Zolpidem, a common but potent sedative–hypnotic drug. Used for severe insomnia.
Ahypnotic (fromGreekHypnos, sleep[1]), also known as asomnifacient orsoporific, and commonly known assleeping pills, are a class ofpsychoactive drugs whose primary function is toinduce sleep[2] and to treatinsomnia (sleeplessness).
This group of drugs is related tosedatives.Whereas the term sedative describes drugs that serve to calm orrelieve anxiety, the term hypnotic generally describes drugs whose main purpose is to initiate, sustain, or lengthen sleep. Because these two functions frequently overlap, and because drugs in this class generally produce dose-dependent effects (ranging fromanxiolysis toloss of consciousness), they are often referred to collectively assedative–hypnotic drugs.[3]
Hypnotic drugs are regularly prescribed for insomnia and other sleep disorders, with over 95% of insomnia patients being prescribed hypnotics in some countries.[4] Many hypnotic drugs are habit-forming and—due to many factors known to disturb the human sleep pattern—a physician may instead recommend changes in the environment before and during sleep, bettersleep hygiene, the avoidance of caffeine andalcohol or other stimulating substances, or behavioral interventions such ascognitive behavioral therapy for insomnia (CBT-I), before prescribing medication for sleep. When prescribed, hypnotic medication should be used for the shortest period of time necessary.[5]
Among individuals with sleep disorders, 13.7% are taking or prescribednonbenzodiazepines (Z-drugs), while 10.8% are takingbenzodiazepines, as of 2010, in the USA.[6] Early classes of drugs, such asbarbiturates, have fallen out of use in most practices but are still prescribed for some patients. In children, prescribing hypnotics is not yet acceptable—unless used to treatnight terrors orsleepwalking.[7] Elderly people are more sensitive to potential side effects of daytime fatigue andcognitive impairment, and ameta-analysis found that the risks generally outweigh any marginal benefits of hypnotics in the elderly.[8] A review of the literature regarding benzodiazepine hypnotics and Z-drugs concluded that these drugs have adverse effects, such asdependence and accidents, and that optimal treatment uses the lowest effective dose for the shortest therapeutic time, with gradual discontinuation to improve health without worsening of sleep.[9]
Falling outside the above-mentioned categories, the neurohormonemelatonin and its analogues (e.g.,ramelteon) serve a hypnotic function.[10]
Barbiturates are drugs that act ascentral nervous systemdepressants, and can therefore produce a broad spectrum of effects, from mildsedation to totalanesthesia. They are also effective asanxiolytics, hypnotics, andanticonvulsant effects; however, these effects are somewhat weak, preventing barbiturates from being used insurgery in the absence of other analgesics. They have dependence liability, bothphysical andpsychological. Barbiturates have now largely been replaced bybenzodiazepines in routine medical practice – such as in the treatment of anxiety and insomnia – mainly because benzodiazepines are significantly less dangerous inoverdose. However, barbiturates are still used in general anesthesia, forepilepsy, and forassisted suicide. Barbiturates are derivatives ofbarbituric acid.
Quinazolinones are also a class of drugs that function as hypnotics/sedatives that contain a 4-quinazolinone core. Their use has also been proposed in the treatment ofcancer.[12]
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 sleep time, and reducing wakefulness.[13][14] Likealcohol, 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 disruptsleep architecture by decreasing sleep time, delaying time to REM sleep, and decreasing deepslow-wave sleep (the most restorative part of sleep for both energy and mood).[15][16][17]
Other drawbacks of hypnotics, including benzodiazepines, are possibletolerance 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.[18][19] The list of benzodiazepines approved for the treatment of insomnia is 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.[14] Longer-acting benzodiazepines, such asnitrazepam anddiazepam, have residual effects that may persist into the next day and are, in general, not recommended.[13]
It is not clear whether the newernonbenzodiazepine (Z-drug) hypnotics are better than the short-acting benzodiazepines. The efficacy of these two groups of medications is similar.[13][19] According to the USAgency for Healthcare Research and Quality, indirect comparison indicates that side effects from benzodiazepines may be about twice as frequent as from nonbenzodiazepines.[19] Some experts suggest using nonbenzodiazepines preferentially as a first-line long-term treatment of insomnia.[14] However, the UKNational 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.[13]
Older adults should not use benzodiazepines to treat insomnia unless other treatments have failed to be effective.[20] When benzodiazepines are used, patients, their caretakers, and their physician should discuss the increased risk of harms, including evidence which shows twice the incidence oftraffic collisions among driving patients, as well as falls and hip fracture for all older patients.[4][20]
Nonbenzodiazepines (Z-drugs) are a class ofpsychoactive drugs that are "benzodiazepine-like" in nature. Nonbenzodiazepinepharmacodynamics are almost entirely the same as benzodiazepine drugs, and therefore entail similar benefits, side effects, and risks. Nonbenzodiazepines, however, have dissimilar or different chemical structures, and are unrelated to benzodiazepines on a molecular level.[22][23]
Examples includezopiclone (Imovane),eszopiclone (Lunesta),zaleplon (Sonata), andzolpidem (Ambien). Since the generic names of all drugs of this type start withZ, they are often referred to asZ-drugs.[24]
Research on nonbenzodiazepines is new and conflicting. A review by a team of researchers suggests the use of these drugs for people who have trouble falling asleep (but not staying asleep),[note 1] as next-day impairments were minimal.[25] 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 thattolerance to nonbenzodiazepines may be slower to develop than with benzodiazepines.[failed verification] A different team was more skeptical, finding little benefit over benzodiazepines.[26]
Melatonin, the hormone produced in thepineal gland in the brain and secreted in dim light and darkness, among its other functions, promotes sleep indiurnal mammals.[27] It activates both melatonin receptors MT1 and MT2 to produce beneficial effects on sleep, therefore being used exogenously for mild insomnia.[28] A small improvement in sleep onset and total sleep time by using melatonin has been shown in recent systematic reviews.[29]
Antihistamines, also known as H1 antagonists, are a class of drugs that inhibit action at H1 receptors. They are clinically used to alleviate allergic reactions includingallergic rhinitis,allergic conjunctivitis, andurticaria, which are mediated byhistamine.[citation needed] First-generation antihistamines, such asdoxylamine anddiphenhydramine, often cause sedation as a side effect, which can be utilized to treat insomnia. Some antihistamines, such as doxylamine, are available for purchaseover-the-counter (OTC) in some countries and can be used for the occasional relief of insomnia.[31] Low-dosedoxepin is approved by the FDA for the treatment of insomnia.[32] Second generation of antihistamines such ascetirizine andloratadine have a much less sedating effect than the first ones with a much lower degree of crossing theblood–brain barrier.[33]
In common use, the termantihistamine refers only to compounds that inhibit action at the H1 receptor.[citation needed]
Clinically, H1 antagonists are used to treat certainallergies. Sedation is a common side effect, and some H1 antagonists, such asdiphenhydramine and doxylamine, are also used to treat insomnia.[citation needed]
While some of these drugs are frequently prescribed for insomnia, such use is not recommended unless the insomnia is due to an underlying mental health condition treatable byantipsychotics as the risks frequently outweigh the benefits.[44][45] Some of the more serious adverse effects have been observed to occur at the low doses used for this off-label prescribing, such asdyslipidemia andneutropenia,[46][47][48][49] and a recent network meta-analysis of 154 double-blind, randomized controlled trials of drug therapies vs. placebo for insomnia in adults found that quetiapine had not demonstrated any short-term benefits in sleep quality.[50] Examples ofantipsychotics with sedation as a side effect that are occasionally used for insomnia:[51]
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, whenchloral hydrate was first used as a soporific.[53]Barbiturates emerged as the first class of drugs in the early 1900s,[54] after which chemical substitution allowed derivative compounds. Although they were the best drug family at the time (with less toxicity and fewer side effects), they were dangerous inoverdose and tended to cause physical and psychological dependence.[55][56][57]
During the 1970s,quinazolinones[58] andbenzodiazepines were introduced as safer alternatives to replace barbiturates; by the late 1970s, benzodiazepines emerged as the safer drug.[53]
Benzodiazepines are not without their drawbacks;substance dependence is possible, and deaths from overdoses sometimes occur, especially in combination withalcohol or otherdepressants. Questions have been raised as to whether they disturb sleep architecture.[59]
Nonbenzodiazepines are the most recent development (1990s–present). Although it is clear that they are less toxic than barbiturates, their predecessors, comparative efficacy over benzodiazepines has not been established. Such efficacy is hard to determine withoutlongitudinal studies. However, some psychiatrists recommend these drugs, citing research suggesting they are equally potent with less potential for abuse.[22]
The use of sedative medications in older people generally should be avoided. These medications are associated with poorer health outcomes, includingcognitive decline, and bone fractures.[61]
^Because the drugs have a shorterelimination half life they are metabolized more quickly: nonbenzodiazepines zaleplon and zolpidem have a half-life of 1 and 2 hours (respectively); for comparison, the benzodiazepine clonazepam has a half-life of about 30 hours. This makes the drug suitable for sleep-onset difficulty, but the team noted sustained sleep efficacy was unclear.
^Brunton LL, Parker K, Lazo KL, Buxton I, Blumenthal D (2006)."17: Hypnotics and Sedatives".Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). The McGraw-Hill Companies, Inc.ISBN978-0-07-146804-6. Retrieved2014-02-06.
^Morin CM, Bélanger L, Bastien C, Vallières A (January 2005). "Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse".Behaviour Research and Therapy.43 (1):1–14.doi:10.1016/j.brat.2003.12.002.PMID15531349.
^Poyares D, Guilleminault C, Ohayon MM, Tufik S (2004-06-01). "Chronic benzodiazepine usage and withdrawal in insomnia patients".Journal of Psychiatric Research.38 (3):327–334.doi:10.1016/j.jpsychires.2003.10.003.PMID15003439.
Finkle WD, Der JS, Greenland S, Adams JL, Ridgeway G, Blaschke T, et al. (October 2011). "Risk of fractures requiring hospitalization after an initial prescription for zolpidem, alprazolam, lorazepam, or diazepam in older adults".Journal of the American Geriatrics Society.59 (10):1883–1890.doi:10.1111/j.1532-5415.2011.03591.x.PMID22091502.S2CID23523742.
Allain H, Bentué-Ferrer D, Polard E, Akwa Y, Patat A (2005). "Postural instability and consequent falls and hip fractures associated with use of hypnotics in the elderly: a comparative review".Drugs & Aging.22 (9):749–765.doi:10.2165/00002512-200522090-00004.PMID16156679.S2CID9296501.
^Olsen RW, Betz H (2006). "GABA and glycine". In Siegel GJ, Albers RW, Brady S, Price DD (eds.).Basic Neurochemistry: Molecular, Cellular and Medical Aspects (7th ed.). Elsevier. pp. 291–302.ISBN978-0-12-088397-4.
^abWagner J, Wagner ML, Hening WA (June 1998). "Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia".The Annals of Pharmacotherapy.32 (6):680–691.doi:10.1345/aph.17111.PMID9640488.S2CID34250754.
^Ryba, N.; Rainess, R. Z-drugs and Falls: A Focused Review of the Literature. The Senior Care Pharmacist 2020, 35 (12), 549-554. DOI: 10.4140/tcp.n.2020.549.
^Benca RM (March 2005). "Diagnosis and treatment of chronic insomnia: a review".Psychiatric Services.56 (3):332–343.doi:10.1176/appi.ps.56.3.332.PMID15746509.Evidence for the utility of currently available nonbenzodiazepine hypnotics points to their primary efficacy as sleep-onset, rather than as sleep-maintenance, agents. Once again, longer-term randomized, double-blind, controlled studies that demonstrate the efficacy of these agents have not been performed, but safety over the longer term has been demonstrated in open-label studies, with minimal evidence of rebound phenomena. By comparison with benzodiazepines, there has been less evidence of subjective and objective next-day residual effects associated with zolpidem or subjective next-day impairment with zaleplon, even when the latter has been delivered in the middle of the night.
^Wagner J, Wagner ML, Hening WA (June 1998). "Beyond benzodiazepines: alternative pharmacologic agents for the treatment of insomnia".The Annals of Pharmacotherapy.32 (6):680–691.doi:10.1345/aph.17111.PMID9640488.S2CID34250754.New developments in benzodiazepine receptor pharmacology have introduced novel nonbenzodiazepine hypnotics that provide comparable efficacy to benzodiazepines. Although they may possess theoretical advantages over benzodiazepines based on their unique pharmacologic profiles, they offer few, if any, significant advantages in terms of adverse effects.
^Haria M, Fitton A, McTavish D (April 1994). "Trazodone. A review of its pharmacology, therapeutic use in depression and therapeutic potential in other disorders".Drugs & Aging.4 (4):331–355.doi:10.2165/00002512-199404040-00006.PMID8019056.S2CID265772823.
^Hajak G, Rodenbeck A, Voderholzer U, Riemann D, Cohrs S, Hohagen F, et al. (June 2001). "Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study".The Journal of Clinical Psychiatry.62 (6):453–463.doi:10.4088/JCP.v62n0609.PMID11465523.
^Maglione M, Maher AR, Hu J, Wang Z, Shanman R, Shekelle PG, Roth B, Hilton L, Suttorp MJ (2011).Off-Label Use of Atypical Antipsychotics: An Update. Comparative Effectiveness Reviews, No. 43. Rockville: Agency for Healthcare Research and Quality.PMID22973576.
^Coe HV, Hong IS (May 2012). "Safety of low doses of quetiapine when used for insomnia".The Annals of Pharmacotherapy.46 (5):718–722.doi:10.1345/aph.1Q697.PMID22510671.S2CID9888209.
^Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis".Lancet.382 (9896):951–962.doi:10.1016/S0140-6736(13)60733-3.PMID23810019.S2CID32085212.
^Pacific Record of Medicine and Surgery - Volume 5 - Page 36 1890
^Voegtle MM, Marzinzik AL (July 2004). "Synthetic Approaches Towards Quinazolines, Quinazolinones and Quinazolinediones on Solid Phase".QSAR & Combinatorial Science.23 (6):440–459.doi:10.1002/qsar.200420018.ISSN1611-020X.
Harrison N, Mendelson WB, de Wit H (2000)."Barbiturates". In Bloom FE, Kupfer DJ (eds.).Psychopharmacology (The Fourth Generation of Progress ed.). New York: Raven Press. discusses Barbs vs. benzos
Godard M, Barrou Z, Verny M (December 2010). "[Geriatric approach of sleep disorders in the elderly]".Psychologie & Neuropsychiatrie du Vieillissement.8 (4):235–241.doi:10.1684/pnv.2010.0232.PMID21147662.
