Treatment of Insomnia

Insomnia
Insomnia is a sleep disorder causing impairment in social, occupational, educational, academic, behavioural, or other areas of functioning. The Diagnostic and Statistical Manual of Mental Disorders, 5^th ed. (DSM-5) categorises insomnia as:

Difficulty in initiating sleep and/or maintaining sleep and/or waking earlier than desired together with

• Sleep difficulty at least three nights per week
• Sleep difficulty for at least three months

Insomnia is more prevalent in women and older adults and can occur as a comorbidity with psychiatric disorders such as depression, anxiety, and dementia or with substance abuse, medications, pain, sleep apnoea, restless legs syndrome, or circadian rhythm disorders. Maladaptive behaviour such as irregular bedtimes, heavy caffeine use, and alcohol dependency can also contribute to insomnia. Treating the aggravating factors may not be sufficient. Therefore, many patients benefit from sleep-promoting medications known as hypnotics.

Hypnotics

Hypnotic drugs can work by the following two mechanisms.

1. Targeting the sleep signalling centre to encourage sleep signals and promote sleep
2. Targeting the wake signalling centre to inhibit these signals and promote sleep

Hypnotics that target the sleep system through gamma-aminobutyric acid (GABA):

GABA is an inhibitory neurotransmitter that promotes sleep by inhibiting the actions of wake-promoting neurons to globally reduce cortical activity. GABA is the primary inhibitory neurotransmitter in the brain and affects nearly every behavioural system including those governing cognition, gait, balance, and mood.

Benzodiazepines such as temazepam, nitrazepam, and flunitrazepam are positive allosteric modulators of the GABA_A receptor. Non-benzodiazepine hypnotics such as zolpidem and zopiclone differ in structure from the traditional benzodiazepines. However, they also potentiate the inhibitory effects of GABA by binding to the α₁ subunit of the GABA_A receptor. These agents often hasten the onset of sleep, reduce the number of arousals from sleep, and can increase the total amount of sleep.

Benzodiazepines are generally well tolerated. However, sedation and mental fogginess in the morning can be bothersome. This is of particular concern with longer-acting agents such as diazepam and flunitrazepam. Dependence and abuse of benzodiazepines can also be problematic. Rebound insomnia and withdrawal symptoms can occur if benzodiazepines are ceased abruptly, or the dose tapered too quickly. Respiratory depression is not a common concern with normal doses. However, these sedatives should not be used in patients with sleep apnoea as hypoventilation and hypoxaemia could result. In older adults, these agents commonly contribute to falls, injury, and confusion.

Hypnotics that target wake-promoting neurotransmitters:

Tricyclic antidepressants such as amitriptyline and doxepin are popular for treating insomnia due to their additional antidepressant and analgesic actions. Neuroleptics such as olanzapine can also aid sleep and have additional antipsychotic actions. Antihistamines such as promethazine, dexchlorpheniramine, and doxylamine are available over-the-counter sleeping aids.

As monoaminergic and cholinergic systems are widespread throughout the body, these agents can be associated with a number of unwanted adverse effects. The anticholinergic properties of tricyclic antidepressants and sedating antihistamines can cause dry mouth and urinary retention. Antihistamines can also cause lingering sedation and impaired cognition. Antipsychotics are associated with a range of adverse effects including hypotension, weight gain, and extrapyramidal reactions. In older adults, these agents can also result in falls, injury, and confusion.

Hypnotics that target the hormone melatonin

Melatonin has many important functions as a signal to the internal biological clock in our brain. It allows the adjustment of physiological functions such as sleep, blood pressure, and certain hormones during the night period. Light inhibits melatonin production which also naturally diminishes with advancing age and in some medical conditions. Commercially produced melatonin products such as Circadin^® are moderately effective at improving sleep onset and have few side effects besides an occasional headache.

Hypnotics that target the wake-promoting neuropeptide molecule orexin

Novel hypnotics such as suvorexant target the relatively newly discovered neurotransmitter orexin (also known as hypocretin). There are two subtypes of orexin, orexin-A and orexin-B (hypocretin-1 and -2), which act on orexin receptors OX1R and OX2R respectively.

Orexin is a central promoter of wakefulness and is also involved in the regulation of food intake, energy expenditure, and visceral function. Orexin neurons are mainly localised in the hypothalamus.

Orexin receptor antagonists such as suvorexant have no direct pharmacologic activity or binding affinity at GABA, serotonin, dopamine, noradrenaline, melatonin, histamine, acetylcholine, or opiate receptors. Therefore, issues such as dependence and abuse, imbalance and falls, respiratory depression, and orthostasis should be less of a concern compared to conventional hypnotics.

Reported side effects include morning or daytime sleepiness, somnolence, and abnormal dreams. However, as orexin receptor antagonists are relatively new agents, other side effects may arise with post-marketing surveillance. It can be anticipated that orexin antagonists may cause dysregulation of REM sleep, hypnagogic hallucination, and sleep paralysis during sleep-wake transitions. Abnormal thinking and behavioural changes may occur also.

Belsomra^® (Suvorexant)

Suvorexant is the first orexin receptor antagonist available in Australia. It is a highly selective reversible antagonist at both the OX1R and OX2R receptors. Suvorexant is indicated for the treatment of insomnia. Following initiation of treatment, continuation should be re-evaluated after three months.

Suvorexant has a high oral bioavailability and can be taken with or without food. However, tablets may be taken on empty stomach for faster onset of sleep. The prescribed dose should be taken no more than once per night and within 30 minutes of going to bed. To avoid daytime drowsiness, the dose should be taken at least seven hours before the planned time of awakening.

The usual recommended dose is 20mg at night (or 15mg for patients 65 years of age or older). This dose should not be exceeded as higher doses demonstrate significantly more adverse effects with similar efficacy.

Adverse effects reported during clinical trials include fatigue, upper respiratory tract infection, diarrhoea, dry mouth, nausea, somnolence, headache, and abnormal dreams. Driving ability may be impaired including an increased risk of falling asleep while driving. Patients should be advised not to consume alcohol in combination with Belsomra^® due to additive effects. Central nervous system (CNS) depressant effects may persist in some patients for up to several days after discontinuing Belsomra^®.

Suvorexant is mainly eliminated by hepatic metabolism, primarily by CYP3A with some involvement from CYP2C19. Interactions can occur with moderate and strong inhibitors of CYP3A such as ketoconazole and diltiazem. These medications can increase suvorexant exposure and may increase adverse effects. In contrast, strong inducers of CYP3A such as rifampicin, carbamazepine, and phenytoin may significantly reduce suvorexant exposure and reduce clinical efficacy.