Hypnotic

History

Hypnotica was a class of somniferous drugs and substances tested in medicine of the 1890s and later, including: Urethan, Acetal, Methylal, Sulfonal, Paraldehyd, Amylenhydrate, Hypnon, Chloralurethan and Ohloralamid or Chloralimid.

Research about using medications to treat insomnia evolved throughout the last half of the 20th century. Treatment for insomnia in psychiatry dates back to 1869 when chloral hydrate was first used as a soporific. Barbiturates emerged as the first class of drugs that emerged in the early 1900s, after which chemical substitution allowed derivative compounds. Although the best drug family at the time (less toxic and with fewer side effects) they were dangerous in overdose.

During the 1970s, quinazolinones and benzodiazepines were introduced as safer alternatives to replace barbiturates; by the late 1970s benzodiazepines emerged as the safer drug.

Benzodiazepines are not without their drawbacks; substance dependence is possible, and deaths from overdoses sometimes occur, especially in combination with alcohol and/or other depressants. Questions have been raised as to whether they disturb sleep architecture.

Nonbenzodiazepines are the most recent development (1990s–present). Although it's clear that they are less toxic than their predecessors, barbiturates, comparative efficacy over benzodiazepines have not been established. Without longitudinal studies, it is hard to determine; however some psychiatrists recommend these drugs, citing research suggesting they are equally potent with less potential for abuse.

Other sleep remedies that may be considered "sedative-hypnotics" exist; psychiatrists will sometimes prescribe medicines off-label if they have sedating effects. Examples of these include mirtazapine (an antidepressant), clonidine (generally prescribed to regulate blood pressure), quetiapine (an antipsychotic), and the over-the-counter sleep aid diphenhydramine (Benadryl – an antihistamine). Off-label sleep remedies are particularly useful when first-line treatment is unsuccessful or deemed unsafe (for example, in patients with a history of substance abuse).

Barbiturate

Barbiturates are drugs that act as central nervous system depressants, and can therefore produce a wide spectrum of effects, from mild sedation to total anesthesia. They are also effective as anxiolytics, hypnotics, and anticonvulsants. Barbiturates also have analgesic effects; however, these effects are somewhat weak, preventing barbiturates from being used in surgery in the absence of other analgesics. They have dependence liability, both physical and psychological. Barbiturates have now largely been replaced by benzodiazepines in routine medical practice – for example, in the treatment of anxiety and insomnia – mainly because benzodiazepines are significantly less dangerous in overdose. However, barbiturates are still used in general anesthesia, for epilepsy, and assisted suicide. Barbiturates are derivatives of barbituric acid.

The principal mechanism of action of barbiturates is believed to be positive allosteric modulation of GABA_A receptors.

Examples include amobarbital, pentobarbital, phenobarbital, secobarbital, and sodium thiopental.

Quinazolinones

Quinazolinones are also a class of drugs which function as hypnotic/sedatives that contain a 4-quinazolinone core. Their use has also been proposed in the treatment of cancer.

Examples of quinazolinones include cloroqualone, diproqualone, etaqualone (Aolan, Athinazone, Ethinazone), mebroqualone, mecloqualone (Nubarene, Casfen), and methaqualone (Quaalude).

Benzodiazepines

Benzodiazepines can be useful for short-term treatment of insomnia. Their use beyond 2 to 4 weeks is not recommended due to the risk of dependence. It is preferred that benzodiazepines be taken intermittently and at the lowest effective dose. They improve sleep-related problems by shortening the time spent in bed before falling asleep, prolonging the sleep time, and, in general, reducing wakefulness. Like alcohol, benzodiazepines are commonly used to treat insomnia in the short-term (both prescribed and self-medicated), but worsen sleep in the long-term. While benzodiazepines can put people to sleep (i.e., inhibit NREM stage 1 and 2 sleep), while asleep, the drugs disrupt sleep architecture: decreasing sleep time, delaying time to REM sleep, and decreasing deep slow-wave sleep (the most restorative part of sleep for both energy and mood).

Other drawbacks of hypnotics, including benzodiazepines, are possible tolerance to their effects, rebound insomnia, and reduced slow-wave sleep and a withdrawal period typified by rebound insomnia and a prolonged period of anxiety and agitation. The list of benzodiazepines approved for the treatment of insomnia is fairly similar among most countries, but which benzodiazepines are officially designated as first-line hypnotics prescribed for the treatment of insomnia can vary distinctly between countries. Longer-acting benzodiazepines such as nitrazepam and diazepam have residual effects that may persist into the next day and are, in general, not recommended.

It is not clear as to whether the new nonbenzodiazepine hypnotics (Z-drugs) are better than the short-acting benzodiazepines. The efficacy of these two groups of medications is similar. According to the US Agency for Healthcare Research and Quality, indirect comparison indicates that side-effects from benzodiazepines may be about twice as frequent as from nonbenzodiazepines. Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia. However, the UK National Institute for Health and Clinical Excellence (NICE) did not find any convincing evidence in favor of Z-drugs. A NICE review pointed out that short-acting Z-drugs were inappropriately compared in clinical trials with long-acting benzodiazepines. There have been no trials comparing short-acting Z-drugs with appropriate doses of short-acting benzodiazepines. Based on this, NICE recommended choosing the hypnotic based on cost and the patient's preference.

Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed to be effective. When benzodiazepines are used, patients, their caretakers, and their physician should discuss the increased risk of harms, including evidence which shows twice the incidence of traffic collisions among driving patients as well as falls and hip fracture for all older patients.

Their mechanism of action is primarily at GABA_A receptors.

Nonbenzodiazepines

Nonbenzodiazepines are a class of psychoactive drugs that are very "benzodiazepine-like" in nature. Nonbenzodiazepines pharmacodynamics are almost entirely the same as benzodiazepine drugs and therefore employ similar benefits, side-effects, and risks. Nonbenzodiazepines, however, have dissimilar or entirely different chemical structures, and therefore are unrelated to benzodiazepines on a molecular level.

Examples include zopiclone (Imovane, Zimovane), eszopiclone (Lunesta), zaleplon (Sonata), and zolpidem (Ambien, Stilnox, Stilnoct).

Research on nonbenzodiazepines is new and conflicting. A review by a team of researchers suggests the use of these drugs for people that have trouble falling asleep but not staying asleep, as next-day impairments were minimal. The team noted that the safety of these drugs had been established, but called for more research into their long-term effectiveness in treating insomnia. Other evidence suggests that tolerance to nonbenzodiazepines may be slower to develop than with benzodiazepines. A different team was more skeptical, finding little benefit over benzodiazepines.

Melatonin

Melatonin, the hormone produced in the pineal gland in the brain and secreted in dim light and darkness, among its other functions, promotes sleep in diurnal mammals. Due to its hypnotic properties, it is available on prescription in many countries and is over-the-counter in others. A timed-release version, trade name Circadin®, was approved in 2007 in Europe (EU) for use as a treatment for primary insomnia.

At the beginning of the 21st century, several melatonin receptor agonists that bind to and activate melatonin receptors were developed. These analogues, prescribed for several sleep disorders, include ramelteon, agomelatine, TIK-301 and tasimelteon. Ramelteon (Rozerem®) was approved for treatment of insomnia in the US in 2005. In 2009 agomelatine (Valdoxan®, Melitor®, Thymanax®), primarily used for depression, was approved in Europe. Both TIK-301 (in 2004) and tasimelteon (Hetlioz®) ten years later were approved in the US for the circadian rhythm sleep disorder non-24-hour sleep–wake disorder in totally blind individuals.

Antihistamines

In common use, the term antihistamine refers only to compounds that inhibit action at the H₁ receptor (and not H₂, etc.).

Clinically, H₁ antagonists are used to treat certain allergies. Sedation is a common side-effect, and some H₁ antagonists, such as diphenhydramine (Benadryl) and doxylamine, are also used to treat insomnia.

Second-generation antihistamines cross the blood–brain barrier to a much lower degree than the first ones. This results in their primarily affecting peripheral histamine receptors, and therefore having a much lower sedative effect. High doses can still induce the central nervous system effect of drowsiness.

Antidepressants

Some antidepressants have sedating effects. Some may increase actual quality of sleep (biologically) in contrast to Benzodiazepines that decrease quality.

Examples include:

Examples include:

Antipsychotics

Examples of antipsychotics with sedation as a side effect:

Miscellaneous others