Cochrane for Clinicians: Putting Evidence Into Practice - December 1, 2002

COCHRANE FOR CLINICIANS
PUTTING EVIDENCE INTO PRACTICE

Can Melatonin Prevent or Treat Jet Lag?

JOHN SMUCNY, M.D.,
State University of New York Upstate Medical University, Syracuse, New York

A patient information handout about jet lag, written by the author of this article, is provided on page 2094.

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. John Smucny, M.D., presents a clinical scenario and question based on the Cochrane Abstract, along with the evidence-based answer and a full critique of the abstract.

Clinical Scenario

A 50-year-old healthy businesswoman is planning to fly to Germany for a conference. She asks you whether she should take melatonin to prevent jet lag.

Clinical Question

Can melatonin prevent or treat jet lag?

Evidence-Based Answer

Daily doses of 0.5 to 5 mg of melatonin, taken at the target bedtime at the destination for two to five days after arrival, lessen the effects of jet lag.

Cochrane Abstract

Background. Jet lag commonly affects air travelers who cross several time zones. It results from the body's internal rhythms being out of step with the day-night cycle at the destination. Melatonin is a pineal hormone that plays a central part in regulating bodily rhythms and has been used as a drug to realign them with the outside world.

Objectives. To assess the effectiveness of oral melatonin taken in different dosage regimens for alleviating jet lag after air travel across several time zones.

Search Strategy. The authors searched the Cochrane Controlled Trials Register, MEDLINE, EMBASE, PsychLit, and Science Citation Index electronically, as well as the journals Aviation, Space and Environmental Medicine, and Sleep by hand. They then searched citation lists of relevant studies for other relevant trials. They also asked principal authors of relevant studies to tell them about unpublished trials. Reports of adverse events linked to melatonin use outside randomized trials were searched for systematically in Side Effects of Drugs (SED) and Side Effects of Drugs Annuals (SEDA), Reactions Weekly, MEDLINE, and the adverse-drug-reactions databases of the WHO Uppsala Monitoring Centre (UMC) and the U.S. Food and Drug Administration (FDA).

Selection Criteria. Randomized trials in airline passengers, airline staff, or military personnel who were given oral melatonin that was compared with placebo or other medication. Outcome measures consisted of a subjective rating of jet lag or related components, such as subjective well-being, daytime tiredness, onset and quality of sleep, psychologic functioning, duration of return to normal, and indicators of circadian rhythms.

Data Collection and Analysis. Ten trials met the inclusion criteria. All compared melatonin with placebo; in addition, one compared it with a hypnotic, zolpidem. Nine of the trials were of adequate quality to contribute to the assessment,¹ and one had a design fault and could not be used. Reports of adverse events outside trials were found in MEDLINE, Reactions Weekly, and the WHO UMC database.

Primary Results. Nine of the 10 trials found that melatonin, taken close to the target bedtime at the destination (10 p.m. to midnight), decreased jet lag resulting from flights crossing five or more time zones. Daily doses of melatonin between 0.5 and 5 mg are similarly effective, except that people fall asleep faster and sleep better after 5 mg than after 0.5 mg. Doses of more than 5 mg appear to be no more effective. The relative ineffectiveness of 2 mg of slow-release melatonin suggests that a short-lived higher peak concentration of melatonin works better. Based on the review, the number needed to treat (NNT) is two. The benefit is likely to be greater if more time zones are crossed and less for westward flights.

The timing of the melatonin dose is important; if it is taken at the wrong time, early in the day, it is liable to cause sleepiness and delay adaptation to local time.

The incidence of other side effects is low. Case reports suggest that people with epilepsy and patients taking warfarin might be harmed by melatonin.

Reviewers' Conclusions. Melatonin is remarkably effective in preventing or reducing jet lag, and occasional short-term use appears to be safe. It should be recommended to adult travelers flying across five or more time zones, particularly in an easterly direction, and especially if they had jet lag on previous journeys. Travelers crossing two to four time zones also can use it if need be.

The pharmacology and toxicology of melatonin needs systematic study, and routine pharmaceutical quality control of melatonin products must be established. The effects of melatonin in people with epilepsy and a possible interaction with warfarin should be investigated.

These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in The Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (www.cochrane.org).

Cochrane Critique

Did the authors address a focused clinical question? Yes.

Were the criteria used to select articles for inclusion appropriate? Yes.

Is it likely that important relevant articles were missed? No. One recent trial that was identified was not included in the review because it still was being assessed.

Was the validity of the individual articles appraised? Yes. Studies were assessed for allocation concealment and blinding.

Were the assessments of studies reproducible? Not mentioned.

Reading the Numbers

The authors of this review stated that the studies that were included had satisfactorily minimized the four major types of bias that lead to erroneous conclusions: selection bias, performance bias, attrition bias, and detection bias. Selection bias is a systematic difference between the participants in the groups that are being compared. It is prevented by proper randomization and concealment of allocation. Performance bias is a systematic difference in the care--apart from the intervention that is being studied--provided to the groups. It is prevented by blinding patients and providers (double blinding). Attrition bias is a systematic difference between groups with regard to the participants who withdraw. It is minimized by intention-to-treat analyses, high rates of follow-up, and by examining the reasons for withdrawal between comparison groups. Detection bias is a systematic difference in outcome assessment and is prevented by blinding the study personnel who perform the outcome measurements.

Were the results similar from study to study? Yes. Nine of the 10 studies showed that volunteers who were given melatonin had better outcomes than volunteers who were given a placebo. The study that did not show benefit consisted of volunteers on a return flight to Europe who had only five days of adaptation in the United States, and therefore might not have been fully adapted before their return flight.

How precise were the results? Fairly precise. A meta-analysis of a global visual analog jet lag score that included data from five studies showed that on a scale of zero to 100 points, there was a difference of 37 points (with a narrow 95 percent confidence interval of 35 to 40) between the melatonin and placebo groups.

Can the results be applied to patient care? Yes.

Do the conclusions make biologic and clinical sense? Yes.

Are the benefits worth the harms and costs? Yes, except for people taking warfarin or who have epilepsy. One bottle of 30 to 100 tablets (1.5 or 3 mg) costs less than $10.

Practice Pointers

The available evidence shows that melatonin reduces the severity of jet lag, with a low risk of complications when used properly. The Cochrane abstract might overstate the evidence, however, because the NNT was based on data from only two trials and a total of 46 travelers (the remaining studies did not report dichotomous data and therefore could not be included in this calculation).

In the United States, the use of melatonin might be problematic. Because it is considered a dietary supplement and not a medication, its safety and efficacy have not been evaluated by the U.S. Food and Drug Administration. Some melatonin products contain one of the contaminants associated with the eosinophilia-myalgia syndrome in l-tryptophan users,² and some do not meet the standards of the U.S. Pharmacopeial Convention General Tests and Assays for Nutritional Supplements.³

The most effective dosage regimen seems to be 0.5 to 5 mg taken at bedtime on the day of arrival and again on the next two to five days, with 5 mg working the best. There does not seem to be any benefit to taking melatonin before departure, and taking it earlier in the day might make jet lag worse.

REFERENCES

Herxheimer A, Petrie KJ. Melatonin for the prevention and treatment of jet lag (Cochrane Review). Cochrane Database Syst Rev 2002;2:CD001520.
Williamson BL, Tomlinson AJ, Naylor S, Gleich GJ. Contaminants in commercial preparations of melatonin. Mayo Clin Proc 1997; 72:1094-5.
Hahm H, Kujawa J, Augsburger L. Comparison of melatonin products against USP's nutritional supplements standards and other criteria. J Am Pharm Assoc 1999;39:27-31.

John Smucny, M.D., is director of undergraduate education in the family medicine department at the State University of New York Upstate Medical University, Syracuse, N.Y.

Address correspondence to John Smucny, M.D., Department of Family Medicine, Upstate Medical University, State University of New York, Syracuse, NY 13210 (e-mail: smucnyj@upstate.edu). Reprints are not available from the author.

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