Gender Differences in Prescribing of Zolpidem in the Veterans Health Administration
Guneet K. Jasuja, PhD; Joel I. Reisman, AB; Renda Soylemez Wiener, MD, MPH; Melissa L. Christopher, PharmD; and Adam J. Rose, MD, MSc
Zolpidem, a nonbenzodiazepine sedative hypnotic, is extensively prescribed in the United States1,2
for short-term treatment of insomnia. However, there have been growing concerns associated with its use, including higher risks of falls and fractures,3,4
motor vehicle collisions,5
central nervous system–associated adverse drug reactions,6
In fact, it has been shown that the mortality implications of taking zolpidem are equivalent to those associated with a benzodiazepine.9
Clinically significant drug interactions of zolpidem with benzodiazepines are associated with increased hospitalizations.10
To add to the complexity, gender differences have been noted, with women reporting greater sensitivity than men to the sedative effects of zolpidem.11
These safety concerns prompted the FDA in 2013 to recommend cutting doses prescribed to women in half, specifically from 10 mg immediate release (IR) daily to a maximum of 5 mg/day and from 12.5 mg controlled release (CR) daily to 6.25 mg/day.12
Usually prescribed for a 30-day period, the IR formulation dissolves much more rapidly than the CR formulation to cause sedation facilitating the induction of sleep.13
Although there was also a recommendation to extend this dose reduction to men, the guidelines remained unchanged for men (5 mg or 10 mg IR and 6.25 mg or 12.5 mg CR). This mandate of a gender-specific guideline for zolpidem was due to the fact that women metabolize the same dose of zolpidem more slowly than men, resulting in 50% higher serum levels.14
Previous studies have found increased compliance among providers, specifically midlevel and physician providers, with reduced-dose zolpidem in women after the FDA-mandated labeling changes.15,16
Although adherence to guidelines was attributed to change in prescribing habits of the providers, it could not be ascertained whether it was driven by the drug safety communication from the FDA or individual patient factors. However, these studies included relatively small sample sizes; they did not evaluate the proportion of women who were still being prescribed an inappropriate dosage after the FDA guidance, nor did they examine predictors of this inappropriate outcome.
In line with this FDA recommendation, the national Veterans Health Administration (VHA) Pharmacy Benefits Management (PBM) Service issued a similar directive to lower the doses of zolpidem in women in 2013.17
However, little is known about zolpidem prescribing patterns in the VHA. Therefore, the goal of this study was to examine utilization trends and inappropriate prescribing of zolpidem in accordance with PBM guidelines in male and female veterans in the VHA. We expected significant differences in inappropriate zolpidem prescribing in male and female veterans by age, with women potentially being more likely to receive zolpidem inappropriately.
The study was approved by the Institutional Review Board of the Bedford Veterans Affairs Medical Center. We examined demographic, diagnostic, and prescription data of patients receiving outpatient prescriptions for zolpidem at any VHA site between October 1, 2011, and September 30, 2016.
We examined all patients who received zolpidem (n = 500,332; 441,734 men and 58,598 women) between fiscal year (FY) 2012 and FY 2016. We defined a zolpidem user as a patient who received 3 or more days of continuous zolpidem prescription during the study period. Additionally, we examined a random 10% sample of patients who did not receive zolpidem (n = 631,449). We also used the full study population (N = 1,131,781) as a basis for calculating prevalence rates.
The index date for zolpidem users was the earliest prescription of zolpidem they received in the entire study period.
We examined the sociodemographic factors gender, age, race, Hispanic ethnicity, marital status, VHA co-payment for prescription drugs based on VHA eligibility status, FY of zolpidem prescription, US region where the patient received care, and the urban versus rural status of the facility where the index prescription was written. These variables, and in particular gender and age, have been previously linked to healthcare utilization.18
We also evaluated a number of physical and mental health conditions that have been shown to be associated with zolpidem use.19-22
The presence of these conditions was determined from inpatient and outpatient diagnoses using International Classification of Diseases, Ninth Revision
) and Tenth Revision
) codes, using a 1-year look-back period prior to the date of the index prescription (eAppendix
[available at ajmc.com
]). We considered a condition to be present when there were at least 2 diagnostic codes for the condition separated by 7 or more days.
In this study, we evaluated 2 outcomes relating to appropriateness of zolpidem prescribing. The first measure was whether the daily dose prescribed to male and female veterans exceeded the 2013 PBM recommended dosage (men: IR ≤10 mg or CR ≤12.5 mg; women: IR ≤5 mg or CR ≤6.25 mg). In our study, we calculated the daily dose by multiplying the inferred tablets per day (quantity divided by days’ supply) by the tablet strength given in the full description of the medication. We also examined a second measure of inappropriate prescribing in both men and women: the overlap in prescribing of zolpidem with the prescribing of a benzodiazepine. We defined overlapping prescribing as a benzodiazepine prescription for more than 3 days written within 30 days before or after the index zolpidem prescription.
As a first step, we generated descriptive characteristics stratified by gender. We used Pearson’s χ2
test to perform statistical comparisons between men and women. We grouped age and race variables into categories to yield a reasonable frequency distribution. Physical and mental health conditions were binary (yes/no) variables. We applied a sampling weight of 10 to the nonzolpidem cases when computing prevalence and initiation. We imputed missing data on all variables except race, marital status, and comorbidities to allow inclusion of all observations in multivariate analyses. Second, we conducted an interrupted time series analysis before and after the 2013 PBM guidelines (which recommended lower zolpidem doses for women) to determine whether these guidelines led to significant improvement in appropriate zolpidem dosing. For this analysis, we excluded 1849 men and 193 women because they had incomplete dose data on the index date of their zolpidem prescription. We calculated the unadjusted proportion of male and female veterans receiving high-dose zolpidem prescriptions from 2011 to 2016. Finally, we generated multivariate logistic regression models to analyze the determinants of the 2 inappropriate prescribing outcomes, specifically dose exceeding guideline recommendations and overlap with benzodiazepines, in separate models for men and women. We used SAS version 9.4 (SAS Institute Inc; Cary, North Carolina) for all analyses. We used P
<.001 as the threshold for statistical significance for all analyses.
Characteristics of Zolpidem Users
reports descriptive characteristics of zolpidem users stratified by gender. Across the VHA, 7.1% of men and 10.0% of women received zolpidem at least once during the study period. Compared with male zolpidem users, female users were younger (45.7 years vs 56.6 years) and were more likely to have anxiety disorders (21.1% vs 13.1%), bipolar disorder (11.4% vs 6.1%), and major depression (44.0% vs 29.8%); P
<.001 for all. Men receiving zolpidem had higher proportions of coronary artery disease (11.1% vs 1.8%), diabetes (21.0% vs 9.2%), and hypertension (38.5% vs 20.3%) compared with women; P
<.001 for all.
Trends in High-Dose Zolpidem Prescribing for Men Versus Women
Unadjusted trends in high-dose zolpidem prescriptions by gender before and after the PBM 2013 recommendations for suggested lower dose in women are shown in the Figure
(A and B). The observed proportion of women receiving the higher dose decreased considerably from 75.9% in 2011 to 29.1% in 2016 (P
<.001), and the 2013 PBM recommendations had a significant effect after adjustment for secular trends and covariates (P
<.001). For men, there was a decline in observed receipt of high-dose zolpidem from 1.7% in 2011 to 0.1% in 2016 (P
<.001), but the recommendations did not have a significant effect (P
Patient Characteristics Associated With Inappropriate Zolpidem Prescribing Stratified by Gender
For our first outcome, inappropriate dose, the analysis was limited to men and women with an index prescription in January 2013 or later, resulting in a sample of 194,355 men and 28,181 women. As reported in Table 2
, compared with 0.1% of men who received more than 10 mg of IR or 12.5 mg of CR, approximately 29.7% of women zolpidem users were receiving an inappropriate dosage, defined as exceeding 5 mg/day for IR or 6.25 mg/day for CR. Men with substance use disorder (adjusted odds ratio [AOR], 3.34; P
<.001 for this and all other findings) and men living in the Midwest (AOR, 1.42) were more likely to receive an inappropriate zolpidem dose after adjusting for covariates. In fully adjusted models, younger women were more likely to receive an inappropriately high dose compared with women 80 years or older (AORs: 21-39 years, 2.75; 40-49 years, 2.97). Further, women with certain conditions, including major depression (AOR, 0.91), were less likely to receive an inappropriate dosage. Women in the West were less likely to receive an inappropriate dose (AOR, 0.80) compared with women residing in the Northeast. Similar to the men, women with substance use disorder were more likely to receive an inappropriately high dose of zolpidem (AOR, 1.48).
Of the 500,332 zolpidem users, 193,355 were also prescribed benzodiazepines at some point in the study period. Table 3
results on the concomitant prescribing of zolpidem and benzodiazepines by gender. A higher proportion of female veterans had an overlapping benzodiazepine prescription along with their zolpidem prescription within a 30-day period (18.8% of women vs 14.3% of men). For men, there was a significant age effect with coprescribing of zolpidem and benzodiazepines, with men aged 40 to 79 years at an increased risk of this coprescribing compared with men 80 years or older (AORs: 40-49 years, 1.12; 50-59 years, 1.33; 60-69 years, 1.23; 70-79 years, 1.14) for all age categories (P
< .001 for all comparisons). Conditions including cancer (AOR, 1.42), anxiety (AOR, 2.66), posttraumatic stress disorder (PTSD) (AOR, 1.47), and schizophrenia (AOR, 2.46) were also associated with overlapping prescribing for male veterans. Further, in fully adjusted models for men, sites in the South (AOR, 0.96) and West (AOR, 0.87) were less likely to prescribe overlapping doses compared with sites in the Northeast. Similarly, for women, mental health conditions such as anxiety (AOR, 2.28), bipolar disorder (AOR, 1.73), PTSD (AOR, 1.44), and schizophrenia (AOR, 2.05) were associated with overlapping prescribing of zolpidem and benzodiazepines. Regions other than the Northeast tended to be associated with less overlapping prescribing.
In this study, we found that inappropriate prescribing of zolpidem is not uncommon in the VHA, particularly among female veterans. Although there was a drastic decrease in prescribing of an inappropriate zolpidem dose in women from before to after the PBM guideline was issued, 30% of female zolpidem users in the VHA continued to be prescribed an inappropriate dose in 2016, contrary to the 2013 PBM guidance.17
Further, these decreasing rates of inappropriate prescribing over time potentially suggest that the guidelines may have had some impact, although they might be slow to fully disseminate into practice. Patient characteristics associated with higher odds of receiving an inappropriate dose among women included younger age and requirement of a co-payment. For both male and female veterans, having a substance use disorder was associated with inappropriate high dose.
We also found that a higher proportion of female compared with male veterans were being coprescribed benzodiazepines along with zolpidem, another form of inappropriate prescribing. Because zolpidem has similar hypnotic effects to benzodiazepines and affects the same receptor,23
this coadministration of the 2 medications may potentially increase harm and incur a higher risk of drug interactions and adverse events; however, to our knowledge, this has not been studied directly. The significant association between mental health conditions, including anxiety, bipolar disorder, PTSD, and schizophrenia, and this inappropriate outcome measure for both men and women suggests the already highlighted risk of dependence on benzodiazepines24
in patients with psychiatric illnesses, as described in the literature.
Although some observers may assume that providers always follow dosing recommendations closely, the findings of this study suggest that they may not. A recent study conducted in the University of Colorado health system compared zolpidem prescribing practices before and after the FDA labeling change in 2013.15
The Colorado study found that providers changed their prescribing habits in response to FDA guidance, reflected by a significant increase in the overall percentage of young women (<65 years) receiving an appropriately low dose of zolpidem after the labeling change. This increase in appropriate prescribing, from 42% before the label change to 70% after the label change, nonetheless implies that 30% of women were still receiving the inappropriate higher dose of zolpidem. Findings from the Colorado study are very similar to those of our study, which also found that 30% of female veterans—88% of them younger than 60 years—continued to receive an inappropriately high dose of zolpidem after the PBM guidance in 2013.17
Compliance among midlevel providers and physicians with FDA-mandated dosing guidelines was also noted in a retrospective cohort study, but only 16% of the prescriptions in that study were in accordance with the FDA recommendation.16
Taken together, these findings potentially suggest a quality of care issue that needs to be addressed both within and outside the VHA. Contrary to our study finding of a higher proportion of women receiving an inappropriately high dose in the post–PBM recommendation period, women reported lower odds of high-dose zolpidem exposure (>10 mg IR; >12.5 mg extended release) compared with men in a recent study conducted among veterans of the Iraq and Afghanistan wars.21
This discrepancy in findings could be due to the focus of the study on a special veteran population characteristically different from the general veteran population.
Potential contributors to this inappropriate prescribing of zolpidem in women could include the fact that the majority of patients served by the VHA are men. Because VHA providers see such a preponderance of male veterans, they may be less familiar with issues specific to treating women, such as the PBM guidance for zolpidem dose reduction for women.17
Similar differential prescribing patterns and adherence to guidelines in male versus female veterans have been reported in previous studies.26-28
Additionally, clinician failure to adhere to recommended guidelines, either due to lack of awareness or unfamiliarity with the guidelines or due to other factors that render it difficult to follow the guidelines,29
could also explain this trend of inappropriate zolpidem prescribing in female veterans.
Our study finding of female veterans, specifically women with existing mental health conditions, as a high-risk group in both the receipt of a guideline-discordant high dose and overlapping prescribing of zolpidem and benzodiazepines compared with male veterans will potentially alert and motivate providers to follow clinical recommendations in their zolpidem prescribing practices with respect to this population. Further, findings may help guide and inform intervention efforts targeted toward female veterans with mental comorbidities to optimize zolpidem prescribing in the VHA. Efforts to reduce inappropriate prescribing among zolpidem users could include targeted dissemination and implementation strategies, including educational outreach, continuing medical education, and audit and feedback.30,31
The objectives of these activities would be to increase clinician awareness of the existing guidelines for prescribing zolpidem and to compare their prescribing practice with that of their peers and with guideline recommendations. Previous studies have suggested that such an approach may contribute to improved prescribing, especially if delivered in a targeted and personalized manner.32
The use of clinical decision support systems may also help guide providers to improve practice over time.33
Even further gains could potentially be made using a more proactive (if more invasive) approach, such as requiring pharmacy approval or a nonformulary consult for inappropriately high doses of zolpidem.
Strengths and Limitations
Our study has important strengths, specifically the detailed nature and large size of the database, which included medication dispensing records, ICD-9
codes, and sociodemographic factors. However, we also acknowledge limitations. First, our study shares the limitations inherent in any analysis of electronic health record data. One such limitation is that diagnosis codes may not always be applied accurately by clinicians. We addressed this concern in part by requiring 2 ICD-9/ICD-10
codes to confirm the conditions. Second, VHA patients and the VHA system may not be typical of the general population or of other healthcare systems due to the disproportionately large population of men served. Hence, results from this study might not be generalizable to the population outside of the VHA. Third, although we used national VHA pharmacy data to account for zolpidem prescriptions, we did not include prescriptions obtained from Medicare Part D in veterans with dual VHA and Medicare Part D pharmacy use. We plan to focus on these dual zolpidem users in a future study. Finally, in this study, we focused only on patient-level predictors of inappropriate prescribing. We recognize the importance of provider- and system-level factors in the prescribing process and plan to focus on these factors in a separate study.
We found that after the VHA PBM formally recommended a lower maximum dose of zolpidem for women in 2013,17
a considerable number of female veterans continued to receive the higher dose or were coprescribed zolpidem and a benzodiazepine. This implies a quality of care problem with implications for patient safety, which may well be amenable to targeted interventions.