Chronic insomnia is a long-lasting condition that greatly affects the day-to-day lives of those who experience it [1]. This article aims to promote awareness of the condition and understanding of its underlying biological pathways by exploring the key approaches to its pharmacological management.
Background
We have all experienced a poor night’s sleep, awakening to a day of irritability, fatigue and reduced focus. However, the estimated 10-30% of adults who suffer from chronic insomnia experience this to an extreme degree, having difficulty achieving high-quality sleep three days or more per week over a minimum of a three-month period [1]. Compared with unaffected individuals, those with chronic insomnia have an increased risk of developing medical conditions such as stroke, asthma, heart disease, depression and anxiety, mental health disorders as well as an increased risk of accidents due to loss of focus [2]. In total, this leads to an estimated global economic burden of US$100 billion per year as a result of treatment costs and loss of productivity [3].
The treatment of chronic insomnia
Overall, 85%–90% of chronic insomnia cases are estimated to be comorbid, meaning that the insomnia is associated with a pre-existing condition, such as chronic pain or a mental health disorder [4]. It is often the unwanted physical or mental stimulation from these conditions that can lead to sleep interruption, prevent an individual falling asleep and/or cause poor-quality sleep [5]. As such, the primary pharmacological means of treating chronic insomnia is the use of sedatives – pharmacotherapies that harness sleep-promoting biological pathways to overcome the waking stimulus.
Sedatives used to alleviate insomnia and promote sleep do so by targeting four distinct neurological systems.
The gamma-aminobutyric acid system
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter of the central nervous system (CNS) [6, 7]. This neurotransmitter functions by binding to either GABAA or GABAB receptors on the surface of neurons, with GABAA receptor binding causing an increased flow of chloride ions into neurons and preventing excitation [6, 7]. The GABAA receptor is composed of five subunits, with constituent subunits varying dependant on where the receptor is positioned in the CNS; drugs targeting different subunits have different physiological effects [6, 7].
Discovered in the late 1950s, benzodiazepines were one of the first interventions used to treat insomnia [7]. Benzodiazepines act upon GABAA receptors through an allosteric mechanism, binding to a range of subunit interfaces away from the GABA binding site and enhancing the sensitivity of the receptor for GABA [6, 7]. These drugs exhibit preferential selectivity for GABAA receptors containing α1, α2, α3 and/or α5 subunits, which are most found in the brain, leading to sedation through reduced neuronal excitation [8]. However, the wide range of subunit targets can lead to multiple unwanted side effects, such as confusion, depression and memory impairment [9].
‘Z-drugs’ are the most commonly prescribed treatment for insomnia globally [10]. They have a similar structure and binding mechanism to benzodiazepines but are designed to bind to only α1 subunit–containing receptors and to degrade faster in the body [8, 11]. Thus, these drugs have reduced off-target effects and are associated with improved sleep quality compared with benzodiazepines [12]. However, tolerance, dependence and withdrawal are hallmarks of both classes of GABA regulators [12].
The orexin system
Discovered in the late 1990s, orexins are neuropeptides that are produced exclusively by a portion of the brain called the hypothalamus and are vital to maintaining a healthy sleep–wake cycle [13, 14]. Orexins bind to orexin receptors type 1 and 2, leading to signalling along a specific subset of orexin neurons and a promotional effect on subsequent serotonin, histamine, acetylcholine and dopamine signalling [14]. This results in increased wakefulness and inhibition of sleep [13, 14].
Dual orexin receptor antagonists (DORAs) bind directly to both orexin receptors, blocking the binding of orexin and the subsequent signalling along orexin neurons [13, 14]. This leads to an overall reduction in wakefulness [13, 14]. Approval for the first DORA was obtained from the US Food and Drug Administration (FDA) in 2014, presenting a new method of insomnia treatment with a potentially reduced risk profile and a reduction in incidents of drug-related motor or memory impairment compared with therapies targeting the GABA system [15].
The histamine system
We most commonly hear of histamine in the context of the allergic response but, as well as being an inflammatory mediator, histamine is also a neurotransmitter in the CNS [16]. Histaminergic neurons are localised within the hypothalamus and act to promote wakefulness through the synthesis of histamine and its binding to H1, H2, H3 and H4 receptors [17]. H1 receptors are particularly interesting as both their active and inactive conformations can be assumed in the absence of histamine, allowing a degree of signalling when their ligand is not present [16].
Antihistamines can be loosely grouped into first-generation and second-generation classes, with the former having the capacity to pass through the blood–brain barrier and affect sleep–wake regulation inside the brain [16]. This allows first-generation H1-targeted antihistamines to bind to, and stabilise, the inactive conformation of the H1 receptor within sleep-associated brain regions, leading to reduced wakefulness-promoting histamine signalling [16]. However, although they may alleviate short term sleep disturbances, antihistamines are not a recommended treatment for chronic insomnia, being associated with poor-quality sleep and rebound wakefulness [16].
The melatonin system
Melatonin is the primary regulator of the circadian rhythm – the biological ‘clock’ within the body by which an array of physiological systems are synchronised, from digestion and blood pressure to hormone production and sleep [18]. In healthy adults, melatonin secretion has a strict daily rhythm, being produced in periods of darkness and thus typically aligning with the day–night cycle [19].
Within the brain the pineal gland produces melatonin in response to a signal from the suprachiasmatic nucleus (SCN) – the control centre of the circadian rhythm [19]. Melatonin then creates a sleep-promoting signal loop, acting upon the SCN to inhibit circadian-associated wakefulness-promoting signals [19]. Melatonin also acts upon a network of brain regions associated with a lack of focus call the default mode network, thus promoting fatigue and reducing wakefulness [19].
Melatonin supplementation therapy is frequently used as a short-term sleeping aid to promote improvements in sleep duration and assist in the treatment of delayed sleep; however, it has limited effect on patients whose insomnia is not associated with reduced melatonin levels [19, 20].
Conclusion
The treatment of chronic insomnia using pharmacotherapies provides a means of directly alleviating insomnia symptoms, providing the critical sleep that patients need. Coupling these therapies with behavioural interventions, such as cognitive behavioural therapy, and the promotion of good sleep hygiene is the gold standard of treatment for insomnia in EU, the UK and the USA [21, 22].
The information in this article is not intended or implied to be a substitute for professional medical advice, diagnosis or treatment. All content is for general information purposes only. Always seek the guidance of your doctor or other qualified healthcare professional with any questions you may have regarding your health or medical condition.
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Author: Owen Dawson, PhD intern, Porterhouse Medical
Group