The consensus on the treatment of chronic insomnia by the US National Institute of Health (2005) indicated the possibility of prescribing certain benzodiazepine receptor agonists for a period longer than previously recommended. This is due to the accumulation of data on the effectiveness and safety of the long-term use of modern non-benzodiazepine hypnotics, such as sedative-meds.com and ramelteon (not registered in Russia). In addition, at present, chronic insomnia involves long-term or lifelong treatment, including non-drug and pharmacological approaches to the prevention of relapse. This can lead to an extension of the time frame for prescribing sleeping pills for chronic insomnia.
In the instructions for many psychotropic drugs, a mysterious recommendation about the use of the drug no longer than three to four weeks is often found. Faced with such a formulation, the doctor is not surprised, because he knows from the course of pharmacology about the problems of addiction and drug dependence. Barbiturates and benzodiazepines are usually given as examples of drugs that are characterized by these phenomena. It remains unclear what the recommended duration of administration is based on. The doctor may suggest that there have been studies specifically dedicated to this topic. Is it so?
First of all, you should decide on the used conceptual apparatus. The basic definitions for the phenomena associated with the prolonged use of psychotropic drugs are given in table. 1 and are discussed further.
Is there a problem with the abuse of psychotropic drugs? Yes there is. In 2014, 21.5 million people who abuse drugs were registered in the United States, 17 million of them alcohol, 1.9 million tranquilizers and 0.7 million sedatives [1]. For sleeping pills, such abuse implies at least a single use of them without a doctor’s prescription. Among patients with chronic insomnia, 22% take alcohol as sleeping pills [2]. According to the Russian continuous population study involving more than 1,500 people, episodic or frequent sleep disorders were observed in 20% of the population, while the prevalence of sleeping pills was comparable – 18.7% [3].
Most undesirable side effects of psychotropic drugs are due to their long-term use. With regard to what should be meant by the word “long-term”, there is no single point of view in medical literature. The World Health Organization in 1996 recommended that the use of the drug be considered prolonged for at least six months a year [4]. The authors of later reviews on this subject adhere to a similar opinion [5].
According to the fifth version of the classification of mental disorders (Diagnostic and Statistical Manual of Mental Disorders – DSM-V), drug use or alcohol is considered to be addictive, despite the developing negative consequences [6]. Compulsive and repeated use of the drug can cause addiction and withdrawal symptoms after stopping it or reducing the dose. Full criteria for this condition are given in table. 2.
The concept of addiction as a special case also includes the concept of addiction (tolerance) – a decrease in the effectiveness of the drug taken and the need to increase its dose to achieve the same effect.
When discussing the phenomena of dependence, they also use the concepts of physical and psychological dependence. Physical dependence develops when structural changes occur in the human body against the background of the use of the drug. Most often this is realized at the receptor level, when there is a phenomenon of desensitization of receptors, accompanied by a decrease in their number against the background of excessive stimulation. For physical dependence, in addition to the acute withdrawal syndrome, the development of a subacute withdrawal syndrome, accompanied by a wave-like course with an increase and decrease in symptoms, sometimes over several years, is also characteristic. Psychological dependence implies the development of emotionally motivational disorders in the structure of withdrawal syndrome. For example, a feeling of dissatisfaction, insecurity, decreased ability to have fun (anhedonia), or increased overall anxiety. With psychological dependence, the drug is not taken for pleasure, but in order to avoid unpleasant sensations when it is canceled.
Sleep disorders, along with chronic pain and mental illness, are one of the leading conditions accompanied by the development of drug dependence. Usually this is discussed on the example of sleeping pills benzodiazepine derivatives, for half a century of use of which great clinical experience has been accumulated.
Oral benzodiazepines are rapidly absorbed in the gastrointestinal tract, and a peak in their concentration in the blood is observed after about an hour. These drugs bind well to proteins and within seven to ten hours are distributed throughout the body, metabolized in the liver and completely eliminated from the body within two to six days. Benzodiazepines have an inhibitory effect on the central nervous system (especially on the limbic system of the brain), enhancing the inhibitory effect of gamma-aminobutyric acid (GABA) in relation to specific receptors (GABAA receptor complex) [7].
Tolerance to benzodiazepines develops with the participation of several mechanisms, which makes this phenomenon clinically heterogeneous:
Changing the configuration of the GABAA receptor, in particular, the separation of the benzodiazepine-binding and GABA-binding subunits, which leads to blocking the connection of the receptor with GABA;
Decreased transcription of genes responsible for the synthesis of benzodiazepine-sensitive subunits of GABAA receptors by the negative feedback mechanism;
Increased sensitivity of glutamatergic receptors as a reaction to the activation of GABA receptors;
Changes in the balance of other neurotransmitters (dopamine, serotonin, acetylcholine) and neurosteroids, which have a modulating effect on GABA receptors, due to the nonspecific effect of benzodiazepines on other cells [7].
The genetic prerequisites for the development of tolerance to sleeping pills were studied. The presence of a congenital predisposition is confirmed by both clinical observations and genetic studies. In a mouse experiment, a gene was identified that is responsible for the synthesis of protein 3 associated with a brain-specific inhibitor of angiogenesis 1 (brain-specific angiogenesis inhibitor 1-associated protein 3 – BAIAP3). This gene is expressed by cells of the mouse brain involved in the fear reaction (tonsils, hypothalamus, periaqueductal gray matter) and behavioral responses corresponding to anxiety reactions in humans [8]. The BAIAP3 protein is involved in the synthesis of synaptic vesicle membranes containing glutamate and GABA. Mutations of genes involved in the synthesis of GABA receptor subunits – H101R (alpha-1- and alpha-2-subunits), H126R (alpha-3), H105R (alpha-5) reduce the sensitivity of receptors to benzodiazepines while maintaining sensitivity to GABA.
Drug tolerance develops at different times in relation to the various effects of benzodiazepines: primarily sedative, muscle relaxant, and then anxiolytic. The addiction to benzodiazepines is characterized by disturbances in the circadian rhythm of the sleep-wake cycle with nocturnal awakenings and the inability to fall asleep without taking the next dose of the drug.
A sharp cessation of the use of sleeping pills, taken for a long time, causes withdrawal syndrome (withdrawal) lasting from several days to two to three weeks, and in some cases up to three to six months. Withdrawal syndrome is a group of mental and somatoneurological symptoms not previously observed. The former include irritability, dysphoria, tension, depressed mood, a significant increase in anxiety and anxiety, agitation, or, conversely, lethargy, increased fatigue, depersonalization, and pronounced sleep disorders, often with nightmare dreams caused by ricocheted increases in REM sleep. Somatoneurological disorders include autonomic disorders: hyperhidrosis, tachycardia, hypotension, hypopnea, and sometimes hyperthermia. Anorexia, nausea, and vomiting are possible. Neurological symptoms are represented by dizziness, headache, fine tremor of the fingers, tongue fibrillation, impaired coordination of movements, vision, and difficulty speaking. Changes in heart rhythm and blood pressure, in turn, can provoke myocardial ischemia or arrhythmia, therefore, at the first signs of withdrawal, the doctor should be ready to take measures to support blood circulation and respiration.
With the cancellation of benzodiazepine sleeping pills, the development of the rebound insomnia phenomenon is also described – the deterioration of both subjective and objective (increase in the proportion of REM sleep) sleep characteristics in the subsequent one to two nights after cancellation. Further, the sleep indicators either return to the level that was achieved while taking the drug, or slightly worsen, usually not dropping below the level that was before treatment. Unlike withdrawal syndrome, with rebound insomnia, new symptoms do not appear.
A meta-analysis of studies on the effectiveness of benzodiazepine sleeping pills showed that the use of these drugs according to polysomnography is accompanied by a decrease in the time to fall asleep by an average of 4.4 minutes (95% CI 0.7–9.2) and an increase in the total sleep time by 61.8 minutes (37 , 4–86.2) [9]. Subjective reports of patients were more optimistic: the time to fall asleep decreased by 14.3 minutes (10.6-18.0).
There are no meta-analyzes of the prolonged use of benzodiazepine sleeping pills for the symptoms of addiction and addiction. Some articles mention only a study with two-month use of temazepam for insomnia, which was not accompanied by the development of addiction and dependence [10]. Some experts estimated the frequency of addiction when taking benzodiazepines as sleeping pills in 20% [11].
Non-benzodiazepine ligands of the GABAA receptor complex include drugs that do not have a benzodiazepine element in their structure (combinations of benzene and diazepine rings), but exhibit affinity for the attachment sites of benzodiazepines. These are the so-called Z-preparations: zopiclone (cyclopyrrolone derivative), zolpidem (imidazopyridine), zaleplon (pyrazolopyrimidine). The action of these substances has such a feature as maximum affinity for the alpha-1 subunit of this receptor complex, which is responsible for sleeping pills, with minimal affinity for binding zones, which are responsible for other undesirable effects of benzodiazepines.
Compared to most available benzodiazepine hypnotics, Z-preparations have a fairly short half-life (from a minimum of one hour for zaleplon to a maximum of five hours for zopiclone). Z-drugs cause less daily side effects than benzodiazepines, so they are more preferable for complaints of night sleep. Nevertheless, there are reports of the development of side effects such as hallucinations and psychoses, complex behavioral reactions while taking these drugs, especially zolpidem. Z-drugs do not use the mechanisms of addiction that are characteristic of less selective benzodiazepines [7]. S. Ancoli-Israel et al. (2005) noted a significant improvement in the time of falling asleep, an increase in the duration of sleep and the number of night awakenings against the background of the use of zaleplon for one year in elderly patients with insomnia. In this case, the development of effects of addiction and dependence was not observed, a distinct effect of rebound insomnia was determined within two to five days after drug withdrawal [12]. There are isolated reports of the development of addiction to highly selective sleeping pills [13].
The most modern of the Z-preparations eszopiclone (stereoisomer of zopiclone) and the form of slow-release zolpidem (not registered in Russia) are recommended for prolonged use in the treatment of insomnia. In a six-month study, J. Walsh et al. (2007) eszopiclone showed a positive effect on the insomnia severity index scale (average score less than 7 was recorded in 50% of patients versus 19% in the placebo group) [14]. In this case, the effects of addiction and dependence on the background of taking the drug were not recorded.
Similar results were obtained in a group of elderly patients with insomnia who received eszopiclone treatment for three months. While taking the drug, subjective indicators of falling asleep time, total sleep time and wakefulness during sleep improved. At the same time, the development of effects of addiction, dependence and rebound insomnia was not noted [15].
In an eight-month placebo-controlled study, T. Roth et al. (2013) studied the effectiveness of sustained release zolpidem in chronic insomnia. While taking the drug, there was an advantage in the number of patients with “significant or noticeable improvement” (85% versus 48% in the placebo group) and the absence of addiction and dependence effects [16]. Similar results were obtained with a six-month use of this form of zolpidem according to the “as needed” scheme in a study by A. Krystal et al. (2008) [17].
The next generation of sleeping pills is represented by melatonin receptor agonists. The pineal gland hormone melatonin has a mild hypnotic and significantly more pronounced chronobiotic (regulating circadian rhythms) effect. It has been shown that the hypnotic effect of melatonin increases with a decrease in its internal production. Meta-analyzes published in the Cochrane database confirm the positive effect of melatonin preparations in relation to falling asleep, the duration and quality of night sleep [18].
The melatonin receptor agonist of the first and second type ramelteon (not registered in Russia) has a half-life of one to 2.5 hours. In studies lasting up to five weeks, no development of the effects of tolerance and dependence was detected with the use of this drug [19]. It is emphasized that taking agonists of melatonin receptors is not accompanied by a “positive reinforcing effect”, and therefore does not cause psychological dependence. The drug distinguishes the proven effect only in relation to reducing the time to fall asleep, it does not affect other characteristics of sleep. In an open study, G. Richardson et al. (2009) used ramelteon for the treatment of chronic insomnia for one year, with no manifestations of withdrawal and addiction to the drug [20].
A new target for the action of sleeping pills is the orexin activating system of the brain, which is also responsible for the alternation of phases of slow and fast sleep [21]. In 2014, in the United States, for the use of insomnia, a drug blocking both types of orexin receptors was approved – suvorexant (not registered in Russia). He has shown a positive effect on pre- and intra-communal disorders and early awakenings. Suvorexant does not suppress the respiratory center, which makes it safe for patients with severe obstructive sleep apnea and pulmonary pathology [22]. In a placebo-controlled study, which was conducted for one year, the use of the drug was not accompanied by the development of addiction. After the withdrawal of suvorexant, the development of negative side effects (withdrawal syndrome) and rebound insomnia were not observed [23]. At present, suvorexant is the only drug for which there are systematic randomized data on the condition of patients after annual use as sleeping pills.
Separately, it is worth mentioning another drug that is universally used as a sleeping pill – a blocker of the histaminergic brain activating system. Doxylamine is a selective antagonist of excitatory H1 receptors, largely present in the brain. According to the results of open clinical trials without placebo control, doxylamine positively affected the subjective and objective indicators of sleep with insomnia. Among them – a decrease in the time of falling asleep and the number of awakenings at night, the total duration of sleep, an improvement in the quality of night sleep and morning awakening, an increase in the duration of REM sleep [24]. The only placebo-controlled double-blind study of 1985 demonstrated the positive effect of the drug on subjective indicators of sleep quality [25]. The clinical use of doxylamine is limited by its M-cholinolytic properties, which does not allow recommending it to persons with glaucoma and benign prostatic hyperplasia.
A. Roussin et al. (2013) in a meta-analysis note that the formation of dependence and withdrawal syndrome with prolonged use of the drug was absent. Only 1.3% of doxylamine-treated patients met the dependence criteria. The authors, however, recorded the development of the phenomenon of rebound insomnia during attempts to discontinue the drug [26].
So, back in 2005, experts from the National Institutes of Health in consensus on the treatment of chronic insomnia indicated the possibility of prescribing certain benzodiazepine receptor agonists for a period longer than previously recommended [27]. At first, this concerned only the new drug eszopiclone. Among other things, a low potential for addiction development with short-term use of benzodiazepine receptor agonists and a lack of information about the consequences of their long-term use were noted.
This consensus served as the basis for the development of clinical guidelines for the treatment of chronic insomnia, which were published in 2008 in the Journal of Clinical Sleep Medicine [28]. These recommendations indicate the possibility of prescribing treatment with sleeping pills for a long period in the presence of severe or refractory insomnia or chronic comorbid disease. Described the use of sleeping pills in the following modes: on an ongoing basis (nightly), on an intermittent basis (for example, three times a week) or “as needed” (level of recommendations “consensus”, that is, level C on a standard scale of recommendations). Agonists of benzodiazepine receptors and ramelteon were named the drugs of choice. Moreover, the duration of the use of sleeping pills was limited to two to four weeks. Separate categories of complex patients (the authors could not more specifically identify this category of patients) were allowed to prescribe sleeping pills for a longer period, depending on the clinical experience of the doctor and the combined opinion of experts, since there is insufficient data on the possibility of long-term use of sleeping pills. At the same time, there was a need for repeated visits of patients at least every six months to evaluate effectiveness, register adverse events, addiction or abuse. It was also recommended to periodically try to reduce the dose of the drug. The abolition of sleeping pills to reduce the risk of rebound insomnia, according to the recommendations, should be carried out by gradually reducing the dose of the drug and the frequency of its administration.
Later recommendations of the British Association of Psychopharmacologists of 2010 on the treatment of insomnia contain an interesting comment regarding the duration of prescription of sleeping pills for insomnia [29]. Analyzing the recommendations of the US National Institute of Health in 1983, experts write: “This point of view is not based on research data that showed a change in the risk – benefit ratio in the undesirable direction after two to three weeks of treatment, but, it seems, only on the fact that there have been no relevant placebo-controlled studies on the use of sleeping pills for more than a few weeks. Despite the fact that the recommendations for the use of sleeping pills indicate a period of two to four weeks, millions of patients around the world continue to take drugs on an ongoing basis. ” The following are data from studies according to which, two years after the successful withdrawal of sleeping pills, 40% of patients begin to take them again. This indicates the chronic remitting nature of insomnia and the possibility of using the same approach as in the treatment of depression [30]. Thus, the recommendations of the British Association of Psychopharmacologists justify the possibility of long-term therapy with sleeping pills with evidence level A. These clinical recommendations are also distinguished by the very low level (D) of the use of antihistamines for the treatment of insomnia and the initiation of treatment for insomnia in people over 55 years of age who need pharmacotherapy with prolonged-release melatonin [29].
So, there is no scientifically based evidence that the duration of sleeping pills should be limited to two to four weeks, as is usually indicated in the instructions for use. Data on the lack of development of the phenomena of addiction and dependence with prolonged use of sleeping pills are also quite scarce. Nevertheless, chronic insomnia is currently considered a long-term disease with a high risk of relapse, which allows international experts to recommend taking sleeping pills for long courses. This primarily concerns the drugs of the latest generations: modified Z-preparations, melatonin agonists and orexin receptor antagonists.