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Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of
psychoactive A psychoactive drug, psychopharmaceutical, mind-altering drug, consciousness-altering drug, psychoactive substance, or psychotropic substance is a chemical substance that alters psychological functioning by modulating central nervous system acti ...
,
depressant Depressants, also known as central nervous system depressants, or colloquially known as "downers", are drugs that lower neurotransmission levels, decrease the electrical activity of brain cells, or reduce arousal or stimulation in various ...
,
sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...
,
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
,
anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...
drugs that are benzodiazepine-like in uses, such as for treating
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
and
anxiety Anxiety is an emotion characterised by an unpleasant state of inner wikt:turmoil, turmoil and includes feelings of dread over Anticipation, anticipated events. Anxiety is different from fear in that fear is defined as the emotional response ...
. Nonbenzodiazepine
pharmacodynamics Pharmacodynamics (PD) is the study of the biochemistry, biochemical and physiology, physiologic effects of drugs (especially pharmaceutical drugs). The effects can include those manifested within animals (including humans), microorganisms, or comb ...
are similar in
mechanism of action In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical Drug interaction, interaction through which a Medication, drug substance produces its pharmacological effect. A mechanism of action usually includes mention o ...
to
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
drugs, acting as GABAA receptor positive allosteric modulators of the
benzodiazepine site The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic tra ...
, and therefore exhibit similar benefits, side effects, and risks. However, nonbenzodiazepines have dissimilar or entirely different
chemical structure A chemical structure of a molecule is a spatial arrangement of its atoms and their chemical bonds. Its determination includes a chemist's specifying the molecular geometry and, when feasible and necessary, the electronic structure of the target m ...
s, so are unrelated to benzodiazepines on a molecular level.


Background

Nonbenzodiazepines have demonstrated efficacy in treating
sleep disorders A sleep disorder, or somnipathy, is a medical disorder affecting an individual's sleep patterns, sometimes impacting physical, mental, social, and emotional functioning. Polysomnography and actigraphy are tests commonly ordered for diagnosing sle ...
. There is some limited evidence that suggests that tolerance to nonbenzodiazepines is slower to develop than with
benzodiazepines Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed to treat co ...
. However, data is limited so no conclusions can be drawn. Data is also limited into the long-term effects of nonbenzodiazepines. Further research into the safety of nonbenzodiazepines and long-term effectiveness of nonbenzodiazepines has been recommended in a review of the literature. Some differences exist between the Z-drugs, for example tolerance and
rebound effects The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued or reduced in dosage. In the case of re- ...
may not occur with
zaleplon Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved fo ...
.


Classes

Currently, the major chemical classes of nonbenzodiazepines are:
Imidazopyridine An imidazopyridine is a nitrogen containing heterocycle that is also a class of medication, drugs that contain this same chemical substructure. In general, they are GABAA receptor, GABAA receptor receptor_agonist, agonists, however recently proto ...
s *
Alpidem Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was list of withdrawn drugs, disconti ...
*
Necopidem Necopidem is a drug in the imidazopyridine family, which is related to the better known drugs zolpidem and alpidem. It is therefore considered a nonbenzodiazepine and as such may have sedative and anxiolytic An anxiolytic (; also antipanic or ...
*
Saripidem Saripidem is a sedative and anxiolytic drug in the imidazopyridine family, which is related to the better known drugs zolpidem and alpidem. Saripidem has a similar pharmacological profile to the benzodiazepine family of drugs including sedative ...
*
Zolpidem Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...
(Ambien, Ambien CR, Intermezzo, Zolpimist, Edluar, Ivadal, Sanval, Stilnox, etc.) Pyrazolopyrimidines * Divaplon * Fasiplon *
Indiplon Indiplon ( INN and USAN) is a unmarketed nonbenzodiazepine, hypnotic sedative that was developed in two formulations—an immediate-release formulation for sleep onset, and a modified-release (also called controlled-release or extended-release) ...
* Lorediplon * Ocinaplon * Panadiplon * Taniplon *
Zaleplon Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved fo ...
(Sonata, Starnoc, Andante)
Cyclopyrrolone Cyclopyrrolones are a family of hypnotic and anxiolytic nonbenzodiazepine drugs with similar pharmacological profiles to the benzodiazepine derivatives. Although cyclopyrrolones are chemically unrelated to benzodiazepines, they function via the G ...
s * Eszopiclone (Lunesta, Valnoc, etc.) * Pagoclone * Pazinaclone * Suproclone * Suriclone * Zopiclone (Imovane, Zimovane, Somnol, etc.) β-Carbolines * Abecarnil * Azocarnil (photoswitchable) * Gedocarnil * SL-651,498 * ZK-93423 Others * CGS-20625 * CGS-9896 * CL-218,872 * ELB-139 * GBLD-345 * HIE-124 * L-838,417 * NS-2664 * NS-2710 *
Pipequaline Pipequaline (International Nonproprietary Name, INN; development code PK-8165) is an anxiolytic drug that was never marketed. It possesses a novel chemical structure that is not closely related to other drugs of this type. The drug has a similar ...
* RWJ-51204 * SB-205,384 * SL-651,498 * SX-3228 * TCS-1205 *
TP-003 TP-003 is an anxiolytic drug with a novel chemical structure, which is used in scientific research. It has similar effects to benzodiazepine drugs, but is structurally distinct and so is classed as a nonbenzodiazepine anxiolytic. TP-003 is a po ...
* TP-13 * TPA-023 * Y-23684 * Etifoxine


Pharmacology

The nonbenzodiazepines are positive allosteric modulators of the GABAA receptor. Like the benzodiazepines, they exert their effects by binding to and activating the
benzodiazepine site The GABAA receptor (GABAAR) is an ionotropic receptor and ligand-gated ion channel. Its endogenous ligand is γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. Accurate regulation of GABAergic tra ...
of the receptor complex.


Functional selectivity

Some nonbenzodiazepines can be subtype-selective, possibly providing
anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...
effects with little to no
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
or amnesic effects or providing hypnotic effects with little or no anxiolytic effect. More recently, a range of non-sedating
anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...
drugs derived from the same structural families as the Z-drugs have been developed, such as
alpidem Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was list of withdrawn drugs, disconti ...
(Ananxyl) and pagoclone, and approved for clinical prescription. The new drugs are much more selective than the older
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
anxiolytic An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...
s, producing effective relief of anxiety/panic with little or no
sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...
,
anterograde amnesia In neurology, anterograde amnesia is the inability to create new memories after an event that caused amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. Thi ...
, or
anticonvulsant Anticonvulsants (also known as antiepileptic drugs, antiseizure drugs, or anti-seizure medications (ASM)) are a diverse group of pharmacological agents used in the treatment of epileptic seizures. Anticonvulsants are also used in the treatme ...
effects, and are thus potentially more precise than older, anti-anxiety drugs. However, anxiolytic nonbenzodiazepines are not widely prescribed and many have collapsed after initial clinical trials and consumption halted many projects, including but not limited to
alpidem Alpidem, sold under the brand name Ananxyl, is a nonbenzodiazepine anxiolytic medication which was briefly used to treat anxiety disorders but is no longer marketed. It was previously marketed in France, but was list of withdrawn drugs, disconti ...
,
indiplon Indiplon ( INN and USAN) is a unmarketed nonbenzodiazepine, hypnotic sedative that was developed in two formulations—an immediate-release formulation for sleep onset, and a modified-release (also called controlled-release or extended-release) ...
, and suriclone. A number of non-sedating benzodiazepine anxiolytics such as imidazenil and
clobazam Clobazam, sold under the brand names Frisium, Onfi and others, is a benzodiazepine class medication that was patented in 1968. Clobazam was first synthesized in 1966 and first published in 1969. Clobazam was originally marketed as an anxiosele ...
also exist, with the caveat that neither is a traditional 1,4-benzodiazepine. The functional selectivity is not unique to the nonbenzodiazepine structural class and has more to do with selectivity among different types of GABAA receptors or partial agonism, though this structural class does have more drug candidates.


Pharmaceuticals

The first three nonbenzodiazepine drugs to enter the market were the "Z-drugs", zopiclone, zolpidem and zaleplon. These three drugs are all
sedative A sedative or tranquilliser is a substance that induces sedation by reducing irritability or Psychomotor agitation, excitement. They are central nervous system (CNS) Depressant, depressants and interact with brain activity, causing its decelera ...
s used exclusively for the treatment of mild
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
. They are safer than the older
barbiturates Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as ...
especially in overdosage and they may, when compared to the benzodiazepines, have less of a tendency to induce
physical dependence Physical dependence is a physical condition caused by chronic use of a tolerance-forming drug, in which abrupt or gradual drug withdrawal causes unpleasant physical symptoms. Physical dependence can develop from low-dose therapeutic use of certa ...
and
addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...
, although these issues can still become a problem. This has led to the Z-drugs becoming widely prescribed for the treatment of insomnia particularly in elderly patients. Almost a third of all prescriptions written for Z-drugs are for adults over the age of 65. Long-term use is not recommended as tolerance and
addiction Addiction is a neuropsychological disorder characterized by a persistent and intense urge to use a drug or engage in a behavior that produces natural reward, despite substantial harm and other negative consequences. Repetitive drug use can ...
can occur. Zolpidem and zaleplon are, in the US, indicated for 7–10 days of use only. Longer periods of use lead to loss of efficacy from tolerance. Tolerance has also been demonstrated with zopiclone, which is indicated for a maximum of 4 weeks of use in New Zealand. A survey of patients using nonbenzodiazepine Z-drugs and benzodiazepine hypnotic users found that there was no difference in reports of adverse effects that were reported in over 41% of users and, in fact, Z-drug users were more likely to report that they had tried to quit their hypnotic drug and were more likely to want to stop taking Z-drugs than benzodiazepine users. Efficacy also did not differ between benzodiazepine and Z-drug users.


Effectiveness

A major
systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...
and network meta-analysis of medications for the treatment of insomnia was published in 2022. It included the
Z-drug Nonbenzodiazepines (), sometimes referred to colloquially as Z-drugs (as many of their names begin with the letter "z"), are a class of psychoactive, depressant, sedative, hypnotic, anxiolytic drugs that are benzodiazepine-like in uses, such as f ...
s and found
effect size In statistics, an effect size is a value measuring the strength of the relationship between two variables in a population, or a sample-based estimate of that quantity. It can refer to the value of a statistic calculated from a sample of data, the ...
s ( standardized mean difference (SMD)) ranging from 0.03 to 0.63 for these agents. More specifically, the SMDs were 0.45 (4weeks) and 0.03 (3months) for
zolpidem Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...
, 0.51 (4weeks) for zopiclone, 0.51 (4weeks) and 0.63 (3months) for eszopiclone, and 0.19 (4weeks) for
zaleplon Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved fo ...
. Eszopiclone had the most favorable profile and best evidence to support its use. For comparison,
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
s had SMDs of 0.58 to 0.83, sedative
antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
s and
antihistamine Antihistamines are drugs which treat allergic rhinitis, common cold, influenza, and other allergies. Typically, people take antihistamines as an inexpensive, generic (not patented) drug that can be bought without a prescription and provides ...
s had SMDs of 0.30 to 0.55, the
antipsychotic Antipsychotics, previously known as neuroleptics and major tranquilizers, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), p ...
quetiapine had an SMD of 0.07, orexin receptor antagonists had SMDs of 0.23 to 0.44, and melatonin receptor agonists had SMDs of 0.00 to 0.13. The certainty of evidence varied and ranged from high to very low depending on the medication.


Side effects

The Z-drugs are not without disadvantages, and all three compounds are notable for producing side effects such as pronounced
amnesia Amnesia is a deficit in memory caused by brain damage or brain diseases,Gazzaniga, M., Ivry, R., & Mangun, G. (2009) Cognitive Neuroscience: The biology of the mind. New York: W.W. Norton & Company. but it can also be temporarily caused by t ...
and more rarely
hallucinations A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
, especially when used in large doses. On rare occasions, these drugs can produce a
fugue state Dissociative fugue ( ), previously referred to as a fugue state or psychogenic fugue,Dissociative Fugue (formerly Psychogenic Fugue) 'DSM-IV 300.13, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition'' is a rare psychiatric con ...
, wherein the patient sleepwalks and may perform relatively complex actions, including cooking meals or driving cars, while effectively unconscious and with no recollection of the events upon awakening. While this effect is rare (and has also been reported to occur with some of the older sedative drugs such as
temazepam Temazepam, sold under the brand name Restoril among others, is a medication of the benzodiazepine class which is generally used to treat severe or debilitating insomnia. It is taken by mouth. Temazepam is rapidly absorbed, and significant hypn ...
and
secobarbital Secobarbital, sold under the brand name Seconal among others, is a short-acting barbiturate drug originally used for the treatment of insomnia. It was patented by Eli Lilly and Company in 1934 in the United States. It possesses anesthetic, antic ...
), it can be potentially hazardous, and so further development of this class of drugs has continued in an effort to find new compounds with further improved profiles. Daytime withdrawal-related anxiety can also occur from chronic nightly nonbenzodiazepine hypnotic usage such as with zopiclone. Side effects can differ within the drug class due to differences in metabolism and pharmacology. For example, long-acting benzodiazepines have problems of drug accumulation especially in the elderly or those with liver disease, and shorter-acting benzodiazepines have a higher risk of more severe withdrawal symptoms. In the case of the nonbenzodiazepines,
zaleplon Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved fo ...
may be the safest in terms of next-day sedation, and − unlike
zolpidem Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...
and zopiclone − zaleplon has been found to have no association with increased motor vehicle accidents even when taken for middle-of-the-night insomnia due to its ultrashort
elimination half-life Biological half-life (elimination half-life, pharmacological half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the blood plasma. ...
.


Increased risk of depression

It has been claimed that insomnia causes depression and hypothesized that insomnia medications may help to treat depression. However, an analysis of data of clinical trials submitted to the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) concerning the drugs
zolpidem Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...
,
zaleplon Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved fo ...
, and eszopiclone found that these sedative hypnotic drugs more than doubled the risks of developing depression compared to those taking placebo pills. Hypnotic drugs, therefore, may be contraindicated in patients with or at risk of depression. Hypnotics were found to be more likely to cause depression than to help it. Studies have found that long-term users of sedative hypnotic drugs have a markedly raised suicide risk as well as an overall increased mortality risk.
Cognitive-behavioral therapy Cognitive behavioral therapy (CBT) is a form of psychotherapy that aims to reduce symptoms of various mental health conditions, primarily depression, PTSD, and anxiety disorders. Cognitive behavioral therapy focuses on challenging and chang ...
(CBT) for insomnia, on the other hand, has been found to both improve sleep quality as well as general mental health.


Other risks

Sleeping pills, including the Z-drugs, have been associated with an increased risk of death. In older people this family of medications increases the risk of
fractures Fracture is the appearance of a crack or complete separation of an object or material into two or more pieces under the action of stress (mechanics), stress. The fracture of a solid usually occurs due to the development of certain displacemen ...
and falls. The 2023 Beers criteria lists all three Z-drugs approved in the US (zolpidem, zaleplon, eszolpiclon) as unsuitable for older people. The Z-drug
zaleplon Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved fo ...
may have fewer side effects compared to benzodiazepines. Much like benzodiazepines, Z-drugs are associated with an increased incidence of dementia. There is overall a 20% increase in dementia risk after adjusting for confounding factors. The effect is more profound in women.


Dependence and withdrawal management

Nonbenzodiazepines should not be discontinued abruptly if taken for more than a few weeks due to the risk of rebound withdrawal effects and acute withdrawal reactions, which may resemble those seen during
benzodiazepine withdrawal Benzodiazepine withdrawal syndrome (BZD withdrawal) is the cluster of signs and symptoms that may emerge when a person who has been taking benzodiazepines as prescribed develops a physical dependence on them and then reduces the dose or stop ...
. Treatment usually entails gradually reducing the dosage over a period of weeks or several months depending on the individual, dosage, and length of time the drug has been taken. If this approach fails, a crossover to a benzodiazepine equivalent dose of a long-acting benzodiazepine (such as
chlordiazepoxide Chlordiazepoxide hydrochloride, sold under the brand name Librium is a sedative and hypnotic medication of the benzodiazepine class. It is used to treat anxiety, insomnia and symptoms of withdrawal from alcohol, benzodiazepines, and other drug ...
or more preferably
diazepam Diazepam, sold under the brand name Valium among others, is a medicine of the benzodiazepine family that acts as an anxiolytic. It is used to treat a range of conditions, including anxiety disorder, anxiety, seizures, alcohol withdrawal syndr ...
) can be tried followed by a gradual reduction in dosage. In extreme cases and, in particular, where severe addiction and/or abuse is manifested, an inpatient detoxification may be required, with flumazenil as a possible detoxification tool.


Elderly

Nonbenzodiazepine
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
drugs, similar to benzodiazepines, cause impairments in body balance and standing steadiness upon waking; falls and hip fractures are frequently reported. The combination with
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
increases these impairments. Partial but incomplete tolerance develops to these impairments. In general, nonbenzodiazepines are not recommended for older patients due to the increased risk of falls and fractures. An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and lasting benefits of non-drug treatments for insomnia in adults of all age groups and that these interventions are underused. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics offer little if any advantages in efficacy or tolerability in elderly persons. It was found that newer agents such as the melatonin agonists may be more suitable and effective for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and is discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (
anterograde amnesia In neurology, anterograde amnesia is the inability to create new memories after an event that caused amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. Thi ...
), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that further research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.


Safety

A review of the literature regarding
hypnotic A hypnotic (from Ancient Greek, Greek ''Hypnos'', sleep), also known as a somnifacient or soporific, and commonly known as sleeping pills, are a class of psychoactive drugs whose primary function is to sleep induction, induce sleep and to trea ...
s including the nonbenzodiazepine Z-drugs concluded that these drugs carry a significant risk to the individual. The risks include dependence, accidents, and other adverse effects. Gradual discontinuation of hypnotics may lead to improved health without worsening of sleep. It is preferred that they should be prescribed for only a few days at the lowest effective dose and avoided wherever possible in the elderly.


History

Z-drugs emerged in the last years of the 1980s and early 1990s, with zopiclone (Imovane) approved by the British
National Health Service The National Health Service (NHS) is the term for the publicly funded health care, publicly funded healthcare systems of the United Kingdom: the National Health Service (England), NHS Scotland, NHS Wales, and Health and Social Care (Northern ...
as early as 1989, quickly followed by
Sanofi Sanofi S.A. is a French Multinational corporation, multinational pharmaceutical and healthcare company headquartered in Paris, France. The corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 200 ...
with
zolpidem Zolpidem, sold under the brand name Ambien among others, is a medication primarily used for the short-term treatment of sleeping problems. Guidelines recommend that it be used only after cognitive behavioral therapy for insomnia and after beh ...
(Ambien). By 1999,
King Pharmaceuticals King Pharmaceuticals, Inc. is a pharmaceutical company, a wholly owned subsidiary of Pfizer based in Bristol, Tennessee. Before being acquired by Pfizer, it was the world's 39th largest pharmaceutical company. On October 12, 2010, King was acqui ...
had finalized approval with the American Food and Drug Administration (FDA) to market
zaleplon Zaleplon, sold under the brand name Sonata among others, is a sedative and hypnotic which is used to treat insomnia. It is a nonbenzodiazepine or Z-drug of the pyrazolopyrimidine class. It was developed by King Pharmaceuticals and approved fo ...
(Sonata, Starnoc) across the US. In 2005, the FDA approved eszopiclone (Lunesta) the (''S'')-
enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...
of zopiclone. That same year, 2005, the FDA finalized approval for Ambien CR, or extended-release zolpidem. Most recently, in 2012 the FDA approved Intermezzo (zolpidem tartate sublingual), which is marketed for middle-of-the-night
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
, available in doses only half of the strength of immediate-release zolpidem tartrate to avoid residual next-day
sedation Sedation is the reduction of irritability or agitation by administration of sedative drugs, generally to facilitate a medical procedure or diagnostic procedure. Examples of drugs which can be used for sedation include isoflurane, diethyl ether, ...
.


References

{{Chemical classes of psychoactive drugs Cyclopyrrolones Imidazopyridines Pyrazolopyrimidines GABAA receptor positive allosteric modulators Hypnotics Sedatives