Beyond Benzos: Treatment Options for Insomnia


What are the treatment options for insomnia when avoiding benzodiazepines? John W. Winkelman MD, PhD, shares insights and guidance at the 2023 Annual Psychiatric Times World CME Conference.




“We don’t just go from insomnia symptoms to treatment—the shortcut. We ask a lot of questions about what the potential contributing factors might be,” John W. Winkelman MD, PhD, told attendees of the 2023 Annual Psychiatric Times World CME Conference. “We hopefully make a diagnosis or at least identify underlying contributors and address them. And only then do we determine treatment.”

Winkelman, chief of the Sleep Disorders Clinical Research Program at Massachusetts General Hospital and Professor of Psychiatry at Harvard Medical School, noted by avoiding the shortcut approach and making these careful considerations, clinicians gain a full picture that will better inform their choice of the varied pharmacological and nonpharmacological treatment options.

John Winkelman, MD, PhD

John Winkelman, MD, PhD

“If you do the full history, you’re going to find that people have a lot of underlying causes, and multiple ones,” he added. “They’ve got a psychiatric illness. They’ve got a primary sleep disorder like sleep apnea, restless leg syndrome, circadian rhythm disorder. They’ve got medical illnesses, pain, shortness of breath that are contributing. They’re taking medications that may influence their sleeplessness: serotonergic reuptake inhibitors, noradrenergic reuptake emitters, beta blockers, and steroids. And, beyond that, they may not be paying attention to the rules that we think are best for supporting adequate sleep.”

First-line treatment for insomnia is cognitive behavioral therapy for insomnia (CBT-I), Winkleman said. As a multicomponent program, CBT-I can address sleep restriction, stimulus control, relaxation, and sleep hygiene. The cognitive therapy component can also address maladaptive beliefs.1

Outside of the benzodiazepines, Winkelman said there are several classes of pharmacological agents that may also prove to be useful: sedating antidepressants, dopaminergic antagonists (eg, antipsychotics), anticonvulsants, melatonin agonists as well as a “miscellaneous” category.

“Why are there so many medications that work for insomnia? It’s because sleep is regulated at so many different places in the nervous system…involving a variety of neurotransmitters,” Winkelman shared. “This is why we have so many different pathways to positively and potentially negatively affect sleep.”

In the antidepressant class, Winkelman pointed to doxepin (which is FDA-approved for sleep-maintenance insomnia) as well as mirtazapine, trazodone, and amitriptyline. Although they are less effective than the benzodiazepines, he noted these agents also have little abuse liability. Other disadvantages of the class of medications include side effects like weight gain and anticholinergic negative effects, daytime sedation, and the risk of switch into mania in patients with bipolar disorder.

Atypical antipsychotics may also prove useful in patients with insomnia, Winkelman said, pointing particularly to quetiapine. Like the antidepressants, these agents hold little abuse liability. He added they are anxiolytic, mood stabilizing in bipolar disorder, and may be advantageous as part of an augmentation strategy in patients with major depressive disorder. In addition to being less effective than the benzodiazepines, other disadvantages include daytime sedation, weight gain, risk of emerging extrapyramidal symptoms, and metabolic (ie, glucose and lipid) abnormalities.

Gabapentin is the example he provided for the anticonvulsant class of medications. Much like the previously noted classes, there is a little abuse liability, with the exception of individuals with opioid use disorder, he explained. Winkleman also noted there is mixed data on gabapentin in alcohol withdrawal, which is often associated with insomnia. He said considering this agent for such patients may be a good idea. Its disadvantages include cognitive impairment, daytime sedation, dizziness, gait stability, and weight gain. It also is probably less effective than the benzodiazepines.

Melatonin was the final class of agents Winkelman discussed. Within this class is the FDA-approved agent for sleep-onset insomnia, ramelteon, but also many over the counter products. “The problem with the over-the-counter agents is that it’s just not clear what’s in it,” he told attendees. Because they are dietary supplements, he noted “the degree of quality control is not good.” An exception to this is RemFresh, which he said is a controlled release form of melatonin and with a well-established PK. On the other hand, Winkelman said patients like these options because they are relatively inexpensive and are accepted as “natural.” “It’s not clear to me that all natural things are good,” he commented. “Just because we dig it out of the earth or it’s released in our body doesn’t mean concentrating and taking it orally is going to be a good idea.”

Winkelman also noted that if taken at an adverse time, melatonin can impact circadian rhythms, and that it works best when melatonin is not being endogenously released. He explained it is not optimal for sleep maintenance, but may show mild benefit for sleep onset. He cautioned attendees about starting with melatonin due to its minimal proven efficacy, because “you may lose the confidence of the patient and then you may not have a shot at actually improving their symptoms.”

Winkelman concluded his presentation with a few words of caution. With the exception of agents with FDA-approved indications, he said there is a paucity of short-term and long-term efficacy data for these agents. As such, assumptions of lack of tolerance and rebound insomnia are unsubstantiated, he added.

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1. Winkelman JW. Clinical Practice. Insomnia Disorder. N Engl J Med. 2015;373(15):1437-1444.

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