from community pharmacies
please visit the journal online BZRA use in the first episode of use was 4.5% (≥180
and does not confirm the patient actually took the
(http://​dx.​doi.​org/​10.​1136/​ days) following their first prescription. Factors associated
bmjopen-​2020-​046916).
drug. However, we performed multiple sensitivity
with ≥180 days of use included male sex (adjusted OR
analyses to address this.
(aOR) 1.33, 95% CI 1.27 to 1.39), age ≥65 (aOR 5.15,
Received 12 November 2020 ►► The databases do not capture participation in psy-
95% CI 4.81 to 5.52), income assistance (aOR 1.68, 95% CI
Accepted 19 October 2021 chological interventions such as cognitive–be-
1.55 to 1.81), previous non-­BZRA psychotropic (aOR 1.93,
havioural therapy.
95% CI 1.83 to 2.02) or opioid use (aOR 1.16, 95% CI 1.11
to 1.22), high comorbidity (aOR 1.43, 95% CI 1.32 to 1.55),
high healthcare use (aOR 1.46, 95% CI 1.33 to 1.60) and
psychiatrist prescriber (aOR 2.11, 95% CI 1.93 to 2.32). a safer alternative to barbiturates.5 However,
© Author(s) (or their Conclusions Less than 1 in 20 patients use BZRAs ≥180 safety concerns such as psychomotor impaired
employer(s)) 2021. Re-­use days in their first treatment episode. Several factors
permitted under CC BY-­NC. No accidents (ie, falls and motor-­ vehicle acci-
were associated with long-­term use following the first
commercial re-­use. See rights dents), dependency and misuse/abuse are
prescription and further investigation into whether these
and permissions. Published by
factors need to be considered at the point of prescribing is now well known.6–8 Recent studies have also
BMJ.
1 warranted. In light of these findings, future research should raised concerns proposing possible links to
College of Pharmacy, University
examine the predictors of cumulative repeat episodes of dementia, recurrence of mood episode, respi-
of Manitoba, Winnipeg,
Manitoba, Canada BZRA exposure. ratory disease exacerbation and suicide with
2
Family Medicine, University of long-­term BZRA use.9–13 However, the asso-
Manitoba, Winnipeg, Manitoba, ciation of BZRA use for these newer harms
Canada INTRODUCTION is uncertain given conflicting evidence and
3
Manitoba Centre for Health
The use of benzodiazepine receptor agonists confounding in previous studies.14
Policy, Winnipeg, Manitoba,
Canada (BZRAs), benzodiazepines (BZD) and In spite of ongoing adverse effect concerns,
4
Psychiatry, Univeristy of Z-­
Drugs, in the treatment of anxiety and justification for less restrictive BZRA use have
Manitoba, Winnipeg, Manitoba, insomnia has shifted based on the evolving stemmed from their clinical utility as rapidly
Canada data on safety risks and limited efficacy on effective anxiolytic sedatives.15 Some view
Correspondence to long-­term use in the literature.1–4 On their that limiting BZRA use is at times imprac-
Dr Christine Leong; initial introduction into clinical practice in tical.16 Moreover, the use of alternative phar-
​christine.​leong@u​ manitoba.​ca the late 1960s, BZD were considered to be macotherapy, including trazodone, atypical

Brandt J, et al. BMJ Open 2021;11:e046916. doi:10.1136/bmjopen-2020-046916 1

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antipsychotics, barbiturates, and tricyclic antidepressants
are not without adverse effects. It should also be noted
that the difficulties with de-­prescribing BZRAs reported
in the literature have added caution to the initiation of
these agents in practice.4 17
Previous studies examining the pattern of BZRA use
have found a decline in benzodiazepine (particularly lora-
zepam) incident use and an increase in the incidence of
Z-­drug use.18 19 Limited studies have examined predictors
of long-­term use after a first prescription.20 21 As such, this
study sought (i) to measure the incidence of long-­term
BZRA use among a cohort of community-­dwelling Cana-
dian adults with anxiety, mood and/or sleep disorders,
and (ii) to determine factors associated with progression
to long-­term BZD use following the first prescription in
this population.

Figure 1 Flow chart of study population. ICD, International

METHODS Classification of Diseases.
Study design and data sources
This was a retrospective, cohort study using routinely
collected administrative healthcare data pertaining to required for cohort inclusion. As such, individuals who
prescription drug dispensations, outpatient physician received a benzodiazepine in the distant past could be
claims, hospitalisation discharge abstracts, income assis- included in the cohort as a new user, provided that the
tance records and prescriber demographics (online benzodiazepine was not used in the past 1 year. A sensi-
supplemental table A1). All data used was extracted tivity analysis was also performed in which incident use
from the Manitoba Centre for Health Policy Popula- was defined as no prescription for a BZRA was received in
tion Research Data Repository. The Repository provides the 3 years prior to the first prescription.23
comprehensive coverage of all Manitoba residents Eligibility was also based on diagnostic criteria for
contact with the primary healthcare system. The Drug anxiety/mood-­related disorders and/or insomnia based
Programme Information Network (DPIN) provides infor- on International Classification of Diseases 9, Clinical
mation on outpatient prescription drugs dispensed in Modification (ICD-­9-­CM) or International Classification
Manitoba with the exception of medications dispensed in of Diseases 10, Canadian Enhancements (ICD-­ 10-­
CA)
hospital and nursing stations. In Manitoba, eligible outpa- medical claims, either at outpatient physician visits or
tient prescriptions are 100% covered for residents after hospitalisations, occurring within a 5-­year period prior to
an income-­based deductible is paid for each fiscal year. the first prescription. The ICD diagnostic criteria chosen
DPIN captures information on the drug name, strength, are a combination of the definitions from two sources;
quantity, day-­supply, and date of all outpatient prescrip- the Canadian Public Health Association on mental
tions dispensed regardless of coverage. Merging of the health surveillance and the MCHP concept dictionary,
various data sources was facilitated via linkage of unique which listed the various past-­case definitions employed in
identified Personal Health Information Numbers.
de-­ previous research within Manitoba for mood and anxiety
The Charlson Comorbidity Score (0 (lowest risk), 1, ≥2 disorders (online supplemental table A2).24–28 Lastly,
(high risk)) was also determined to examine the effects because reliance on ICD codes is expected (and has been
of comorbidity of duration of use. This was determined previously shown) to underestimate capture of sleep
based on 17 categories of comorbidities using ICD-­9-­CM disorder cases, we also accepted receipt of a Z-­drug in the
or ICD-­10-­CA equivalent codes in administrative data definition for insomnia as this was their sole approved
to provide the weight-­ based adjusted risk of death or indication.29
resource use.22 To reduce confounding, we established cohort exclu-
sion criteria that otherwise may have justified long-­term
Cohort inclusion/exclusion criteria use of BZDs in clinical scenarios beyond the scope
Eligible patients were adults age 18 years and older who of general guideline recommendations for anxiety
initiated a new benzodiazepine or Z-­drug prescription and insomnia. Namely, patients were excluded if they
(defined as no use in the 1 year prior to the first prescrip- had ≥1 ICD code for cancer, a seizure disorder or if
tion20 21 between 1 April 2001 and 31 March 2015, with no there was placement in the Manitoba palliative care drug
preceding dispensations from 1 April 2000 to 31 March programme at any point in the 5 years preceding their
2001 (first year of the dataset) to avoid prevalent user bias first prescription for a BZRA (online supplemental table
(figure 1). All individuals with at least 1 year of registry A3). Where patients became palliative ≥1 year after the
coverage prior to and after the first prescription was initial BZRA dispensation, their ongoing use of BZRA was

2 Brandt J, et al. BMJ Open 2021;11:e046916. doi:10.1136/bmjopen-2020-046916

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censored beginning from the date of their placement, index date, at the index date or up to 6 months past the
but all use prior to their palliative status was retained. index date (in the case of prescription opioids and other
Clobazam use was excluded entirely from the evaluated psychotropics, such as antidepressants, antipsychotics
drug claims because it is approved only as an adjunc- and mood stabilisers).
tive agent for epilepsy in Canada. Finally, patients were
excluded if they lacked at least 1 year of registry coverage Statistical analysis
from their first-­prescription index date. This was to elim- Standard reporting criteria were followed in the approach
inate any biasing effect from early mortality, moving out to logistic regression modelling (online supplemental
of province or other lost to follow-­up. tables A6 and A7).32 Univariate analysis was performed
first in the form of simple logistic regression. The multi-
Main outcome measures variable model was constructed to determine the most
Long-­term use was defined as ≥180 days based on the parsimonious model for prediction of long-­term BZRA
recommendation from a previous systematic review of use defined as ≥180 days in the first episode of use with
similar studies.24 This duration is longer than clinical adjustment of clinically relevant covariates based on
practice guideline duration recommendations and is previous literature.24 Differences between models in their
believed to be of sufficient length for risk of dependence maximum log-­likelihood estimation, likelihood ratios and
to occur.30 One-­third of individuals who use BZDs for other goodness-­ of-­
fit statistics enabled model discrimi-
longer than 6 months have been previously reported to nation.32 Multicollinearity and effect-­measure modifica-
be unable to stop completely due to withdrawal symptoms tion (ie, interaction effects) were assessed when it was
(eg, anxiety, insomnia, muscle spasms).30 A sensitivity suspected that variables may be either correlated or non-­
analysis, ranging from 60 to 365 days, was also used in our independent.32 In order to perform these diagnostics,
study to account for varying definitions of long-­term use the binary dependent variable was first substituted for a
reported in the literature.24 linear variable (first-­episode duration in days) to conduct
Patients were followed forward in time from the date a multiple linear regression. Specifically, collinearity was
of their first BZRA prescription. BZRA ‘use episodes’ determined to be a model threat if any correlation coeffi-
were determined according to consecutive prescription cient in the independent variable correlation matrix was
overlap based on dispensation dates and coded day supply ≥ │0.8│ or if any variance inflation factor was unreason-
values. The allowable gap between prescriptions was the ably high (≥10) while the corresponding tolerance factor
greater of either 30 days or 50% of the last prescription was minuscule (≤0.1).33 Analyses were assessed at p<0.01
day supply after the prescription end date (end date=dis- threshold set a priori for statistical significance.
pensation date+day-­ supply) of the prior prescription. For the multiple logistic regression, ‘complete-­ case
This gap was chosen to account for those who regularly analysis’ was used because the extent of missing data
or frequently used ‘as needed’ BZRA in the ‘use episode’ was too small to justify the need for multiple imputa-
duration. The episode end date was calculated as the date tion procedures.34 In this study, no claims were excluded
of the last prescription in a given ‘use episode’ plus its on the basis of missing data fields. Only 1568 claims
associated day-­supply. To account for immeasurable time (<0.01%) were excluded for being spurious (ie, ‘0’ day/
bias, hospitalisation time was assumed to be a continua- quantity supply or incredibly high dispensed quantity to
tion of BZD use given that in-­patient drug use data was day-­supply ratio) Furthermore, observed missing data
limited.31 The provincial drug programme subsidises was believed to be missing at random.35 The only variable
dispensations of up to a 100 day-­supply. with significant missing data was that of ‘prescriber type’
Individuals were able to have multiple use episodes (~38 000 missing observations or 17.5% of final sample).
over the entire study duration. First episode duration A subgroup analysis of each of the 17 categories of the
and average episode duration were calculated for each Charlson Comorbidity Score was also performed using
user. If patients only had one use episode both of these Z-­test of two proportions to describe the specific comor-
values were the same. Patients were allowed to switch bidities that may contribute to the relationship between
from one BZRA to another without it interrupting their Charlson Comorbidity Score and long-­term use.
‘use episodes’. This included switching from a BZD to a
Z-­drug and vice versa. Sensitivity analysis
To assess the robustness of the primary outcome, six
Independent variables sensitivity analyses (online supplemental tables A8 and
Variables used for statistical prediction of long-­ term A9) were conducted to determine how the proportion
use were determined a priori and included age, sex, of long-­ term use changed under differing parameter
geographical residence, residential mobility, socioeco- assumptions.36 The threshold duration for long-­ term
nomic status, marriage, concurrent opioid or prescription use was adjusted to values ranging from 60 days to 365
psychotropic use, comorbidity burden, healthcare usage, days. Additionally, the episode lapse criteria (ie, prescrip-
time period of first prescription and prescriber character- tion gap rule) was changed. While the analysis was not
istics (online supplemental tables A4 and A5). Variables exhaustive for every conceivable combination of these
were assessed at baseline; either within 1 year before the key parameters, the selected values were chosen because

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they were judged to be representative of how peers in the Both the crude and adjusted ORs are presented for the
international clinical community may have defined or full cohort in table 2.
measured ‘long-­term use’ of BZRA. All data were cleaned A subanalysis of the higher comorbidity scores in the
and analysed using SAS V.9.4. long-­term user groups shows that this relationship was
mainly driven by cardiovascular diseases, diabetes and
dementia (table 3). Proportions for these particular diag-
noses were 2–5 times higher in the long-­term user group,
RESULTS with the greatest difference existing for dementia (long
Episodic BZD/Z-drug use term; 8.5% vs short term; 1.5%). A sensitivity analysis was
Study population demographics are presented in table 1. performed changing the definition of incident user to no
There were 206 933 patients in our cohort representing receipt of BZRA prescription in the 3 years prior to the
931 271 unique BZRA dispensations over the 15-­ year first BZRA prescription. No change in results were found.
study duration. Over the study period, cohort individ-
uals had a median of three and average of 4.5 BZRA
use episodes, respectively. First episodes of use were of a DISCUSSION
median duration of 20 days (IQR=10–30 days). For all use This study found approximately 4.5% of the full cohort
episodes, the median average use duration was 30 days and 7.4% of the Z-­drug cohort were ‘long-­term’ first-­
(IQR=15–111 days). Evaluation of long-­term use revealed episode users according to the best available evidence-­
that 4.51% of patients used a BZRA for ≥180-­days in their based consensus definition of 180 days.24 Restricting the
‘first’ episode of use. At most, this proportion increased analysis to Z-­drug use showed that the frequency of long-­
to 9.64% when a sensitivity analysis of 60 days or greater term use was higher than that of the main cohort. Practice
was used for the definition of ‘long-­term use’ for the guidelines typically recommend a shorter duration of use
first episode of use. However, the proportion of long-­ for Z-­drugs in the treatment of insomnia (range of ≤2–6
term users increased considerably after averaging for all weeks)37–39 compared with BZD for anxiety disorder
episodes for each user (sensitivity analysis range: 15.6%– (up to ≤12 weeks depending on indication).40–42 There-
35.1%) (online supplemental table A7). fore, these results suggest greater disparity from practice
To evaluate treatment duration for insomnia, a sensi- guidelines in the case of Z-­drug use for insomnia. Of
tivity analysis was performed on only Z-­drugs (n=1 10 663), note, more recent insomnia guidelines have recognised
which found similar results (online supplemental tables that while non-­drug alternatives have a favourable safety
A9–A12). profile, these interventions may be difficult to achieve for
certain populations, which could explain the deviation
Factors predicting long-term first episode use between practice recommendations and real-­world use of
Logistic regression analysis revealed that male sex these agents.38
(adjusted OR 1.33, 95% CI 1.27 to 1.39), older age The proportion of patients who met criteria for ‘long-­
(adjusted OR 2.24, 95% CI 2.11 to 2.38) and 5.15 (95% CI term’ use after accounting for all of their use-­episodes (ie,
4.81 to 5.52) for aged 45–64 years and ≥65 years, respec- rather than just the first episode of use) was approximately
tively, compared with <45 years), receipt of income assis- 3.5 times higher than the proportion of patients meeting
tance (adjusted OR 1.68, 95% CI 1.55 to 1.81), previous criteria after only their first episode of use. These results
non-­BZRA psychotropic (adjusted OR 1.93, 95% CI 1.83 may indicate that repeated episodes of BZRA use may be
to 2.02) or opioid use (adjusted OR 1.16, 95% CI 1.11 to associated with a higher risk of being exposed to a BZRA
1.22), high comorbidity (Charlson Comorbidity Index for a duration of ≥180 days in one episode. An area of
1 and ≥2, adjusted OR 1.11, 95% CI 1.04 to 1.17) and future research is to examine whether repeated episodes
1.43, 95% CI 1.32 to 1.55, respectively), high health- of BZRA use is associated with progression to long-­term
care resource use (resource utilisation band of 4 and 5, use as demonstrated in a previous study that observed the
adjusted OR 1.15, 95% CI 1.07 to 1.23 and 1.46, 95% CI number of episodes of dispensing in the first month was
1.33 to 1.60, respectively), first prescription from psychia- a significant predictor of the total duration of dispensing
trist (adjusted OR 2.11, 95% CI 1.93 to 2.32) and receipt in the later period.43 Of note, the majority of people with
of first prescription after 2006 (2006–2011, adjusted OR repeated use still only take BZRAs for intermittent, short-­
1.74, 95% CI 1.64 to 1.85; 2011–2015, adjusted OR 2.99, term periods. Furthermore, confounding variables such
95% CI 2.80 to 3.18), were all predictive of long-­term as age and accrued comorbidity over time may influence
use of ≥180 days in the first episode. Rural residence the risk of future long-­term use in some patients. None-
(adjusted OR 1.10, 95% CI 1.04 to 1.15) and high residen- theless, these results support the observed difficulty in
tial mobility (adjusted OR 1.14, 95% CI 1.08 to 1.21) were deprescribing once BZRA use has become chronic, which
also associated with a higher risk of long-­term use in the has also been reported in previous literature.4 44 Lastly,
first episode. Married status was associated with a lower other clinical considerations such as risk of protracted
risk of meeting the long-­term use definition (adjusted OR withdrawal symptoms, risk of rebound insomnia and/
0.79, 95% CI 0.76 to 0.83). These findings were also repli- or anxiety, severity of indication, patient dissatisfaction,
cated in the sensitivity analysis restricted to Z-­drug users. limited alternate drug and non-­ drug interventions, or

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Table 1 Characteristics of BZRA users by first use episode duration
No of users Short term Long term Total
197 606 (100%) 9327 (100%) 206 933 (100%)
Sex distribution* Male 74 487 (37.7%) 4295 (46.1%) 78 782 (38.1%)
Female 123 057 (62.3%) 5029 (53.9%) 128 086 (61.9%)
Age category 18–44 101 709 (51.5%) 2776 (29.8%) 104 487 (50.5%)
45–64 66 752 (33.8%) 3320 (35.6%) 70 072 (33.9%)
65+ 29 143 (14.7%) 3231 (34.6%) 32 374 (15.6%)
SEFI-2 score ≤1 24 955 (12.6%) 1089 (11.7%) 26 044 (12.6%)
−1 to 0 81 718 (41.4%) 3835 (41.1%) 85 553 (41.3%)
0 to 1 64 967 (32.9%) 3274 (35.1%) 68 241 (33.0%)
>1 25 966 (13.1%) 1129 (12.1%) 27 095 (13.1%)
Residence distribution Urban 125 950 (63.7%) 5802 (62.2%) 131 752 (63.7%)
Rural 71 656 (36.3%) 3525 (37.8%) 75 181 (36.3%)
High residential mobility 36 392 (18.4%) 2385 (25.6%) 38 777 (18.7%)
Receipt of income assistance 18 530 (9.4%) 1222 (13.1%) 19 752 (9.5%)
Marriage record 102 461 (51.9%) 4618 (49.5%) 107 079 (51.8%)
Johns Hopkins Healthcare Resource 0 3001 (1.5%) 349 (3.7%) 3350 (1.6%)
Utilisation Band†† (no utilisation)
1 5798 (2.9%) 182 (2.0%) 5980 (2.9%)
2 33 974 (17.2%) 1192 (12.8%) 35 166 (17.0)
3 127 824 (64.7%) 5151 (55.2%) 132 975 (64.3%)
4 20 065 (10.2%) 1486 (15.9%) 21 551 (10.4%)
5 6882 (3.5%) 964 (10.3%) 7846 (3.8%)
(high utilisation)
Charlson Comorbidity Index Score 0 148 257 (75.0%) 5783 (62.0%) 154 040 (74.4%)
1 36 261 (18.4%) 2031 (21.8%) 38 292 (18.5%)
2+ 13 088 (6.6%) 1513 (16.2%) 14 601 (7.1%)
Non-­BZRA psychotropic prescription 0 111 216 (56.3%) 3862 (41.4%) 115 078 (55.6%)
dispensations
1 17 661 (8.9%) 518 (5.6%) 18 179 (8.8%)
2+ 68 729 (34.8%) 4947 (53.0%) 73 676 (35.6%)
Opioid prescription dispensations 0 132 027 (66.8%) 5855 (62.8%) 137 882 (66.6%)
1 30 530 (15.5%) 1011 (10.8%) 169 423 (15.2%)
2+ 35 049 (17.7%) 2461 (26.4%) 37 510 (18.2%)
Sex of prescriber issuing first Male 143 619 (75.3%) 6928 (76.5%) 150 547 (75.3%)
prescription††*
Female 47 128 (24.7%) 2126 (23.5%) 49 254 (24.7%)
Age of prescriber issuing first 50+ years 95 629 (52.1%) 4775 (53.9%) 100 404 (52.2%)
prescription‡‡
<50 years 87 833 (47.9%) 4.076 (46.1%) 91 909 (47.8%)
Type of prescriber issuing first General practitioner 146 823 (91.6%) 7013 (87.5%) 153 836 (91.4%)
prescription§§
Psychiatry 6338 (4.1%) 624 (7.8%) 6962 (4.1%)
Other 7183 (4.5%) 375 (4.7%) 7558 (4.5%)
Period of first prescription 2001–2006 90 008 (45.5%) 2608 (28.0%) 92 616 (44.8%)
2006–2011 65 750 (33.3%) 3170 (34.0%) 68 920 (33.3%)
2011–2016 41 848 (21.2%) 3549 (38.1%) 45 397 (21.9%)

*N=197 544 (short-­term users); N=9324 (long-­term users); N=206 868 (total users).
†N=197 544 (short-­term users); N=9324 (long-­term users); N=206 868 (total users).
‡N=183 462 (short-­term users); N=8851 (long-­term users); N=192 313 (total users).
§N=160 344 (short-­term users); N=8012 (long-­term users); N=168 356 (total users).
BZRA, benzodiazepine receptor agonist; SEFI-­2, socioeconomic factor index.

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Table 2 Statistical associations between predictor variables and long-­term use of BZRAs
Use duration
≥180 days ≥90 days ≥60 days
Open access

Independent variable Crude OR (95% CI) Adjusted OR (95% CI) Crude OR (95% CI) Adjusted OR (95% CI) Crude OR (95% CI) Adjusted OR (95% CI)

Male 1.41 (1.35 to 1.47) 1.33 (1.27 to 1.39) 1.40 (1.35 to 1.45) 1.34 (1.29 to 1.40) 1.30 (1.26 to 1.34) 1.27 (1.23 to 1.31)
Age 18–44 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref)
45–64 1.82 (1.73 to 1.92) 2.24 (2.11 to 2.38) 1.77 (1.70 to 1.85) 2.00 (1.91 to 2.10) 1.81 (1.75 to 1.86) 1.89 (1.82 to 1.97)
65+ 4.06 (3.86 to 4.28) 5.15 (4.81 to 5.52) 3.56 (3.41 to 3.72) 4.11 (3.88 to 4.36) 3.34 (3.22 to 3.47) 3.52 (3.36 to 3.70)
Rural residence 1.07 (1.02 to 1.11) 1.10 (1.04 to 1.15) 0.97 (0.93 to 1.00) 0.97 (0.94 to 1.02) 0.90 (0.87 to 0.92) 0.92 (0.88 to 0.95)
High residential mobility 1.52 (1.45 to 1.60) 1.14 (1.08 to 1.21) 1.35 (1.29 to 1.40) 1.06 (1.01 to 1.11) 1.14 (1.10 to 1.18) 1.01 (0.97 to 1.06)
Income assistance 1.46 (1.37 to 1.55) 1.68 (1.55 to 1.81) 1.14 (1.08 to 1.21) 1.35 (1.26 to 1.45) 0.88 (0.84 to 0.93) 1.12 (1.06 to 1.20)
Socio-­Economic Factor ≤1 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref)
Index-­2
−1 to 0 1.08 (1.00 to 1.15) 0.99 (0.92 to 1.07) 0.96 (0.91 to 1.02) 0.91 (0.86 to 0.97) 0.90 (0.87 to 0.95) 0.89 (0.85 to 0.94)
Score
0 to 1 1.16 (1.07 to 1.24) 1.02 (0.94 to 1.10) 0.98 (0.93 to 1.04) 0.92 (0.87 to 0.98) 0.87 (0.83 to 0.91) 0.89 (0.84 to 0.94)
>1 1 (0.92 to 1.09) 0.93 (0.84 to 1.03) 0.78(0.73 to 0.84) 0.80 0.63 0.73
(0.74 to 0.87) (0.59 to 0.67) (0.68 to 0.78)
Married 0.91 (0.87 to 0.95) 0.79 (0.76 to 0.83) 1.01 (0.98 to 1.05) 0.89 (0.85 to 0.92) 1.13 (1.10 to 1.16) 0.95 (0.92 to 0.99)
Opioid use 1.19 (1.14 to 1.27) 1.16 (1.11 to 1.22) 1.08 (1.04 to 1.12) 1.09 (1.05 to 1.14) 0.99 (0.96 to 1.02) 1.05 (1.01 to 1.09)
Psychotropic Rx Use (non-­BZRA) 1.82 (1.75 to 1.90) 1.93 (1.83 to 2.02) 1.62 (1.56 to 1.67) 1.75 (1.69 to 1.83) 1.34 (1.30 to 1.38) 1.49 (1.44 to 1.54)
Charlson Comorbidity 0 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref)
Index Score
1 1.44 (1.36 to 1.51) 1.11 (1.04 to 1.17) 1.33 (1.27 to 1.39) 1.08 (1.02 to 1.13) 1.24 (1.19 to 1.29) 1.04 (1.00 to 1.08)
2+ 2.96 (2.79 to 3.15) 1.43 (1.32 to 1.55) 2.41 (2.29 to 2.54) 1.33 (1.24 to 1.42) 2.01 (1.92 to 2.11) 1.23 (1.15 to 1.31)
Resource Utilisation 0–3 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 (ref)
Band
4 1.84 (1.73 to 1.95) 1.15 (1.07 to 1.23) 1.58 (1.50 to 1.66) 1.08 (1.01 to 1.14) 1.37 (1.31 to 1.43) 1.00 (0.94 to 1.05)
5 3.48 (3.24 to 3.73) 1.46 (1.33 to 1.60) 2.73 (2.56 to 2.92) 1.31 (1.20 to 1.42) 2.21 (2.08 to 2.35) 1.17 (1.09 to 1.27)
Male prescriber of first prescription 1.07 (1.02 to 1.12) 1.03 (0.98 to 1.09) 1.07 (1.02 to 1.11) 1.04 (0.99 to 1.09) 1.01 (0.98 to 1.05) 0.98 (0.94 to 1.02)
Prescriber age ≥50 years 1.08 (1.03 to 1.12) 0.98 (0.94 to 1.03) 1.08 (1.04 to 1.12) 0.99 (0.95 to 1.03) 1.15 (1.11 to 1.18) 1.08 (1.04 to 1.11)
Type of prescriber of first GP 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 1 (ref)
prescription
Psychiatrist 2.06 (1.89 to 2.25) 2.11 (1.93 to 2.32) 1.85 (1.72 to 2.00) 1.89 (1.75 to 2.05) 1.54 (1.44 to 1.65 1.63 (1.51 to 1.75)
Other 1.09 (0.98 to 1.21) 0.92 (0.82 to 1.03) 1.07 (0.98 to 1.17) 0.92 (0.84 to 1.01) 1.16 (1.07 to 1.24) 1.03 (0.96 to 1.11)
Period of first 2001–2006 1 (ref) 1 (ref) 1 (ref) 1 (ref) 1 1 (ref)
prescription
2006–2011 1.66 (1.58 to 1.75) 1.74 (1.64 to 1.85) 1.58 (1.51 to 1.65) 1.65 (1.57 to 1.7) 1.41 (1.36 to 1.46) 1.48 (1.42 to 1.54)
2011–2015 2.93 (2.78 to 3.08) 2.99 (2.80 to 3.18) 2.59 (2.48 to 2.71) 2.71 (2.57 to 2.8) 1.97 (1.90 to 2.05) 2.07 (1.98 to 2.16)

BZRA, benzodiazepine receptor agonist; GP, general practitioner; SEFI-­2, Socio-­Economic Factor Index-­2.

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Table 3 Frequency of Charlson Comorbidity Group diagnoses by first use episode duration for BZD/Z-­Drug cohort
Short-­term ‘first-­episode’ users Long-­term ‘first-­episode’
Charlson diagnosis (n=197 606) users (n=9327)  
Z-­test of two proportions
Myocardial infarction 2474 (1.3%) 281 (3.0%) P<0.01
Congestive heart failure 3943 (2.0%) 628 (6.7%) P<0.01
Peripheral vascular disease 2367 (1.2%) 256 (2.7%) P<0.01
Cerebrovascular disease 3690 (1.9%) 544 (5.8%) P<0.01
Dementia 2928 (1.5%) 796 (8.5%) P<0.01
COPD 23 064 (11.7%) 1163 (12.5%) P=0.02
Connective tissue/rheumatic 2793 (1.4%) 222 (2.4%) P<0.01
disease
Peptic ulcer disease 2140 (1.1%) 114 (1.2%) P=0.20
Mild liver disease 2406 (1.2%) 135 (1.4%) P=0.05
Moderate/severe liver disease 341 (0.1%) 28 (0.0%) P<0.01
Uncomplicated diabetes 14 131 (7.2%) 1099 (11.8%) P<0.01
Complicated diabetes 1611 (0.8%) 252 (2.7%) P<0.01
Paraplegia and hemiplegia 794 (0.4%) 136 (1.5%) P<0.01
Renal disease 1858 (0.9%) 238 (2.6%) P<0.01
Cancer 829 (0.4%) 64 (0.1%) P<0.01
Metastatic carcinoma 64 (0.0%) 13 (0.0%) P<0.01
HIV/AIDS 50 (0.0%) 10 (0.0%) P<0.01
BZD, benzodiazepines; COPD, chronic obstructive pulmonary disease.

interference with another prescriber’s decisions likely unmeasured ‘health’ anxiety or associated mental health
undermine potential deprescribing efforts. issues arising secondary to physical comorbidities or by
Older age and female sex have also been identified additional disruptive effects of physical illness on sleep.
in previous studies as being associated with long-­term The Charlson Comorbidity Score findings were not
use.45–51 While we found females to have greater repre- surprising given the relatively higher proportion of older
sentation in all patterns of BZRA use, we found males adults in the long-­ term use group. Nonetheless, the
were more specifically predictive of long-­term use after greater degree of BZRA exposure among those patients
the first episode of use.52–54 As with almost all of the previ- with dementia is of concern given the risk of BZD use
ously published studies, older age was strongly associated in this population.9 Similar to previous studies, prescrip-
with long-­term BZRA use.51–55 It should be noted that tions for an opioid or a psychotropic agent, such as anti-
older individuals may have had a greater opportunity to depressants, antipsychotics or mood stabilisers, during
be exposed to BZRA use. the baseline period were modestly predictive for future
As supported by previous evidence, income assistance long-­term use.48 52 54 56 58 61 Those having received a non-­
was associated with long-­term BZRA use.48 56 Our study BZD prescription agent for a psychiatric disorder could
also found frequent moving, unmarried status and rural be expected to have had greater disease severity on
residence to be associated with increased odds of long-­ average than those BZRA users who did not receive such
term use. Frequency of moving and income assistance treatment early on.
could be a proxy for general life stability.50 57 58 Rural An unexpected finding was the increased odds of long-­
residence may have a small effect on longer-­term BZRA term use associated with the more recent time period
use due to the relative limitations of timely scheduled of the first prescription. This is contrary to what may
follow-­up, which may necessitate prescriptions of greater be expected from cumulative knowledge on BZRA and
quantity or for longer periods. Another study also found the long-­standing emphasis on short-­term use advised in
rural adults to be at higher odds of inappropriate BZD guidelines and clinical literature. This finding may reflect
use .59 the growing awareness that BZRAs should not be used
Healthcare use and the presence of various physical as a first-­line treatment resulting in only those who have
illnesses have been consistent predictors of long-­ term not responded to other alternatives to be more likely to
BZRA use.47 49 50 60 In this study, as both of these variables receive BZRAs long-­term.
increased, so did the odds of long-­term use. We specu- This study has a number of strengths. This study used a
late that the positive relationship between these two large administrative data source that were near complete
indices and long-­term use may be partially explained by in their coverage of the study population’s prescription

Brandt J, et al. BMJ Open 2021;11:e046916. doi:10.1136/bmjopen-2020-046916 7

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drug dispensations and healthcare contact. Application explore whether these factors need to be considered at
of cohort inclusion and exclusion criteria in a care- the point of prescribing in clinical practice.
fully constructed new user longitudinal design limited
confounding and bias to the extent possible. Multiple Acknowledgements The authors wish to acknowledge Dr Sheryl Zelenitsky for
her helpful comments on earlier drafts of this manuscript. The authors acknowledge
sensitivity analyses on the main outcome measure, the the Manitoba Centre for Health Policy for use of data contained in the Manitoba
duration of BZRA use measurement method and the Population Research Data Repository under Research Ethic Board approval
association between the independent and dependent HS20498 (HIPC#2016/2017-­062). The results and conclusions are those of the
variables for two cohorts reduced quantitative bias to authors and no official endorsement by the Manitoba Centre for Health Policy,
Manitoba Health, or other data providers is intended or should be inferred.
increase confidence in the results.
A few important limitations should be acknowledged. Contributors JB is guarantor and contributed to the conception, design, acquisition
of data, analysis and writing of the manuscript. DJ contributed to the analysis,
First, administrative data are prone to some misclassifi- interpretation and writing of the manuscript. SA-­S contributed to the interpretation
cation of variables. For instance, diagnostic criteria for and writing of the manuscript. DC contributed to the interpretation and analysis
cohort case inclusion and exclusion will differ in their of the study. ME contributed to the interpretation and writing of the study. AS
true sensitivity and specificity, regardless of prior valida- contributed to the interpretation and writing of the study. CL contributed to the
conception, design, interpretation and writing of the manuscript.
tion of case definitions. Drugs used during any hospi-
Funding This work was supported by the College of Pharmacy at the University
talisations were not available and was assumed to be
of Manitoba. Additional student funding for JB was granted by the Provincial
continued BZD exposure. As all independent variables Government of Manitoba in the form of a Manitoba Graduate Scholarship stipend.
were only measured cross-­ sectionally before or at the Disclaimer Funding sources had no role in the conduct of research and/or
time of the first prescription of the first use episode, the preparation of the article.
logistic regression model was only predictively valid for Competing interests None declared.
the first use episode duration and not users’ average
Patient and public involvement statement We have a patient advisory group
episode duration. Since DPIN only captures the days who provided feedback on the dissemination of research findings.
supply provided, it is possible that not all of the medica- Patient consent for publication Not applicable.
tion was actually taken by the patient. However, this study
Ethics approval Access to the data for this project was approved by the
was able to provide insight into the prescribing practices University’s Health Research Ethics Board (HREB, registration number H2017:052
of BZD that are filled in the pharmacy in this population. (HS20498) and the Health Information Privacy Committee (HIPC, no. 2016/2017-­
Our study did not evaluate the extent of concurrent use 62) of the provincial government. Consent for this study was not required by HREB
of multiple BZD or other psychiatric diagnoses such as given the retrospective nature of the study and data agreements in place through
HIPC.
substance use disorder. The databases also do not capture
Provenance and peer review Not commissioned; externally peer reviewed.
participation in psychological interventions such as
cognitive behavioural therapy. Moreover, while the data- Data availability statement All data relevant to the study are included in the
article or uploaded as online supplemental information. Data used in this article
bases are able to link several data on health information were derived from administrative health and social data as a secondary use. The
regardless of age and coverage, they do not capture other data were provided under specific data sharing agreements only for approved use
potential confounding factors such as education status at MCHP. The original source data is not owned by the researchers or MCHP and as
and ethnicity. This study was done in a setting where there such cannot be provided to a public repository.
is a universal healthcare system and medication costs are Supplemental material This content has been supplied by the author(s). It has
covered for all Manitobans after an income-­based deduct- not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been
peer-­reviewed. Any opinions or recommendations discussed are solely those
ible is met every year. As a result, findings may be gener- of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and
alisable to similar settings. Future research should aim to responsibility arising from any reliance placed on the content. Where the content
examine the association of repeat exposure to BZRA and includes any translated material, BMJ does not warrant the accuracy and reliability
risk of chronic use. Future research could also examine of the translations (including but not limited to local regulations, clinical guidelines,
terminology, drug names and drug dosages), and is not responsible for any error
specific benzodiazepine type and formulations on risk of and/or omissions arising from translation and adaptation or otherwise.
long-­term use.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
and license their derivative works on different terms, provided the original work is
CONCLUSION properly cited, appropriate credit is given, any changes made indicated, and the use
is non-­commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/.
Prescribing of BZRAs was used for less than 6 months
duration for the majority of individuals with a prior ORCID iD
history of anxiety, depression or insomnia. However, the Christine Leong http://​orcid.​org/​0000-​0003-​0033-​6877
proportion of long-­term use among new users was up to
one in three based on the average of all episodes of use,
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