Description of the condition
Affecting between 5% to 20% of the adult population in Western countries, insomnia is a major public health issue (Ohayon 2002) because of its high prevalence and its impact on physical and psychosocial well-being. About one-third of adults report sleeping problems and between 6% and 10% meet the criteria for a diagnosis of insomnia (Ohayon 2002; Roth 2003; Morin 2006; Ohayon 2009).
The predominant symptom of insomnia is difficulty initiating sleep (sleep-onset insomnia), maintaining sleep (sleep-maintenance insomnia) or a poor and non-restorative quality of sleep (Ohayon 2001). For a diagnosis of insomnia, commonly used diagnostic systems like the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (American Psychiatric Association 2000), the International Classification of Diseases (ICD-10) (World Health Organization 1992) and the International Classification of Sleep Disorders (ICSD) (American Academy of Sleep Medicine 2005) require that these sleeping problems i) persist over a period of at least one month, ii) cause next-day impairments including social, occupational or other important areas of functioning, and iii) do not result from mental disorders (e.g. major depression, generalised anxiety disorder), substance abuse (e.g. alcohol, medications, illegal drugs) or other sleep disorders (e.g. narcolepsy, breathing-related sleep disorder). The ICD-10 diagnosis of insomnia in addition demands a frequency of sleeping problems of at least three times a week and the occurrence of preoccupation with sleepiness and excessive concern.
Most models of insomnia refer to a common framework proposed by Spielman 1991, distinguishing between predisposing, precipitating and perpetuating factors. While predisposing factors such as maladaptive coping stress strategies, cognitive-emotional hyperarousal and older age make individuals more vulnerable to sleeping problems (Fernández-Mendoza 2010), increased life-stress, irregular sleep habits and poor sleep hygiene further precipitate their occurrence (Bastien 2004). If sleep is repeatedly disturbed, a further perpetuation of the problem results from the selective attention directed towards the inability to fall asleep, creating a vicious cycle that often leads to chronicity. The neurocognitive model of insomnia (Perlis 2007) emphasises the role of hyperarousal, including an increased level of somatic, cognitive and cortical activity, which is enforced through classical conditioning and which promotes abnormal levels of sensory and information processing, thought to render the insomniac individual especially vulnerable to perturbation by environmental or other stimuli (Riemann 2009). The inhibition model developed by Espie 2002 conceptualises insomnia as the failure to inhibit wakefulness rather than the inability to induce sleep and underscores the originally functional role of wakefulness in the presence of stressors. If the 'threat' is not eliminated, attention is increasingly focused on sleep and motivational processes such as the conscious intent to fall asleep are activated, both interfering with the otherwise automatic response of inhibiting wakefulness.
Insomnia is not a trivial complaint. Besides causing psychological distress during the night, insomnia leads to next-day cognitive and psychomotor impairments, irritability and decreased job performance (Metlaine 2005). In the longer term, reduced sleep increases the risk of substance abuse (Johnson 2001; Falcón 2009) and psychiatric comorbidity (Riemann 2007), and reduces life quality (Zammit 1999; Rosekind 2010) and longevity (Roth 2009). Untreated insomnia does usually not remit with time (Angst 1989; Leshner 2005), underscoring the need for effective and safe treatment interventions.
Description of the intervention
Even though recommended as first-line treatments for chronic insomnia (Hajak 1997; Ramakrishnan 2007), non-pharmacological treatment strategies such as sleep restriction, stimulus control, relaxation techniques and cognitive behavioral therapy (CBT) are rarely used in clinical practice. Benzodiazepines are effective for short-term treatment of insomnia (Buscemi 2007), but carry the risk of rebound insomnia, physical and psychological dependence, serious withdrawal symptoms (Royal College of Psychiatrists 1997; Lader 1999; Ballenger 2000) and next-day hangover effects, responsible for traffic and machine operation accidents (Barbone 1998), self injuries and hip fractures, commonly seen in elderly patients (Bolton 2008; Woolcott 2009).
In the 1980s and early 1990s, a new group of hypnotic agents, known as new-generation hypnotics, non-benzodiazepine hypnotics, benzodiazepine receptor agonists or 'z-drugs' were introduced to the markets. Meanwhile, zolpidem, zopiclone, zaleplon and eszopiclone, four different non-benzodiazepine hypnotic compounds have been developed and introduced as insomnia therapies (Nutt 2010). In 1992, the Food and Drug Administration (FDA) approved zolpidem, a non-benzodiazepine hypnotic of the imidazopyridine class for the short-term treatment of insomnia. Today, zolpidem is the most widely prescribed hypnotic drug in the USA and is one of the most frequently used drugs used for insomnia treatment worldwide (Verster 2007; Greenblatt 2012). Approved doses of zolpidem in its standard immediate-release form are 10 mg for adults and 5 mg for elderly patients (Greenblatt 2012). Zolpidem is rapidly absorbed (maximum plasma concentration (Tmax) ˜ 2 hours) and rapidly eliminated (elimination half-life time (t½) ˜ 2 to 3.5 hours), while there is high interindividual variability in plasma levels (de Haas 2010; Nutt 2010; Greenblatt 2012). Furthermore, zolpidem does not have active metabolites and does not accumulate during repeated administration (Fraisse 1996).
Since 2005, besides the immediate-release tablet preparation, zolpidem has also been provided as an extended-release formulation in the USA, prepared as two-layer tablets with a biphasic release profile, releasing the first layer immediately and the second layer at a slower rate. This maintains plasma concentrations for a longer period of time than immediate-release zolpidem formulations (Barkin 2007). In 2008, the FDA approved an aerosolised form of zolpidem, which delivers an approved dose into the oral cavity. In 2009, a sublingual formulation of zolpidem was approved for the US market, assumed to be more rapidly absorbed after dosing without altering the absolute bio-availability of the drug (Roth 2008).
How the intervention might work
Similar to benzodiazepines, new-generation hypnotics develop their sedative properties through activity at the gamma-aminobutyric acid-A (GABA-A) receptor, whose endogenous ligand, GABA, is the major inhibitory neurotransmitter in the central nervous system, involved in anxiolysis, sedation, seizure suppression and muscle relaxation (Bateson 2004; Rudolph 2011). The GABA-A receptor is composed of five protein subunits and at least 19 distinct subunit isoforms, mediating different behavioural and pharmacological responses (Drover 2004; Dündar 2004b; Sieghart 2006; Dolder 2007). Alpha 1 subunits of the GABA-A receptor are thought to be mainly responsible for the mediation of sedative drug effects, alpha 2 and alpha 3 subunits for anxiolytic and antidepressant drug activities and alpha 5 receptor subunits for cognitive effects including memory and learning (Lingford-Hughes 2002; Nutt 2010). While benzodiazepines modulate different subunits of the GABA-A receptor, most new-generation hypnotics selectively bind to the alpha 1-containing receptor subtypes responsible for sedation. Accordingly, new-generation hypnotics are assumed to produce an advantageous clinical profile compared to benzodiazepines, particularly with respect to the residual effects as well as the development of tolerance and dependence (Follesa 2002; Drover 2004). Among new-generation hypnotics, zolpidem has the highest affinity to alpha 1-containing receptor subtypes and in contrast comparatively low affinity to other alpha 2, 3 and 5 subtypes (Nutt 2010), suggesting that zolpidem has specific sedative properties and a reduced propensity to produce cognitive and motor impairments (Nutt 2010; Greenblatt 2012). Nevertheless, even though evidence from ex-vivo and animal studies confirms its specific profile of effectiveness, evidence from clinical studies with zolpidem is not consistent (Greenblatt 2012).
Further differences in the clinical effects of new-generation hypnotics are assumed to be associated with their unique pharmacokinetic profiles, including the bioavailability of the drug, the volume of distribution and the elimination half-life time (Drover 2000). With a comparatively rapid onset of action and a relatively short brain receptor occupancy, standard immediate-release zolpidem appears to be particularly beneficial for patients with sleep-onset insomnia (Drover 2000; Nutt 2010). In contrast to immediate-release formulations of zolpidem, extended-release formulations were shown to maintain plasma concentration over a longer period of time and thus - unlike original zolpidem - are indicated for both sleep-onset and sleep-maintenance insomnia (Barkin 2007; Lieberman 2007).
Why it is important to do this review
Based on the assumption that new-generation hypnotics are just as effective as benzodiazepines while having a lower risk for abuse and dependence, new-generation hypnotics have continuously replaced benzodiazepines as the most commonly prescribed hypnotic drugs and have emerged as the first-line drug for insomnia treatment (Erman 2005; Siriwardena 2008; Hausken 2009; Hoffmann 2009; NHS Prescribing Service 2010). In fact, various reviews (Montplaisir 2003; Drover 2004; Dündar 2004a; Dündar 2004b; Zammit 2009), post-marketing surveillance studies (Delahaye 1990) and case study reports (Lader 1999; Soyka 2000; Hajak 2003) conclude that because of their pharmacokinetic and pharmacodynamic properties, new-generation hypnotics have some important advantages over benzodiazepine hypnotics, including a lower risk for next-day impairments and a lower potential for abuse and dependence. Nevertheless, the evidence is not entirely consistent. Two studies comparing subjective and performance-related effects of new-generation hypnotics (zolpidem, zaleplon) and a short-acting benzodiazepine (triazolam) indicated similar pharmacologic-behavioural profiles of the tested hypnotics (Rush 1999a; Rush 1999b). Studies with baboons showed even higher self injection rates for zolpidem than for benzodiazepines and the occurrence of withdrawal symptoms after zolpidem was substituted with saline, indicating reinforcing properties of the drug as well as its potential to cause physical dependence (Griffiths 1992; Weerts 1998). Following a recommendation of the World Health Organization (WHO) in 2002, zolpidem was added to Schedule IV of the UN Convention on Psychotropic Substances (United Nations 1971).
When therapeutic decisions about the pharmacological treatment of insomnia are made, safety issues including a drug's potential for tolerance, abuse and dependence, as well as the risk for next-day residual effects, have to be considered (Lieberman 2007). Thus, an integration of the available evidence on zolpidem appears to be indispensable to provide best evidence to practising physicians and health decision-makers. This review will form part of a suite of four reviews on new-generation hypnotics for insomnia; the other three will assess the effectiveness and safety of zopiclone (Rösner 2013a), zaleplon (Rösner 2013b) and eszopiclone (Rösner 2013c).