New Study Finds Frequent Unsafe Use of the Sleep Aid Zolpidem

Zolpidem (AMBIEN, EDLUAR, INTERMEZZO, ZOLPIMIST) was approved by the Food and Drug Administration (FDA) in 1992 for the short-term treatment of insomnia characterized by difficulty initially falling asleep. It belongs to a family of drugs known as non-benzodiazepine hypnotics or "Z drugs," which work similarly to benzodiazepines (for example, diazepam [VALIUM]) — a class of drugs that target the brain to treat anxiety, depression and insomnia — but have a different chemical structure.

We have designated zolpidem and all other Z drugs as Do Not Use because their risks of adverse effects far outweigh their benefits. There has long been evidence that zolpidem has been widely misused, and a recent study published in the Journal of the American Medical Association Internal Medicine (JAMA Internal Medicine) confirmed the frequent misuse of the drug for the treatment of insomnia.[1]

About zolpidem

Zolpidem binds to a specific receptor in the brain to induce sleep. Research suggests that doctors often incorrectly perceive zolpidem and other Z drugs as being safer and more effective for insomnia than benzodiazepines and, as a result, prescribe them more readily.[2],[3]

However, like benzodiazepines, zolpidem is a controlled substance because it is habit-forming. Misuse of the drug can lead to serious adverse effects and dependence.[4] A 2014 study published by researchers at the Centers for Disease Control and Prevention revealed that zolpidem was the most commonly implicated drug for emergency department visits for psychiatric drug-related adverse events among adults in the U.S.[5]

One of the most troubling and dangerous adverse effects of zolpidem is next-day drowsiness and impairment, which can make it unsafe to drive or operate heavy machinery, leading to motor vehicle accidents.[6] The drug also can cause abnormal thinking and behavioral changes, including aggressive or bizarre behavior, agitation and hallucinations. Patients using zolpidem also can get out of bed without being fully awake and engage in activities, such as sleepwalking, sleep driving, sex and eating, without remembering such activities the following day. The risk of these adverse events increases if the zolpidem is taken with alcohol or other sedating drugs that depress the central nervous system (CNS).

Zolpidem also can impair balance, which increases the risk of falls and injuries (including hip fractures), particularly in the elderly.[7],[8] Severe allergic and anaphylactic reactions also have been reported when taking this medication.[9]

Importantly, the effectiveness of zolpidem decreases substantially after two weeks of continuous use.[10] As with other habit-forming drugs, the body builds up tolerance to the effects of zolpidem, and individuals taking it for extended periods of time require higher doses to achieve the same desired effect.[11] Furthermore, abrupt cessation after prolonged use of the drug can lead to rebound insomnia and serious withdrawal symptoms, including stomach cramps, nausea, vomiting, sweating, shakiness, irritability and craving for the drug.[12]

Despite these serious adverse effects, zolpidem is misused by a significant proportion of users.

The JAMA Internal Medicine study[13]

For the study, researchers at the Institute for Safe Medication Practices analyzed data from a large government-funded national survey of patients, doctors, pharmacies and hospitals regarding the use of prescription drugs and other medical services to assess patterns of zolpidem use among U.S. adults in 2015. They specifically determined how often patients, doctors and pharmacists adhered to safety recommendations regarding dosage, duration of use and avoidance of other medications known to increase the risk of zolpidem’s adverse effects, as described in the FDA-approved product labeling and the agency’s drug safety announcements regarding the drug.

Nearly four million adults age 18 to 85 reported one or more prescriptions for zolpidem in 2015. Women were almost twice as likely as men to use zolpidem. Furthermore, zolpidem use became more common with increasing age.

The FDA recommends a lower zolpidem dose (5 milligrams [mg] for the immediate-release form and 6.25 mg for the slow-release form) for all women and for men older than 65 because they clear the drug more slowly from their bodies. However, the researchers found that 68 percent of women and 64 percent of all adults age 65 or older used a higher dose that exceeded these recommendations.

More troubling, the researchers found that 68 percent of zolpidem users took the drug on a sustained basis, defined as three or more prescriptions or a single prescription for at least a two-month supply. Among those patients using zolpidem on a sustained basis in 2015, the median total number of days supplied was 192, more than half a year, and the range was 117 to 292 days.

In addition, 41 percent of zolpidem users were sustained users of at least one other CNS depressant medication that can exacerbate the adverse effects of zolpidem. For example, 27 percent were taking opioids, and 20 percent were using benzodiazepines. The FDA-approved product labeling for zolpidem warns against using zolpidem concomitantly with other CNS depressants, including alcohol, because this can increase the risk of adverse effects such as next-day impairment and behaviors that occur while not fully awake.[14]

Finally, the study found that more than three-quarters of zolpidem users failed to adhere to two or more safety recommendations related to dosing, duration or concomitant medication use.

In conclusion, this study shows that the vast majority of patients prescribed zolpidem use it in a manner that greatly increases the risks of harm. Primary responsibility for these failures rests with the health care professionals who are recklessly misprescribing the drug.

What You Can Do

Do not use zolpidem or any other drug for insomnia. There are many steps you can take to sleep better and longer without resorting to drugs (see text box, below). If you are experiencing insomnia and have tried nonpharmacologic means to improve sleep, ask your physician for a referral to a cognitive behavioral therapy program.

DO NOT suddenly stop taking sleeping pills without consulting your physician; doing so carries a risk of severe withdrawal reactions.

References

[1] Moore TJ, Mattison DR. Assessment of patterns of potentially unsafe use of zolpidem. JAMA Intern Med. 2018. 178(9):1275-1277.

[2] Hoffmann F. Perceptions of German GPs on benefits and risks of benzodiazepines and Z-drugs. Swiss Med Wkly. 2013 Jan 17;143: w13745. .

[3] Dundar Y, Boland A, Dodd S, et al. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation. Health Technol Assess. 2004. 8(24):iii-x, 1-125.

[4] Drug profile: Zolpidem. Worst Pills, Best Pills. July 31, 2018. /monographs/view/89. Accessed November 8, 2018.

[5] Hampton LM, Daubresse M, Chang HY, et al. Emergency department visits by adults for psychiatric medication adverse events. JAMA Psychiatry. 2014;71(9):1006-1014.

[6] sanofi-aventis U.S. Label: zolpidem tartrate tablets (AMBIEN). September 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019908s042lbl.pdf. Accessed December 3, 2018.

[7] sanofi-aventis U.S. Label: zolpidem tartrate tablets (AMBIEN). September 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019908s042lbl.pdf. Accessed December 3, 2018.

[8] Bracchi R, Donnelly K, Hewitt J, et al. Benzodiazepines, Z-drugs and the risk of hip fracture: a systematic review and meta-analysis. PLoS One. 2017;12(4):e0174730.

[9] sanofi-aventis U.S. Label: zolpidem tartrate tablets (AMBIEN). September 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019908s042lbl.pdf. Accessed December 3, 2018.

[10] Moore TJ, Furberg CD, Mattison DR, Cohen MR. QuarterWatch 2014, Quarter 2: New Safety Perspectives. Institute for Safe Medication Practices. May 6, 2015. https://www.ismp.org/sites/default/files/attachments/2018-01/2014Q2_0.pdf. Accessed December 3, 2018.

[11] Gunja, N. The clinical and forensic toxicology of z-drugs. J Med Toxicol. 2013. 9(2):155–162.

[12] American Addiction Centers. Ambien withdrawal – symptoms, timeline and tips. November 16, 2018. https://americanaddictioncenters.org/withdrawal-timelines-treatments/ambien/. Accessed December 3, 2018.

[13] Moore TJ, Mattison DR. Assessment of patterns of potentially unsafe use of zolpidem. JAMA Intern Med. 2018. 178(9):1275-1277.

[14] sanofi-aventis U.S. Label: zolpidem tartrate tablets (AMBIEN). September 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/019908s042lbl.pdf. Accessed December 3, 2018.