Nonbenzodiazepines (/ˌnɒnˌbɛnzoʊdaɪˈæzɪpiːn,-ˈeɪ-/^[1][2]), sometimes referred to colloquially asZ-drugs (as many of their names begin with the letter "z"), are a class ofpsychoactive,depressant,sedative,hypnotic,anxiolytic drugs that arebenzodiazepine-like in uses, such as for treatinginsomnia^[3] andanxiety.^[4]

Nonbenzodiazepinepharmacodynamics are similar inmechanism of action tobenzodiazepine drugs, acting asGABA_A receptor positive allosteric modulators of thebenzodiazepine site, and therefore exhibit similar benefits, side effects, and risks. However, nonbenzodiazepines have dissimilar or entirely differentchemical structures, so are unrelated to benzodiazepines on a molecular level.^[5][6]

Nonbenzodiazepines have demonstrated efficacy in treatingsleep disorders. There is some limited evidence that suggests thattolerance to nonbenzodiazepines is slower to develop than withbenzodiazepines.^[7] 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.^[8] Some differences exist between the Z-drugs, for exampletolerance andrebound effects may not occur withzaleplon.^[9]

Currently, the major chemical classes of nonbenzodiazepines are:

Imidazopyridines

• Alpidem
• Necopidem
• Saripidem
• Zolpidem (Ambien, Ambien CR, Intermezzo, Zolpimist, Edluar, Ivadal, Sanval, Stilnox, etc.)

Pyrazolopyrimidines

• Divaplon
• Fasiplon
• Indiplon
• Lorediplon
• Ocinaplon
• Panadiplon
• Taniplon
• Zaleplon (Sonata, Starnoc, Andante)

The nonbenzodiazepines arepositive allosteric modulators of theGABA_A receptor. Like the benzodiazepines, they exert their effects by binding to and activating thebenzodiazepine site of thereceptor complex.

Some nonbenzodiazepines can be subtype-selective, possibly providinganxiolytic effects with little to nohypnotic oramnesic effects or providing hypnotic effects with little or no anxiolytic effect.

More recently, a range of non-sedatinganxiolytic drugs derived from the same structural families as the Z-drugs have been developed, such asalpidem (Ananxyl) andpagoclone, and approved for clinical prescription. The new drugs are much more selective than the olderbenzodiazepineanxiolytics, producing effective relief of anxiety/panic with little or nosedation,anterograde amnesia, oranticonvulsant 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 toalpidem,indiplon, andsuriclone.

A number of non-sedating benzodiazepine anxiolytics such asimidazenil andclobazam 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 GABA_A receptors or partial agonism, though this structural class does have more drug candidates.^[4]

The first three nonbenzodiazepine drugs to enter the market were the "Z-drugs", zopiclone, zolpidem and zaleplon. These three drugs are allsedatives used exclusively for the treatment of mildinsomnia. They are safer than the olderbarbiturates especially in overdosage and they may, when compared to the benzodiazepines, have less of a tendency to inducephysical dependence andaddiction, 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.^[13][14][15] Almost a third of all prescriptions written for Z-drugs are for adults over the age of 65.^[16]

Long-term use is not recommended astolerance andaddiction can occur.^[17] 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.^[18] Tolerance has also been demonstrated with zopiclone,^[19] which is indicated for a maximum of 4 weeks of use in New Zealand.^[20]

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.^[21]

A majorsystematic review andnetwork meta-analysis of medications for the treatment of insomnia was published in 2022.^[22] It included theZ-drugs and foundeffect sizes (standardized mean difference (SMD)) ranging from 0.03 to 0.63 for these agents.^[22] More specifically, the SMDs were 0.45 (4 weeks) and 0.03 (3 months) forzolpidem, 0.51 (4 weeks) forzopiclone, 0.51 (4 weeks) and 0.63 (3 months) foreszopiclone, and 0.19 (4 weeks) forzaleplon.^[22] Eszopiclone had the most favorable profile and best evidence to support its use.^[22] For comparison,benzodiazepines had SMDs of 0.58 to 0.83, sedativeantidepressants andantihistamines had SMDs of 0.30 to 0.55, theantipsychoticquetiapine had an SMD of 0.07,orexin receptor antagonists had SMDs of 0.23 to 0.44, andmelatonin receptor agonists had SMDs of 0.00 to 0.13.^[22] Thecertainty of evidence varied and ranged from high to very low depending on the medication.^[22]

The Z-drugs are not without disadvantages, and all three compounds are notable for producing side effects such as pronouncedamnesia and more rarelyhallucinations,^[23][24] especially when used in large doses. On rare occasions, these drugs can produce afugue state, 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 astemazepam andsecobarbital), 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.^{[25][26][27][28][29]}

Daytime withdrawal-related anxiety can also occur from chronic nightly nonbenzodiazepine hypnotic usage such as withzopiclone.^[30]

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.^[31][32] In the case of the nonbenzodiazepines,zaleplon may be the safest in terms of next-day sedation, and − unlikezolpidem andzopiclone − zaleplon has been found to have no association with increasedmotor vehicle accidents even when taken formiddle-of-the-night insomnia due to its ultrashortelimination half-life.^{[33][34][35][36]}

It has been claimed that insomnia causesdepression and hypothesized that insomnia medications may help to treat depression. However, an analysis of data of clinical trials submitted to theFood and Drug Administration (FDA) concerning the drugszolpidem,zaleplon, andeszopiclone found that these sedative hypnotic drugs more than doubled the risks of developing depression compared to those taking placebo pills.^[37] 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 increasedmortality risk.Cognitive-behavioral therapy (CBT) for insomnia, on the other hand, has been found to both improve sleep quality as well as general mental health.^[37]

Sleeping pills, including the Z-drugs, have been associated with an increased risk of death.^[38]

In older people this family of medications increases the risk offractures and falls.^[39] The 2023Beers criteria lists all three Z-drugs approved in the US (zolpidem, zaleplon, eszolpiclon) as unsuitable for older people.^[40]

The Z-drugzaleplon may have fewer side effects compared to benzodiazepines.^[41]

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.^[42]

Nonbenzodiazepines should not be discontinued abruptly if taken for more than a few weeks due to the risk ofrebound withdrawal effects and acutewithdrawal reactions, which may resemble those seen duringbenzodiazepine withdrawal. 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 abenzodiazepine equivalent dose of a long-acting benzodiazepine (such aschlordiazepoxide or more preferablydiazepam) 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, withflumazenil as a possible detoxification tool.^[43][44][45]

Nonbenzodiazepinehypnotic drugs, similar to benzodiazepines, cause impairments in body balance and standing steadiness upon waking; falls and hip fractures are frequently reported. The combination withalcohol increases these impairments. Partial but incomplete tolerance develops to these impairments.^[46] In general, nonbenzodiazepines are not recommended for older patients due to the increased risk of falls and fractures.^[47] 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 themelatonin 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), 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.^[48]

A review of the literature regardinghypnotics including the nonbenzodiazepine Z-drugs concluded that these drugs carry a significant risk to the individual. The risks includedependence, 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.^[49]

Z-drugs emerged in the last years of the 1980s and early 1990s, withzopiclone (Imovane) approved by the BritishNational Health Service as early as 1989, quickly followed bySanofi withzolpidem (Ambien). By 1999,King Pharmaceuticals had finalized approval with the AmericanFood and Drug Administration (FDA) to marketzaleplon (Sonata, Starnoc) across the US. In 2005, the FDA approvedeszopiclone (Lunesta) the (S)-enantiomer 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-nightinsomnia, available in doses only half of the strength of immediate-release zolpidem tartrate to avoid residual next-daysedation.

• Cyclopyrrolones
• Imidazopyridines
• Pyrazolopyrimidines
• Nonbenzodiazepines
• GABAA receptor positive allosteric modulators
• Hypnotics
• Sedatives

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