Case scenario

Penny, 45, is planning a trip from Sydney to Los Angeles to attend a conference, where she is presenting her latest nursing research the day after her arrival. Penny’s previous international trips have been complicated by daytime sleepiness, impaired concentration, irritability, and difficulty falling and staying asleep in the new time zone. She wants to know what she can do to avoid jet lag. Penny does not take any other medicines.

Learning objectives 

After reading this article, pharmacists should be able to: 

  • Explain the pathophysiology of jet lag and contributing factors
  • Discuss the role of immediate-release melatonin for jet lag
  • Describe key advice for patients when supplying melatonin over the counter for jet lag 
  • Discuss the non-pharmacological interventions to reduce jet lag. 

Competency standards: 1.1, 1.4, 1.5, 3.1, 3.5

Already read the CPD in the journal? Scroll to the bottom to SUBMIT ANSWERS.

Introduction

Long-haul air travel across multiple time zones is often associated with jet lag (also known as time zone change syndrome).1 Jet lag is a result of desynchronisation (a mismatch) between the body’s circadian rhythm and the final flight destination’s day/night cycle.2

Symptoms of jet lag include disrupted or poor nocturnal sleep, daytime sleepiness, impaired alertness and performance, malaise, irritability, and gastrointestinal symptoms (constipation and diarrhoea).2,3 While jet lag spontaneously resolves within a few days to several weeks, in the short term it can severely impair general functioning and performance.3,4

The Therapeutic Goods Administration (TGA) has down- scheduled – to Schedule 3 Pharmacist Only – immediate-release melatonin preparations (containing 5 mg or less melatonin) for the treatment of jet lag in adults aged 18 years or older.5

Pharmacists can offer advice and treatment to minimise the effects of jet lag and must ensure that pharmacological treatment is used safely and correctly.5

Pathophysiology of jet lag 

To comprehend jet lag and its effects an understanding of the body’s circadian rhythm and regulation is needed. 

Circadian comes from the Latin phrase “circa diem,” which means “around a day”.3 Circadian rhythm is a 24-hour internal clock in our brain that helps to regulate alertness and sleepiness (sleep/ wake cycle) in response to changes in environmental light.6 It also regulates several other physiological processes, including body temperature, hormone secretion and gastrointestinal function.3,7

The retinohypothalamic tract (RHT) transmits information from the eye’s retina, which detects information about environmental light, to the brain’s hypothalamus, specifically the suprachiasmatic nucleus (SCN).6,8

When the SCN (also known as the circadian pacemaker)9 detects exposure to light, it indirectly reduces the pineal gland’s secretion of melatonin into circulation, whereas exposure to darkness increases melatonin secretion. Hence, melatonin is commonly called the ‘hormone of darkness’.8 Melatonin then binds to MT1 and MT2 receptors that are present in the SCN and hypothalamus, promoting fatigue and sleep.10,11

Melatonin receptors are also widely distributed throughout the rest of the brain (e.g. the cerebellum, cerebral cortex) and the body (e.g. the retina adipose tissue).12 Increased circulating melatonin coincides with a reduction in core body temperature.11

When is jet lag most severe? 

Jet lag is more severe and longer lasting when an individual travels across multiple time zones and when travel is eastward.13

A difference of 15 degrees between longitudinal lines (which run north to south) equates to a 1-hour time zone difference. Crossing five or more longitudinal time zones is associated with greater jet lag, as there is a greater mismatch between an individual’s circadian rhythm and the day/night cycle of the destination.14,15

Melatonin

There is a large body of evidence that exogenous melatonin is a safe and effective treatment to prevent or reduce the severity of jet lag.16,17 This evidence has informed the recent decision by the TGA to add immediate-release melatonin for jet lag to Schedule 3 of the Poisons Standard.17

In Australia, pharmacists can recommend and supply melatonin as a Pharmacist Only medicine:

  • To treat jet lag in adults aged 18 or older with an immediate-release preparation containing 5 mg or less melatonin.5,17 The Therapeutic Guidelines4 recommend:
    • Immediate-release melatonin 0.5-5 mg orally to be taken on the plane at bedtime of the final destination. Melatonin can be taken for up to 3 more nights.4,17
    • Note: immediate-release melatonin is currently accessible via the Special Access Scheme and from compounding pharmacies.8 A commercial product may become available given this scheduling change. 
  • For short-term use as monotherapy in primary insomnia with poor sleep quality in people aged 55 or older (with a modified-release tablet containing 2 mg or less of melatonin).17,18 The Australian Medicines Handbook recommends: 
    • 2 mg of controlled-release tablet swallowed whole, 1-2 hours before bedtime and after food. This dosage may be continued for up to 13 weeks.10 

Adverse effects

Current evidence suggests melatonin has a favourable safety profile.19 A recent systematic review found that daytime sleepiness, headache, dizziness and hypothermia were the most common adverse events of melatonin.20 Other adverse effects include nasopharyngitis, back pain and arthralgia.21 Interestingly, recent research suggests that melatonin may actually reduce the severity of chronic back pain.22

Drug interactions 

Pharmacists should be aware of the following interactions and advise patients accordingly: 

  • Alcohol should not be consumed when taking melatonin, as both exogenous and endogenous melatonin’s effectiveness is reduced.23-25
  • Melatonin taken in combination with other sedatives (e.g. benzodiazepines and non-benzodiazepines) can potentiate sedative effects.23-26 Concomitant administration should be avoided.23
  • Concurrent administration of melatonin and fluvoxamine should be avoided.23 Melatonin is a substrate for and metabolised by CYP1A2 and fluvoxamine is an CYP1A2 Inhibitor. When taken in combination, fluvoxamine inhibits melatonin metabolism, increasing melatonin concentration and subsequent drowsiness.23

Non-pharmacological interventions for jet lag 

The pharmacist can recommend non- pharmacological interventions to reduce jet lag, as outlined in Table 1: Interventions to reduce jet lag. A systematic review by Bin et al27 explored the effectiveness of non-pharmacological interventions and found that light exposure and avoidance before, during and after the flight to reduce circadian misalignment should reduce jet lag symptoms. However, there is a paucity of high-quality research to determine the effectiveness of other non-pharmacological interventions.27

Table 1: Interventions to reduce jet lag

Before travel During travel After travel (i.e. at the final destination) 
  • Plan the journey in advance and determine how many time zones are being crossed, and the direction of travel.
  • Starting 3 days before departure, shift both sleep and wake time by 30 minutes per day so that the sleep cycle more closely resembles the time zone at the travel destination.
  • For eastward travel, go to sleep 30 minutes earlier and avoid light in the evening (including electronics), wake earlier and seek bright light in the morning.
  • For westward travel, go to sleep later and seek bright light in the evening, wake later and avoid light in the morning.
  

  • Set watch to destination time at the start of the flight.
  • Plan in-flight sleep as if it was the time at the destination.
  • Prevent dehydration – drink plenty of water, avoid alcohol, tea and coffee, and apply lubricant eye drops as needed.
  • Eat small meals frequently, choosing lighter foods like fruit and vegetables (fibre-containing foods).
  • Whenever possible, walk around the cabin during destination daytime.
  • Use layers of clothing to allow adjustment to temperature variation.
  • Delay sleep until night-time in the new time zone; if sleep deprived, take a short nap (up to 30 minutes).
  • Remain in the dark during the night, even if unable to sleep.
  • Only sleep during the night.
  • Maximise exposure to natural light during the day.
  • Adults: consider drinking 1–3 caffeinated beverages in the morning to improve daytime alertness; avoid caffeine after midday in the new time zone because it can delay night-time sleep.
  • Change the daily routine (meals, activities) to the new time schedule as soon as possible.
  • Control external environmental cues that push the body’s circadian rhythm towards the destination’s day/night cycle.

References: Up to Date2, Therapeutic Guidelines4, Herxheimer15

Knowledge to practice 

With the recent scheduling change of immediate-release melatonin for jet lag to Pharmacist Only (Schedule 3), pharmacists can now recommend an evidence-based treatment for this condition. While melatonin is considered a relatively safe treatment, pharmacists should counsel on the common adverse effects and potential interactions and advise the individual about non-pharmacological interventions to reduce jet lag. 

Conclusion 

Jet lag commonly affects air travellers who cross several time zones and is a result of a misalignment between the body’s circadian rhythm and the final flight destination’s day/night cycle. To speed up the circadian phase shift, a short course of immediate-release melatonin can be recommended and supplied by a pharmacist, with appropriate counselling, to prevent or reduce jet lag symptoms. 

Case scenario continued 

As Penny is travelling eastwards across multiple time zones, jet lag is likely. You recommend a short course of immediate-release melatonin 5 mg, to be taken for the treatment of jet lag. You supply the maximum pack size of 10 tablets. You advise Penny to take one tablet at the new time zone’s night-time, for up to 4 consecutive days. The first can be taken in-flight at the destination’s night-time. The same can be done to help realign her body clock when travelling home. You advise Penny that to help reduce the duration of jet lag, she should delay sleep until night-time in the new time zone, remain in the dark during the destination’s night-time (even if unable to sleep) and only sleep when it is dark.

Key points

  • Jet lag is a result of desynchronisation between the body’s circadian rhythm and the final flight destination’s day/night cycle. 
  • Immediate-release melatonin (preparations containing 5 mg or less) can be recommended for individuals 18 years of age and over to reduce the duration and symptoms of jet lag. 
  • Non-pharmacological interventions may also be effective (see ‘Interventions to reduce jet lag’, p52) 

This article is accredited for group 2 CPD credits. Click submit answers to complete the quiz and automatically record CPD against your record.

SUBMIT ANSWERS

If you do get an enrolment error, please click here

References

  1. Pandi-Perumal S. Melatonin Signaling as a link between sleep and circadian biology: practical implications. Synopsis of Sleep Medicine. Apple Academic Press;2016:143–170.
  2. Goldstein C. Jet lag. UpToDate, Wolters Kluwer. At: www-uptodate-com.ezproxy.canberra.edu.au/contents/jet-lag?search=melatonin%20jetlag&source=search_result&selectedTitle=1~133&usage_type=default&display_rank=1#H3958420951. 2023.
  3. Sack RL. The pathophysiology of jet lag. Travel Med Infect Dis 2009;7:102–10.
  4. Therapeutic Guidelines, Psychotropic Jet lag. Therapeutic Guidelines Limited. https://tgldcdp.tg.org.au/viewTopic?etgAccess=true&guidelinePage=Psychotropic&topicfile=delirium&guidelinename=auto&sectionId=r_ptg8-c44-ref1#r_ptg8-c44-ref1. 2021.
  5. Therapeutic Goods Administration. Notice of final decisions to amend (or not amend) the current Poisons Standard – 3 May 2023. 2023. At: www.tga.gov.au/sites/default/files/2023-05/notice-of-final-decision-to-amend-or-not-amend-the-current-poisons-standard-acms-40-accs-34-joint-acms-accs-32.pdf
  6. Reddy S, Reddy V, Sharma S. Physiology, circadian rhythm. In: StatPearls [Internet]. StatPearls Publishing; 2022.
  7. Danilov A, Kurganova J. Melatonin in chronic pain syndromes. Pain Ther 2016;5:1–17.
  8. Zisapel N. New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation. Br J Pharmacol 2018;175:3190–99.
  9. Bernard S, Gonze D, Čajavec B et al. Synchronization-induced rhythmicity of circadian oscillators in the suprachiasmatic nucleus. PLoS Comput Biol 2007;3:e68.
  10. Rossi S, ed. Other drugs for anxiety and sleep disorders. Australian Medicines Handbook 2023; [updated 2023 Jan]. At: https://amhonline.amh.net.au/chapters/psychotropic-drugs/drugs-anxiety-sleep-disorders/other-drugs-anxiety-sleep-disorders?menu=vertical
  11. Doghramji K. Melatonin and its receptors: a new class of sleep-promoting agents. J Clin Sleep Med 2007;3(5 Suppl):S17–23.
  12. Cecon E, Oishi A, Jockers R. Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol 2018;175:3263–80.
  13. Roach GD, Sargent C. Interventions to minimize jet lag after westward and eastward flight. Front physiol 2019;10:927.
  14. Herxheimer A, Petrie KJ, Group CCMD. Melatonin for the prevention and treatment of jet lag. Cochrane Database of Systematic Reviews. 1996;2010.
  15. Herxheimer A, Waterhouse J. The prevention and treatment of jet lag: It’s been ignored, but much can be done. In: British Medical Journal Publishing Group; 2003:296-–7.
  16. Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag. Cochrane Database of Systematic Reviews 2002, Issue 2.
  17. Therapeutic Goods Administration. Notice of interim decisions to amend (or not amend) the current Poisons Standard – 3 February 2023. 2023. At: www.tga.gov.au/sites/default/files/2023-02/public-notice-of-interim-decisions-acms-40-accs-35-joint-acms-accs-32-november-2022.docx
  18. Therapeutic Goods Administration. Summary for ARTG Entry: Circadin melatonin 2 mg prolonged release tablet blister pack. Department of Health and Aged Care. 2022. At: www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=153959&agid=(PrintDetailsPublic)&actionid=1
  19. Foley HM, Steel AE. Adverse events associated with oral administration of melatonin: a critical systematic review of clinical evidence. Complement Ther Med 2019;42:65–81.
  20. Besag FMC, Vasey MJ, Lao KSJ, et al. Adverse events associated with melatonin for the treatment of primary or secondary sleep disorders: a systematic review. CNS Drugs. 2019;33:1167–86.
  21. Emet M, Ozcan H, Ozel L, et al. A review of melatonin, its receptors and drugs. Eurasian J Med 2016;48(2):135–41.
  22. Kurganova YM, Danilov A. A role of melatonin in the treatment of low back pain. Zh Nevrol Psikhiatr Im S S Korsakova 2015;115:30–5.
  23. Rossi S, ed. Interactions. Australian Medicines Handbook 2023; [updated 2023 Jan]. At: https://amhonline.amh.net.au/interactions/melatonin-inter
  24. Circadin Product Information. eMIMS cloud, [2023]. At: www.emims.com.au/Australia/drug/info/Circadin/Circadin?type=full
  25. Gendy MNS, Lagzdins D, Schaman J, et al. Melatonin for treatment-seeking alcohol use disorder patients with sleeping problems: a randomized clinical pilot trial. Sci Rep 2020;10(1):8739.
  26. Otmani S, Demazieres A, Staner C, et al. Effects of prolonged‐release melatonin, zolpidem, and their combination on psychomotor functions, memory recall, and driving skills in healthy middle aged and elderly volunteers. Human Psychopharmacology: Clinical and Experimental. 2008;23:693–705.
  27. Bin YS, Postnova S, Cistulli PA. What works for jetlag? A systematic review of non-pharmacological interventions. Sleep Med Rev 2019;43:47–59.

Our author

Dr Mary Bushell (she/her) BPharm (Hons), GCTLHE, PhD, AACPA, MPS is a pharmacist and a Clinical Assistant Professor at the University of Canberra.

Our reviewer

Julie Briggs (she/her) BPharm, AcSHP, MPS

RELATED ARTICLESMORE FROM AUTHOR