Assessment of Patterns of Potentially Unsafe Use of Zolpidem

Abstract

This study evaluates data from the US Medical Expenditure Panel Survey to determine the extent of unsafe use of zolpidem.

Zolpidem was the most widely used prescription hypnotic medication and the fourth most frequently prescribed psychiatric drug in 2013.¹ It achieves its effects as an agonist of γ-aminobutyric acid (GABA) receptors. However, the prescribing information² and US Food and Drug Administration (FDA) Drug Safety Communications³ include limitations to reduce adverse effects, including (1) short-term use because of loss of efficacy; (2) a lower dose of 5 mg/d for those 65 years or older, and the lower starting dose for women because of 45% to 50% higher blood concentrations²; and (3) increased risks when combined with other central nervous system (CNS)-depressant drugs. These precautions were intended to reduce the risks of next-day impairment, abnormal behavioral changes, and dependency. We compared patterns of reported use with these recommendations in data from the largest publicly available national survey of prescription medication.

Methods

We used the US Medical Expenditure Panel Survey (MEPS) for 2015⁴ to calculate the noninstitutionalized adult population characteristics and patterns of zolpidem use. The lower recommended daily dose was 5 mg for immediate and 6.25 mg for extended release products; the higher daily dose was 10 mg or 12.5 mg. Sustained use was defined as 3 or more prescriptions or 61 days or more of supply. Other drugs sharing CNS-depressant effects were any opioid agonist, any other GABA agonist (primarily benzodiazepines), and any form of synthetic GABA (primarily gabapentin). Multiple CNS-depressant risks were limited to those reporting sustained use of the CNS medications. We estimated the exposed populations and 95% confidence intervals (CIs) using the MEPS multistage probability design, based on a clustered sample of 35 427 individuals and 330 453 reported prescriptions during 2015. Because this was not a study with direct patient participants, no informed consent was needed, and since any personal information was deidentified in this publicly available research survey, institutional review board approval was not sought.

Results

Overall, 3.8 million adults (95% CI, 3.2-4.4 million) aged 18 to 85 years reported 1 or more prescriptions for zolpidem in 2015. Population characteristics, detailed in Table 1, indicate that women were nearly twice as likely as men to use zolpidem, and use grew with increasing age. Percentages of patients at increased risk for adverse events are summarized in Table 2. The higher dose was being taken by 64.0% (95% CI, 53.0%-75.0%) of adults 65 years or older and 68.0% (95% CI, 60.7%-75.3%) of women. Sustained—vs short-term—use was reported by 68.2% (95% CI, 62.5%-73.9%) of those exposed to zolpidem. The sustained-use zolpidem group reported a median of 192 days’ supply (interquartile range, 117-297 days). Among zolpidem users, sustained use of at least 1 other CNS-depressant medication was reported by 41.4% (95% CI, 34.9%-47.9%), including 26.5% taking opioids, and 20.3% using benzodiazepines. Overall, 77.4% (95% CI, 70.5%-84.3%) were not observing 2 or more recommendations to reduce risk.

Table 1. Characteristics of US Adults Exposed to Zolpidem.

Demographic Characteristic	Zolpidem Users, % (95% CI)
Sex
Male	34.8 (28.5-41.1)
Female	65.2 (58.9-71.5)
Age, y
18-30	3.4 (1.2-5.6)
31-44	19.1 (13.8-24.4)
45-64	42.5 (36.2-48.8)
65-85	35.0 (28.9-41.1)
Race/ethnicity
Whitea	80.7 (75.8-85.6)
Black	8.5 (5.6-11.4)
Hispanic	8.1 (4.4-11.8)
Asian	2.6 (0.6-4.6)

^aIncludes multiple races and other.

Table 2. Increased Risks Among Zolpidem Users.

Increased Risk	Zolpidem Users, % (95% CI)
Sustained use	68.2 (62.5-73.9)
Higher dose
Female	68.0 (60.7-75.3)
Age ≥65 y	64.0 (53.0-75.0)
Other CNS depressant usea	41.4 (34.9-47.9)
Opioid	26.5 (21.8-31.2)
Benzodiazepine	20.3 (16.8-23.8)
≥2 Safety issues	77.4 (70.5-84.3)

Abbreviation: CNS, central nervous system.

^aSustained use; more than 1 medication possible.

Discussion

These data show that optimal safe use of zolpidem is uncommon. Although efficacy declines substantially after 14 days of continuous administration,⁵ most zolpidem patients reported sustained use, with increased risk of dependence, given that zolpidem is a class IV controlled substance. Overdose and next-day impairment risks were increased with the 41.4% combining zolpidem with sustained use of other CNS-depressant drugs.

These data have several limitations. They are not capable of assessing the harms of zolpidem, only self-reported patterns of drug use. Some women reporting the higher zolpidem dose could have been started at the recommended 5-mg daily dose and later increased the dose. MEPS data likely underestimate exposure because they are self-reported, and the data could not account for the start of medication use and permanent discontinuation occurring part way through the 12-month survey period. Other key safe use recommendations—abstaining from alcohol, avoiding over-the-counter sleep aids, and limiting next-day driving—could not be assessed in these data. In conclusion, this study of zolpidem shows that there are many opportunities to reduce the risks of next-day impairment, abnormal behavior changes, and dependence.