The Role of Melatonin in the Management of Insomnia in the Elderly

  

    
Sleep Disorder
    
Diagnosis
    
Non-pharmacological Management
    
Pharmacological Management
  
  

    
Insomnia
    
History, screening questionnaires, and polysomnograph as    supportive diagnostic measure
    
Insomnia CBT or digital CBT-I, sleep hygiene education,    relaxation and mindfulness exercises
    
Second-line and short-term
  
  

    
Sleep-disordered Breathing
    
Polysomnograph or portable home-based device
    
Positive airway pressure (PAP) and patient weight reduction
    
Consider decreasing the use of sedatives
  
  

    
Restless Leg Syndrome
    
History, screening questionnaires may help
    
None, lack of evidence
    
Iron supplementation, dopamine agonists, alpha-2 calcium    channel ligands, levodopa, benzodiazepines, and opioids (usage with caution)
  
  

    
REM Sleep Disorder
    
Polysomnograph, screening questionnaires may help
    
Sleep environment modification
    
Identification of drugs causing exacerbation. There is not    much evidence on the use of melatonin and clonazepam.
  

Table 2: Diagnosis and Management of Sleep Disorders in The Elderly [4].

In addition, non-pharmacological management also plays an important role in insomnia in patients with dementia. Evidence shows a statistically significant increase in sleep efficiency in patients who are given non-pharmacological intervention compared to those who are not. However, there was no significant difference in sleep duration and the number of awakenings during the night. There is still a small number of studies regarding Cognitive Behavioral Therapy interventions for insomnia (CBT-I) in patients with dementia. Based on studies, patients with mild cognitive impairment who are given six sessions of CBT-I can improve their sleep quality [4].

Melatonin Synthesis [6,7]

Melatonin is a hormone produced by the pineal gland and is derived from the essential amino acid tryptophan (N-acetyl-5-methoxytryptamine).

There are two types of exogenous melatonin, namely long-acting (prolonged release) and short-acting (short release). There have been no reports of dependence or adverse side effects when using oral melatonin. Minimal side effects that may arise are headaches and dizziness when consumed at low dose levels, which can slightly affect the quality of life. Various doses of melatonin can be taken without a doctor's prescription. Meanwhile, melatonin receptor agonists such as ramelteon can also be used to treat insomnia. Ramelteon is an MT1 and MT2 melatonin receptor agonist that has a specific effect on melatonin receptors in the suprachiasmatic nucleus. In clinical studies, it was found that the use of ramelteon is safe for the treatment of insomnia [7,8].

A meta-analysis by Kuriyama found that ramelteon is associated with an increase in the amount of total sleep time and sleep efficiency. Another meta-analysis found that melatonin can reduce sleep onset latency and increase total sleep time and overall sleep quality. However, because the diagnosis of insomnia is a subjective complaint, objective measurements are needed to properly evaluate the therapy.

E. Melatonin Receptors [7,8]

Melatonin secretion from the pineal gland activates the paired G protein MT1 and MT2 receptors. The production of melatonin in the pineal gland is controlled by the SCN and is affected by the changes in weather and environmental light-dark cycles. Endogenous melatonin produced by the pineal gland at night will signal the SCN and activate MT1 and MT2 receptors to regulate circadian rhythms.

Melatonin acts on the MT1 and MT2 receptors. There are differences between MT1 and MT2 in terms of structure, pharmacological characteristics, and chromosome location. MT1 increases the phosphorylation of mitogen-activated protein kinase, inhibits forskolin-stimulated cAMP, and increases potassium conduction through Kir channels. The MT2 receptor inhibits forskolin-stimulated cAMP and activates the Protein Kinase C (PKC) in the SCN and decreases calcium-dependent dopamine production in the retina.

Simultaneous activation of MT1 and MT2 receptors either on the same or different cells can create addiction, synergy, or even opposite effects that can even eliminate the effects of each other. The rate of MT1/MT2 heterodimer formation is 3 to 4 times lower than that of MT1/MT2 homodimers. MT1 or MT2 receptor monomers desensitize differently with exposure to melatonin depending on the concentration, exposure time, cellular background, and whether the receptor is active or not. Ligands that have high affinity and high selectivity can make heterodimer MT1/M2 receptors give higher effects than melatonin or synthetic non-selective ligands [8].

MT1/MT2 can also form a heterodimer with the serotonin receptor (5-HT2c). Thus, antidepressant mechanisms such as agomelatine could have effects as both melatonin receptor agonists and 5-HT2c receptor antagonists [8].

Melatonin and the Circadian Rhythm [6]

Melatonin acts as a diurnal regulator in humans. A sharp increase in the amount of melatonin in the body occurs 2 hours after endogenous production. Circadian rhythms are caused by the rhythms of melatonin production and are related to sleep rhythms. In elderly people, autonomic nerve degeneration, diabetic neuropathy, Alzheimer's disease, and various drugs (such as β-blockers, clonidine, naloxone, and NSAIDs) can interfere with melatonin production and are associated with sleep disturbances. For this reason, people who are given melatonin during the day will have symptoms of drowsiness and fatigue. However, melatonin is not a sedative, in nocturnal (active at night) animals, melatonin is associated with wakefulness, not sleep.

The effect of exogenous melatonin can be seen significantly when the endogenous melatonin production rate is at its lowest but difficult to see when it is at its highest. Melatonin acts on the SCN to interfere with the wake signal of the circadian rhythm, causing a person to fall asleep. Melatonin also works on the Default Mode Network (DMN) area of the brain which causes fatigue and sleepiness by activating the precuneus. The DMN is an area of the brain that is active during rest. The DMN is composed of the medial prefrontal cortex, posterior cingulate cortex, precuneus, inferior parietal lobes, lateral temporal cortex, and hippocampus.

The precuneus itself has a multitude of functions including memory consolidation, integration of perceptual information, mental strategies, and affective responses to pain. When sleeping, the connection at the DMN will decrease and be interrupted during the Slow Wave Sleep (SWS) phase. Melatonin when given during the day to a healthy young person will interfere with the activation of the precuneus and cause fatigue. If given at night, when endogenous melatonin production increases, the effect of exogenous melatonin is unclear. Melatonin is said to not increase the duration of SWS, so melatonin's effect is primarily on circadian rhythms in sleep regulation. For this reason, research on melatonin, which can increase and improve sleep cycles, continues to be carried out, especially in people with sleep and circadian rhythm disorders.

Melatonin acts as a marker in the absence of light or dark responses. Melatonin and several current melatonin analogues, such as ramelteon, agomelatine, and tasimelteon, are used clinically to modulate circadian rhythms and neuroendocrine function in both humans and animals. However, these are all non-selective agonists and have the same affinity for MT1 and MT2. Ramelteon has a 10 times higher affinity for MT1 than MT2, and 17 times higher than endogenous melatonin. Agomelatine and tasimelteon have a slightly higher affinity for the MT2 receptor. However, all melatonin analogues (ramelteon, agomelatine, and tasimelteon) are selective and specific to melatonin receptors and have no affinity for other G protein receptors [7,8].

Melatonin as Supplementation for Insomnia in the Elderly [9]

Melatonin can make a person sleep and to maintain it, melatonin therapy can also be used to help improve sleep quality. In the 2015 study by Roth et al, giving 0.5 – 1 mg of melatonin once a day in the evening for several months can improve circadian rhythms for 24 hours [10-12]. There are two forms of oral melatonin, simple melatonin with short half life and prolonged release melatonin with longer half-life but neither have been found to be superior for the treatment of insomnia [13]. The use of exogenous melatonin has not been reported to be associated with tolerance, dependence, or a hangover effect but, minimal side effect (headache, dizziness, nausea) can be found [14]. One study also reported no effect of melatonin on cognition or activities of daily living, and no serious side effects [24]. Melatonin is absorbed rapidly following oral administration and undergoes first pass hepatic metabolism with peak plasma levels occuring between 20 min and 2 h, and levels persist for up to 1.5h, depending on the dose [18]. In the United States, the most recent National Health Interview Survey showed that the overall use of melatonin among adults more than doubled between 2007 and 2012, to an estimated 3.1 million users [21]. For chronic insomnia, melatonin has a statistically significant but relatively smalleffect on sleep latency, with a mean reduction of 9min relativeto placebo [22]. the British Association for Psychopharmacology consensus statement recommends prolonged-release melatonin as a first-line option for older patients when a hypnotic is indicated [23]. But, before giving a melatonin, first-line therapy for insomnia, cognitive behavioural therapy should be recommended like eduction on sleeping hygiene [25].

Circadian rhythm disturbances such as Delayed Sleep Phase Syndrome (DSPS) or Advanced Sleep Phase Syndrome (ASPS) are said to be related to the pacemaker in the heart. DSPS is a disorder in which there are sleep onset insomnia and difficulty waking up. Meanwhile, ASPS is a disorder in which there are early or rapid onset of sleep and early awakening. In DSPS, endogenous melatonin rhythms are slower than normal. Melatonin therapy for these conditions is said to be able to improve sleep onset and wake time compared to placebo controls and can improve the patient's cognitive function.

Melatonin serves as a time cue (signal of darkness) to various organs including the SCN itself and in the absence of light, may entrain the sleep-wake and neuroendocrine rythms to the 24h cycle [17]. Activation of melatonin receptors in the Suprachiasmatic Nucleus (SCN) plays an important role in regulating circadian rhythms. Phase shifting of the circadian rhythm by melatonin is mediated by MT1 receptor activation. Thus, therapy using melatonin receptor agonists can be used to treat primary insomnia and circadian rhythm disorders. Some of the widely available melatonin receptor agonists are ramelteon and tasimelteon.

Ramelteon is a melatonin receptor agonist that has a high affinity for MT1 and MT2. It is said ramelteon can help patients fall asleep without causing impairment of memory, learning, or motor function. In subjects with chronic primary insomnia, ramelteon can be used to decrease sleep onset latency and increase total sleep time without causing side effects the next day. Repeated use of ramelteon before going to bed is said to improve circadian rhythms through the activation of the MT1 receptor. Kuriyama et al, found in 13 studies involving 5812 subjects concluded that ramelteon was associated with improvement in TST (total sleep time) and sleep efficiency [15].

Tasimelteon is also used to treat insomnia, especially in non-24-hour sleep-wake disorder (N24HSWD) which usually occurs in people with blindness. Tasimelteon is said to have a high but non-selective affinity for MT1 and MT2 receptors and no affinity for other G protein receptors. In phase III clinical trials, it is said that tasimelteon can have a better effect compared to placebo in 5 hours of wake and sleep cycles. In addition, tasimelteon usage could significantly replace the endogenous melatonin rhythms, reduce sleep onset latency, and improve sleep efficiency without causing side effects.

Currently, melatonin agonists are being developed which are more selective for MT1 or MT2 receptors. UCM765 is a selective preparation for MT2 which can reduce sleep latency and increase the amount of Non-Rapid Eye Movement (NREM) sleep. IIK7 is also a selective MT2 receptor agonist that can improve sleep onset latency and NREM count. Thus, it is said that MT2 receptors agonist could improve sleep structure. In an experiment on rats, it was found that MT2 is responsible for NREM, whereas MT1 is for REM [9].

In addition to melatonin receptor agonists, there are also exogenous melatonin preparations. Circadin is a prolonged-release melatonin that mimics endogenous melatonin secretion. It is said that circadin can improve sleep quality and sleep onset latency in elderly insomnia patients. Circadin may also improve sleep quality in adults with non-24-hour sleep-wake disorder (N24HSWD). The use of circadin has not been associated with memory impairment and has no withdrawal symptoms.

Conclusion

The number of people with old age in Indonesia is moderately high. Older people have various comorbidities, one of which is sleep disturbance or insomnia. Insomnia can be triggered by various factors, both internal and external. Possible complications caused by insomnia can also vary, including depression and increased cardiovascular risk. Therefore, insomnia is a problem that needs proper attention when treating elderly patients. A variety of diagnostic methods can be used to diagnose insomnia in the elderly. The main recommended therapy is Cognitive Behavior Therapy (CBT). However, various pharmacological agents can also be administered if CBT therapy is ineffective or unavailable, including melatonin and melatonin receptor agonists. These therapies can improve sleep quality, reduce sleep onset latency, and increase the amount of total sleep time. Melatonin and melatonin receptor agonists can be taken without a doctor's prescription. However, melatonin usage is better to be monitored by a doctor to ensure the insomnia has been completely resolved. Thus, the use of melatonin and melatonin receptor agonists can be an alternative therapy in elderly insomnia cases in Indonesia.

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