Original ArticleEffects of ramelteon on insomnia symptoms induced by rapid, eastward travel
Introduction
Jet lag disorder is the result of a temporary misalignment between environmental time cues and the body’s internal circadian clock due to rapid travel across time zones [1]. There are no studies on the prevalence of jet lag disorder since the severity of symptoms is dependent on the number of time zones crossed, the ability to sleep while traveling, the availability and intensity of circadian time cues at the travel destination, individual phase tolerance, and the direction of travel [2]. Eastward travel most often leads to difficulties with sleep onset while westward travel may lead to difficulties with sleep maintenance [1], [3]. Symptoms of jet lag disorder include sleep disturbances, excessive sleepiness, fatigue, gastrointestinal disturbances, and impaired daytime functioning that can persist for several days [1], [3].
Treatment for jet lag disorder includes therapies that accelerate circadian alignment as well as therapies that target sleep disturbances and daytime functional impairment. These treatments include the use of melatonin, light, sedative hypnotics, and stimulants. The American Academy of Sleep Medicine Practice Guidelines recommend the use of melatonin at the appropriate time to reduce the symptoms of jet lag and improve sleep, while light therapy, sedative hypnotics, and caffeine are indicated for optional use [2], [4]. Although light is the strongest synchronizing agent for the circadian clock [5], bright light therapy is often impractical for travelers, and studies have yielded mixed results [2], [6], [7], [8], [9]. Strategies for bright light and melatonin therapy are based on the human light and melatonin phase response curves [5], [10], [11]. For example, jet lag prevention and treatment for eastward travel include advancing circadian rhythms with morning bright-light exposure, nighttime light avoidance several days before travel and avoidance of morning bright light after arrival to align the endogenous phase to the destination environment [10], [12].
In most studies that have assessed the effectiveness of exogenous melatonin treatment for jet lag, melatonin was found to successfully realign the circadian rhythms and alleviate some of the sleep disturbances associated with jet lag. In a study of eight healthy men (age range 30–48 years), melatonin 3 mg taken at 20:00 h local time accelerated re-entrainment of the endogenous melatonin rhythm after an 11-h eastward flight [13]. In another study of 17 healthy men and women (age range 29–68 years) flown across eight time zones, melatonin 5 mg taken at 18:00 h 3 days prior to the flight and at 23:00 h for 4 days after the flight significantly improved subjective sleep parameters and jet lag ratings compared with placebo [14]. In addition, the timing of endogenous melatonin and cortisol rhythms re-entrained more rapidly in the melatonin-treated group compared with the placebo group [14].
Sedative-hypnotics that act on the benzodiazepine site of the GABAA receptor (i.e., zolpidem, zopiclone, temazepam, triazolam) have also been used to treat jet lag, although they target mostly the insomnia symptoms and do not address the circadian misalignment or daytime symptoms [2], [3], [15]. Most of the short-acting hypnotics have been shown to be generally effective at improving sleep after flights across several time zones [3], [16]. In one study, the effects of zolpidem 10 mg on sleep were evaluated in 133 men and women (mean age, 44.9 years) flown eastward across 5–9 time zones. Zolpidem given at bedtime (local time) significantly increased subjective total sleep time on the first night compared with placebo (+64.4 min zolpidem and +12.9 min placebo) [17]. In another study, zopiclone 7.5 mg increased sleep duration on Nights 2 (+0.3 min from baseline) and 3 (+4.0 min from baseline) after a 5-h westward flight in 33 healthy adults (mean age, 51.2 years) compared with placebo on Nights 2 (−30.0 min from baseline) and 3 (−37.0 min from baseline) [18].
Stimulants (i.e., caffeine, modafinil) have been used to decrease fatigue and improve daytime functioning in circadian rhythm sleep disorders [3], [19], [20]. But caffeine is the only agent that has been studied specifically for jet lag. In a study on the effects of caffeine, 27 healthy adults (mean age, 35.3 years) were flown eastward across seven time zones and given either slow-release caffeine 300 mg in the morning after awakening, melatonin 5 mg at bedtime, or placebo on the same schedule [20]. Caffeine decreased sleepiness and increased daytime wrist activity levels compared with placebo and melatonin but it interfered with sleep (increased sleep latency and decreased total sleep time) [20].
Ramelteon is a melatonin receptor agonist that has shown both sleep-promoting and circadian rhythm phase-shifting properties in clinical trials. Ramelteon is an agonist at the MT1 and MT2 melatonin receptors, which are located within the suprachiasmatic nucleus (SCN) of the hypothalamus and play an important role in modulating the sleep–wake cycle [21], [22]. During the day, the SCN produces an alerting signal that helps maintain wakefulness, working in opposition to the accumulation of homeostatic drive for sleep. During the night and under dim-light conditions, melatonin is secreted by the pineal gland and binds to the melatonin receptors in the SCN. Melatonin has both sleep-promoting and circadian phase-shifting properties [23], [24]. The synchronizing and circadian phase re-setting properties of melatonin are thought to be mediated primarily by the MT2 receptor [23], [24], [25], while the sleep-promoting properties are thought to be mediated by the MT1 receptor through acute inhibition of SCN firing [23]. Nevertheless, recent studies have suggested that the functional distinction between the two receptor subtypes may not be so clean and that MT1 and MT2 may play roles in both phase shifting and sleep promotion [26], [27]. Because ramelteon acts on both types of melatonin receptors, it has sleep-promoting and circadian phase re-setting properties. In previous clinical trials, ramelteon has demonstrated the ability to promote sleep and phase-shift circadian rhythms. In participants with transient insomnia, ramelteon 8 and 16 mg significantly reduced latency to persistent sleep (LPS) [28], [29], and in patients with chronic insomnia, ramelteon doses ranging from 4 to 32 mg significantly reduced sleep latencies and increased total sleep times compared with placebo [30], [31], [32], [33]. In a phase-shifting study of 18 healthy adults, ramelteon 4 and 16 mg administered at 17:00 h produced a significant phase advance of the endogenous melatonin rhythm compared with placebo [34]. In another study, 75 healthy adults were given ramelteon 1, 2, 4, or 8 mg or placebo after a 5-h phase advance in their sleep–wake cycle. The lower doses of ramelteon (1, 2, and 4 mg) significantly advanced the endogenous melatonin rhythm compared with placebo [35].
The current study was designed to evaluate the ability of ramelteon to relieve the sleep-onset difficulties and circadian misalignment induced by an eastward flight across five time zones.
Section snippets
Study participants
Healthy adults, aged 18–50 years, with a history of sleep disturbances associated with jet lag (⩾2 occurrences of altered sleep after extended jet travel in the last 3 years) were recruited for this study. Participants were diagnosed with jet lag disorder based on the International Classification of Sleep Disorders diagnostic criteria [36]. All participants were residents of Hawaii and had not left the island for more than 4 consecutive days within 30 days of the initial screening visit.
Participants
A total of 110 participants were randomized to receive study drug, and 109 completed the trial. The flow of participants through the study is shown in Fig. 2. The mean age of all participants was 30.1 years, and 52.7% were male. None of the participants reported difficulties falling asleep or commonly used pharmacological assistance to sleep. The demographics for participants in each group are shown in Table 1.
Sleep parameters
There was a significant reduction in mean LPS for Nights 2–4 in participants taking
Discussion
The results of the current study show that, after a 5-h phase advance due to eastward jet travel, ramelteon 1 mg taken before bed for four nights significantly reduced mean LPS on Nights 2–4 relative to placebo in healthy adults. Ramelteon 4 and 8 mg also reduced mean LPS but did not reach significance compared with placebo. The lack of significant reductions in the higher doses might reflect the smaller sample sizes used in this study (n = 27 for each ramelteon group). There did not appear to be
Conflict of interest
Phyllis Zee has served as a consultant for Takeda, sanofi-aventis, Cephalon, Jazz, Boeringher-Ingelheim, Zeo Inc., Philips and Merck; she has received research and education grants from Takeda and sanofi-aventis; she has participated in speaking programs for sanofi-aventis Japan.
Sherry Wang-Weigand is an employee of Takeda Global Research and Development Center.
Kenneth P. Wright Jr. has received consulting fees, speaker’s fees, clinical trial research contracts and investigator-initiated
Acknowledgements
Assistance with writing and manuscript preparation was provided by Sara Sarkey, PhD, an employee of Takeda Pharmaceuticals North America. This study was funded by the Takeda Pharmaceutical Company Ltd.
References (51)
- et al.
Jet-lag
Lancet
(1997) - et al.
Jet lag: trends and coping strategies
Lancet
(2007) - et al.
The prevention and treatment of jet lag
Sleep Med Rev
(1999) - et al.
How to travel the world without jet lag
Sleep Med Clin
(2009) The sleep–wake cycle and sleeping pills
Physiol Behav
(2007)- et al.
A clinical approach to circadian rhythm sleep disorders
Sleep Med
(2007) - et al.
Zolpidem reduces the sleep disturbance of jet lag
Sleep Med
(2001) - et al.
Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist
Neuropharmacology
(2005) - et al.
Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock
Neuron
(1997) Melatonin receptors: role on sleep and circadian rhythm regulation
Sleep Med
(2007)
Sleep-promoting action of IIK7, a selective MT2 melatonin receptor agonist in the rat
Neurosci Lett
The effects of ramelteon in a first-night model of transient insomnia
Sleep Med
An efficacy, safety, and dose–response study of ramelteon in patients with chronic primary insomnia
Sleep Med
Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia
Sleep Med
Validation of the Karolinska sleepiness scale against performance and EEG variables
Clin Neurophysiol
A human phase-response curve to light
Neurosci Lett
Jet lag: therapeutic use of melatonin and possible application of melatonin analogs
Travel Med Infect Dis
Circadian rhythm sleep disorders. Part I: basic principles, shift work and jet lag disorders
Sleep
Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine Report
Sleep
Influence of light on circadian rhythmicity in humans
How to trick mother nature into letting you fly around or stay up all night
J Biol Rhythms
Light treatment for sleep disorders: consensus report. VII. Jet lag
J Biol Rhythms
Effects of bright light on circadian rhythmicity and sleep after transmeridian flight
Sleep Res
Scheduled exposure to daylight: a potential strategy to reduce “jet lag” following transmeridian flight
Psychopharmacol Bull
A three pulse phase response curve to three milligrams of melatonin in humans
J Physiol
Cited by (58)
Recommended timing of medications that impact sleep and wakefulness: A review of the American Prescribers’ Digital Reference
2023, Sleep Medicine ReviewsCitation Excerpt :This is exemplified by the delayed-release special drug-delivery stimulant formulation of methylphenidate hydrochloride, Jornay PM®; it is not recommended for dosing in the morning like conventional immediate and extended-release methylphenidate hydrochloride products but, rather, in the evening between 18:30 and 21:30 h. Some sleep-impacting medications, especially the prescription melatonin-receptor agonists of ramelteon (Rozerem®) and tasimelteon (Hetlioz®) and OTC melatonin remedies, utilized to treat either insomnia, Smith-Magenis syndrome, delayed sleep-onset insomnia/extreme eveningness phenotype, jet lag, or N24 [30–33] require strict and consistent adherence to recommended scheduling, because the time when dosed can advance, delay, or otherwise disrupt the endogenous 24 h temporal organization [34–38], which can result in compromised wellbeing and even illness [39]. Initially, use of melatonin in the USA was restricted to adults for the self-management of insomnia or jet lag symptoms arising from travel by jet aircraft across multiple time zones.
Body rhythms/biological clocks
2023, Encyclopedia of Mental Health, Third Edition: Volume 1-3Medication effects
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionReview of Select Sleep Medicine Pharmacology: Treatments of Insomnia and Circadian Rhythm Sleep-Wake Disorders
2022, Comprehensive PharmacologyJet lag
2018, Travel MedicineMedication effects
2016, The Curated Reference Collection in Neuroscience and Biobehavioral Psychology