The nonbenzodiazepines, also called benzodiazepine-like drugs, are a class of psychoactive drugs pharmacologically resembling the benzodiazepines, with similar benefits, side effects and risks, despite having dissimilar or entirely different chemical structures.[1][2]
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There are currently three major chemical classes of nonbenzodiazepines:
The nonbenzodiazepines are positive allosteric modulators of the GABA-A receptor. Like the benzodiazepines, they exert their effects by binding to and activating the benzodiazepine site of the receptor complex.
Nonbenzodiazepines have demonstrated efficacy in treating sleep disorders. There is some limited evidence that suggests that tolerance to nonbenzodiazepines is slower to develop than with benzodiazepines. 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.[3] Some differences exist between the Z-drugs, for example tolerance and rebound effects may not occur with zaleplon.[4]
The first three nonbenzodiazepine drugs to enter the market were the "Z-drugs", zopiclone, zolpidem and zaleplon. These three drugs are all sedatives used exclusively for the treatment of mild insomnia. They are safer than the older 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.[5][6][7] Long term use is not recommended as tolerance and addiction can occur.[8] A survey of patients using nonbenzodiazepine Z drugs and benzodiazepine hypnotic users found that there was no difference in reports of adverse effects which 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 didn't differ between Z drugs and benzodiazepine users.[9]
The Z-drugs are not without disadvantages, and all three compounds are notable for producing side effects such as pronounced amnesia and more rarely hallucinations,[10][11] especially when used in large doses. More rarely these drugs can produce a fugue state where 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.[12][13][14][15][16]
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.[17][18] In the case of the nonbenzodiazepines, zaleplon may be the safest in terms of next day sedation and unlike zolpidem 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 ultra short elimination half life.[19][20][21][22]
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 FDA concerning the drugs zolpidem, zaleplon 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 suffering from 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 (CBT) for insomnia on the other hand has been found to both improve sleep quality as well as general mental health.[23]
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. 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 cross over to a benzodiazepine equivalent dose of a long acting benzodiazepine such as chlordiazepoxide or preferably diazepam can be tried followed by a gradual reduction in dosage. In extreme cases and particularly where severe addiction and or abuse is manifested an inpatient detoxification may be required with flumazenil as a possible detoxification tool.[24][25][26]
The Journal of Clinical Sleep Medicine published a paper which had carried out a systematic review of the medical literature concerning insomnia medications and raised concerns about benzodiazepine receptor agonist drugs, the benzodiazepines and the Z-drugs that are used as hypnotics in humans. The review found that almost all trials of sleep disorders and drugs are sponsored by the pharmaceutical industry. It was found that the odds ratio for finding results favorable to industry in industry-sponsored trials was 3.6 times higher than non-industry-sponsored studies and that 24% of authors did not disclose being funded by the drug companies in their published papers when they were funded by the drug companies. The paper found that there is little research into hypnotics that is independent from the drug manufacturers. Also of concern was the lack of focus in industry sponsored trials on their own results showing that use of hypnotics is correlated with depression.
The author was concerned that there is no discussion of adverse effects of benzodiazepine agonist hypnotics discussed in the medical literature such as significant increased levels of infection, cancers and increased mortality in trials of hypnotic drugs and an overemphasis on the positive effects. No hypnotic manufacturer has yet tried to refute the epidemiology data that shows that use of their product is correlated with excess mortality. The author stated that "major hypnotic trials is needed to more carefully study potential adverse effects of hypnotics such as daytime impairment, infection, cancer, and death and the resultant balance of benefits and risks." The author concluded that more independent research into daytime impairment, infection, cancer, and shortening of lives of sedative hypnotic users is needed to find the true balance of benefits and risks of benzodiazepine agonist hypnotic drugs in the treatment of insomnia.[27] Significant increases in skin cancers and tumors are found in clinical trial data of the nonbenzodiazepine hypnotics compared to trial subjects who took placebo tablets. Other cancers of the brain, lung, bowel, breast and bladder also occurred. An increase of infections, possibly due to decreased immune function also occurred in the nonbenzodiazepine users. It has been hypothesised that either depressed immune function or the viral infections themselves were the cause of the increased rates of cancer.
Initially the FDA was hesitant to approve some of the nonbenzodiazepines due to concerns regarding increases in cancers. The author reported that due to the fact that the FDA requires reporting of both favourable and unfavourable results of clinical trials that the FDA NDA data is more reliable than the peer reviewed literature which is subject to serious bias regarding hypnotics. In 2008 the FDA analysed their data again and confirmed an increased rate of cancers in the randomised trials compared to placebos but concluded that the rate of cancers did not warrant any regulatory action.[28]
Nonbenzodiazepine hypnotic drugs, similar to benzodiazepines causes impairments in body balance and standing steadiness in individuals who wake up during the night or the next morning; falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.[29] Nonbenzodiazepines are not generally recommended for older patients due to the increased risk of falls and fractures.[30] 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 under used. 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.[31]
A review of the literature regarding hypnotics including the nonbenzodiazepine Z drugs concluded that these drugs caused an unjustifiable risk to the individual and to public health and lack evidence of long term effectiveness due to tolerance. The risks include dependence, accidents and other adverse effects. Gradual discontinuation of hypnotics leads to improved health without worsening of sleep. Preferably they should be prescribed for only a few days at the lowest effective dose and avoided altogether wherever possible in the elderly.[32]
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 and pagoclone and are starting to be marketed. These drugs are also much more selective than the older benzodiazepine anxiolytics, producing effective relief of anxiety symptoms but with little or no sedative or amnestic side effects, and so offer considerable advantages over the older anxiolytic drugs; however, they are still new to the market and have not yet been widely prescribed.
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