Jet Lag: The Role of Sleeping Tablets and Other Treatments

Jet lag is commonly understood as a state of fatigue experienced as a result of air travel, most often long-haul flights that involve moving from one time zone to another. Some researchers dismiss this condition as a subjective manifestation of sleep disruption while on the flight, and the stresses of returning to normal functions after disembarking from a plane. However, other studies have reported links between the perception of jet lag and physiological measures of the sleep-wake (or circadian) cycle, which is largely controlled by the brain.

Jet lag is popularly understood to involve feelings of tiredness and sluggishness following air travel, but may also include other symptoms. These may include:

• Impaired alertness
• Increased confusion
• Difficulty in getting to sleep at night
• Decreased appetite
• Reduced coordination
• Negative and/or depressive mood

Some research indicates that jet lag may also be associated with negative effects on some pre-existing mood disorders, including seasonal affective disorder.

Jet lag may be associated with disruptions in the body's physiological 'internal clock' or light-dark cycle. This is also known as the circadian (meaning 'roughly 24 hours') system, which is basically controlled by a region of the brain called the suprachiasmatic nucleus (SCN). Jet lag may be caused by the discrepancy between these rhythms (i.e. by the SCN 'telling' the body what 'time' it is) and the 'actual' hour in the time zone of the destination in question.

Therefore, effective treatment of jet lag may be achieved by strategies that 'reset' the body's internal clock to compensate for this and 're-align' it with the new external time-frame. Alternatively, treatments that combat the insomnia often associated with jet lag may help the body adjust, by accounting for sleep discrepancies and thus restoring normal circadian rhythms.

Treatments for Jet Lag

Melatonin

This is a hormone-like molecule that plays an important role in the control of the sleep-wake cycle. The SCN is regulated by melatonin receptors, and is 'activated' by levels of melatonin that reach a 'peak' at a subjective bed-time, which is usually concurrent with decreased light exposure. This causes the SCN to send signals to other parts of the brain, which culminates in an urge to sleep at the end of the day. The secretion of melatonin, and thus normal circadian cycling, is thought to become disrupted in response to prolonged air travel. Therefore, supplemental melatonin (which is commercially available with a prescription in Australia) may effectively prevent jet lag. It is recommended that this is taken before departure for journeys crossing up to eight time zones.

In the case of destinations further away than this, taking melatonin two to three days in advance may be advisable. This strategy has also been shown to effectively treat jet lag post-flight, if taken between the hours of 10pm and midnight in the destination time zone when crossing five time zones or more.

A review of ten trials suggests that short-term courses of 5mg melatonin supplements are most effective in the treatment of jet lag. Melatonin has some side-effects, the most common of which are sleepiness and sedation during waking hours. However, melatonin has a short duration of activity when ingested. In response to this, drugs that mimic its chemical structure - but have an enhanced ability to activate the receptors of the SCN - have been developed to treat circadian rhythm disorders such as jet lag. These are known as melatonin agonists.

Melatonin agonists

These drugs are similar in structure and function to melatonin, but have a longer duration of effect. The most prominent of these are:

Ramelteon: This is a drug developed with the goal of higher affinity (the ability to bind to and activate) at melatonin receptors than melatonin itself. Ramelteon is indicated for disorders such as insomnia. A double-blind trial randomised 110 adults to 0mg (i.e. placebo), 1mg, 4mg or 8mg doses of ramelteon five minutes before bedtime for four nights following an eastward flight over five time zones.

The time taken to achieve sleep decreased to a moderately significant degree on the second night onward in the 1mg group. In addition, negative effects in immediate recall tests were significantly increased in all groups except the placebo group on the fourth day of the trial.

Agomelatine: This is a drug which also has strong affinity for the melatonin receptor. It is regarded as effective in the treatment of disorders such as insomnia. However, there is little research into its effects on patients with jet lag. A double-blind trial randomised eight elderly adults (a group associated with impaired adaptation to circadian disruption compared to younger adults) to 50mg agomelatine or placebo for 15 days. The agomelatine group experienced changes in physiological measures of the circadian rhythm, but no significant effect on any measures of sleep.

Sedatives (benzodiazepines)

These are often termed 'sleeping tablets' (or 'hypnotics' or 'anxiolytics'), despite their lack of direct effect on the SCN. Instead, they mimic the effects of a neurotransmitter called GABA, which has inhibitory effects on movement, anxiety, alertness and memory formation. In other words, they are sedative medications. Benzodiazepines are often indicated in the treatment of anxiety disorders and insomnia, but are also associated with adverse effects such as addiction, drowsiness and amnesia. The research on the effects of benzodiazepines in jet lag is limited. A small-scale trial of 17 adults flying westward across five time zones were randomised to 10mg temazepam or a placebo. The results were inconclusive, but indicated that benzodiazepine had no effect on subjective or objective measures of jet lag. The short-acting benzodiazepine triazolam has been shown to be effective in animal models of jet lag. Two double-blind trials randomised six adults to 0.5mg triazolam or placebo in an experimental model of jet lag (which simulated a westward flight resulting in an eight-hour circadian discrepancy) four days following this simulation at bedtime. There was a significantly improved return to normal sleep-wake rhythms in the triazolam group compared to placebo. Systematic review indicates that there is little data supporting a beneficial effect of these drugs in other forms of sleep disorders. In addition, there is increasing evidence that certain brain processes controlled by GABA may actively disrupt optimal circadian cycling.

Hypnotics

These drugs are also known as non-benzodiazepine hypnotics, as they act at a receptor for GABA­, but with a shorter duration of action and thus reduced adverse effects. Hypnotics include popular drugs such as zolpidem.

A multi-centre, double-blind trial randomised 130 adult travellers to 10mg zolpidem or placebo for three to four nights following eastward flights crossing between five and nine time zones.

Sleep quality and total sleep time were significantly improved in the treatment group compared to the placebo group. However, hypnotics may still cause side-effects such as nausea, drowsiness and amnesia. Therefore, they may be unsuitable for those who travel for professional purposes.

Alternative and/or Novel Treatments

As mentioned above, circadian rhythms are influenced by a cycle of light exposure and darkness throughout a period of approximately 24 hours. Therefore, light therapy (in which the patient is exposed to bright light meant to replicate or compensate for natural light exposure) may contribute to the 'circadian reset' needed to address conditions such as jet lag, thus promoting the ability to sleep normally after a long-haul flight. Laboratory studies (using fruit flies, which are commonly used in clinical trials of sleep medicine interventions as their circadian rhythms (and the genes involved) are similar to those of humans) on dim light exposure in the 'dark phase' following experimental models of jet lag have yielded promising results. In addition, there is some support for the combination of light therapy and melatonin for the treatment of jet lag, although the results of this may vary due to individual differences in circadian rhythms, the direction of travel and the number of time zones crossed.

References

1. Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Jet lag: therapeutic use of melatonin and possible application of melatonin analogs. Travel medicine and infectious disease. 2008;6(1-2):17-28.
2. Fowler P, Duffield R, Howle K, Waterson A, Vaile J. Effects of Northbound Long-haul International Air Travel on Sleep Quantity and Subjective Jet-Lag and Wellness in Professional Australian Soccer Players. International journal of sports physiology and performance. 2015.
3. Kostoglou-Athanassiou I. Therapeutic applications of melatonin. Therapeutic advances in endocrinology and metabolism. 2013;4(1):13-24.
4. Sinam B, Sharma S, Thakurdas P, Kasture M, Shivagaje A, Joshi D. Dim scotopic illumination accelerates the reentrainment following simulated jetlags in a diurnal experimental model, Drosophila. Communicative & integrative biology. 2013;6(1):e22279.
5. Becker T, Penzel T, Fietze I. A new German Charite Jet Lag Scale for jet lag symptoms and application. Ergonomics. 2014:1-10.
6. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. The Cochrane database of systematic reviews. 2002(2):Cd001520.
7. Choy M, Salbu RL. Jet Lag: Current and Potential Therapies. Pharmacy and Therapeutics. 2011;36(4):221-231.
8. Zee PC, Wang-Weigand S, Wright KP, Jr., Peng X, Roth T. Effects of ramelteon on insomnia symptoms induced by rapid, eastward travel. Sleep medicine. 2010;11(6):525-533.
9. Ferguson SA, Rajaratnam SM, Dawson D. Melatonin agonists and insomnia. Expert review of neurotherapeutics. 2010;10(2):305-318.
10. Leproult R, Van Onderbergen A, L'Hermite-Baleriaux M, Van Cauter E, Copinschi G. Phase-shifts of 24-h rhythms of hormonal release and body temperature following early evening administration of the melatonin agonist agomelatine in healthy older men. Clinical endocrinology. 2005;63(3):298-304.
11. Morin CM, Daley M, Ouellet MC. Insomnia in Adults. Current treatment options in neurology. 2001;3(1):9-18.
12. Reilly T, Atkinson G, Budgett R. Effect of low-dose temazepam on physiological variables and performance tests following a westerly flight across five time zones. International journal of sports medicine. 2001;22(3):166-174.
13. Buxton OM, Copinschi G, Van Onderbergen A, Karrison TG, Van Cauter E. A benzodiazepine hypnotic facilitates adaptation of circadian rhythms and sleep-wake homeostasis to an eight hour delay shift simulating westward jet lag. Sleep. 2000;23(7):915-927.
14. McCleery J, Cohen DA, Sharpley AL. Pharmacotherapies for sleep disturbances in Alzheimer's disease. The Cochrane database of systematic reviews. 2014;3:Cd009178.
15. Liira J, Verbeek JH, Costa G, et al. Pharmacological interventions for sleepiness and sleep disturbances caused by shift work. The Cochrane database of systematic reviews. 2014;8:Cd009776.
16. Freeman GM, Jr., Krock RM, Aton SJ, Thaben P, Herzog ED. GABA networks destabilize genetic oscillations in the circadian pacemaker. Neuron. 2013;78(5):799-806.
17. Jamieson AO, Zammit GK, Rosenberg RS, Davis JR, Walsh JK. Zolpidem reduces the sleep disturbance of jet lag. Sleep medicine. 2001;2(5):423-430.
18. Parry BL. Jet lag: minimizing it's effects with critically timed bright light and melatonin administration. Journal of molecular microbiology and biotechnology. 2002;4(5):463-466.