The tried and true and what might be new Philippe Lagacé Wiens, MD FRCPC, DTM&H

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1 The tried and true and what might be new Philippe Lagacé Wiens, MD FRCPC, DTM&H

2 Accepted honoraria from Bayer. Travel grants from Siemens Healthcare Diagnostics and Sanofi Pasteur. Owns shares in Astra Zeneca as part of a diversified portfolio. None are relevant to the content of this presentation.

3 1. Define jet lag in terms of symptoms and cause. 2. Describe the role of light and melatonin in the normal circadian rhythm 3. Explain how light and melatonin can be used to reset the circadian clock. 4. Give two behavioural strategies to treat/prevent jet lag 5. Name three drugs that can be used to alleviate symptoms of jetlag.

4 Diagnosis is straightforward: Following transmeridian jet travel of at least two time zones (30º), there is: Presence of insomnia or excessive daytime sleepiness. Impairment of daytime function, general malaise or somatic symptoms such as gastrointestinal disturbance within 1 2 days of travel. Disturbance is not better explained by another current sleep disorder, medical or neurological disorder, mental disorder, medication or substance use disorder. Travel in the North/South direction does not lead to jet lag no matter the distance. Travel Med Infect Dis Mar;7(2):

5 Jet lag is associated with the developments of severe psychoses that depend on the direction of travel. Major depressive episodes after Westbound travel Bipolar affective disorder (mania) after Eastbound journeys. One study found that severe psychiatric illness in travellers occurred 2.5x more often in those who travelled >7 time zones compared to those that travelled less. Curr Psychiatry Rep Mar 2. Travel Med Infect Dis Jan-Mar;6(1-2):17-28.

6 Jet lag is caused by a misalignment between the internal clock (circadian clock) and the external environment. Circadian time is out of phase with local time. Is a direct consequence of transmeridian travel speed exceeding the circadian clocks intrinsic resetting ability. Circadian clock resets slowly: 92 minutes per day for Westbound travel 57 minutes per day of Eastbound travel N Engl J Med 2010; 362:

7 Number of time zones crossed. Direction of travel Usually worse with Eastbound travel Jet lag does not occur with travel in the North or South Direction. Sleep debt Pre travel sleep debt and ongoing sleep loss during travel. Availability of local time cues at destination, mainly light. N Engl J Med 2010; 362:

8 Generally increasing age is associated with less tolerance. There is substantial individual variability in the susceptibility to jet lag. Genetic factors (PER, TIMELESS and CLOCK genes) regulate circadian rhythm and variations lead to tolerance or susceptibility to jet lag (and shift work) PER3 variant associated with extreme morningness is associated with reduced tolerance to jet lag. In general morning people are less tolerant to jet lag. Sleep Med Rev Aug;13(4): N Engl J Med 2010;362:440-7.

9 Circadian rhythms are very primitive Exist in the simplest multicellular organisms. Evolved in concert with Earth s rotation on itself and around the sun. Serve to synchronize species appropriate behaviours with the changing environment and to anticipate changes in environment. Predicts both daily changes (day/night) and seasonal changes. Travel Med Infect Dis Mar;7(2): Travel Med Infect Dis Mar;7(2):60-8.

10 In animals, including humans, circadian rhythms are driven by the suprachiasmatic nuclei in the hypothalamus. The neurons of the nuclei express clock related genes in an endless feedback loop resulting in cyclical expression. As genes are expressed, their products increase until they inhibit their own expression One full cycle of gene expression lasts ~24.5 hours. The free cycling internal clock has ~24.5 hours. Travel Med Infect Dis Mar;7(2): N Engl J Med 2010;362:440-7.

11 The suprachiasmatic nuclei are located just above the optic nerves and are part of the hypothalamus. The nuclei receive signals from the optic nerves and the brain. The nuclei send signals to other parts of the hypothalamus, and the pineal gland. Travel Med Infect Dis Mar;7(2):102-10

12

13 On off signals from the SCN drive a variety of physiological events including body temperature, cortisol production, appetite, gastrointestinal function, feeding, sleep/wake cycle and melatonin production by the pineal gland. Cycle occurs without any external stimuli. The timing of the on off switch (the phase) and fine tuning is driven by internal and external stimuli called zeitgebers. Travel Med Infect Dis Mar;7(2):102-10

14 The most important cue for determining circadian phase is light. Signals directly from the optic nerve adjust the phase of the SCN activity. Blind individuals usually have a free running cycle regardless of time of day. Other weak time keepers include meal times, clocks, exercise, activity. The most important internal time keeper is melatonin. Travel Med Infect Dis (2):60-8. Travel Med Infect Dis (2): Travel Med Infect Dis (2): 69-81

15 When the circadian clock is aligned with the environment, the system is said to be in phase or entrained. When the circadian clock is not aligned with the environment, the system is said to be out of phase or unentrained. Systems unentrained are unstable and revert to entrained systems in the presence of external and internal stimuli. Travel Med Infect Dis (2):60-8. Travel Med Infect Dis (2): Travel Med Infect Dis (2): 69-81

16 When internal circadian signals (e.g. signal to sleep) occur later than they do in the environment, a phase advancement is required. When internal circadian signals (e.g. signal to sleep) occur earlier than they do in the environment, a phase delay is required. N Engl J Med ;362(5):440-7.

17 Circadian rhythm is in phase with environment (start of night mode begins at correct time). Circadian rhythm is out of phase with environment. Entrainment requires a shift to earlier time (Phase advancement) Entrainment requires a shift to later time (Phase delay) N Engl J Med ;362(5):440-7.

18 The direction and magnitude of light effect on the circadian phase is highly dependant on timing. Intense light in the evening of the cycle promotes a phase delay. Light given in the morning of the cycle promotes phase advancement. At a point during the night, the effect of light abruptly changes from phase delay (brain interprets light as dusk) to phase advancement (brain interprets light as dawn). Infection point Phase alteration is strongest just before and just after infection point. In most people, inflection point occurs between 4AM and 5AM. Light before 4AM is interpreted as afternoon/evening light and light after 5AM is interpreted as morning light. Light has no effect on phase during the middle part of the day. N Engl J Med ;362(5): Travel Med Infect Dis (2):102-

19 Sleep Medicine Reviews 13 (2009)

20 Adjusting to a new time zone can be dramatically accelerated by targeted exposure to intense light during the most sensitive parts of the response curve. Targeted exposure to light between midnight and 3AM leads to a 2.5 hour phase delay. Between 5 and 8AM leads to a 2.5 hour phase advancement. Key to successful timed light exposure for reentrainment is to have light exposure during the correct period and avoiding light during counterproductive periods. Travel Med Infect Dis Mar;7(2): N Engl J Med 2010;362: Travel Med Infect Dis Mar;7(2):60-8.

21 In a trip from Winnipeg to Paris, a seven hour phase advancement is needed. Timed exposure to light from 5 6AM to noon Winnipeg time (noon to 7PM Paris time) is ideal to accelerate phase adjustment. Light should be avoided between 8PM and 2AM Winnipeg time (3AM and 9AM Paris time) as this will cause unwanted phase delays (interpreted as an extension of dusk by the circadian clock) Timed exposure to light should step back 1 2 hours per day for 3 4 days. Travel Med Infect Dis Mar;7(2): N Engl J Med 2010;362: Travel Med Infect Dis Mar;7(2):60-8.

22 In a trip from Winnipeg to Maui, a five hour phase delay is needed. Timed exposure to light from 8PM to 2AM Winnipeg time (3PM to 9PM Maui time) is ideal to accelerate phase adjustment. Light should be avoided between 5AM and noon Winnipeg time (midnight and 7AM Maui time) as this will cause unwanted phase advancement (interpreted as an earlier dawn by the circadian clock) Timed exposure to light should continue for 2 3 days, stepping forward 1 2 hours per day. Travel Med Infect Dis Mar;7(2): N Engl J Med 2010;362: Travel Med Infect Dis Mar;7(2):60-8.

23 N Engl J Med 2010;362:440-7.

24 Ideal timed exposures are seldom feasible during travel. Practical recommendations that still mostly respect circadian physiology can be made: When travelling East <9 zones, get exposure to light in the morning (but not too early!). When travelling West <9 zones, get exposure to light in the evening (but not too late!) When travelling East 9 zones, avoid light for 3 hours after dawn for 3 days, then get exposure to light in the morning When travelling West 9 zones, avoid light for 3 hours before dusk for 3 days, then get exposure to light in the evening N Engl J Med 2010;362: Travel Med Infect Dis. 2009; 7(2):69-81.

25 A hormone produced by the pineal gland in response to the night signals from the SCN. Only secreted in darkness (even if night signal is on) Function is largely unknown. Modulates species specific nocturnal behaviours. Duration of secretion modulates seasonal behaviours and mood. Lowers body temperature Is only mildly sedating at large doses. Is not a sleeping pill and should not be considered as one for the purpose of jet lag management. Travel Med Infect Dis Mar;7(2): Sleep Med Rev Aug;13(4): N Engl J Med Feb 4;362(5): Sleep Med Rev Aug;13(4): Travel Med Infect Dis Jan-Mar;6(1-2):17-28

26 Melatonin is the strongest internal modulator of circadian phase. Receptors on the SCN respond in a feedback mechanism to presence of melatonin and adjust the internal clock accordingly. Peak levels of melatonin mark the middle of night phase, and adjust the suprachiasmatic nuclei s rhythm accordingly. Travel Med Infect Dis Mar;7(2): Sleep Med Rev Aug;13(4): N Engl J Med Feb 4;362(5): Sleep Med Rev Aug;13(4): Travel Med Infect Dis Jan-Mar;6(1-2):17-28

27 Melatonin effect on circadian rhythm is approximately the opposite of light. Direction and magnitude of effect on phase is dependant on timing of administration. Administration in the circadian early morning causes a phase delay while administration in the late afternoon causes a phase advance. There is virtually no effect of melatonin given during the circadian night. Travel Med Infect Dis Mar;7(2): Sleep Med Rev Aug;13(4): N Engl J Med Feb 4;362(5): Sleep Med Rev Aug;13(4): Travel Med Infect Dis Jan-Mar;6(1-2):17-28

28 Sleep Medicine Reviews 13 (2009)

29 Sleep Medicine Reviews 13 (2009)

30 Melatonin works effectively to re entrain circadian rhythms to environment after jet travel. Shortens duration of insomnia, daytime fatigue and reduces time to normal function. To be effective, has to be given at the appropriate time (in line with the endogenous clock). Ideally, timing needs to be individualized. N Engl J Med Feb 4;362(5): Travel Med Infect Dis Mar;7(2):69-81 Cochrane Database Syst Rev. 2002;(2):CD

31 Travelling from Winnipeg to Paris, a 7 hour phase advancement is required on arrival. At the time of arrival, circadian time = Winnipeg time. Optimal time for melatonin induced phase advancement is 4 5PM (Winnipeg time) = 11PM midnight Paris time. Ideally, ~3 mg melatonin should be taken at ~11PM for optimal phase advancement. If taken earlier will have much less pronounced effect. Melatonin taken at 9PM (2PM Winnipeg time) will have virtually no effect on phase. Melatonin taken at 8PM may have the opposite effect (phase delay) and be counterproductive. Melatonin should be taken for 3 5 days, each day 1 2 hours earlier.

32 Travelling from Winnipeg to Hawaii, a 5 hour phase delay is required on arrival Optimal time for melatonin induced phase delay is 7 8AM (Winnipeg time) = 2 3 AM Hawaii time. Ideally, mg melatonin should be taken at 2 AM for optimal phase delay. Shorter acting dose If taken earlier (anywhere between 8PM and 1 AM), there will be NO beneficial effect. Melatonin taken between 10AM and 7PM may have the opposite effect (phase advance) and be counterproductive. Melatonin should be taken for 3 5 days, each day 1 2 hours later.

33 N Engl J Med 2010;362:440-7.

34 Strict adherence to melatonin dosing times is easier than timed light exposure, but still hard to swallow. Basic recommendations can be made that are mostly effective: For eastbound travel, take melatonin at the destination bedtime. For westbound travel <9 zones, take melatonin sometime in the second half of the destination night. For westbound travel 9 zones, take melatonin at the destination bedtime. There is no strong evidence that pre departure melatonin improves symptoms more than postarrival. N Engl J Med 2010;362: Cochrane Database Syst Rev. 2002;(2):CD

35 Jet lag psychosis (mania and depression) appears to be related to circadian dysrhthmia. Individuals who suffer from jet lag associated mania may be misdiagnosed as having either true depressive or bipolar disorders or medication/drug induced psychosis. Melatonin appears to be curative in small case series. Role for use in prevention? Curr Psychiatry Rep Mar 2. J Clin Psychopharmacol. 2001;21(3):

36 Melatonin appears safe and has very few side effects in the doses and duration prescribed for jet lag management. Randomized trials show no significant difference in side effects between placebo and melatonin groups. Case reports suggest the possibility of warfarin interaction (increased bleeding risk). Case reports suggest the possibility of reducing seizure threshold (cause versus impact on anti convulsant levels?). Case reports of drug rash. Rare reports of palpitations and mood changes. Not readily attributable to melatonin. Cochrane Database Syst Rev. 2002;(2):CD

37 Ramelteon is a long acting melatonin analog. Studied in eastbound jetlag, given before bed. 1 mg dose significantly reduced the duration of jet lag symptoms. Tasimelteon is another analog recently evaluated for sleep time shift mg was associated with significant improvement in sleep function. Agomelatine is an antidepressant with both melatonin like activity and SSRI activity. Animal studies suggest re entrainment occurs more quickly after phase shifts. Phase alterations in hormone release (melatonin, cortisol) have been observed in humans. Anti depressant activity suggests a possible role in preventing depressive disorders associated with jet lag. Travel Med Infect Dis (1-2):17-28 Sleep Med Rev. 2009;13(4): Travel Med Infect Dis. 2009; 7(2):69-81

38 Melatonin and timed light exposure do not alleviate symptoms of jet lag, they reduce the duration of the circadian misalignment. Generally the improvement is in number of days travellers experience insomnia, fatigue etc Neither melatonin nor light exposure significantly improve the quality or quantity of sleep in the days immediately after travel. Melatonin works quite effectively, but only if taken the right way. Travel Med Infect Dis (1-2):17-28 Sleep Med Rev. 2009;13(4): Travel Med Infect Dis. 2009; 7(2):69-81

39 Some behavioural strategies can help reduce the impact of jet lag. Get well rested prior to the trip. Stay up and sleep in for a few days before a westbound flight. Tuck in early and rise early for a few day prior to an eastbound flight. Remain hydrated. Use caffeine strategically. Optimize comfort especially on the flight Maintaining home time Works for short trips. Sleep Med Rev. 2009;13(4): N Engl J Med. 2010; 362(5):440-7.

40 Travellers are frequently faced with uncomfortable symptoms with jet lag that are not immediately relieved by re entrainment. Symptomatic management of the principle symptoms of jet lag is possible: Insomnia Daytime sleepiness Cravings for hamburgers at 4AM or beer at 7AM cannot be treated. N Engl J Med Feb 4;362(5):440-7.

41 Use of sedative hypnotics for short periods has been shown to improve sleep and reduce awakenings caused by jet lag. In general, short acting drugs should be used during jet travel and short or medium acting drugs for preventing insomnia on arrival. Benzodiazepines: Lorazepam (1mg), triazolam (0.5mg), temazepam (15mg) Non benzodiazepines: Zopiclone (5mg), zolpidem (5 10mg), zaleplon (10mg), eszopiclone (2mg) N Engl J Med Feb 4;362(5): Curr Psychiatry Rep Mar 2.

42 All hypnotics should be used with caution as reports of confusion, amnesia, including global amnesia are not uncommon. Avoid alcohol, try test dose. Start at the lowest recommended dose unless patient is experienced with sedatives. Warn patient of side effects. Some studies have shown potentiating of confusion and grogginess when given with melatonin. N Engl J Med Feb 4;362(5):440-7.

43 Naps during the day are a good way to combat sleepiness. Short naps do not interfered with circadian reentrainment. Ideally taken between 9AM and 5PM home time. Avoids endogenous melatonin production. Avoid napping during key times for light exposure. Light during these times is critical for re entrainment. Two drugs have shown benefit for daytime somnolence associated with jet lag: Caffeine and Armodafinil N Engl J Med Feb 4;362(5):440-7.

44 Caffeine, given as a 300mg sustained release capsule in the morning has been studied in eastbound travel. Reduces subjective daytime sleepiness. Some apparent effect on circadian re entrainment Caused subjectively more complaints in nocturnal sleep. Caffeine should be avoided in the afternoon. Immediate release capsules or coffee may reduce nocturnal complaints compared to sustained release forms. N Engl J Med Feb 4;362(5):440-7.

45 Armodafenil is a wakefulness promoting agent originally marketed for narcolepsy. Mechanism not clearly understood Shown to be effective for shift work sleep disorder and jet lag at a dose of 150mg at 7AM (local time). Improved alertness using both objective measurements and subjective reports. Headache and nausea are the most commonly reported side effects. Modafenil is a related drug which should provide the same benefits. Mayo Clin Proc Jul;85(7):630-8.

46 Three strategies to fight jet lag Behaviours Rest, hydration, pre adjustment of sleep. Re entrainment: Shortens duration of symptoms Strategic light exposure Melatonin (or analogs?) Symptom relief: Management of insomnia and daytime fatigue. Sedative/hypnotics Caffeine, modafenil, armodafenil

47 1. Arendt J. Managing jet lag: Some of the problems and possible new solutions. Sleep Med Rev Aug;13(4): Auger RR, Morgenthaler TI. Jet lag and other sleep disorders relevant to the traveler. Travel Med Infect Dis Mar;7(2): Brown GM, Pandi Perumal SR, Trakht I, Cardinali DP. Melatonin and its relevance to jet lag. Travel Med Infect Dis Mar;7(2): Coste O, Lagarde D. Clinical management of jet lag: what can be proposed when performance is critical? Travel Med Infect Dis Mar;7(2): Herxheimer A. Jet lag. Clin Evid (Online) Dec 4;2008. pii: Herxheimer A, Petrie KJ. Melatonin for preventing and treating jet lag. Cochrane Database Syst Rev. 2001;(1):CD Review. Update in: Cochrane Database Syst Rev. 2002;(2):CD Katz G, Durst R, Knobler HY. Exogenous melatonin, jet lag, and psychosis: preliminary case results. J Clin Psychopharmacol Jun;21(3): Katz G, Durst R, Knobler HY. Exogenous melatonin, jet lag, and psychosis: preliminary case results. J Clin Psychopharmacol Jun;21(3): Rosenberg RP, Bogan RK, Tiller JM, Yang R, Youakim JM, Earl CQ, Roth T. A phase 3, double blind, randomized, placebocontrolled study of armodafinil for excessive sleepiness associated with jet lag disorder. Mayo Clin Proc Jul;85(7): Sack RL. Clinical practice. Jet lag. N Engl J Med Feb 4;362(5): Sack RL. The pathophysiology of jet lag. Travel Med Infect Dis Mar;7(2): Srinivasan V, Spence DW, Pandi Perumal SR, Trakht I, Cardinali DP. Jet lag: therapeutic use of melatonin and possible application of melatonin analogs. Travel Med Infect Dis Jan Mar;6(1 2): Waterhouse J, Reilly T. Managing jet lag. Sleep Med Rev Aug;13(4):247 8.

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