Key Words
elderly - older adult - zolpidem - zopiclone - zaleplon
Introduction
Over one-third (35%) of the US population experiences short sleep, of less
than 7 hours [1]. Nearly 50%
of people over 60 years report sleep disorder symptoms, while 12–20%
of older adults have been diagnosed with insomnia [1]. Symptoms include difficulty initiating and maintaining sleep,
fatigue, mood disturbances, and impaired daytime performance [2]. Older adults are considered a
“special population,” as they are at an increased risk for adverse
drug effects and frequently suffer from comorbidities such as heart disease, stroke,
diabetes, depression, and cancer [3].
Nonbenzodiazepine hypnotics zolpidem, zaleplon, zopiclone, and eszopiclone, commonly
referred to as ‘Z-drugs,’ are a class of sedatives approved by the
US Food and Drug Administration for sleep initiation and maintenance. While most
Z-drugs act as selective agonists at the GABAA α1
subunit, zopiclone and eszopiclone are non-selective and bind to the
α1, α2, α3, and
α5 subunits (i. e., the same mechanism as
benzodiazepines) [4]. Z-drugs have been shown
to increase the risk of fall-related injuries, such as fractures and traumatic brain
injuries, in older adults [5]. A systematic
review determined that zolpidem was associated with a 92% increase in risk
of fracture [6]. Among patients over age 65,
the risk of zopiclone-associated fracture increased with age [7]. Additionally, withdrawal symptoms for these
Schedule IV drugs include delirium, which can potentiate the risk of fall-related
injuries. These adverse effects are reflected in the American Geriatrics Society
(AGS) Beers criteria guidelines for these drugs, which, in 2015 and 2019, strongly
recommended avoiding prescribing Z-drugs for patients 65 years and older [8]. The Fit for the Aged (FORTA) list also
strongly recommends avoiding prescribing Z-drugs to older adults, listing them as
class D – “avoid if at all possible, in the elderly, omit first, and
use alternative substances” [9]. The
AGS and FORTA list also report that Z-drugs provide only minimal improvement in
sleep duration and latency in older adults [8]
[9].
Therefore, it is important to track the prescription patterns of these drugs to
patients aged 65 or older in the United States. This study provides a nationwide
examination of Z-drug prescriptions to Medicare Part D patients.
Methods
Procedures
Medicare Part D data was acquired from the Centers for Medicare and Medicaid
Services State Drug Utilization Data (CMS SDUD) for 2018 [10]. Both generic and name brand
formulations of Z-drugs were considered for analysis (zolpidem, Ambien, Edluar,
Intermezzo, Zolpimist, eszopiclone, Lunesta, zopiclone, zaleplon, and Sonata,
Supplemental Table 1).
Data-analysis
Z-drug prescriptions were summed and divided by the number of Medicare enrollees
in that state, as reported by the CMS, to find the number of prescriptions per
enrollee for each state. These values were then multiplied by 100 and reported
as the number of Z-drug prescriptions per 100 Medicare enrollees. States that
were ≥±1.96 standard deviations (SD) outside the mean were
categorized as statistically significant (p<0.05). Additionally,
the supply for the total number of days was divided by the total number of
prescriptions for each state and reported as days-supply per prescription. The
providers prescribing Z-drugs were also analyzed. Prescriber data was obtained
from the Medicare Part D Prescriber Dataset from CMS [10]. The sum of the total claim counts for
each specialty was calculated Using a Python script (Supplemental Appendix 2) to
determine the percentage of all Z-drug prescriptions prescribed by each
specialty. Additionally, the total number of Z-drug prescriptions within each
specialty with greater than 100 providers was divided by the number of providers
within that specialty, as reported in CMS. Specialties with a
prescriptions-per-provider value ≥1.96 SD outside the mean were
identified as statistically significant (p<.05).
Results
Overall, zolpidem accounted for the vast preponderance (95.0%) of Z-drug
prescriptions in 2018. Additionally, generic formulations made up 99.7% of
prescriptions.
The average number of prescriptions per 100 Medicare enrollees was 17.5±4.0.
There was a three-fold (3.04) difference between the highest and lowest states. The
numbers of prescriptions per 100 Medicare enrollees for Utah (28.2) and Arkansas
(26.7) were significantly elevated, and Hawai’i (9.3) was significantly
lower relative to the state mean ([Fig. 1]).
The average days-supply per prescription was 34.9; it was significantly longer for
Delaware (40.2) and significantly shorter for New York (29.3) than the national mean
(Supplemental Figure 1). States with more prescriptions per enrollee
tended to have shorter days' supply, but this was not significant
(r(51)=0.26, p=0.063).
Fig. 1 Z-drug prescriptions per 100 Medicare enrollees ranked by
state. States with a *were>1.96 SD and #
were>1.50 SD.
Three medical specialties comprised three-quarters (75.2%) of all Z-drug
prescriptions. Family medicine (2,351,301; 32.1%) had the highest number of
prescriptions, followed by internal medicine (2,298,487; 31.4%) and
psychiatry (853,649; 11.7%). All other specialties combined comprised
24.8% (Supplemental Figure 2). The average number of Z-drug
prescriptions per provider was 40.3±12.1. Psychiatry was significantly
elevated relative to the average, with 76.5 prescriptions per provider in 2018
([Fig. 2]).
Fig. 2 Z-drug prescriptions by specialty to Medicare patients in 2018.
* were>1.96 SD and #
were>1.50 SD.
Discussion
Clearly, Medicare Part D patients are being prescribed Z-drugs, predominantly
zolpidem, at high rates despite guidelines to avoid the use of these drugs in older
adults due to the increased risk of adverse effects, including fractures from falls,
stroke, and psychological distress [6]
[7]
[8].
While older adults are being prescribed these drugs nationwide, we also identified
substantial state-level differences in Z-drug prescriptions. We are skeptical that
the identified three-fold difference between states in prescribing rates is matched
by a three-fold difference in the prevalence of sleep problems. While Utah and
Arkansas had the highest Z-drug prescription rates, Hawaii had the lowest number of
Z-drug prescriptions per 100 Medicare enrollees. This is consistent with other data
showing that Hawaii also has the lowest rates of opioid and antibiotic prescriptions
[12]
[13]. This could be explained by both cultural differences and an overall
healthier population (i. e., low rates of obesity and preventable
hospitalizations and high rates of insurance coverage) in Hawaii [14]
[15].
However, more research is necessary to understand the most significant influencing
factors in keeping the number of Z-drug prescriptions in Hawaii low and those in
Arkansas and Utah high.
In the analysis of Z-drug prescriptions per specialty, family medicine, internal
medicine, and psychiatry took the largest share of prescriptions. The predominance
of family medicine and internal medicine over psychiatry may be explained by
patients with sleep problems presenting more often to their primary care physician
rather than a specialist provider [16]. This
disparity may also be because only 23% of US psychiatrists are covered by
Medicare [17]. However, it did not escape
notice that 100% of the working group for the American Psychiatric
Association’s Diagnostic and Statistical Manual for Sleep/Wake
Disorders had ties with the pharmaceutical industry which raises concerns about even
further relaxation of the diagnostic criteria in the future revisions of the
Diagnostic and Statistical Manual of Mental Disorders (DSM) [18]. Other studies have documented mixed
perspectives of general practitioners on Z-drug prescription, noting that many
general practitioners experienced tension between their desire to help patients with
insomnia and their fear of contributing to the over-prescription of drugs with such
potentially severe adverse effects [19].
It is important to emphasize that the populations eligible for Medicare coverage
include all adults aged 65 and over, patients with disabilities, and patients with
end-stage renal disease. While not all Medicare beneficiaries are older adults, as
of 2018, 91% of Medicare beneficiaries were age 65 and older, while only
9% were under age 65 [20]. In
addition, less than 3% of Medicare enrollees received hospice care in 2018
[21]. Thus, while Beer’s Criteria
and FORTA list are not applicable to some Medicare recipients, the vast majority of
beneficiaries are older adults who require these special prescribing considerations.
Therefore, it is clear that in 2018 a significant number of Medicare enrollees
received Z-drug prescriptions that were inconsistent with the Beers Criteria and
FORTA List. Other research in Nordic countries has found that the use of Z-drugs was
highest for those over the age of 80 [22]. As
this report was limited to Medicare Part D patients in the US, further research with
other databases, including electronic health records, will be necessary to identify
additional subsets of Medicare patients where guidelines were not applicable, as
well as determination of patient subgroups (e. g., nursing home residents
and obese patients) at greatest risk of receiving potentially inappropriate Z-drug
prescriptions.
Conclusion
Sleep disorders in older adults remain a significant problem and should not be
ignored. Considering the guidelines in the US state of contraindication of Z-drug
use in older adults due to the risk of adverse events, especially falls, it is
important to implement changes in treatment practices. Alternative options that have
proven successful include cognitive behavior therapy or the development of healthy
sleeping habits. Pharmacotherapies may be appropriate if patients remain
symptomatic; however, existing alternatives, such as melatonin receptor agonists
(e. g., ramelteon), should still be used cautiously in older adults due to
adverse effects [23]. Further research is
needed to ascertain whether these alternative therapies are not being initiated, the
reason for regional differences in the number of prescriptions of Z-drugs per
individual prescribers, and compare Z-drug usage among different age groups.
Author contributions
All authors contributed to the study conception and design. Data collection and
analysis were performed by Kaitlin E. Anderson, James L. Basting, Rachel I.
Gifeisman, Donovan J. Harris, and Antonica R. Rajan. The first draft of the
manuscript was written by Kaitlin E. Anderson. All authors commented on previous
versions of the manuscript and read and approved the final manuscript.
Role of Sponsor: The sponsor played no role in this research.
