Jeffrey Fudin
Jeffrey Fudin
Dr. Jeff Fudin graduated from Albany College of Pharmacy & Health Sciences with a bachelor's degree and PharmD. He is a Diplomate to the American Academy of Pain Management, a Fellow to ACCP, a Fellow to ASHP, and a member of several other professional organizations. He is founder and CEO of Remitigate, LLC (remitigate.com), a software platform for interpreting urine drug screens (Urintel) and pharmacogenetics(Phenotel). Dr. Fudin is a section editor for Pain Medicine and serves on the editorial board for Practical Pain Management. He is founder/chairman of Professionals for Rational Opioid Monitoring & Pharmacotherapy (PROMPT), an advocacy group in favor of safe opioid prescribing. He practices as a clinical pharmacy specialist (WOC) and director of PGY-2 pharmacy pain residency programs at the Stratton Veterans Administration Medical Center in Albany, New York. He is an adjunct associate professor of pharmacy practice at Western New England University College of Pharmacy and Albany C

Comprehensive Zolpidem Counseling Could Save Lives

APRIL 01, 2015
Imagine yourself as a single apartment dweller, taking a 10 mg zolpidem tablet, jumping into bed, grabbing the TV remote, and nodding off to sleep.

Seven hours later, you awaken on your couch. You look around and see an open pizza box with 4 slices left from a local pizzeria that closed 2 hours before your bedtime, 3 empty beer cans, and clothes strewn throughout your living room. Last you remember, you tucked yourself into bed after taking your zolpidem. So, how did the pizza get there, who drank the beer, how did the clothes get on the floor, and how did you get on the couch?
 
Zolpidem, branded as Ambien, Edular, Intermezzo, and Zolpimist, was first approved by the FDA in 1992 for short-term treatment of insomnia. It is classified chemically as an imidazole pyridine, non-benzodiazepine hypnotic that exerts its sedating effects by acting on the inhibitory amino acid neurotransmitter, gamma-amino-butyric-acid (GABA).1 

There are 2 types of GABA receptors: GABA-A and GABA-B.2 While GABA-B receptors are not affected, GABA-A receptors are ligand-gated ion channels that have most effect on sedation and anxiety.1,2 GABA-A receptors consist of 5 different protein subunits (2 alphas, 2 betas, and 1 gamma) that form a chloride-conducting channel.2

The channel opens upon GABA's binding to GABA-A receptors, allowing an influx of chloride ions. This results in hyperpolarization and decreases neuron excitability.2 

Subunits of alpha include alpha 1, 2, 3, and 5. Alpha 1 is linked to sedating effects, while alpha 2 and 3 are linked to anxiety, and alpha 5 is linked to cognitive effects such as memory and motor skills. Traditional benzodiazepines, such as lorazepam, temazepam, and diazepam, work by acting on the different alpha subunits, whereas non-benzodiazepines are formulated to selectively bind to the alpha 1 subunit attributable to sedation.1 

Anyone skilled in the art of pharmacology would suspect that the elective activity of zolpidem would lead to fewer memory and motor impairments. However, the evidence over the years has suggested otherwise. 
           
Although zolpidem has not been linked to a wide variety of adverse events, there are clinically relevant nuances that require careful attention by every health care professional who prescribes, dispenses, or administers the drug.

One of the more concerning issues is complex sleep-related behaviors (CSBs) being widely associated with zolpidem.4 The third edition of the International Classification of Sleep Disorders includes these medication-induced CSBs as part of its definition of parasomnia due to the unwanted physical events that occur during sleep, with sleep induction, or arousal from sleep.5

Examples of these CSBs include sleep walking with or without object manipulation, sleep talking, sleep eating, sleep driving, and even sleep sex.4 Other features of zolpidem-related CSBs include poor motor control, ataxia, responsiveness to the surrounding environment, confusion, impaired memory usually lasting 1 to 5 hours depending on dosage and formulation, and onset/offset of symptoms from 1 to 6 hours.6 

While some of these activities may seem innocuous, sleep driving could result in a disastrous outcome. Sometimes, these actions may even have legal consequences.
           
Health care professionals have to rely mostly on case reports of zolpidem-induced sleep driving/automatism and the potential fatality associated with it, probably given that it would be difficult to study in a controlled environment with large subject groups.

Nevertheless, a clinical and legal case series published in the Journal of Clinical Sleep Medicine outlined the potential severity of associated zolpidem risks. Of the 8 clinical cases detailed in the series, 3 took zolpidem at their usual bedtime dose and time. One patient sleep drove, though no accident occurred; another sleep walked, took a bath, and flooded the apartment; and the third reported sleep eating on a nightly basis.6

All of the 6 legal cases examined involved patients sleep driving, in which 2 patients used alcohol concomitantly and pleaded guilty to DUI charges.6

These cases illustrate just how dangerous and costly zolpidem-related adverse events can be. The question then becomes: are there certain factors that put patients at higher risk to develop these events, and can pharmacists help mitigate them?
           
A 2006 cross-sectional study attempted to stratify risk factors in patients taking hypnosedative medications and experiencing CSBs. Of the 125 subjects, 19 had CSBs, and 100% of those patients were taking zolpidem.7

The investigators then identified 4 risk factors that were formidably associated with CSB occurance. These included doses of zolpidem >10 mg/day, female gender, and younger age. However, the only independent, significant risk predictor of CSBs was taking higher doses of zolpidem. Alcohol use was not found to be a significant CSB risk predictor in this study, although sedation alone is likely synergistic.7
 
Known as the “new-generation hypnotics,” non-benzodiazepines are now the most prescribed first-line medications for treating insomnia.1 Almost 4 billion prescriptions were filled at retail pharmacies alone in the United States in 2013.3 

One advantage zolpidem has over traditional benzodiazepines is that associated tolerance or rebound insomnia after continued use is less likely. Zolpidem is also less disruptive during the various sleep stages compared with traditional benzodiazepines.1

Given the severity of zolpidem-associated CSBs and certain risk predictors, however, prescribers and pharmacists have a corresponding responsibility to provide proper education to all patients receiving this medication. Pharmacists are strongly encouraged to counsel patients not to take more zolpidem than prescribed in an attempt to enhance immediate sleep induction shortly after taking the medication. All patients should also be carefully counseled about the potential risks of CSBs, particularly sleep walking and sleep driving. 

Patients must never drink alcohol while taking zolpidem, as intentional alcohol use places them at greater risk for legal consequences. Patients need to understand these risks and be prepared to take appropriate steps to avoid situations that might place them or innocent bystanders in harms way. 
 
As drug information experts, and the last stop before a patient receives zolpidem, pharmacists play a unique yet essential role. Pharmacists need to be visibly available within the community setting and institutional pharmacies, as well as maintain their role as patient advocates and educators.
 
This article was collaboratively written with PharmD Candidates Erika Prouty and Jeffrey J. Bettinger.

Erika Prouty, BS Bio, BS Environmental Sci, is a 2015 PharmD Candidate at the Western New England University's College of Pharmacy and currently completing a Mini-Residency at the Stratton VA Medical Center in Albany, NY. Her future plans include working in the community setting for Stop and Shop pharmacy.

Jeffrey J. Bettinger is a 2017 PharmD Candidate at Albany College of Pharmacy and Health Sciences, with a concentration in Nephrology. He is a volunteer Student Pharmacist engaged in the Stratton VA’s national Opioid Safety Initiative under the mentorship of Dr. Fudin and was recently awarded an opportunity to participate in their VALOR program. His future plans include a general practice residency followed by a to-be-determined specialty practice PGY2 program.
 
This article is the sole work of the authors and stated opinions/assertions do not reflect the opinion of employers, employee affiliates, and/or pharmaceutical companies listed.
 
References:
1) Rösner S, Soyka M, Hajak G, Wehrle R, Englbrecht C. Zolpidem for insomnia. Cochrane Database of Systematic Reviews. 2013, Issue 8. Art. No.: CD010700. DOI: 10.1002/14651858.CD010700
2) Pharmacotherapy: A Pathophysiological Approach, 9e. Dipiro, JT; Talbert RL; Yee GC, Matzke GR, Wells BG, Posey LM.  McGraw-Hill Education. 2014.
3) Total Number of Retail Prescription Drugs Filled at Pharmacies. State Health Facts . The Henry J. Kaiser Family Foundation. Accessed on 17, Mar 2015. Available at: http://kff.org/other/state-indicator/total-retail-rx-drugs/.
4) MacFarlane J, Morin CM, Montplaisir J. Hypnotics in Insomnia: The Experience of Zolpidem. Clinical Therapeutics. 2014; 36 (11): 1676-1701.
5) Sateria MJ. International Classification of Sleep Disorders-Third Edition Highlights and Modifications. CHEST. 2014; 146 (5): 1387–1394.
6) Hwang TJ, Ni HC, Chen HC, et al. Risk Predictors for Hypnosedative-Related Complex Sleep Behaviors: A Retrospective, Cross-Sectional Pilot Study. Journal of Clinical Psychiatry. 2010;71(10):1331–1335.
7) Poceta JS. Zolpidem Ingestion, Automatisms, and Sleep Driving: a Clinical and Legal Case Series. The Journal of Clinical Sleep Medicine. 2011; 7 (6): 632-638.


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