Nonbenzodiazepine

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Chemical structure of the prototypical Z-drug zolpidem

Nonbenzodiazepines (

psychoactive drugs that are benzodiazepine-like in uses, such as for treating insomnia[3] and anxiety.[4]

Nonbenzodiazepine

benzodiazepine site, and therefore exhibit similar benefits, side effects, and risks. However, nonbenzodiazepines have dissimilar or entirely different chemical structures, so are unrelated to benzodiazepines on a molecular level.[5][6]

Classes

Core structures of selected nonbenzodiazepines (left three diagrams) and the structure of benzodiazepines (right) for comparison.

Currently, the major chemical classes of nonbenzodiazepines are:

Imidazopyridines

Pyrazolopyrimidines

Pharmacology

The nonbenzodiazepines are

amnesic
effects or providing hypnotic effects with little or no anxiolytic effect.

Background

Nonbenzodiazepines have demonstrated efficacy in treating

rebound effects may not occur with zaleplon.[9]

Pharmaceuticals

Comparison of nonbenzodiazepines[10][11]
Drug Reduces sleep onset latency? Encourages sleep maintenance? Observed causing
rebound insomnia
? 		Observed causing physical dependence?
Zolpidem instant-release Yes Maybe Maybe Yes
Zolpidem extended-release Yes Yes Yes Yes
Sublingual zolpidem Yes Maybe Maybe Yes
Zolpidem oral spray Yes Maybe Maybe Yes
Eszopiclone Yes Yes Yes Yes
Zaleplon Yes Maybe No Yes

The first three nonbenzodiazepine drugs to enter the market were the "Z-drugs", zopiclone, zolpidem and zaleplon. These three drugs are all

barbiturates especially in overdosage and they may, when compared to the benzodiazepines, have less of a tendency to induce physical dependence and addiction, 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.[12][13][14] Almost a third of all prescriptions written for Z-drugs are for adults over the age of 65.[15]

Long-term use is not recommended as tolerance and addiction can occur.[16] 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.[17]

Effectiveness

A major

certainty of evidence varied and ranged from high to very low depending on the medication.[18]

Side effects

The Z-drugs are not without disadvantages, and all three compounds are notable for producing side effects such as pronounced

fugue 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 as temazepam and secobarbital), 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.[21][22][23][24][25]

Daytime withdrawal-related anxiety can also occur from chronic nightly nonbenzodiazepine hypnotic usage such as with zopiclone.[26]

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.

elimination half-life.[29][30][31][32]

Increased risk of depression

It has been claimed that insomnia causes

Cognitive-behavioral therapy (CBT) for insomnia, on the other hand, has been found to both improve sleep quality as well as general mental health.[33]

Other risks

Sleeping pills, including the Z-drugs, have been associated with an increased risk of death.[34]

In older people this family of medications increases the risk of

fractures and falls.[35]

The Z-drug zaleplon may have fewer side effects compared to benzodiazepines.[36]

Dependence and withdrawal management

Nonbenzodiazepines should not be discontinued abruptly if taken for more than a few weeks due to the risk of

benzodiazepine equivalent dose of a long-acting benzodiazepine (such as chlordiazepoxide or more preferably diazepam) 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.[37][38][39]

Elderly

Nonbenzodiazepine hypnotic 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 increases these impairments. Partial but incomplete tolerance develops to these impairments.[40] In general, nonbenzodiazepines are not recommended for older patients due to the increased risk of falls and fractures.[41] 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), 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.[42]

Safety

A review of the literature regarding hypnotics 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.[43]

New compounds

More recently, a range of non-sedating anxiolytic drugs derived from the same structural families as the Z-drugs have been developed, such as alpidem (Ananxyl) and pagoclone, and approved for clinical prescription. Nonbenzodiazepine drugs are much more selective than the older benzodiazepine anxiolytics, producing effective relief of anxiety/panic with little or no sedation, anterograde amnesia, or anticonvulsant 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, indiplon, and suriclone.

History

Z-drugs emerged in the last years of the 1980s and early 1990s, with

Sanofi with zolpidem (Ambien). By 1999, King Pharmaceuticals had finalized approval with the American Food and Drug Administration (FDA) to market zaleplon (Sonata, Starnoc) across the US. In 2005, the FDA approved eszopiclone (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-night insomnia, available in doses only half of the strength of immediate-release zolpidem tartrate to avoid residual next-day sedation
.

References

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