Currently Viewing:
The American Journal of Managed Care March 2019
Fragmented Ambulatory Care and Subsequent Emergency Department Visits and Hospital Admissions Among Medicaid Beneficiaries
Lisa M. Kern, MD, MPH; Joanna K. Seirup, MPH; Mangala Rajan, MBA; Rachel Jawahar, PhD, MPH; and Susan S. Stuard, MBA
Incorrect and Missing Author Initials in Affiliations and Authorship Information
From the Editorial Board: Austin Frakt, PhD
Austin Frakt, PhD
Implications of Eligibility Category Churn for Pediatric Payment in Medicaid
Deena J. Chisolm, PhD; Sean P. Gleeson, MD, MBA; Kelly J. Kelleher, MD, MPH; Marisa E. Domino, PhD; Emily Alexy, MPH; Wendy Yi Xu, PhD; and Paula H. Song, PhD
Factors Influencing Primary Care Providers’ Decisions to Accept New Medicaid Patients Under Michigan’s Medicaid Expansion
Renuka Tipirneni, MD, MSc; Edith C. Kieffer, PhD, MPH; John Z. Ayanian, MD, MPP; Eric G. Campbell, PhD; Cengiz Salman, MA; Sarah J. Clark, MPH; Tammy Chang, MD, MPH, MS; Adrianne N. Haggins, MD, MSc; Erica Solway, PhD, MPH, MSW; Matthias A. Kirch, MS; and Susan D. Goold, MD, MHSA, MA
Did Medicaid Expansion Matter in States With Generous Medicaid?
Alina Denham, MS; and Peter J. Veazie, PhD
Access to Primary and Dental Care Among Adults Newly Enrolled in Medicaid
Krisda H. Chaiyachati, MD, MPH, MSHP; Jeffrey K. Hom, MD, MSHP; Charlene Wong, MD, MSHP; Kamyar Nasseh, PhD; Xinwei Chen, MS; Ashley Beggin, BS; Elisa Zygmunt, MSW; Marko Vujicic, PhD; and David Grande, MD, MPA
Medicare Annual Wellness Visit Association With Healthcare Quality and Costs
Adam L. Beckman, BS; Adan Z. Becerra, PhD; Anna Marcus, BS; C. Annette DuBard, MD, MPH; Kimberly Lynch, MPH; Emily Maxson, MD; Farzad Mostashari, MD, ScM; and Jennifer King, PhD
Common Elements in Opioid Use Disorder Guidelines for Buprenorphine Prescribing
Timothy J. Atkinson, PharmD, BCPS, CPE; Andrew J.B. Pisansky, MD, MS; Katie L. Miller, PharmD, BCPS; and R. Jason Yong, MD, MBA
Specialty Care Access for Medicaid Enrollees in Expansion States
Justin W. Timbie, PhD; Ashley M. Kranz, PhD; Ammarah Mahmud, MPH; and Cheryl L. Damberg, PhD
Currently Reading
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
Health Insurance Literacy: Disparities by Race, Ethnicity, and Language Preference
Victor G. Villagra, MD; Bhumika Bhuva, MA; Emil Coman, PhD; Denise O. Smith, MBA; and Judith Fifield, PhD

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
We found inappropriate prescribing of zolpidem, in terms of both guideline-discordant dosage and coprescribing with benzodiazepines, with female veterans affected more than male veterans.

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 and zolpidem25 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/ICD-10 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.

Author Affiliations: Center for Healthcare Organization and Implementation Research, Edith Nourse Rogers Memorial VA Medical Center (GKJ, JIR, RSW), Bedford, MA; Department of Health Law, Policy and Management, Boston University School of Public Health (GKJ), Boston, MA; The Pulmonary Center (RSW) and Section of General Internal Medicine (AJR), Department of Medicine, Boston University School of Medicine, Boston, MA; Pharmacy Benefits Management Academic Detailing Services, Veterans Health Administration (MLC), San Diego, CA.

Source of Funding: The research reported/outlined here was supported by the Department of Veterans Affairs (VA), Veterans Health Administration, Health Services Research and Development (HSR&D) Service. Dr Jasuja is a VA HSR&D Career Development awardee at the Bedford VA (CDA 13-265). The views expressed in this article are those of the author(s) and do not necessarily represent the views of the VA. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

Author Disclosures: The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

Authorship Information: Concept and design (GKJ, RSW, MLC, AJR); acquisition of data (GKJ, JIR); analysis and interpretation of data (GKJ, JIR, AJR); drafting of the manuscript (GKJ, JIR, MLC); critical revision of the manuscript for important intellectual content (GKJ, RSW, MLC, AJR); statistical analysis (JIR); and supervision (GKJ, RSW, AJR).

Address Correspondence to: Guneet K. Jasuja, PhD, Center for Healthcare Organization and Implementation Research, Bedford VA Medical Center, 200 Springs Rd, Bedford, MA 01730. Email:

1. Huedo-Medina TB, Kirsch I, Middlemass J, Klonizakis M, Siriwardena AN. Effectiveness of non-benzodiazepine hypnotics in treatment of adult insomnia: meta-analysis of data submitted to the Food and Drug Administration. BMJ. 2012;345:e8343. doi: 10.1136/bmj.e8343.

2. Kaufmann CN, Spira AP, Alexander GC, Rutkow L, Mojtabai R. Trends in prescribing of sedative-hypnotic medications in the USA: 1993-2010. Pharmacoepidemiol Drug Saf. 2016;25(6):637-645. doi: 10.1002/pds.3951.

3. Kolla BP, Lovely JK, Mansukhani MP, Morgenthaler TI. Zolpidem is independently associated with increased risk of inpatient falls. J Hosp Med. 2013;8(1):1-6. doi: 10.1002/jhm.1985.

4. Wang PS, Bohn RL, Glynn RJ, Mogun H, Avorn J. Zolpidem use and hip fractures in older people. J Am Geriatr Soc. 2001;49(12):1685-1690. doi: 10.1111/j.1532-5415.2001.49280.x.

5. Chang CM, Wu EC, Chen CY, et al. Psychotropic drugs and risk of motor vehicle accidents: a population-based case-control study. Br J Clin Pharmacol. 2013;75(4):1125-1133. doi: 10.1111/j.1365-2125.2012.04410.x.

6. Mahoney JE, Webb MJ, Gray SL. Zolpidem prescribing and adverse drug reactions in hospitalized general medicine patients at a Veterans Affairs hospital. Am J Geriatr Pharmacother. 2004;2(1):66-74.

7. Heydari M, Isfeedvajani MS. Zolpidem dependence, abuse and withdrawal: a case report. J Res Med Sci. 2013;18(11):1006-1007.

8. Kripke DF, Langer RD, Kline LE. Hypnotics’ association with mortality or cancer: a matched cohort study. BMJ Open. 2012;2(1):e000850. doi: 10.1136/bmjopen-2012-000850.

9. Glass J, Lanctôt KL, Herrmann N, Sproule BA, Busto UE. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ. 2005;331(7526):1169. doi: 10.1136/bmj.38623.768588.47.

10. Gunja N. The clinical and forensic toxicology of Z-drugs. J Med Toxicol. 2013;9(2):155-162. doi: 10.1007/s13181-013-0292-0.

11. Greenblatt DJ, Harmatz JS, Singh NN, et al. Gender differences in pharmacokinetics and pharmacodynamics of zolpidem following sublingual administration. J Clin Pharmacol. 2014;54(3):282-290. doi: 10.1002/jcph.220.

12. FDA requiring lower recommended dose for certain sleep drugs containing zolpidem [news release]. Silver Spring, MD: FDA; January 10, 2013. Accessed September 6, 2017.

13. Nevriana A, Möller J, Laflamme L, Monárrez-Espino J. New, occasional, and frequent use of zolpidem or zopiclone (alone and in combination) and the risk of injurious road traffic crashes in older adult drivers: a population-based case–control and case-crossover study. CNS Drugs. 2017;31(8):711-722. doi: 10.1007/s40263-017-0445-9.

14. Cubała WJ, Wiglusz M, Burkiewicz A, Gałuszko-Węgielnik M. Zolpidem pharmacokinetics and pharmacodynamics in metabolic interactions involving CYP3A: sex as a differentiating factor. Eur J Clin Pharmacol. 2010;66(9):955; author reply 957-958. doi: 10.1007/s00228-010-0854-x.

15. Norman JL, Fixen DR, Saseen JJ, Saba LM, Linnebur SA. Zolpidem prescribing practices before and after Food and Drug Administration required product labeling changes. SAGE Open Med. 2017;5:2050312117707687. doi: 10.1177/2050312117707687.

16. Harward JL, Clinard VB, Jiroutek MR, Lingerfeldt BH, Muzyk AJ. Impact of a US Food and Drug Administration drug safety communication on zolpidem dosing: an observational retrospective cohort. Prim Care Companion CNS Disord. 2015;17(2). doi: 10.4088/PCC.14m01728.

17. Zolpidem and FDA-proposed lower doses due to impaired mental alertness. US Department of Veterans Affairs Pharmacy Benefits Management Services website. Published January 16, 2013. Accessed November 30, 2017.

18. Morgan SG, Cunningham CM, Hanley GE. Individual and contextual determinants of regional variation in prescription drug use: an analysis of administrative data from British Columbia. PLoS One. 2010;5(12):e15883. doi: 10.1371/journal.pone.0015883.

19. Huang WS, Tsai CH, Lin CC, et al. Relationship between zolpidem use and stroke risk: a Taiwanese population-based case-control study. J Clin Psychiatry. 2013;74(5):e433-e438. doi: 10.4088/JCP.12m08181.

20. Kripke DF. Greater incidence of depression with hypnotic use than with placebo. BMC Psychiatry. 2007;7:42. doi: 10.1186/1471-244X-7-42.

21. Shayegani R, Song K, Amuan ME, Jaramillo CA, Eapen BC, Pugh MJ. Patterns of zolpidem use among Iraq and Afghanistan veterans: a retrospective cohort analysis. PLoS One. 2018;13(1):e0190022. doi: 10.1371/journal.pone.0190022.

22. Kao CH, Sun LM, Liang JA, Chang SN, Sung FC, Muo CH. Relationship of zolpidem and cancer risk: a Taiwanese population-based cohort study [erratum in Mayo Clin Proc. 2012;87(7):704. doi: 10.1016/j.mayocp.2012.06.001]. Mayo Clin Proc. 2012;87(5):430-436. doi: 10.1016/j.mayocp.2012.02.012.

23. Gunja N. In the Zzz zone: the effects of Z-drugs on human performance and driving. J Med Toxicol. 2013;9(2):163-171. doi: 10.1007/s13181-013-0294-y.

24. Schmidt LG, Grohmann R, Müller-Oerlinghausen B, Otto M, Rüther E, Wolf B. Prevalence of benzodiazepine abuse and dependence in psychiatric in-patients with different nosology: an assessment of hospital-based drug surveillance data. Br J Psychiatry. 1989;154(6):839-843. doi: 10.1192/bjp.154.6.839.

25. Inagaki T, Miyaoka T, Tsuji S, Inami Y, Nishida A, Horiguchi J. Adverse reactions to zolpidem: case reports and a review of the literature. Prim Care Companion J Clin Psychiatry. 2010;12(6):e1-e8. doi: 10.4088/PCC.09r00849bro.

26. Rinne ST, Elwy AR, Liu CF, et al. Implementation of guideline-based therapy for chronic obstructive pulmonary disease: differences between men and women veterans. Chron Respir Dis. 2017;14(4):385-391. doi: 10.1177/1479972317702141.

27. Stock SA, Stollenwerk B, Redaelli M, Civello D, Lauterbach KW. Sex differences in treatment patterns of six chronic diseases: an analysis from the German statutory health insurance. J Womens Health (Larchmt). 2008;17(3):343-354. doi: 10.1089/jwh.2007.0422.

28. Dales RE, Mehdizadeh A, Aaron SD, Vandemheen KL, Clinch J. Sex differences in the clinical presentation and management of airflow obstruction. Eur Respir J. 2006;28(2):319-322. doi: 10.1183/09031936.06.00138105.

29. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? a framework for improvement. JAMA. 1999;282(15):1458-1465. doi: 10.1001/jama.282.15.1458.

30. Jamtvedt G, Young JM, Kristoffersen DT, Thomson O’Brien MA, Oxman AD. Audit and feedback: effects on professional practice and health care outcomes. Cochrane Database Syst Rev. 2006;2:CD000259. doi: 10.1002/14651858.CD000259.pub2.

31. Goetz LL, Nelson AL, Guihan M, et al. Provider adherence to implementation of clinical practice guidelines for neurogenic bowel in adults with spinal cord injury. J Spinal Cord Med. 2005;28(5):394-406.

32. Wagner EH, Austin BT, Von Korff M. Organizing care for patients with chronic illness. Milbank Q. 1996;74(4):511-544.

33. Beeler PE, Bates DW, Hug BL. Clinical decision support systems. Swiss Med Wkly. 2014;144:w14073. doi: 10.4414/smw.2014.14073.
Copyright AJMC 2006-2020 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
Welcome the the new and improved, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up