Benzodiazepines are Prescribed More Frequently to Patients Already at Risk for Benzodiazepine-Related Adverse Events in Primary Care
Benzodiazepines are Prescribed More Frequently to Patients Already at Risk for Benzodiazepine-Related Adverse Events in Primary Care
David S. Kroll 1 2
Harry Reyes Nieva 0 2
Arthur J. Barsky 1 2
Jeffrey A. Linder 0 2
0 Division of General Medicine and Primary Care, Brigham and Women's Hospital , Boston, MA , USA
1 Department of Psychiatry, Brigham and Women's Hospital , Boston, MA , USA
2 Harvard Medical School , Boston, MA , USA
BACKGROUND: Benzodiazepine use is associated with adverse drug events and higher mortality. Known risk factors for benzodiazepine-related adverse events include lung disease, substance use, and vulnerability to fracture. OBJECTIVE: To determine whether benzodiazepine prescribing is associated with risk factors for adverse outcomes. DESIGN: Longitudinal cohort study between July 1, 2011, and June 30, 2012. PARTICIPANTS: Patients who visited hospital- and community-based practices in a primary care practicebased research network. MAIN MEASURES: Odds ratio of having a target medical diagnosis for patients who received standard and highdose benzodiazepine prescriptions; rates per 100 patients for outpatient and emergency department visits and hospitalizations. KEY RESULTS: Among 65,912 patients, clinicians prescribed at least one benzodiazepine to 15 % (9821). Of benzodiazepine recipients, 5 % received high doses. Compared to non-recipients, benzodiazepine recipients were more likely to have diagnoses of depression (OR, 2.7; 95 % CI, 2.6-2.9), substance abuse (OR, 2.2; 95 % CI, 1.9-2.5), tobacco use (OR, 1.7; 95 % CI, 1.5-1.8), osteoporosis (OR, 1.6; 95 % CI, 1.5-1.7), chronic obstructive pulmonary disease (OR, 1.6; 95 % CI, 1.5-1.7), alcohol abuse (OR, 1.5; 95 % CI, 1.3-1.7), sleep apnea (OR, 1.5; 95 % CI, 1.31.6), and asthma (OR, 1.5; 95 % CI, 1.4-1.5). Compared to low-dose benzodiazepine recipients, high-dose benzodiazepine recipients were even more likely to have certain medical diagnoses: substance abuse (OR, 7.5; 95 % CI, 5.5-10.1), alcohol abuse (OR, 3.2; 95 % CI, 2.2-4.5), tobacco use (OR, 2.7; 95 % CI, 2.1-3.5), and chronic obstructive pulmonary disease (OR, 1.5; 95 % CI, 1.2-1.9).
psychopharmacology; benzodiazepines; anxiety; sleep disorders; J Gen Intern Med 31(9); 1027-34 DOI; 10; 1007/s11606-016-3740-0 © Society of General Internal Medicine 2016
Previous Presentations Preliminary data from this study were presented
at the 61st Annual Meeting of the Academy of Psychosomatic Medicine,
Fort Lauderdale, Florida, November
; additional data will be
presented in part at the 62nd Annual Meeting of the Academy of
Psychosomatic Medicine, New Orleans, Louisiana, November 13, 2015.
Benzodiazepines are commonly used to treat anxiety and sleep
disorders, as well as a number of primary medical conditions.
However, they are often prescribed to patients who either do
not have a clear indication1 or have poor indications such as
The use of benzodiazepines is associated with higher
mortality.3,4 National registries in Europe and the United States
have linked benzodiazepines use to elevated rates of
respiratory suppression in patients with chronic obstructive
pulmonary disease (COPD)5 and with overdose death in substance
use disorders.6,7 Benzodiazepines may also be linked to
cancer risk and to exacerbation of obstructive sleep apnea
(OSA) severity.8,9 In the elderly, benzodiazepines are
associated with delirium in the hospital10,11 and with hip fractures,12
disability,13 and dementia14,15 in the community.
Although benzodiazepines are frequently prescribed by
primary care physicians (PCPs),16 few studies have described in
detail which primary care patients receive benzodiazepine
prescriptions. Most studies that have explored this question
were performed outside of North America.17–26 These works
identified some demographic predictors of benzodiazepine
prescription (e.g., increased age and female gender) and an
association with higher medical comorbidity in general, but
did not focus on specific medical diagnoses. While
benzodiazepines have known risks of adverse events in the elderly,
including fractures, and in patients with lung disease and
substance use disorders, no prior studies have examined
benzodiazepine prescriptions within the distribution of conditions
that increase the risk of benzodiazepine-related adverse events
in primary care in North America.
We hypothesized that clinicians prescribe benzodiazepines
disproportionately to primary care patients with factors or
diagnoses that increase the risk of benzodiazepine-related adverse
events, and that patients who receive benzodiazepines have
higher healthcare utilization rates. If confirmed, such risk factors
and utilization rates could explain some of the association
between benzodiazepine use and higher mortality. We performed a
longitudinal cohort study to identify associations between
benzodiazepine prescribing, risk factors for benzodiazepine-related
adverse events, and healthcare utilization.
The Brigham and Women’s Primary Care Practice-Based
Research Network (BWPC PBRN) includes 16 hospital- and
community-based practices and community health centers in
eastern Massachusetts. The BWPC PBRN practices used a
fully functional, Certification Commission for Healthcare
Information Technology (CCHIT)-certified electronic health
record (EHR), which included problem lists, medication lists,
and prescriptions. By policy, all medicines were prescribed
through the EHR. Medications not prescribed by affiliated
clinicians were listed in the EHR without dosing information.
Sociodemographic information was collected during
registration and was updated periodically. Billing codes were
recorded in a separate, dedicated billing system. Partners
HealthCare—an integrated health delivery system in eastern
Massachusetts, of which Brigham and Women’s Hospital is a
part—had an information system that captured outpatient
visits, emergency room visits, and hospitalizations for all Partners
Approval for the conduct of this study was obtained from
the Partners HealthCare Institutional Review Board.
We used the Partners HealthCare Research Patient Data
Repository, which aggregates data from throughout Partners
HealthCare facilities, to identify all patients who made at least
one visit to any of the ten BWPC PBRN practices that were
participating in an unrelated clinical trial between July 1, 2011,
and June 30, 2012.27–29 We extracted and combined
sociodemographic and clinical information from the EHR with
We included all coded benzodiazepine prescriptions and
listings. From the EHR we extracted prescription details that
included the name of the medication, dose, frequency, total
number of units prescribed, number of refills, and prescribing
clinician. Our data source included prescriptions; we could not
measure prescription fills or actual benzodiazepine use by
We extracted medical diagnoses from the EHR problem list
and ICD-9 billing codes associated with individual encounters
(see online appendix). We extracted medical diagnoses
defined by the Healthcare Effectiveness Data and Information
Set (HEDIS; asthma, COPD, cardiovascular disease,
depression, diabetes, hypertension, obesity, osteoporosis, and
tobacco use),30 psychiatric diagnoses for which benzodiazepines are
commonly prescribed (anxiety and insomnia), and diagnoses
for which benzodiazepines are contraindicated or
controversial (alcohol abuse, sleep apnea, and substance abuse).6,7,9,31
We also extracted data about antidepressant medication
prescribing from the EHR, because these are commonly
considered first-line agents for depression and anxiety. We
included the antidepressants fluoxetine, sertraline, paroxetine,
citalopram, escitalopram, fluvoxamine, mirtazapine, bupropion,
venlafaxine, desvenlafaxine, duloxetine, nefazodone,
amitriptyline, amoxapine, clomipramine, desipramine, doxepin,
imipramine, nortriptyline, protriptyline, trimipramine, phenelzine,
tranylcypromine, isocarboxazid, trazodone, and vilazodone.
We extracted medical encounters from encounter-level
billing data, including primary care visits (both any visit to the
primary care clinic and any visit with the PCP of record),
specialist outpatient visits, emergency department (ED) visits,
and hospitalizations, and length of stay for patients with one or
more hospitalizations. We defined a patient’s PCP as the PCP
of record from the EHR. Listed PCPs are nearly always
primary care clinicians.
We calculated benzodiazepine dosing and days prescribed
based on a combination of pill dose/strength, dosing
frequency, and number of pills prescribed during the study period. We
converted prescriptions of lorazepam, clonazepam, and
alprazolam—which, together with diazepam, accounted for 97 %
of benzodiazepine prescriptions—to Baverage daily
diazepamequivalent dosages.^ Only days for which benzodiazepines
were prescribed were included in the calculation of average
High-dose benzodiazepine prescribing has been defined in
the literature as a daily dose equivalent of ≥30 mg per day of
diazepam.32 Although potency equivalence between
benzodiazepine agents is not clearly established, we defined 30 mg
diazepam equivalents as 3 mg/d alprazolam, 3 mg/d
clonazepam, and 5 mg/d lorazepam.32,33 For patients with multiple
benzodiazepine agents (3 % of patients receiving
benzodiazepines) for which diazepam-equivalent dosing could be
calculated, we added them together as though they were concurrent
or consecutive prescriptions of a single diazepam-equivalent
agent. Other benzodiazepine prescriptions and benzodiazepine
prescriptions without complete prescribing information were
not included in the comparison between high-dose and
To determine which patients were most likely to receive
benzodiazepine prescriptions, we compared patients who
received at least one benzodiazepine prescription with those
who did not. We assessed differences in demographic
variables, medical diagnoses, and inpatient and outpatient
encounters. Among benzodiazepine recipients, we made parallel
comparisons between patients who did and did not receive
We used means, medians, percentages, odds ratios, and rate
ratios with 95 % confidence intervals to compare patients who
did and did not receive benzodiazepines and those who
received high doses versus standard doses. We compared
categorical variables using the chi-square test and continuous
variables using Student’s t test. We performed the Mann–
Whitney–Wilcoxon test to compare days dosed among
categorical variables with two groups and the Kruskal-Wallis test
for the same comparison among categorical variables with
three or more groups. We calculated odds ratios using logistic
regression, and we used Poisson regression to calculate rate
ratios. We used SAS software (version 9.3; Cary, NC) for all
analyses and considered p values < 0.05 statistically significant.
Among 65,912 patients who visited one of the ten included
primary care practices during the study year, at least one
benzodiazepine prescription was issued to 15 % (9821); of
these patients, 44 % received at least one benzodiazepine
prescription from their PCPs of record as opposed to other
providers within or outside their primary care practices.
Among the 9821 patients who received a benzodiazepine
prescription, the mean age was 55 years, 77 % were white,
7 % were black, and 59 % had private insurance. Patients
received a median of 30 (IQR = 10–60) days of
benzodiazepines at a mean daily diazepam dose equivalent of 11 mg.
There were 9532 (97 %) patients who received only one type
of benzodiazepine agent during the study period, 280 (3 %)
who received two, eight (<1 %) who received three, and one
(<1 %) who received more than three. The most commonly
prescribed benzodiazepines were lorazepam (n = 5057;
51 %;), clonazepam (n = 2007; 20 %), diazepam (n = 1372;
14 %), and alprazolam (n = 1371; 14 %). The mean daily dose
prescribed, by benzodiazepine, was 1.7 mg for lorazepam
(10.0 mg diazepam-equivalent), 1.5 mg for clonazepam
(14.5 mg diazepam-equivalent), 10.8 mg for diazepam, and
1.0 mg for alprazolam (10.1 mg diazepam-equivalent).
Clinicians prescribed benzodiazepines more commonly to
patients who were older, were women, had Medicare or
Medicaid insurance, and were divorced, widowed, or
separated (Table 1). Clinicians prescribed to white patients at
a higher rate than to non-white patients. Medical diagnoses
associated with a higher likelihood of being prescribed a
benzodiazepine included substance abuse, depression, tobacco
use, alcohol abuse, osteoporosis, chronic obstructive
pulmonary disease (COPD), sleep apnea, and asthma. Clinicians
prescribed a higher median days dosed to Medicare recipients
and a lower median days dosed to black patients. Only 43 % of
patients who were prescribed a benzodiazepine had a
diagnosis of anxiety or insomnia noted on a problem list or coded in
billing data, and 44 % were concurrently prescribed
Patients to whom benzodiazepines were prescribed were
higher users of medical care. On average, they made more
primary care, specialist outpatient, and emergency department
visits, were hospitalized more frequently, and when
hospitalized, had a slightly longer length of stay (Table 2).
High-Dose Benzodiazepine Prescribing
Among patients with benzodiazepine prescriptions, the PCPs
of record prescribed high doses to 5 %, including to 3 % of
lorazepam recipients, 9 % of clonazepam recipients, 2 % of
diazepam recipients, and 6 % of alprazolam recipients. Other
clinicians prescribed high doses to 5 % of lorazepam
recipients, 10 % of clonazepam recipients, 3 % of diazepam
recipients, and 6 % of alprazolam recipients.
Demographic characteristics associated with a higher
likelihood of being prescribed a high-dose benzodiazepine
included younger age, male gender, Medicaid insurance,
nonmarried status, and lower education level (Table 3). Medical
diagnoses associated with a higher likelihood of receiving a
high-dose benzodiazepine prescription included alcohol
abuse, anxiety, asthma, COPD, depression, diabetes, obesity,
substance abuse, and tobacco use. Among patients with
highdose prescriptions, 52 % were concurrently prescribed
On average, patients who received high-dose
benzodiazepine prescriptions had a greater number of emergency visits
and hospitalizations compared to patients who received
standard-dose prescriptions (Table 2).
Benzodiazepine prescriptions come from multiple sources
within the healthcare system, including PCPs, specialists,
and ED and inpatient clinicians. In our sample, close to half
of the patients who received benzodiazepine prescriptions
received at least one from their PCPs, reflecting the relevance
of benzodiazepine prescribing among clinicians who work in
primary care. Benzodiazepines have a well-established role in
the treatment of several conditions commonly seen in primary
care, including anxiety and insomnia, and it is likely that
benzodiazepine prescribing is safe for many patients,
‡The referent for odds ratios for diagnoses and other prescriptions is patients who did not have that diagnosis or prescription
particularly when treatment is limited in dose and duration.34
Our finding that clinicians prescribed benzodiazepines
disproportionately to patients with at least some known risk factors
for benzodiazepine-related adverse events—including
increased age, pulmonary diseases, osteoporosis, and substance
use disorders—may help to explain the relationship between
benzodiazepine use and poor health outcomes.
Benzodiazepines are associated with adverse effects,
including higher mortality.3,4 Although causality has not been
definitively determined, strong associations between
benzodiazepine prescribing and mortality have been described
in certain patient groups. Higher mortality rates have been
found in patients with COPD, presumably due to respiratory
suppression.5 Patients with opioid use disorders have a higher
risk of overdose death—both suicide and non-suicide—when
taking benzodiazepines.6,7,35 Senior patients are particularly
vulnerable, because benzodiazepines are associated with
falls,36–39 hip fractures,12 delirium,10,11 disability,13
dementia,14,15 and motor vehicle accidents.40 Osteoporosis has been
linked to fractures alongside benzodiazepine prescriptions in
*All patients included in the analysis made at least one primary care visit
patients at risk of falls, although no direct relationship between
osteoporosis and benzodiazepine prescriptions has been
described.41,42 Prescribing benzodiazepines disproportionately to
patients with COPD, substance use disorders, and osteoporosis,
and who are older may contribute to their mortality risk through
these mechanisms. Associations between benzodiazepines and
tobacco use have been cited as a possible explanation for the
association between benzodiazepines and cancer risk;8 our
finding of a similar association supports the hypothesis that tobacco
use confounds the relationship between benzodiazepines and the
risk of cancer, although we did not measure cancer diagnoses
directly, and this relationship remains poorly understood.
Our finding that high-dose prescribing was also associated with
diagnoses of COPD and substance use disorders raises special
concern. The magnitude of the association between
benzodiazepines and mortality in general appears to be dose-dependent,3,4
and dose-dependent relationships between benzodiazepines and
mortality have been described independently for COPD5 and
overdose deaths.43 Therefore, the disproportionate prescribing of
high-dose benzodiazepines to patients with COPD and substance
use disorders may amplify the effect of prescribing standard-dose
benzodiazepines to patients already at risk of adverse outcomes.
The association between higher days dosed and receipt of
Medicare may reflect an association between older age and longer
benzodiazepine prescriptions, but we did not measure this directly
and therefore cannot conclude that this is true. That clinicians
prescribed shorter and fewer benzodiazepine prescriptions to black
patients is notable, although we do not draw conclusions about
medical risks of prescribing from this. We combined very brief
prescriptions (e.g., single doses) with longer prescriptions in our
analysis because mortality risk is associated with single
benzodiazepine doses in a dose–response fashion.4,8
The increased frequency of medical diagnoses and higher rates
of healthcare utilization associated with benzodiazepine
prescriptions indicate that, in general, patients who receive
benzodiazepines have higher levels of medical comorbidity. Prior studies in
Brazil, the Netherlands, and Australia have linked
benzodiazepine prescriptions—without a dose relationship—to patient
selfreporting of poorer health status.21–23 Benzodiazepine
prescriptions were similarly linked to higher frequencies of medical
diagnoses in two population-based Canadian studies,40,41 and
with a higher score on the Charlson comorbidity index in an
Israeli study.18 Studies linking benzodiazepines to a higher
number of medical visits21 and increased length of hospital stay26
have been conducted in Israel and Japan, respectively.
The fact that the use of benzodiazepines was associated with
higher rates of inpatient and outpatient utilization in our study is
consistent with two hypotheses: that patients with higher medical
comorbidity are more likely to receive a benzodiazepine
prescription, and that benzodiazepines may increase a patient’s risk of
adverse health outcomes. Both may be correct; our findings
suggest a possible mechanism by which benzodiazepine prescriptions
are associated with adverse outcomes for at least some patients.
Our findings of an association do not necessarily signify
causation. Some high-risk medical diagnoses such as
respiratory illnesses44 and substance use disorders45 are associated
†The OR for patient age is per decade
COPD chronic obstructive pulmonary disease; CVD cardiovascular disease
*We defined high-dose benzodiazepine prescribing as a dose of ≥30 mg per day of diazepam or equivalent
‡The OR for whites vs. non-whites receiving a high benzodiazepine dose was 0.96 (95 % CI, 0.75–1.23)
§The referent for odds ratios for diagnoses and other prescriptions is patients who did not have that diagnosis or prescription
with anxiety, which may be appropriate indications for a
benzodiazepine prescription. Benzodiazepines may be
employed directly to treat breathlessness, particularly as a
palliative intervention at the end of life, although the evidence
supporting a favorable risk/benefit ratio for this is limited, 46
and we would expect these numbers to be small.
Benzodiazepines also have a role in the treatment of alcohol withdrawal,
although their use in alcohol disorders or withdrawal is not
typically recommended in ambulatory settings.31 We did not
record other medical indications for benzodiazepines such as
muscle spasms. Our study relied on electronic documentation
of information, which approximates but may not equal actual
benzodiazepine use by patients. Our study could
underestimate benzodiazepine use if patients receive care outside of our
health system. Conversely, it could overestimate
benzodiazepine use because we rely on prescribing data rather than filled
prescriptions or claims. Because 56 % of prescriptions came
from providers outside primary care, and prescriptions from all
providers were grouped together in our data, our findings may
not reflect prescribing patterns for PCPs specifically, although
we do not believe this detracts from the relevance of our
findings. Our definition of high-dose benzodiazepine
prescribing might be considered arbitrary, given the absence of clearly
established potency comparisons between benzodiazepine
agents; however, the cutoffs we used were close to other
measurements of the 90th percentile of mean daily doses.33
We found that clinicians prescribed benzodiazepines more
f r e q ue n t l y t o p a t i e n t s w i t h k n o w n r i s k fa c t o r s f o r
benzodiazepine-related adverse events. Prescribers should
take into account their patients’ risk factors for adverse events
when considering a benzodiazepine. For patients with COPD,
substance use disorders, osteoporosis, and advanced
age—those who appear to be the most likely to receive
benzodiazepine prescriptions and, for the two former categories, at the
highest doses—the choice of prescribing a benzodiazepine
should be made with great caution.
ACKNOWLEDGMENTS: We acknowledge Joji Suzuki, MD, Brigham
and Women’s Hospital, for assistance with our study design.
Corresponding Author: David S. Kroll, MD; Department of
Psychiatry, Brigham and Women’s Hospital, 75 Francis Street,
Boston, MA 02120, USA (e-mail: ).
Compliance with Ethical Standards:
Conflict of Interest: The authors declare that they do not have a
conflict of interest.
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