Treating Insomnia Outside the (Black) Box

Elaine K. Howley


July 29, 2019

The modern scourge of insomnia takes a heavy toll, with 40 million Americans having trouble falling asleep, staying asleep, or waking up feeling unrefreshed.

No matter which type of insomnia a patient is dealing with, there are ways to manage and improve the situation. Most sleep medicine practitioners prefer behavioral interventions over pharmacologic solutions, but prescription medications have been part of the treatment picture for more than a century. And, since the 1990s, clinicians have had a powerful group of drugs called sedative-hypnotic medications at their disposal to treat sleep disorders. Unfortunately, many of these drugs come with their own set of problems.

Three of these medications in particular—eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien, Ambien CR, Edluar, Intermezzo, and Zolpimist)—have gained widespread adoption by clinicians and patients for their effectiveness over the past quarter century. The US Food and Drug Administration (FDA) reports that in 2018, an estimated 5.1 million total patients received a zolpidem prescription, 600,000 total patients received an eszopiclone prescription, and 200,000 total patients received a zaleplon prescription.

But side effects are a concern. Although these medications have long carried warning labels that have been strengthened in the past, in April 2019, the FDA took the additional step of adding black-box warnings, the strongest notice the FDA offers.

Although nonmedical interventions have long been at the top of the American Academy of Sleep Medicine (AASM) recommendations, at least one expert hopes the warnings will encourage practitioners to consider alternatives to the commonly prescribed sedative-hypnotic drugs. "Oftentimes, the hypnotic 'Z' drugs, such as zolpidem, are a Band-Aid or cosmetic fix for something more involved," says Alex Dimitriu, MD, a sleep medicine specialist in Menlo Park, California.

A History of Adverse Effects

In the case of these three insomnia medications, the new warnings come after the FDA had identified 66 cases over the past 26 years of complex sleep behaviors resulting in serious injuries and death among people taking the medications, according to the agency's announcement. Of those 66 events, 46 were nonfatal and 20 were fatal, with the causes of death including carbon monoxide poisoning, drowning, falls, hypothermia, motor vehicle collisions with the patient driving, and apparent suicide.

Dimitriu says that in his own clinical practice, he's seen patients have adverse reactions to the medications. "I have witnessed falls; sleepwalking; nighttime eating; and, in very rare instances, even driving, which people will not recall the next day." The intensely sedative nature of these drugs can trigger these behaviors in certain individuals, resulting "in, what we call in sleep medicine, 'disorders of confusional arousal.' This is almost the same as sleepwalking; however, in these cases, other complex behaviors can occur," he explains.

Disorders of confusional arousal can occur in anyone, but "they normally occur when something disturbs sleep, which can be breathing issues due to sleep apnea, loud noises or bed partners, or even when alcohol wears off after an evening of drinks," Dimitriu notes. The incidence of such events spikes in people taking prescription sleep aids "because now there are two opposed forces—one is the natural insomnia for which the medicine is prescribed, competing with the sedating effects of the sleep medication. When it is not a clear victory for either side, disorders of confusional arousal, or these complex behaviors, can arise." 

Despite the new warning labels being mandated by the FDA, these adverse effects aren't new. "An association between these drugs, called sedative-hypnotics, and complex sleep behaviors has already been established and included in the label," and it's been that way for some time, FDA spokesperson Kristofer Baumgartner says. Since the medications were initially approved for patient use beginning in the 1990s, the FDA has been closely monitoring reports of adverse events related to their use, and "the labels have been updated continually to note additional safety issues as issues were identified," Baumgartner says.

The purpose of black-box warnings, Baumgartner says, is to "highlight for prescribers certain contraindications or adverse drug events, especially those that may cause death or serious harm. A contraindication occurs when the risk of using the drug in a patient outweighs any benefit. An adverse drug event, also called an 'adverse drug experience,' occurs when there is an undesired side effect associated with the drug, or when there is a lack of effect (the drug does not do what it is supposed to do)."

Although these medications have potential dangers, it's important to note that the most serious adverse events don't occur very often, and these drugs can provide significant relief of a major medical problem for some patients. "The agency continues to believe that for certain people with insomnia, the benefits of sedative-hypnotics outweigh the risks," Baumgartner says. "Serious adverse events associated with sedative-hypnotics are rare, and based on the available evidence, the FDA believes it is appropriate to maintain these drugs as treatment options for patients."

Will the Warnings Change the Practice of Sleep Medicine?

Although the introduction of more prominent warnings might seem alarming at first, it may not vastly change the way most sleep medicine doctors practice, said Kelly Carden, MD, president of the AASM and a sleep medicine physician in Nashville, Tennessee. "Medical providers who have expertise in sleep medicine are already aware of the limitations of sleeping pills and the risks associated with their use," she says. Carden does think patient awareness of the issues surrounding these medications could be heightened because of the new warnings, and she says that "may affect how patients look at their medication and hopefully increase the dialogue" they have with their healthcare providers.

In her practice, Carden says she frequently sees patients "whose goal is to discontinue use of these types of medications, and they just need help doing so." She doesn't anticipate that the heightened warnings will change how she works with patients. "I will continue to prescribe cognitive-behavioral therapy (CBT) for insomnia as the primary intervention for chronic insomnia in adults, reserving hypnotic medications as an adjunctive treatment when necessary."[1]

Dimitriu agrees that the new warnings aren't going to have a significant impact on how he practices, but he does think they could lead other practitioners to become more conservative with their prescribing of such meds, "which may be a good direction." Dimitriu says he has long counseled his patients of the risks for parasomnias or disorders of confusional arousal that can be triggered by these medications, and how to mitigate them. "I always warn my patients of such risks, recommend getting into bed soon after taking any sedating medications, and being very careful with driving the morning after. Sedating effects can linger, and people are poor at gauging how impaired these medications can make them."

He hopes that the intensified warnings will help other clinicians look beyond just the disordered sleep to discover—and treat—the underlying problem, such as sleep apnea or nocturia.

What Clinicians Should Know Now

For practitioners who aren't specialized in sleep medicine but may meet with patients experiencing insomnia, Carden emphasizes that CBT is the safest and most effective treatment for chronic insomnia in adults. "Sleeping pills should be prescribed only when necessary, and their use should be monitored carefully."

Baumgartner adds that clinicians should not prescribe eszopiclone, zaleplon or zolpidem to patients who have previously experienced complex sleep behaviors after taking any of these medicines, and that patients should always be counseled about the potential dangers.[2] "Tell the patient to discontinue taking these medicines if they experience an episode of complex sleep behavior." And, though it should go without saying, it bears repeating: "It's extremely important for patients to avoid alcohol when taking a sleeping pill," Carden says.

She also points out that the various sleep aids on the market today are designed for different types of sleep issues, and it's important to know which one works best for which problem.[3] "Some sleeping pills are better for people who have trouble falling asleep, known as 'sleep onset insomnia,' whereas others are more effective for people who have difficulty staying asleep, which is called 'sleep maintenance insomnia,'" Carden says. The AASM's guidelines include recommendations for which drugs to prescribe for particular types of insomnia, and which drugs, such as Benadryl and melatonin, are not recommended.

In all of the AASM's clinical practice guideline documents, the society emphasizes a preference for using CBT as the primary intervention, reserving medications for chronic insomnia for patients who are unable to participate in CBT or have refractory symptoms.[4] In the context of sleep medicine, CBT is sometimes referred to as CBT-i, and this type of therapy includes sleep assessments and counseling to help patients change the way they sleep, improve sleep hygiene, and develop a healthier sleep-wake pattern. There are several validated, online CBT-i programs that can be helpful for people who have chronic insomnia. For example, the CBT-i Coach app was developed by the Department of Veteran Affairs' National Center for PTSD, Stanford School of Medicine, and the Department of Defense's National Center for Telehealth & Technology.[5]

CBT-i is not a quick fix, but rather a long-term solution that introduces virtually no side effects and has been deemed safe and effective.


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