Chapter 103 Melatonin

image Introduction

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone synthesized in reply to neuronal signals arriving from the suprachiasmatic nucleus (SCN) of the anterior hypothalamus.1,2 Its action in promoting sleep and the associated sleep/wake cycle is primarily the result of two G protein-coupled receptors within the SCN called MT1 and MT2.3 Both receptors modulate neuronal activity within the SCN and influence circadian rhythm activation.4 Biochemically, melatonin is synthesized as follows: l-tryptophan to 5-hydroxytryptophan to serotonin. The biogenic amine serotonin is then converted to N-acetylserotonin and ultimately into melatonin with the rate-limiting steps for melatonin production catalyzed by two enzymes, arylalkylamine N-acetyl transferase and hydroxyindole-O-methyltransferase.5 Melatonin is secreted by the pineal gland in response to darkness. This latter action has been elegantly described as the “opening of the sleep gate.”6

image Pharmacokinetics

Peak plasma concentrations of endogenous melatonin in adults reach a high of 60 to 70 pg/mL and typically occur between 2:00 and 4:00 am.5 Supplementary exogenous melatonin, according to the result of one human study, has a 15% absolute bioavailability at the 2- and 4-mg oral doses.7 In another study using 250 mcg of daytime melatonin in healthy volunteers, it was noted that melatonin had a rapid absorption, with a mean time to reach maximal concentration (Tmax) of 23 minutes. The mean terminal half-lives of melatonin were 36 ± 6 minutes and 45 ± 14 minutes, in men and women, respectively.8 Sustained-release melatonin (2 mg), in contrast, has a Tmax of 3 hours, which is delayed in the presence of food (Tmax 0.75 hours). Terminal half-life is 3.5 to 4 hours.9

image Clinical Applications

Jet Lag

Melatonin for the treatment of jet lag has been extensively studied in controlled studies and proven to be remarkably successful in reducing jet lag symptoms.10 In one early double-blind, placebo-controlled study, 20 healthy volunteers (8 women, 12 men; 28 to 68 years) engaging in long-haul air flights across five time zones were invited to participate to explore the effects of melatonin on their jet lag symptoms. Subjects were randomly assigned to 5 mg of melatonin or placebo for three days before their outward flight (London to New Zealand) and during the flight between 10:00 am and 12:00 pm local time, as well as for three days after their arrival between 10:00 pm and 12:00 am. According to the results of visual analogue scale (VAS) testing, those using the melatonin had less overall jet lag symptoms at day 10 (mean score 2.15) versus placebo (3.40; P <0.01). Moreover, the melatonin group experienced a better adaptation pattern in terms of sleep pattern, daytime tiredness, and normal energy levels than the placebo group (P <0.05).11 Although this latter study suggested an optimal time pattern for melatonin use in an eastbound flight, another author noted that bedtime may not be an ideal time to employ melatonin on a westbound flight that crosses less than six to eight time zones. He suggested employing a lower dose of melatonin (0.5 mg) on the westbound flight later in the evening as “melatonin has the least phase shifting effects when it overlaps with endogenous secretion.”12

Acute Sleep

It is estimated that 50 to 70 million American adults have difficulty sleeping.13 This issue of poor sleep quality can have profound consequences for the individual and society at large, including an increased risk of accidents and mood and behavioral changes, as well as a reduction in work productivity.14 One of the numerous options available to help improve overall sleep is melatonin, both in healthy adults as an acute remedy for insomnia and in the elderly dealing with issues of chronic insomnia.

The acute use of melatonin in healthy adults without insomnia at doses of 0.3 to 1 mg at 8:00 or 9:00 pm significantly reduces sleep-onset latency and latency to stage 2 sleep compared with the placebo (P <0.001). Moreover, melatonin does not produce any “sleep hangover” symptoms (according to the Profile of Mood States and Four Choice Reaction Time Test) commonly associated with benzodiazepine-type drug use.15

Prolonged Release Melatonin in the Elderly

After a 2-week single blind run-in period, 354 elderly men and women (55 to 80 years of age) with primary insomnia were randomized to receive 2 mg of a prolonged release (PR) melatonin or placebo 2 hours before bedtime, for 3 weeks. Subjects enrolled in the study were asked to complete a sleep diary measuring quality of day and night, plus a battery of sleep questionnaires including the Pittsburg Sleep Quality Index (PSQI), Leeds Sleep Evaluation Questionnaire (LSEQ), as well as quality of life (World Health Organization-5 [WHO-5] Well Being Index) and clinician Clinical Global Impression (CGI) scores. At the conclusion of the trial, those who took the melatonin had improved (26%) quality of sleep and morning alertness as recorded by the LSEQ in contrast to placebo (15%) (P = 0.014). Sleep latency, as noted by the PSQI results, improved in subjects employing the PR melatonin by 24.3 minutes compared with 12.9 minutes for the placebo group (P = 0.028). Quality of life as recorded by the WHO-5 Index was also improved in the active group (P = 0.034).19 A similar study supported the latter conclusion with a positive effect found on the restorative value of sleep in elderly patients using 2 mg of PR melatonin. Moreover, melatonin users did not experience any rebound insomnia or withdrawal symptoms at the conclusion of the controlled study. The authors noted that plasma cortisol increased in middle-aged adults, and this phenomenon might impair sleep. Administration of PR melatonin in older adults with primary insomnia may delay the production of nighttime cortisol, with subsequent improvements in both sleep quality and morning alertness.20


Fibromyalgia (FM) is a challenging condition with characteristic symptoms that include widespread and variable chronic pain, as well as fatigue, stiffness, cognitive disturbances, depression, and insomnia.25 Although alterations in the secretion of melatonin have been observed in FM patients, whether or not this latter phenomenon contributes to the pathophysiology of this disease remains controversial.26 Several studies suggested, however, that melatonin is of value in treating this chronic musculoskeletal condition.

Twenty-one female patients (average age 51 years) who met the American College of Rheumatology (ACR) criteria for primary FM for at least 6 months before their participation in a uncontrolled pilot study were invited to help evaluate the effects of a 3 mg capsule of melatonin 30 minutes before bedtime for 1 month. Of the 21 patients who completed the study, 19 were found to have a significant reduction from baseline in musculoskeletal tender point count (−28.6%), severity of pain (−33.4%), and sleep disturbances (−67.2%) as measured by VAS (P <0.05). Although fatigue, depression, and anxiety did not show statistical improvement on VAS, the overall physician and patient VAS global treatment assessment scores of FM disease status (with 10 representing the worst score) improved from 7.6 to 5.7 and 7 to 4.7, respectively. Four patients experienced mild and transient side effects during the trial, including tremor, heartburn, anxiety, and somnolence.27

In another randomized, double-blind placebo-controlled trial, 101 patients (6 men, 95 women; 18 to 65 years) with ACR confirmed primary FM were randomized to one of four treatment groups: (A) 20 mg/day fluoxetine and placebo; (B) 5 mg/day melatonin and placebo; (C) 20 mg/day fluoxetine with 3 mg/day melatonin; and (D) 20 mg/day fluoxetine and 5 mg/day melatonin for 2 months. Using the Fibromyalgia Impact Questionnaire (FIQ) to evaluate the clinical outcomes, the researchers determined that compared with baseline, both fluoxetine and melatonin as single therapies significantly reduced within-group symptom scores by 21.5% and 18.9%, respectively (P <0.05). However, those volunteers combining fluoxetine and melatonin at both 3 and 5 mg doses experienced nearly comparable (28.8% vs 28.9%) and highly significant reductions in their FIQ scores (P <0.001). Although all treatments reduced FIQ pain scores, it was interesting to note that the reduction in fatigue scores in groups B, C, and D by 23.7%, 20.3%, and 34.7%, respectively, compared with only 9.9% in the fluoxetine only treatment group. Fluoxetine as a single agent did not alter the rest/sleep score compared with the significant improvements seen in groups B, C, and D.28

Children with Insomnia and Attention Deficit Hyperactivity Disorder

Twenty-seven children (6 to 14 years of age) diagnosed with ADHD and insomnia and employing stimulant medications (i.e., methylphenidate, dextroamphetamine), participated in a controlled trial. Those subjects who did not respond to a 10-day sleep hygiene regimen were randomized to receive 5 mg of melatonin or placebo 20 minutes before bedtime for 1 month. Compared with the placebo, children who took melatonin had a significant reduction in sleep-onset latency as measured by somnolog (46.4 minutes vs 62.1 minutes placebo) and actigraphy (P <0.01) at the conclusion of the trial. Adverse events were considered mild by the investigators. Melatonin treatment and the subsequent improvement in sleep did not, however, improve ADHD symptoms as noted by Conner’s Attention Deficit Scale, Parent version scores.34

One hundred and five medication-free children (aged 6 to 12 years) with ADHD were randomized to receive 3 mg of melatonin or 6 mg of melatonin if body weight was less than 30 kg or greater than 30 kg, respectively, or placebo at 7:00 PM for 30 days. Those subjects who used melatonin had advancements in sleep onset as measured by actigraphy, (26.9 ± 47.8 minutes) compared with a delay (10.5 ± 37.4 minutes) in the placebo group (P <0.0001). Additionally, there was a significant increase in total sleep time (19.8 ± 61.9 minutes) versus a reduction (13.6 ± 50.6) seen in the placebo group (P = 0.01). Children treated with the active compound showed an advance in DLMO of 44.4 ± 67.9 minutes compared with a delay in children who received the placebo (P <0.001). No changes were noted in behavior and cognition. Adverse events did not differ between active groups and placebo.35 A long-term 3.7-year follow-up using the same group of children (93% response rate) verified that melatonin use was not associated with any serious side effects, but also did not provide a permanent cure for insomnia in ADHD children.36

Functional Dyspepsia

Postprandial fullness and early satiation, along with epigastric pain and burning without evidence of upper gastrointestinal structural pathology on endoscopy are the hallmark of Rome III diagnostic criteria for functional dyspepsia.39 One group of researchers suggested that melatonin use stimulates enterocytes to produce bicarbonate, which in turn may help neutralize gastric hydrogen chloride and, therefore, reduce symptoms as evidenced by the following study.40 Sixty patients (18 men, 42 women; ages 19 to 39 years) with a 3 to 12-year history of nonulcer dyspeptic symptoms (i.e., chronic or recurrent epigastric pain) were randomized to receive 5 mg of melatonin or placebo in the evening for 3 months. After 12 weeks of treatment and using a 10-point scale (0 = no symptoms; 10 = maximum symptoms) for therapeutic evaluation, 17 of 30 (56.6%) patients using the melatonin had their condition resolve completely, such that they did not require further treatment, whereas an additional 9 of 30 (30%) patients experienced a partial improvement in symptoms (i.e., reduction in nighttime gastric pain) (P <0.01). Although four patients in the active treatment group noted no change in symptoms, a larger percentage of subjects (93.3%) using placebo noted no change in their condition. The authors noted that those who had a previous infection with Helicobacter pylori were less likely to respond to melatonin treatment.40

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Sep 12, 2016 | Posted by in MANUAL THERAPIST | Comments Off on Melatonin

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