Insomnia

Insomnia

Insomnia refers to a sleep disorder marked by persistent difficulty initiating or maintaining sleep, or experiencing non-restorative sleep, despite adequate opportunity for sleep. It can be categorized as episodic, lasting up to three months, or persistent, lasting more than three months.

Several neurotransmitters play essential roles in regulating the sleep-wake cycle. The neuronal systems in which neurotransmitters and neuropeptides act to control the sleep–wake cycle lie in the brainstem, hypothalamus, and basal forebrain, with connections in the thalamus and cortex.

Noradrenergic, histaminergic, and acetylcholine-containing neurons, the neuropeptides, orexin A and orexin B, excitatory amino acids, such as glutamate, and stimulating neuropeptides (e.g., substance P, thyrotropin-releasing factor, corticotropin-releasing factor) all promote wakefulness.

Sleep takes over as the wakefulness-maintaining neuronal systems weaken and sleep-promoting neurons become active. Serotonin-containing neurons, opiate peptides (e.g., enkephalin, endorphin), the inhibitory neurotransmitter, GABA, adenosine, and melatonin, (a hormone released by the pineal gland in response to darkness) all promote sleep.

The drugs used in treating insomnia modulate the effects of the neuropeptides and neurotransmitters involved in sleep-wake cycle.

Management of Insomnia

Non-pharmacologic approaches are considered the first-line treatment for insomnia. These interventions aim to improve sleep hygiene, promote relaxation, and establish healthy sleep patterns. Non-pharmacologic management strategies include sleep hygiene education, cognitive behavioral therapy for insomnia (considered standard of care) and optimizing the sleep environment.

If nondrug interventions fail or cannot be implemented or when insomnia is severe and significantly impacting an individual's quality of life, then pharmacotherapy is indicated. The drugs used are classified as sedatives, hypnotics, or both. A sedative drug decreases activity, moderates excitement, and calms the recipient. A hypnotic drug produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep and from which the recipient can be aroused easily.

Commonly prescribed pharmacological options include:

Benzodiazepine receptor agonists: These sedative-hypnotic benzodiazepines including triazolam, temazepam and flurazepam, enhance the effect of GABA in the brain, promoting sedation and relaxation. Zolpidem, zaleplon and eszopiclone are unrelated to benzodiazepines but they interact with the benzodiazepine GABA receptor complex. Thus, they similarly enhance the effect of GABA in the brain but they have less potential for dependence than the benzodiazepines.

Melatonin receptor agonists: These medications, including ramelteon, target melatonin receptors (MT1 and MT2) to promote sleepiness and adjust circadian rhythms.

Orexin receptor antagonists: These drugs, which include suvorexant, promote sleep by blocking the binding of the wake-promoting neuropeptides orexin A and orexin B to their receptors (OX1R and OX2R).

Doxepin, a tricyclic antidepressant, promotes sleep maintenance through its affinity for H1-histamine receptors which is considered to be responsible for its sedating effect. It is used in much lower doses that those used for treating depression. It is used for sleep maintenance.

Hypnotics with a rapid onset of action are preferable when the problem is falling asleep. If the problem is staying asleep, a hypnotic with a slower rate of elimination may be more appropriate. The table below summarizes the onset and duration of action, and recommended uses of the hypnotics.

Drug Onset of action Duration of action Recommended uses
Zaleplon <30 min Ultra-short

Sleep onset

Zaleplon can be taken in the middle of the night.

Zolpidem <30 min Ultra-short/Short

Sleep onset

Sleep maintenance

Zolpidem can be taken in the middle of the night.

Triazolam <30 min Short Sleep onset
Ramelteon <30 min Short Sleep onset
Eszopiclone 60 min Intermediate

Sleep onset

Sleep maintenance

Suvorexant 60 min Intermediate

Sleep onset

Sleep maintenance

Temazepam 30-60 min Intermediate

Sleep onset

Sleep maintenance

Flurazepam <30 min Long

Sleep onset

Sleep maintenance

Useful if management of daytime anxiety is required

It is important for health professionals to consider the underlying causes of insomnia, and its severity and duration of symptoms in tailoring a management approach. Combining non-pharmacologic strategies with pharmacologic interventions can provide comprehensive and effective treatment for insomnia.