Current, Emerging, and Newly Available Insomnia Medications

Andrew D. Krystal, MD, MS

Insomnia and Sleep Research Program, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina

New research into the sleep-wake system is providing a better understanding of insomnia and promising treatment targets. Insomnia treatment has been dominated by agents that enhance sleep-promoting systems, such as benzodiazepines, so-called “nonbenzodiazepine” hypnotics, and melatonin agonists, but new and emerging treatments are focusing on blocking wake-promoting systems. The goal for these new treatments is to provide an improved benefit-to-side-effect ratio compared with existing therapies. This activity will provide a brief overview of sleep-wake processes and a description of insomnia medications that enhance sleep-promoting systems and those that block wake-promoting systems.

Sleep-Wake Processes

The sleep-wake cycle is believed to be driven by 2 processes: (1) the homeostatic process, which regulates the amount of sleep, and (2) the circadian process, which regulates the timing of sleep.1 These 2 processes are controlled by the interaction of cell groups that cause arousal with others that induce sleep, such as the ventrolateral preoptic nucleus.2 The sleep-promoting and wake-promoting systems are mutually inhibitory, meaning that the one with greater activity inhibits the other, producing either sleep or wakefulness (AV 1).1,3 The orexin system appears to play a central role in maintaining wakefulness, as driven by the circadian clock.2 For more detail on sleep processes, see Dr. Scammell’s activity “Overview of Sleep: The Neurologic Processes of the Sleep-Wake Cycle.”

Medications for insomnia have traditionally increased the activity of sleep-promoting systems, the most important of which is GABA. The most commonly prescribed medications for treating insomnia, including benzodiazepines and nonbenzodiazepine hypnotics such as zolpidem, zaleplon, and eszopiclone, all augment the effects of GABA when it binds to the GABAA receptor.4 The newer approach to alleviating insomnia is to block wake-promoting systems, which include norepinephrine, serotonin, acetylcholine, histamine, and orexin/hypocretin. The clinical effects of modulating each of these systems differ, providing the potential for a number of specific, targeted interventions.

AV 1. Neurologic Systems Involved in the Sleep-Wake Cycle (00:23)

Based on Krystal et al1 and Saper et al3

Agents That Enhance Sleep-Promoting Systems

Agents that enhance activity in sleep-promoting systems inhibit arousal systems and shift the balance toward sleep. Benzodiazepines and nonbenzodiazepine hypnotics enhance GABAergic inhibition, while agents including ramelteon and melatonin increase melatoninergic activity.5

Benzodiazepines. Benzodiazepines are widely used medications for the short-term treatment of insomnia. The benzodiazepines that are FDA-approved for insomnia treatment include quazepam, triazolam, estazolam, temazepam, and flurazepam (Table 1).1,6 These agents share a related chemical structure and enhance GABAergic neurotransmission, which may be diminished in people with insomnia.7 The GABAA receptor complex forms a channel that controls the flow of chloride ions in and out of the neuron.8 Generally, chloride ions are greater in concentration outside compared with inside neurons. GABA binding opens the channel and allows chloride ions to flow in and hyperpolarize the membrane, resulting in inhibition of the capacity to fire action potentials. Benzodiazepines bind to a site on the α subunit of the GABAA receptor and enhance this GABA-mediated inhibition. Because of the wide distribution of GABAA receptors, benzodiazepines broadly inhibit brain function, including wake-promoting systems. This inhibition can result in sedation, muscle relaxation, cognitive and psychomotor impairment, the potential for tolerance and dependence, and anxiety reduction.8 The effects of GABA-enhancing agents are largely proportional to blood level.

Patients should be maintained on the lowest effective dose for the shortest time necessary to treat insomnia due to greater risks of adverse effects being associated with higher doses and the costs and potential risks of long-term usage.5 Benzodiazepines should be avoided in patients who are pregnant or who have a history of substance abuse and used with caution in elderly patients due to the risk of falls and confusion.5

Nonbenzodiazepines. Nonbenzodiazepine hypnoptics also bind to α subunits on GABA receptors, but they generally bind more specifically to particular types of GABAA receptor α subunits than benzodiazepines. Although this binding profile would suggest that they might have a better safety profile than benzodiazepines, this difference has never been established. They are referred to as nonbenzodiazepine agents because they do not have the benzodiazepine chemical structure, a feature that all benzodiazepines share, although they share a common mechanism of action with the benzodiazepines. These agents include zaleplon, eszopiclone, zolpidem, and zolpidem ER and SL, which are all FDA-approved for treating insomnia.1,5

In general, both benzodiazepines and nonbenzodiazepine hypnotics promote sleep and may have myorelaxant, anxiolytic, and antiseizure effects, but their adverse effects can include psychomotor impairment, complex sleep-related behaviors (sleep-walking, sleep-driving), and, as controlled substances, they also have abuse potential.1,5,8

Melatonin agonists. Ramelteon is the only FDA-approved melatonin receptor agonist and promotes sleep onset by binding to MT1 and MT2 receptors, which help regulate the sleep-wake cycle without the adverse effects or risk of dependence of GABA-enhancing agents.5 Studies9,10 of ramelteon showed no significant abuse potential or motor or cognitive impairment. However, the therapeutic effects of melatonin agonists seem quite modest,1 and their mechanism of action is not well understood. Over-the-counter melatonin has demonstrated only small effects on sleep improvement and may be more beneficial as a phase-shifting agent than as a hypnotic.11

Current Agents That Block Wake-Promoting Systems

Potential mechanisms for enhancing sleep through blocking activity in wake-promoting systems include antagonism of orexin, histamine, serotonin, norepinephrine, dopamine, and acetylcholine. Agents that block these receptors have been around for many years, including antidepressants, antipsychotics, and antihistamines. However, many of these agents are nonselective, and their effect on wake-promoting systems is not well understood.

Antidepressants. Antidepressants may block serotonin, norepinephrine, acetylcholine, or histamine receptors, but they are mainly used off-label for insomnia because little research has been done on their sleep-promoting effects. The only exception is doxepin, which is FDA-approved for insomnia treatment. A study12 of 67 adults with primary insomnia found that doxepin improved sleep compared with placebo, with no significant differences in next-day sedation, anticholinergic effects, or memory impairment. Other antidepressants used off-label for insomnia include the TCAs trimipramine and amitriptyline, as well as trazodone and mirtazapine.11 These medications are used at lower doses than for depression, and no agent is recommended above the others because evidence of their efficacy for insomnia is fairly weak.11

Antipsychotics. Antipsychotics are FDA-approved for treatment of psychosis, mania, and depression, but their use for primary insomnia is off-label and is discouraged.1 They may block serotonin, norepinephrine, acetylcholine, dopamine, or histamine. Quetiapine and olanzapine are 2 antipsychotics associated with treating sleep problems, but evidence is lacking for their efficacy and safety in the treatment of primary insomnia.13


Antihistamines. Antihistamines are common over-the-counter sleep aids, although prescription antihistamines are also available, and they block wake-promoting effects at the H1 receptor.4 Examples include diphenhydramine and doxylamine, which are FDA-approved for sleep.1 Anticholinergic properties affect both the therapeutic and adverse effect profiles. Antihistamines are not recommended for chronic insomnia due to the lack of safety and efficacy data and the potential for tolerance to develop.1,11

Summary. When considering the use of antidepressants, antipsychotics, or antihistamines, clinicians should keep in mind that these agents are often nonspecific and affect areas besides sleep. For example, antihistamines have therapeutic effects for allergies but may increase appetite; antipsychotics alleviate psychosis and mania but are associated with EPS. For patients with insomnia and comorbid conditions, which are common, certain agents will be more appropriate than others, depending on the mechanism of action and the combination of symptoms. For example, a patient with anxiety may benefit from a norepinephrine α1 antagonist, which has anxiolytic effects, although orthostatic hypotension should be monitored. In conclusion, the current drugs that block wake-promoting systems have not been well understood or developed in terms of antagonism specificity and optimum dosage, but this situation is changing with the development of more selective agents.

New and Emerging Agents That Block Wake-Promoting Systems

A new focus for selective antagonism of wake-promoting systems is the orexin system. Orexin neurons are increasingly active over the course of the day and counteract the sleep drive that accumulates throughout the day.14 The effects of orexin receptor antagonism have been examined with several agents, including suvorexant. A study15 in patients with primary insomnia demonstrated significant dose-related improvements of suvorexant versus placebo in sleep efficiency (P<.01), and improvements were also noted in sleep induction and maintenance. A study16 of suvorexant also noted greater efficacy than with placebo for subjective measures of sleep onset and maintenance in patients with insomnia. Suvorexant was well-tolerated, with the most common adverse event, somnolence, reported in 13% of participants. Although suvorexant is the only orexin receptor antagonist with current FDA approval for the treatment of insomnia, other agents in development have shown similar results for improving sleep efficiency.1,17 Altogether, the orexin system holds promise for efficacious and tolerable insomnia treatment.

Other agents that block wake-promoting systems include APD125, a selective 5-HT2A receptor inverse agonist that has shown improvements in sleep for adults with insomnia,18 and a selective norepinephrine α1 antagonist prazosin, which has very specific effects on sleep disturbance (nightmares) in patients with PTSD.19


Research into the sleep-wake cycle has provided new treatment targets for patients with insomnia as well as a better understanding of how current medications affect sleep processes. Traditional insomnia medications focused on enhancing sleep-promoting systems through broad antagonism of GABA or melatonin. These medications, including benzodiazepines, nonbenzodiazepine hypnotics, and melatonin agonists, provide improvements in sleep but have varying risks of dependency, abuse, and adverse effects. Agents that promote sleep by blocking wake-promoting systems include antidepressants, antipsychotics, and antihistamines, but adverse effects and nonspecific therapeutic effects limit their use. New and emerging insomnia medications are focusing on blocking wake-promoting systems via more selective antagonism in systems including orexin, serotonin, and norepinephrine. These medications should offer sleep enhancement with fewer adverse effects.

Clinical Points

  • Understand that the orexin system plays a key role in the balance between sleep and wakefulness
  • Choose FDA-approved insomnia medications based on mechanism of action, adverse effects, and patients’ comorbid conditions
  • Recognize that new insomnia medications with selective antagonism of wake-promoting systems may improve sleep with fewer adverse effects than traditional medications such as benzodiazepines and nonbenzodiazepines

Drug Names

doxepin (Zonalon, Silenor, and others), doxylamine (Diclegis), eszopiclone (Lunesta and others), mirtazapine (Remeron and others), olanzapine (Zyprexa and others), prazosin (Minipress and others), quazepam (Doral), quetiapine (Seroquel and others), ramelteon (Rozerem and others), suvorexant (Belsomra), temazepam (Restoril and others), trazodone (Oleptro and others), triazolam (Halcion and others), trimipramine (Surmontil and others), zaleplon (Sonata and others), zolpidem (Ambien, Intermezzo, and others)


5-HT = serotonin, EPS = extrapyramidal symptoms, ER = extended release, FDA = US Food and Drug Administration, GABA = γ-aminobutyric acid, H = histamine, MT = melatonin, PTSD = posttraumatic stress disorder, SL = sublingual, TCA = tricyclic antidepressant


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