• WOO YUN KIN

CHAPTER 1

INTRODUCTION

1. Research Background

Sleep is not always a luxury. Insomnia is defined as a sleep disorder in which there is an inability to fall asleep or stay asleep as long as desired (Roth T. 2007). It is estimated that up to 34% of adults in the United States and 37% in Europe have some forms of insomnia (Leger D. 2005). Insomnia can be classified to mild, moderate and severe according to the International Classification of Sleep Disorder (ICSD).

Melatonin (5-methoxy-N-acetyltryptamine) is a lipid soluble hormone secreted by the pineal gland during hours of darkness. Melatonin has several physiological functions including regulation of the circadian rhythms, modulation of seasonal change and a powerful antioxidant (Gitto et al. 2013). With age, it has been shown that the 24hour melatonin secretion is significantly reduced thus affecting the normal circadian cycle (Iguchi et al. 1982).

At present, insomnia is typically treated symptomatically, often with benzodiazepine or antidepressants. However chronic insomnia requires long term treatment which may cause significant side effects and unwanted drug-drug interaction. Approximately 29-61% of older adults with insomnia complaints have preexisting sleep apnea (Krakow et al. 2001). With the combination of insomnia and sleep apnea, sedative-hypnotic treatments may worsen the sleep apnea (Mendelson et al. 1981).

Exogenous melatonin is a chronobiotic drug with some hypnotic properties (Zhdanova et al. 1997), it has become of the most frequently non-prescribed sleep aid due to its role in regulating and promoting sleep (Wagner et al. 1998). some studies have shown that supplemental melatonin can increase sleep propensity, although it may not be as effective as prescribed sleep medication (Zhdanova I. 2005).

2. Problem Statement

Sleep adequacy includes, quality, timing and also duration. It has been estimated that the direct health cost of sleep disorder amounts to $1144 million Australian dollars in 2001 (NHS Aus. 2001), and 7.6% of the total motor vehicle accidents(MVA) in 2004 are indirectly caused by sleep disorders amounting to $808million net health costs. Studies have been done to show the benefits of exogenous melatonin for sleep disorders on individuals with intellectual disabilities and adolescence however very little has been done to show its effectiveness on the general population. Malaysia, has one of the highest rate of MVA in the world where according to Malaysian Institute of Road Safety (MIROS), from 1997 to 2007, there has been an increase of 59% of MVA and the main reason identified was driving fatigue due to awkward working hours/shift works (Kee et al. 2010). Availability of exogenous in Malaysia is scarce and it is not fully understood.

3. Research Question

1. How effective is exogenous melatonin in treating insomnia in general population?
2. How safe is exogenous melatonin?

4. Research Objective

1. To review efficacy of exogenous melatonin in treating insomnia
2. To access the safety of exogenous melatonin

5. Significance of Research

Data from available clinical trials and studies done on the efficacy of exogenous melatonin in insomnia will be compiled and compared to enable a more comprehensive and easily accessible result database. With the comprehensive database, clinicians will have a better understanding on the efficacy of MSCs and the best treatment option for the patient, thus improving patients quality of life.

CHAPTER 2

LITERATURE REVIEW

2.1 INSOMNIA

Insomnia is often defined by the presence of an individual’s report of difficulty with sleep (Roth T 2007). The criteria often used in diagnosing insomnia includes i)difficulty falling asleep, staying asleep or nonrestorative sleep, ii) this opportunity is present despite adequate opportunity and circumstance to sleep, iii) this impairment in sleep is associated with daytime impairment or distress and iv) this sleep difficulty occurs at least 3 times per week and has been a problem for the past 1 month (Roth T 2007). The pathophysiology of insomnia can be due to the disorder of the hyper-arousal state throughout the whole day which causes alertness during the day and difficulty in falling or maintaining sleep (Stepanski E, 1988). A cross sectional study done on 156 US air force personal found that 40% suffered from sleep disorder and 75% reported diminished sleep quality while deployed overseas (Peterson AL, 2008). A study done in 2013 (Lentino et al, 2013) showed that 25% of the 14148 army and national guard personal reported to be poor sleepers thus affecting the quality of sleep and the quality of service.

2.2 CURRENT TREATMENT FOR INSOMNIA

Currently the medications used for treating insomnias and other sleep disorders includes benzodiazepine receptor agonist (eg. Zolpidem, zipoclone) which are only limited to short term use (4 weeks) (Sanofi Aventis, 2007). The medication large affects the brain through the GABA receptors and long term use has been associated with memory and balance impairment, rebound imsomnia, withdrawal symptoms and abuse potential (Rush CR, 1999). Recent short termed studies have shown that discontinuation of the benzodiazepines lead to disruption of the sleep architecture and also increases sleep latency which makes withdrawing from treatment difficult (Mann K, 1996).

2.3 MELATONIN

Melatonin (5-methoxy-N-acetyltryptamine) is a lipid soluble hormone that is shown to be involved with the sleep physiology (Dijk D-J, 1997).it is also regulates the modulation of season change, in reproduction, antioxidant, oncostatic, anti inflammatory and anti-convulsant effect (Gitto E, 2013). Melatonin is mostly produced in the pineal gland in the brain during the hours of darkness and is involved in the regulation of the sleep-wake cycle (circadian cycle).the circadian process is maintained by the suprachiasmatic nucleus (SCN) which contains high number of melatonin receptors. During daytime, the SCN produces an arousal signal that maintains the wakefulness and prevents sleep drive however in darkness, there is a feedback loop which causes the release of melatonin which feeds back and inhibits the SCN (Geert et al, 2009) It has been documented that melatonin decreases with age especially in post menopausal women (Okatani Y, 2000). Other than to promote sleep, melatonin also shows sedative and anti-excitory effects (Hardeland R, 2008).

2.4 EXOGENOUS MELATONIN

Exogenous melatonin has become one of the most frequently prescribed over the counter drug for those looking for non-prescription sleep medication (Wagner J, 1998). The exogenous melatonin is marketed to help promote quality sleep, helps in jet lag, or to regulate the circadian cycle due to jet lag or shift work due to its regulator role in the internal timing of biological rhythm. Some studies have shown that exogenous melatonin can help increase the sleep propensity although it may not be as effective as prescribed sleep medications (Zhdanova I, 2005). Studies have also been done regarding the use of exogenous melatonin in the treatment of sleep problems in individuals with sleep disability (Turk 2003) however there are still doubts on the efficacy of exogenous melatonin usage for the general public.

CHAPTER 3

METHODOLOGY

3.1 Research Design

This research was based on the PICOS guidelines :

Population (P): All types of insomnia patients

Intervention (I): Exogenous melatonin

Comparitor (C): Insomnia patients on treatment with exogenous melatonin

compared with other treatment by questionnaires

Outcome (O): Efficacy and safety of treatment

Study design (S): Randomized Controlled trials (RCT), Surveys

3.2 Database

Literature search was done on electronic articles/ journals in Central, PubMed and Google Scholar.

3.3 Keywords

Key words used to search articles with MESH terms were:

1. Insomnia
2. Exogenous melatonin

3.4 Quality Assessment

Quality assessment of the paper was done using Jadad scoring for randomized controlled trials (RCT) and Newcastle-Ottawa Scale (NOS) for case-control and cohort studies.

1.Jaded score assesses the quality of published clinical trials based on methods relevant to random assignment, double blinding and the flow of patients. There are 7 criteria evaluated, whereby 1 point is given if the criteria is met and the last 2 crietria carries a negative mark. Range of score is from 0 (bad) to 5 (good) (Jadad et al. 1996).

i. Was the study described as randomized (this include words such as randomly, random, and randomization)? [+1 point]

ii. Was the method used to generate the sequence of randomization described and appropriate (table of random numbers, computer generated etc)? [+1 point]

iii. Was the study described as double blind? [+1 point]

iv. Was the method of double blinding described and appropriate (identical placebo, active placebo, dummy, etc)? [+1 point]

v. Was there a description of withdrawals and dropouts? [+1point]

vi. Deduct one point if the method used to generate the sequence of randomization was described and it was inappropriate (patients were allocated alternately, or according to date of birth, hospital number, etc)?

vii. Deduct one point if the study was described as double blind but the method of blinding was inappropriate (eg. comparison of table vs. injection with no double dummy)

2. Newcastle-Ottawa Scale (NOS) is developed to assess the quality of the non-randomized studies with its design, content and ease of use directed to the purpose of incorporating the quality assessments in the interpretation of the results. A ‘star system’ is developed to judge on 3 broad perspectives (Wells et al. 2014):

i. The selection of the study groups

ii. The comparability of the groups

3. The ascertainment of either the exposure or outcome of interest for case-control or cohort studies respectively

3.5 Inclusion and Exclusion Criteria

Inclusion criteria

Studies included in this review were chosen according to the flowing criteria :

i. Papers published in English language (2010-2015)

ii. All study designs were included to maximize the data collection

4. Study subjects includes all types of insomnia patients

Exclusion criteria

Studies that were done in foreign language and animal studies were excluded in this review

3.6 Ethical Clearance

The ethical committee of UCSI was notified regarding this thesis write-up

3.7 GAANT Chart

3.8 Milestone

Proposal presentation: 27.02.2015

Submission: 31.03.2015

Data analysis complete: 30.05.2015

Thesis submission: 15.07.2015

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