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 not usually 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 behavioural 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, zopiclone, zolpidem, zaleplon and eszopiclone, four different non-benzodiazepine hypnotic compounds, have been developed and introduced as insomnia therapies (Nutt 2010). Zaleplon, a pyrazolopyrimidine derivative hypnotic with a chemical structure unrelated to benzodiazepines or other known hypnotics, was approved in 1999 by the FDA for short-term treatment of insomnia and is used as an hypnotic in many countries worldwide (Moore 2000). The recommended dose for zaleplon is 10 mg in non-elderly adults and 5 mg in elderly patients (Barbera 2005). With a maximum plasma concentration (Tmax) of approximately one hour after oral administration, zaleplon is quickly and almost completely absorbed and with an elimination half-life time of one hour it is extensively and rapidly eliminated (Moore 2000; Nutt 2010).
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, new-generation hypnotics bind more selectively to the alpha 1-containing receptor subtypes responsible for sedation (Monti 2007). 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). Zaleplon displays the most selective binding to the alpha 1-containing receptor subtypes of all new-generation hypnotic compounds (Barbera 2005; Najib 2006; Nutt 2010), suggesting a predominantly sedative profile of effectiveness with a low risk of next-day impairments.
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). Zaleplon, with its rapid onset of action and its short brain receptor occupancy, may be considered as the first-line drug treatment for patients with sleep-onset insomnia, but would be expected to be less efficacious in patients suffering sleep-maintenance insomnia (Drover 2000; Nutt 2010).
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. In a study undertaken to assess the abuse potential of zaleplon, patients with a history of drug abuse rated drug liking, psychoactive effects and monetary street value of zaleplon in doses between 25 mg and 75 mg as comparable with that of the short-acting benzodiazepine triazolam (0.25 mg to 0.75 mg), leading the authors to conclude that the behavioural pharmacological profile of zaleplon might not be more advantageous than that of benzodiazepines (Rush 1999).
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 the risk for next-day residual effects, have to be considered (Lieberman 2007). Thus, an integration of the available evidence on zaleplon 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 zolpidem (Rösner 2013a), zopiclone (Rösner 2013b) and eszopiclone (Rösner 2013c).