Non-Benzodiazepine Sedative Hypnotic Prescriptions Among Combat-Injured U.S. Service Members

Introduction

In response to the attacks on the World Trade Centers on September 11, 2001, the United States initiated Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF). Since then, there have been more than 5 million deployments in support of these operations, with many service members experiencing multiple combat tours.[1] Among those deployed, more than 50,000 service members incurred combat injuries.[2] The increased survivability of combat casualties relative to previous conflicts emphasizes the need to evaluate long-term outcomes. These outcomes include sleep disturbances such as insomnia, which are particularly common among injured service members.[3]

Insomnia is associated with a range of adverse outcomes, such as depression, posttraumatic stress disorder (PTSD), processing difficulties, behavioral irregularities, and anxiety.[4-5] Due to the unique and stressful nature of military operations, obtaining sufficient sleep can be difficult, and service members show a 2-fold increased risk of insomnia relative to the general population.[11-13] Similar rates are seen across all branches of military service.[14]Estimates from previous studies show that 3.4% of veterans are diagnosed with insomnia,[4] compared with 20% of active duty service members.[5-7] Since combat deployments are associated with increased diagnoses of insomnia,[3,15] it is not surprising that the use of pharmacological sleep aids has dramatically increased among military and veterans since 2003, spiking considerably after initiation of the conflicts in Iraq and Afghanistan.[16] Pharmacological treatment for insomnia in service members is reported as high as 42% of those with diagnosed sleeping disorders, increasing considerably since 2009.[16]

Introduced in the 1990s, non-benzodiazepine sedative hypnotics (n-BSH) (e.g., zolpidem, zaleplon, and eszopiclone) were marketed as safer alternatives to benzodiazepines for treatment of insomnia.[17]They have continued to be the treatment of choice for insomnia in military populations due to the perception of limited side effects.[18] Recent studies, however, provide evidence that n-BSH have adverse outcomes, including falls,[19-22] cognitive impairment,[22-26] and psychological disorders such as depression,[4,5]addiction, and suicidal ideation.[27,28] Additionally, long-term n-BSH use is associated with increased risk of depression and anxiety by as much as 75% among n-BSH users compared with non-users.[29]Research in civilian populations shows that long-term use of n-BSH may be associated with adverse outcomes, and these studies prompted the development of guidelines recommending use of these medications on a short-term basis. Specifically, in recently published treatment guidelines for chronic insomnia, the American College of Physicians recommended that n-BSH be used only on a short-term basis and only if behavioral treatments alone are ineffective.[31]

Despite concerns for cognitive impairment, n-BSH remain commonly prescribed in military service members with insomnia.[11]An Australian military study reported that approximately 70% of those taking n-BSH had more than six months of continuous use.[32] While U.S. military research is limited, reports show that n-BSH prescriptions have increased and that refills may be driving the increase.[11,30,33,34] To date, no military research has explored n-BSH prescriptions among combat-injured service members. Considering successful treatment of service members with combat injuries is necessary for retention, understanding n-BSH prescriptions in this population is critical. The aim of this study was to describe n-BSH prescription patterns in combat-injured service members who were diagnosed with insomnia within 2 years after injury.

Patients and Methods

Study Sample

We identified U.S. service members who were injured in combat during operations Iraqi Freedom (OIF) and Enduring Freedom (OEF) from the Expeditionary Medical Encounter Database (EMED).[35] This study included only those who: (1) were injured during combat deployment in OEF and OIF between January 2001 and August 2019; (2) received a diagnosis code for insomnia within 2 years after combat injury (International Classification of Diseases, 9th Revision[ICD-9] 307.42, 327.00, 327.01, 327.02, 327.09, 780.51, 780.52; [ICD-10] F51.01, F51.03, F51.04, F51.05, F51.09, G47.00, G47.01, G47.09)[35,36]; and (3) were prescribed a medication that is commonly used to treat insomnia within 2 years after  combat injury.[35,37] We excluded those who died due to injury or during the follow-up period (n=519). 

Measures

Service members injury severity was classified via the Injury Severity Score (ISS), an anatomical scoring system that values the combined effects of multiple injuries, calculated by certified coders following review of the EMED clinical records.[38] ISS ranges from 1 to 75 and were categorized as 1–8 (mild-to-moderate injuries) or 9 or greater (serious-to-severe injuries) similar to other ISS liturature.[37-39] We only included the most severe injury event for each service member. Injury body location was then categorized according to the Barrell injury diagnosis matrix, a CDC endorsed matrix for the classification of traumatic injuries by anatomical location, such as head and neck, spine and back, torso, extremities, and other.[40]

Prescription records were obtained from the Pharmacy Data Transaction Service (PDTS), which provides detailed listings of outpatient medication names and dispensing dates of all prescribed medications for military service members.Prescriptions in the PDTS are identified by medication therapeutic codes for treatment of sleep disturbances (i.e., 281604, 282400, 282404, 282408, 282492, and 562208). This study included prescriptions for n-BSH (eszopiclone, zaleplon, zolpidem) and other medications in pharmacological treatment classes commonly used to treat insomnia, including benzodiazepines (Estazolam, Flurazepam, Temazepam, Triazolam), melatonin receptor agonists, or MRA (ramelteon), antihistamines (Diphenhydramine, Doxylamine, Hydroxyzine), and antidepressants (Trazodone, Doxepin, Mirtazapine).[42] Antidepressant medications were only recorded if dosing was within guidelines for insomnia treatment (as opposed to higher doses needed for depression treatment), which include Trazodone (<=100mg),[43] Doxepin (<=6mg),[42] and Mirtazapine (<=30mg).[44] Service members were categorized into a medication class if they had a prescription equal to or greater than 30 consecutive days.[16,30] We calculated prevalence rates of n-BSH prescriptions (proportion of n-BSH / number of participants with insomnia) and annual prevalence rates (proportion of n-BSH for that given year / number of participants with insomnia). We then summed the total number of days service members received n-BSH prescriptions from the PDTS database.

Duration of n-BSH prescriptions were categorized as: (1) prescription for n-BSH less than 90 days,[16] (2) greater than 90 days and less than 180 days,[30,45] and (3) greater than 180 days and less than two years.[28,30] Participants prescribed more than one n-BSH were categorized according to duration of the prescription (short-, mid-, and long-term as described above) for each n-BSH. We then coded these participants according to the n-BSH prescribed the longest.[30,46] Participants with n-BSH refills more than 60 days apart indicated breaks in prescriptions and were separately coded as intermittent.

We also explored dosage type (e.g., normal vs high dose) of n-BSH for two years following combat injury.[35] N-BSH dosage was defined dichotomously: (1) normal dose (eszopiclone 3mg, zaleplon 10 mg, zolpidem immediate release 10mg for males and 5 for females, zolpidem tartrate extended release 12.5mg for males and 6.25mg for females), and (2) high dose (eszopiclone >3mg, zaleplon, >10mg, zolpidem immediate release >10mg for males and >5mg for females, zolpidem tartrate extended release >12.5mg for males and >6.25mg for females).[6,47]

Demographic characteristics were included to describe participants by n-BSH prescriptions. Age was calculated as the difference between participants’ date of birth and date of injury and was categorized in 10 year increments (<24, 25-34, 35-44, 45-64, 65+).[16]Sex was dichotomized as male and female. Race and ethnicity were categorized as Non-Hispanic White, Non-Hispanic Black, Hispanic, and Other, consistent with other military research.[48] Branch of service was extracted from the Defense Manpower Data Center (DMDC) records and categorized as Air Force, Army, Navy, and Marine Corps.[16] Number of previous deployments was also recorded from DMDC records based on the beginning and end dates for all deployments to Iraq (OIF) or Afghanistan (OEF). Deployment was defined as greater than 30 days, but less than 18 months for each deployment.[49] We recorded the number of deployments prior to the deployment resulting in injury and then reported deployment history dichotomously (yes/no).[49]

We extracted clinically diagnosed conditions to characterize comorbidities for each service member similar to other military research,[11] using ICD-9 and ICD-10 codes from the MDR as dichotomous variables (yes/no). These included obstructive sleep apnea (ICD-9 327.20, 327.21, 327.23, 327.29, 786.03, 780.53 and ICD-10 G47.30, G47.33, G47.39), anxiety (ICD-9 300.0, 300.2, 300.3, 309.8 and ICD-10 F41.9), chronic pain (ICD-9 338.2, 338.4 and ICD-10 G89.2, G89.21, G89.4), history of traumatic brain injury (TBI; ICD-9 850, 851, 852, 853. 854.0 and ICD-10 S02.0, S02,1, S02.8, S02.91, S04.02, S04.03, S04.04, S06.9, S09.8 S09.90), depression (ICD-9 296.20, 296.22, 296.21, 296.23, 296.24, 296.30, 296.31, 296.32, 296.33, 296.34, 296.82, 298.0, 300.4, 309.0, 309.1, 311 and ICD-10 F43.21, F32.89, F32.0, F32.2, F32.3, F32.9, F34.1, F43.21, F32.3, F33.3, F33.2, F33.0, F33.1, F33.9) and PTSD (ICD-9 309.81 and ICD-10 F43.12).[50] We reported comorbid conditions individually and as the total number comorbidities for each participant, which were then categorized as none, 1, or 2+.[41,47,49,51]

Statistical Analysis

All descriptive statistical analyses were conducted using SAS (version 9.4; SAS Institute Inc., Cary, North Carolina). The overall sample of combat injured service members with insomnia were reported according to their demographic characteristics and injury severity and type at baseline. We used Chi squared statistics to indicate statistical significance at 0.05 for each table.

Results

Table 1. Demographic characteristics of combat injured service members with pharmacological treatment for insomnia within 2 years of combat injury (n=8071)

* medication classes are not mutually exclusive, so percentages do not total 100%
bolded numbers indicate p values below 0.05
Abbreviations of Terms: PTSD = Post Traumatic Stress Disorder, TBI = Traumatic Brain Injury, n-BSH = non-benzodiazepine
sedative hypnotic, BZD = benzodiazepine, MRA = Melatonin Receptor Agonist

Table 1 describes insomnia prescription classes by demographic and comorbidity characteristics. Of the 8,071 participants in the study sample, the majority were less than 34 years old (90.2%), male (96.3%) and non-Hispanic White (75.1%). The most frequently prescribed medication of interest was n-BSH (61.6%), followed by low dose antidepressants (39.3%), antihistamines (15.9%), benzodiazepines (7.8%), and melatonin receptor agonists (2.1%). Prescriptions did not vary significantly across age groups or the number of previous deployments. The number of diagnosed comorbidities also related to medication prescriptions; those with more comorbid conditions were more likely to receive any of the prescription medication classes than those with fewer comorbidities. Specifically, n-BSH and antidepressant prescriptions represented the largest proportion of prescriptions in service members with PTSD, depression, anxiety, and chronic pain. ISS also varied by prescription, and those with more severe injuries represented a larger proportion of all classes of prescriptions except benzodiazepines.   

Table 2. Medication classes and names reported by duration of use category

* Acute users are defined as therapy lasting less than 30 days, intermittent users 31-89 days or breaks in refills of at least 31 days, and Continuous users are those with 90+ days of continuous use

Table 2 describes prescription patterns by medication class as well as medication names in non-mutually exclusive groups.  Service members classified as chronic were more likely to be prescribed n-BSH and antidepressants. Most antihistamine prescriptions (59.3%) were prescribed for less than 30 days. The benzodiazepine group was less likely to be intermittent or chronic prescriptions. The most frequently prescribed medications were zolpidem (54.2%), trazodone (35.4%), and eszopiclone (22.1%). Of the n-BSH medications (zolpidem, eszopiclone, zaleplon), zolpidem was prescribed more frequently for 30 days or less (40.2%), eszopiclone was prescribed more frequently for 90 or more days of continuous use (36.8%), while zaleplon only represented 1.2% of n-BSH prescriptions but was also prescribed more frequently for 30 days or less (56.7%). Of the low dose antidepressants medications prescribed for insomnia (trazodone, doxepin, mirtazapine), all three were prescribed more frequently for less than 30 days (43.0%, 67%, and 48.8% respectfully). Among prescribed benzodiazepines, temazepam was more frequently prescribed for 90 days or more (22.9%), while triazolam was more frequently prescribed 30 days or less (77.9%).

Table 3. N-BSH characteristics by severity of injury sustained during combat

* Duration of n-BSH use is the cumulative number of days receiving prescriptions for n-BSH

Table 3 describes duration of use and dosage for n-BSH prescriptions according to the severity of injury. Of the 4,968 service members who were prescribed n-BSH at any time within 2 years of injury, 32.6% received prescriptions for less than three months, 24.8% between three and six months, and 42.6% for at least six months. Those with mild-to-moderate injuries were more likely to receive shorter duration of prescriptions, while serious-to-severe injuries were more likely to receive n-BSH for at least six months. Service members prescribed high dose n-BSH only represented 0.5% of the sample (n=40). Of these, 10 (25.0%) had serious-to-severe injuries.

Discussion

To our knowledge, this is the first study on prescription patterns of medications commonly used to treat insomnia among U.S. service members with combat injuries and diagnosed insomnia. We report all prescription treatment classes used for insomnia, including low dose antidepressants documented by the PDTS. N-BSH were the most frequently prescribed pharmacological treatment class across all services. The majority of n-BSH prescriptions were at least 3 months. This is concerning when considering that previous research shows n-BSH medications are associated with several adverse health outcomes.4,5,21-28 In addition, the American College of Physicians (ACP) recommends prescriptions for short-term periods only after a trial of behavioral therapy, such as cognitive behavioral therapy for insomnia (CBT-I).[53-55] The results of the present study provide important information for military healthcare providers by addressing a knowledge gap in the pharmacological treatment of combat-injured service members diagnosed with insomnia.  

Our results align with a recent military study about n-BSH use, which showed that many n-BSH users receive prescriptions longer than 6 months and that long-term use may be associated increased prescription trends.[32] Only 33% of service members in our cohort were prescribed n-BSH medications for short-term periods, which is considerably lower than the 80% reported among service members in another military study.[16] We also found that a higher proportion of service members with serious-to-severe injury, compared with those with mild-to-moderate injuries, were prescribed n-BSH for at least 6 months. It is plausible that more severe injuries may worsen insomnia and could result in longer n-BSH prescriptions. Although we explored whether service members with more severe injuries were prescribed higher n-BSH doses, our results were inconclusive due to the small number with high dose prescriptions.

Almost half of service members with n-BSH prescriptions received medications for least 6 months, whereas most service members with prescriptions in other classes (BZD, MRA, and Antihistamines) received prescriptions for less than 3 months. Zolpidem was the most frequently prescribed medication, followed by low-dose Trazodone, an antidepressant. An approved and common treatment for insomnia after head injuries is either Trazodone or n-BSH, so it unsurprising that these two would be frequently prescribed among combat injured service members given the relative high rate of concurrent TBI diagnosis (42.5%) and previous military studies show that combat injuries have a high rate of TBI.[35,41]

Overall, the proportion of n-BSH prescriptions decreased slightly over time compared with other treatment classes. However, the most prominent subgroup for n-BSH prescriptions was long-term prescriptions, and this group remained the highest prescribed subgroup despite the decrease in overall n-BSH prescriptions in 2016 and 2017. The FDA introduced several recommendations on n-BSH medications between 2013 and 2019, including recommending lower doses, warning against driving after daily use or when combed with opioid medications, and warning of risks of serious injuries caused by sleepwalking.[52] These warnings may account for some of the reduction in new n-BSH prescriptions over time, but given that most n-BSH prescriptions still exceeded 3 months even by the end of 2017, these service members still exceeded these revisions throughout these conflicts. It is important to note that the figure in this study only reports the annual proportion of pharmacological prescription treatments among combat-injured service members and does not illustrate the total number of pharmacological treatments. However, it may suggest that other non-pharmacological treatment options may be underutilized in the DoD given the high proportion of long-term prescriptions. Therefore, although there was a decrease in n-BSH prescriptions over time, it is possible that the total burden of pharmacological insomnia treatment is still increasing as shown in VA studies.[56]

The high prevalence of service members who exceed the recommended length of use guidelines of n-BSH medications provides evidence that other treatment options for insomnia (e.g., Cognitive Behavioral Therapy, or CBT-I) need additional attention and resources within military treatment systems. CBT-I is shown more effective than pharmacological treatment alone for long-term insomnia.[57] CBT-I has traditionally been limited in military health, but integration of remote CBT-I courses may increase this availability to broader military service members.[58,59]

This study had two important several strengths. First, the study represents the largest sample and most comprehensive analysis of prescription patterns among combat- injured service members with diagnosed insomnia to date. Second, we used prescription records for treatment characteristics, which increases the accuracy of data concerning dosing and duration of prescriptions over the 2 years of follow-up. 

While this study has many strengths, there are noteworthy limitations to consider. This study analyzed prescription patterns and did not capture the use of the prescribed medications, nor any behavioral therapies and strategies. It is also important to note that, in defining the study sample, insomnia diagnosis and prescriptions may have occurred at any point within 2 years after injury. Future research on use and timing of these medications along with alternative treatments is warranted. In addition, this cohort only includes those diagnosed with insomnia after combat injury and may not generalize to the combat-injured population as a whole. Last, we restricted follow-up to 2 years combat injury since we were primarily concerned with insomnia prescription patterns in close temporal proximity to combat injury. Long-term assessment of insomnia medication prescriptions, use, and outcomes are needed.  

In conclusion, this study is an important step in understanding n-BSH prescription patterns among U.S. service members diagnosed with insomnia after combat injury. The results confirm that n-BSH prescriptions were common and often prescribed for 6 months or more, and that the majority of n-BSH prescriptions of OIF and OEF injured service members exceed the length of the FDA’s recommendations. Given the potential deleterious effects of long-term n-BSH use, military medical leadership should examine current policies, and consider education and training of military health care providers on effective alternatives to insomnia treatment, such as CBT-I.[60]

LCDR Daniel J. Crouch, PhD, MPH,[1] Andrew J. Macgregor, PhD, MPH,[1] James M. Zouris, MS,[1] Christopher N. Kaufmann, PhD, MHS,[2] Atul Malhotra, MD,[3] Stephanie K. Brodine, MD,[4] Linda C. Gallo, PhD,[4] Natasha K. Martin, PhD,[3] Sonia Jain, PhD,[3]Richard A. Shaffer, PhD, MPH,[4] Michael M. Galarneau, MS[1]  

Author Affiliation 

[1] Epidemiology and Data Management Support, Naval Health Research Center, San Diego, California, USA

[2] University of Florida, Gainesville, Florida, USA

[3] University of California San Diego, La Jolla, California, USA

[4] San Diego State University, San Diego, California, USA

Author Contact Information

LCDR Daniel Crouch, [email protected]

Andrew MacGregor, [email protected]

James Zouris, [email protected]

Stephany Brodine, [email protected]

Linda Gallo, [email protected]

Sonia Jain, [email protected]

Christopher Kaufmann, [email protected]

Atul Malhotra, [email protected]

Natasha Martin, [email protected]

Richard Shaffer, [email protected]

Michael Galarneau, [email protected]

Address correspondence to: Daniel J. Crouch, Epidemiology and Data Management Support, Naval Health Research Center, 140 Sylvester Road, San Diego, California 92106 USA. E-mail: [email protected]. Primary author ORCID ID: 0000-0001-9007-6161. 

Authors’ Contributions
D.J.C. designed the study and drafted the article. D.J.C. and J.M.Z. prepared and analyzed the data. A.J.M. and R.A.S. were advisors to sample selection. All authors interpreted the data, critically revised the manuscript for important intellectual content, and approved the final version to be published.

Author Disclosure Statement
No competing financial interests exist. Dr. Malhotra reports income related to medical education from Livanova, Eli Lilly, Jazz and Zoll. ResMed provided a philanthropic donation to UCSD. 

Funding Statement
This work was supported by the U.S. Navy Bureau of Medicine and Surgery under work unit no. 60808. Dr. Malhotra is funded by NIH.

Data Availability Statement
The datasets generated and/or analyzed during the current study are not publicly available due to security protocols and privacy regulations, but they may be made available on reasonable request by the Naval Health Research Center Institutional Review Board (contact phone +1 619 553 8400).

Disclaimer: I am a military service member or employee of the U.S. Government. This work was prepared as part of my official duties. Title 17, U.S.C. §105 provides that copyright protection under this title is not available for any work of the U.S. Government. Title 17, U.S.C. §101 defines a U.S. Government work as work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties. Report No. 24-43 was supported by the U.S. Navy Bureau of Medicine and Surgery under work unit no. 60808. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the U.S. Government. The study protocol was approved by the Naval Health Research Center Institutional Review Board in compliance with all applicable Federal regulations governing the protection of human subjects. Research data were derived from an approved Naval Health Research Center Institutional Review Board protocol, number NHRC.2003.0025.

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Date: 01/30/2025