FAQ
Warnings regarding sedative-hypnotic medications: an update
Insomnia, defined as difficulty initiating or maintaining sleep, waking up too early or poor-quality sleep, is the most common sleep disorder in adults. In fact, one third of adults experience occasional insomnia and 1 in 10 has chronic insomnia (at least 3 nights per week for more than a month). It is more likely to occur in women than men and older versus younger adults; other risk factors include high stress levels, depression, variable work hours and travel with time changes. Most cases are comorbid with other conditions that may disrupt sleep, particularly depression and substance use, cardiopulmonary disorders, and conditions associated with somatic complaints such as pain and gastrointestinal disorders. Chronic insomnia is a serious problem that can impact mood, safety, cognitive function, work performance and quality of life. Insomnia affects not only individual patients but also families, caregivers, and friends. It is associated with high health care utilization; annual direct and indirect costs of chronic insomnia are estimated to be tens of billions of dollars. Available treatments for insomnia include a variety of cognitive and behavioral therapies; antidepressant, antipsychotic or antihistamine medications; and sedative-hypnotic medications.
Many people turn to prescription sedative-hypnotic medications for relief of insomnia. The benzodiazepine receptor agonists consist of benzodiazepines (estazolam, flurazepam, quazepam, temazepam, and triazolam) and non-benzodiazepines (zaleplon, zolpidem, and eszopiclone). The newest agent for the treatment of insomnia is ramelteon, a melatonin receptor agonist. Adverse effects associated with sedative-hypnotics include residual daytime sedation, cognitive impairment, motor incoordination, dependence and rebound insomnia; however, the frequency and severity are much lower for the non-benzodiazepines.
"Ambien drivers" have made news headlines as blood levels of the drug have been found in drivers arrested for erratic behavior or suspected intoxication, and researchers have reported instances of complex sleep-related behaviors. The published literature contains a number of case reports associated with sedative-hypnotic use including sleepwalking, nocturnal eating and sleep related eating disorder, compulsive repetitive behaviors such as cleaning and shopping, and other complex behaviors such as attempting to fill a lawn mower with gasoline, often with amnesia for the events. Cases of amnesia with robbery, sexual assault, automatism and attempted murder have also been reported in patients taking benzodiazepines.
Researchers' data and adverse events reported to MedWatch prompted the FDA to examine the sedative-hypnotic drugs' potential for causing sleep driving. Over a dozen complex sleep-related behaviors associated with the medications, such as driving, eating, cooking, and having sex while asleep, were reported. The behaviors can be triggered by concomitant alcohol or other drugs affecting the central nervous system. The FDA also examined the potential for allergic reactions after receiving reports of angioedema in patients taking ramelteon. Reports of anaphylaxis and sleep behaviors were rare, and no deaths have been reported as a direct result of taking the drugs.
In March 2007, the FDA issued new warnings for sedative-hypnotics and requested the following of manufacturers: (1) label change to include stronger language regarding potential risks, including complex sleep-related behaviors, such as sleep-driving, and severe allergic reactions (anaphylaxis and angioedema) which can occur as early as the first use; (2) letters to healthcare providers regarding revised labeling; and (3) Patient Medication Guides for distribution by pharmacists to patients receiving sedative-hypnotics to provide information on risks and precautions to be taken, proper use and avoidance of alcohol and/or other central nervous system depressants. The FDA also recommended that manufacturers conduct clinical studies to investigate the frequency of complex sleep-related behaviors associated with individual products.
The revised labeling and Patient Medication Guides warn against complex sleep-related behaviors. The zolpidem and eszopiclone package inserts (PIs) state “There have been reports of people getting out of bed after taking a sedative-hypnotic and driving their cars while not fully awake, often with no memory of the event. If a patient experiences such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can be dangerous. This behavior is more likely to occur when Ambien CR [or Lunesta] is taken with alcohol or other central nervous system depressants. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with “sleep-driving”, patients usually do not remember these events.” The zapelon PI adds that the events can occur in sedative-hypnotic-naïve or -experienced persons.
Patients should be instructed to report all concomitant medications to their prescriber, as well as events such as “sleep-driving” and other complex behaviors immediately. Neuropsychiatric symptoms and amnesia are unpredictable. Because of the risk to both the patient and the community, discontinuation of the medication should be strongly considered in patients who experience a “sleep-driving” episode.
Medications affected by the warnings include: Ambien/Ambien CR (zolpidem), Lunesta (eszopiclone), Sonata (zaleplon), Rozerem (ramelteon), Butisol Sodium (butabarbital), Dalmane (flurazepam hydrochloride), Doral (quazepam), Halcion (triazolam), Prosom (estazolam), Restoril (temazepam) and Seconal (secobarbital sodium).
References
Food and Drug Administration. MedWatch. March 14, 2007. http://www.fda.gov/MedWatch/safety/2007/safety07.htm#Sedative. Accessed February 14, 2008.
American Society of Health-System Pharmacists. News. March 14, 2007. http://www.ashp.org/s_ashp/article_news.asp?CID=167&DID=2024&id=19101. Accessed February 14, 2008.
Logan BK, Couper FJ. Zolpidem and driving impairment. J Forensic Sci. 2001;46(1):105-110. http://www.astm.org/cgi-bin/SoftCart.exe/JOURNALS/FORENSIC/PAGES/JFS4610105.htm?L+mystore+nprv7510. Accessed February 14, 2008.
U.S. Department of Health & Human Services, National Institutes of Health, National Heart, Lung and Blood Institute. Insomnia. http://www.nhlbi.nih.gov/health/dci/Diseases/inso/inso_whoisatrisk.html and http://www.nhlbi.nih.gov/health/dci/Diseases/inso/inso_summary.html. Accessed February 14, 2008.
NIH State-of-the-Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults. http://consensus.nih.gov/2005/2005InsomniaSOS026html.htm. Accessed February 14, 2008.
National Sleep Foundation. http://www.sleepfoundation.org/site/c.huIXKjM0IxF/b.2449049/k.5C33/Healthcare_Professionals.htm. Accessed February 14, 2008.
Food and Drug Administration. FDA News. March 14, 2007. http://www.fda.gov/bbs/topics/NEWS/2007/NEW01587.html. Accessed February 14, 2008.
Ambien [package insert]. Bridgewater, NJ: Sanofi-Aventis; January 2008. http://products.sanofi-aventis.us/ambien_cr/ambienCR.pdf
Ambien and Ambien CR Dear Healthcare Professional Letter. March 2007. http://ambiencr11.intouch-dev.com/HCP/AmbienIRCRDHCPletter.pdf
Lunesta [package insert]. Marlborough, MA: Sepracor Inc; April 2007. http://www.lunesta.com/PostedApprovedLabelingText.pdf
Sonata [package insert]. Bristol, TN: King Pharmaceuticals Inc; December 2007. http://www.kingpharm.com/kingpharm/uploads/pdf_inserts/Sonata_PI_20071200.pdf
Rozerem [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; April 2006. http://www.rozerem.com/consumer/Home.aspx. Accessed February 14, 2008.
SansoneRA, Sansone LA. Zolpidem, somabulism, and nocturnal eating. Gen Hosp Psychiatry. 2008;30:90-91.
Morgenthaler TI, Silber MH. Amnestic sleep-related eating disorder associated with zolpidem. Sleep Med. 2002;3:323-327.
Yang W, Dollear M, Ranjini Muthukrishnan S. One rare side effect of zolpidem—sleepwalking: a case report. Arch Phys Med Rehabil. 2005;86:1265-1266.
Gorman C. Sleeping-pill puzzler. Time. 2006;167(13):71.
Barrett J, Underwood A. Perchance to…eat? A few Ambien users find themselves at the fridge. Newsweek. 2006;147(13):54.
Lange CL. Medication-associated somnambulism. J Acad Child Adolesc Psychiatry. 2005;44:211-212.
Harazin J, Berigan TR. Zolpidem tatrate and somnambulism. Mil Med. 1999;164:664-670.
Iruela LM. Zolpidem and sleepwalking. J Clin Psychopharmacol. 1995;15:223.
Sharma A, Dewan VK. A case report of zolpidem-induced somnambulism. Prim Care Companion J Clin Psychiatry. 2005;7:74.
Goulle JP, Anger JP. Drug-facilitated robbery or sexual assault. Ther Drug Monit. 2004;26:206-210.
Najjar M. Zolpidem and amnestic sleep related eating disorder. J Clin Sleep Med. 2007;3(6):637-638.
Tsai MJ, Tsai YH, Huang YB. Compulsive activity and anterograde amnesia after zolpidem use. Clin Toxicol (Phila). 2007;45(2):179-180.
Ramakrishnan K, Scheid DC. Treatment options for insomnia. Am Fam Physician. 2007;76:517-526.
Liskow B, Pikalov A. Zolpidem overdose associated with sleepwalking and complex behavior. J Am Acad Child Adolesc Psychiatry. 2004;43(8):927-928.
Mendelson, WB. Sleepwalking associated with zolpidem. J Clin Psychopharmacol. 1994;14(2):150.