Disequilibrium: Jet Lag, Motion Sickness, Cold Exposure, and Heat Illness

Melatonin

A nonvisual, photoreceptive, monosynaptic retinohypothalamic tract directly mediates the synchronization of the sleep–wake cycle with the light–dark cycle. Melatonin from the pineal gland modulates this link, as does the light–dark cycle. Melatonin is produced only during nighttime darkness in sighted individuals and is affected only by exposure to bright light. Melatonin resets the phase shift curve marking the circadian phase position. Ingestion of an appropriately timed physiologic dose (0.5 mg) of exogenous melatonin can shift the phase response curve the required number of hours of time zone change. Several studies demonstrate benefits on subjective rating of jet lag. Melatonin delays circadian rhythm when taken in the morning and advances it when taken later in the day. Table 9.1 shows one possible schedule for timing melatonin ingestion for eastward and westward travel beginning the day before departure and continuing for 3 days after arrival. This is time zone traverse-specific.

Times for exposure to bright light are also given there, since light exposure is synergistic with melatonin. The suggested physiologic melatonin dose can produce drowsiness before departure, so the dose can be adjusted downward to that which does not cause unacceptable drowsiness and repeated every 2 hours to a total of 0.5 mg. Over-the-counter preparations available in the United States in health food stores are not standardized nor can potencies be guaranteed. Liquid preparations allow titration of an appropriate dose for an individual. Melatonin is not available in some countries and in others only by prescription. There are no data on long-term safety of exogenous melatonin ingestion nor any reports of safety during pregnancy. A Cochrane review by Herxheimer found reports of short-term adverse effects of melatonin to include confusion, ataxia, headache, convulsant effects, and blood-clotting issues (prothrombin increased or decreased, suspected interaction with warfarin), as well as cardiovascular symptoms including chest pain and dyspnea. People with epilepsy and those taking warfarin or other anticoagulants should not use melatonin without an informed medical discussion.

An alternative dosing schedule is to take melatonin at bedtime on arrival at the destination. Most trials have used large doses, 5-8 mg, continued for 3-7 days after arrival. A commonly reported side effect on this regimen is drowsiness after ingestion.

Nonbenzodiazepine Benzodiazepine-Receptor Agonists (NBRAs)

Short-term pharmacologic manipulation of the sleep–wake cycle with hypnotic drugs to induce sleep is a convenient way to manage jet lag in healthy travelers. There may not be much improvement in performance, and hypnotics do not appear to adjust circadian rhythms in humans. The short-acting drugs known as nonbenzodiazepine benzodiazepine-receptor agonists (NBRAs) have become very popular sleep agents, as typified by zolpidem. Others include zopiclone or the enantiomer eszopiclone, and the even shorter-acting zaleplon. They may be used to treat early awakening, while using melatonin, although studies are lacking and more adverse effects may be expected. Zolpidem, like some short-acting benzodiazepines such as triazolam, has been shown to have idiosyncratic side effects including amnesia, dysphoria, excitability, and somnambulism. Consider a home-based trial before departure to gauge the side effects. Some travelers use these agents during flights, taking them at the destination's sleep time.

The usual adult dose of hypnotics should be halved for first-time users and for geriatric patients, and travelers on NBRAs should be warned not to drink alcoholic beverages or to use other medications that cause drowsiness (e.g., antihistamines) concurrently. Triazolam has been banned or allowed only limited use in several European countries due to reported adverse side effects (psychosis). Other benzodiazepines are longer acting and less suitable for use. Use of these drugs has been associated with increased mortality.

Ramelteon

Ramelteon is a melatonin receptor agonist approved for insomnia and is said to not cause rebound insomnia like the NBRAs and benzodiazepines. It appears to have phase-shifting effects for treating jet lag. One study found that doses of 1 mg at bedtime for four nights in the new destination decreased sleep latency, but light exposure may be more beneficial. Drug interactions and hepatotoxicity may limit extensive use in those with co-morbidities. Ramelteon could also be used like the NBRAs above.

Table 9.2 lists pharmaceuticals to consider for jet lag.

Armodafinil

One study has found that armodafinil, a wakefulness-promoting drug, increased wakefulness after eastward travel in a dose of 150 mg in the morning on arrival. Side effects such as headache, nausea, and diarrhea may limit its use. Modafinil may also be useful but neither drug is FDA-approved for this use.

Agomelatine

Older people who adapt less well to jet lag could be treated with agomelatine, a melatonergic antidepressant, although studies of its efficacy are lacking, and it is not available in the United States.

Sleep Schedule Adjustment

Traditional advice has been to adjust the sleep schedule, beginning 3 days before departure, gradually moving bedtime closer to the customary time at the destination. For instance, if traveling eastward, a traveler would try to go to bed 1 hour earlier each succeeding night in the 3-day period before departure. Smartphone applications are available to help calculate sleep times. If traveling westward, the traveler would try to stay up 1 hour later each night in the pre-travel period. Because it is easier to stay up later than to retire earlier, westward flights across a few meridians result in faster adaptation than eastward ones. Naps should be avoided on eastbound trips. It is useful to exercise before, during, and after the flight and to maintain good hydration.

If traveling across multiple time zones and returning after a day or two, it is better not to try to adjust to the proximate destination but to maintain the home sleep schedule. If traversing more than three time zones, scheduling a stop-over of a day or more in the travel itinerary may help with readjustment of the sleep–wake cycle. Resetting the watch early on each flight to the new local time at destination is advisable for orientation. On arrival at the destination, activities should be scheduled that are appropriate for the new local time. For the first few days after arrival at a destination, major decisions should be avoided if possible, and important meetings should be scheduled at the individual's most alert time of the day at home. Vigorous physical exercise on arrival—mid-morning for travel east and late afternoon for going west—helps.

Bright Light Exposure

The circadian clock can be shifted by exposure to bright light. Such techniques are of no value for the blind. To use principles of phototherapy to reset the circadian clock, the traveler should expose him- or herself to intense bright light (7000-12,000 lux, comparable to that of natural sunlight at sunrise). An exposure time of approximately 5-9 hours is needed. Light episodes before 0400 (at the originating time zone) retard the circadian clock, whereas those after 0400 (at the originating time zone) advance the clock. Thus travelers going eastward should expose themselves to bright light for a few hours early every morning after arrival at the destination. Those traveling westward should expose themselves to bright light in the late afternoon. Three to four days of such light exposure will entrain the original clock and allow it to be reset for sleeping at the destination time zone bedtime ( Table 9.3 ).

The required light level can be measured with a digital camera (operating in manual mode). When set for ISO50, a camera meter reading of f:5.6 at 1/60 s indicates the brightness comparable to 11,000 lux. Short wavelength light exposure (blue, green), even if less intense, may be more effective than white light.

Wearing an eye shield on the plane or sitting by an unshaded window at the appropriate times can contribute toward circadian clock resetting during the journey. Enhancing destination time–appropriate sleep with ear plugs or playing soothing sounds on an audio device may help. On arrival, sunglasses are best not worn when it is necessary to get exposed to bright light, and it is advisable to be outdoors when possible. Wear a visor and/or sunglasses when outdoors in bright light that is not at an appropriate time. When indoors, the window curtains should be open and bright room lights should be kept on during the period of phototherapy. Indoor light is much dimmer than required, but it can shift the circadian clock.

Often travel schedules and conditions may prevent a traveler from using scheduled exposures to bright light to facilitate an adaptation to the new time zone.

Jet Lag Diet and Other Remedies

The Argonne National Laboratory Jet Lag Diet tries to reset the circadian rhythm by alternative feasting and fasting, beginning 3 days before departure, and by timing the consumption of high-protein breakfasts and lunches, high-carbohydrate dinners, and caffeine. There is one study using it to advantage in US soldiers traversing nine time zones. Websites calculate this timed diet, and there are apps for smartphones to help adjust to the new time zone. Slow-release caffeine in a dose of 300 mg taken in the morning on arrival appears to have benefits to increase wakefulness. This may be more beneficial than 2 cups of espresso coffee. Other remedies, such as “anti-jet lag” pills sold over the counter or plant products, are of questionable efficacy.

In summary, jet lag is unavoidable; there are substantial individual variations in symptoms; and there are many ways of minimizing its effects.