Sleep Arghhh! (Part 2: Light and melatonin treatments)

This post addresses special circumstances where people may require more than just behavioural treatment for sleep disturbances.

The following topics will be covered: Jet Lag, Shift Work Disorder, Delayed Sleep Phase Disorder (more common in adolescence) and treatment of sleep disturbance in people with an Autism Spectrum Disorder (ASD).

Feel free to skip to the heading that interests you but I strongly recommend reading the background information on the body clock and the effects of artificial light on sleep (first two headings). I will summarize some of the main points and terms at the end of these two sections to make it a little easier to understand.

It is important that you refer to the additional information on exogenous melatonin*at the end of this post, as melatonin may pose risks for certain groups of people.

Sleep and the Body Clock

Sleep is maintained by two processes; a homeostatic process where the less sleep you get the more tired you feel and the easier it is to fall asleep and a circadian process1;2.

At the centre of the circadian process of sleep is the ‘body clock’. The suprachiasmatic nuclei, located in the hypothalamus, are the site of the body clock2. Among other functions, the body clock promotes activity in the daytime and recovery and restitution during the night2.

The body clock coordinates the secretion of melatonin by the pineal gland3. The body clock, secretion of melatonin and core body temperature rhythms are synchronized to one another and responsible for the regulation of circadian rhythms including the sleep-wake, neuroendocrine and core body temperature cycles2.

The body clock and circadian rhythms will operate in the absence of environmental cues with a period that is a little over 24 hrs (hence the use of the term circadian)2. This period of time is intrinsic to the body clock2.

Light is a powerful suppressor of melatonin secretion, and as a result melatonin is mainly produced during the night4;5. Melatonin acts as a ‘darkness’ indicator and acts to synchronise the sleep-wake cycle with the light-dark cycle2;6.

FYI: There is not enough evidence that diet can shift the body clock timing2. Therefore there will be no discussion of diet this in this post. Exercise may assist to synchronize the body clock to the optimal sleep –wake cycle but to a much lesser extent than light as it exerts a much weaker effect2. I will not expand on the effects of exercise in this post. Perhaps I will revisit it in a later post.

When the body clock sleep-wake cycle does not match the light-dark cycle or the demands of the environment it may result in sleep disorders such as in the case of travel across multiple time zones (jet lag), night shift work and delayed circadian phase disorder (more common in adolescence). Fortunately, light therapy and exogenous melatonin* can be useful to manage these disorders and I will expand on the use of these later in this post.

Summary:

Among other functions the body clock is responsible for coordinating the sleep-wake cycle i.e. when you wake and when you sleep. The body clock helps to coordinate the sleep-wake cycle by producing more melatonin at night, which has a hypnotic effect (makes you sleepy). The sleep-wake cycle is programmed to repeat approximately every 24 hours, with the ideal starting and finishing times for sleep determined by the body clock.

The light-dark cycle refers to the environmental cycle of day and night. Day is usually defined by light and night by dark. We are usually more active during the day and less active during the night.

Usually when the sleep-wake cycle (determined by the body clock) is synchronized with the light-dark cycle (determined by the environment) then the better the quality of sleep at the set times.

Effects of Artificial Light on Sleep

Czeisler (2013) quotes Thomas Edison, in his perspective article on artificial light and the sleep-wake cycle: ‘The use of electricity for lighting is in no way harmful to health, nor does it affect the soundness of sleep’5. On the contrary, Czeisler (2013) argues that the invention of the electric light is the primary reason why people now experience insufficient sleep with the more recent invention of Light Emitting Diodes (LEDs) compounding the problem.

Why is artificial light (regardless of the source) such a problem for night-time sleep? The answer is simple, light exposure after sunset signals ‘daytime’ to the body clock, delaying the secretion of melatonin and shifting the sleep-wake cycle later 5. Demands of the day (eg. work, school) are likely to result in us needing to wake before the delayed sleep component of the sleep-wake cycle is complete resulting in less sleep and increased sleepiness

LED lighting is unique in several aspects to other sources of artificial light. Solid-state LED lighting tends to be more durable, compact, versatile and energy efficient5. It is widely used in TVs and computer screens, laptops, tablets and hand-held devices5.

Solid-state white light is more rich in blue light than other artificial light sources and melatonin secretion is most sensitive to blue and blue-green light5;7;8. In fact, night-time exposure to LEDs has been shown to be more disruptive to circadian rhythms, melatonin secretion and sleep than other artificial lighting5;7;8.

It is not surprising to me that we are more sensitive to the light reflected from the sky, water, grass and trees (blue and blue-green). It would make sense that our bodies would be optimally evolved to synchronize with our natural environment. If grey buildings and smog filled skies are all we have access too, perhaps that impacts our quality of sleep too?

It is undeniable that exposure to bright light (regardless of the source of light) in the evening does affect the soundness of sleep (most of the references for this post will support that). Therefore an important good sleep habit is to avoid bright light sources and LED technology such as televisions, tablets and computers close to bedtime.

Summary:

Light exposure in the evening suppresses the secretion of melatonin and delays the sleep-wake cycle. The sleep-wake cycle remains the same length of time (of approximately 24 hours) but the start and finish of sleep is delayed  i.e. the body finds it easier to go to sleep later and wake up later and the quality of sleep at this new set 24 hour period is therefore better. This is unlikely to be ideal if sleeping-in is not compatible with daytime functioning and waking up earlier will result in a reduced duration of sleep and increased daytime sleepiness.

Jet Lag

Jet lag is a sleep disorder that results from crossing time zones too rapidly for the body clock’s sleep-wake cycle to adapt6.

The symptoms of jet lag consist primarily of insomnia and daytime sleepiness but can also include increased stress, diminished physical performance, cognitive impairment and gastrointestinal disturbances2;6.

Jet lag is distinct from nonspecific travel fatigue, which occurs as a consequence of prolonged immobility, irregular sleep times and mealtimes, dehydration and other factors associated with travel that are not related directly to the crossing of time zones6.

It usually only takes a day or two to recover from travel fatigue with adequate diet, rest and sleep but symptoms of jet lag persist until the body clock is synchronized with the new light-dark cycle, which is often much longer6.

Jet lag symptoms vary between individuals and some people experience little to no jet lag while others who take the same flight are extremely affected9.

Fortunately, for those who are more extremely affected, carefully timed exposure to light has been shown to help hasten the adjustment of the body clock’s sleep-wake cycle by delaying or advancing it. Appropriately timed melatonin ingestion can also be useful in preventing jet lag2;6;9.

However, if you are only staying for a few days or less before returning home, it may be easier to try to maintain the sleep-wake schedule from home after arrival at your destination but this may not suit your travel arrangements or obligations6.

If you are staying for longer than three days and/or maintaining your home sleep-wake schedule is not suitable, a simple recommendation for travel across up to eight time zones is to seek exposure to bright light in the morning after eastward travel and in the evening after westward travel 6. You might want to think of a simple phrase to help you remember when to seek light exposure like ‘Easty toast, Westy roast’ (I’m sure you can think of a better phrase).

Because advancing the clock is usually more difficult than delaying it, some experts recommend that all flights that cross more than 8 to 10 time zones be treated as if they were westward2;6 (Gutsy Easty roast, Westy roast’).

For Eastward flights it may be of benefit to partially adjust the sleep-wake cycle to the new time zone in the days before the flight by combination of advancing sleep time (bringing bedtime forward by 1-2 hrs per day) with bright light on rising for the 3 days before the flight2;6. Advancement of more than this amount is likely to cause sleep disturbances and be difficult to implement2.

Melatonin* may also be used to advance the body clock before eastward flights by ingestion in the evening in the days before departure2.

With regard to melatonin, as many as one in two people who use exogenous melatonin* to combat jet lag may benefit3 (Waterhouse 2003). It is not known whether exogenous melatonin* works due to it’s natural hypnotic effect or because it promotes adjustment of the body clock3. Generally 3-5mg of melatonin* taken close before bedtime has been shown to be effective in improving sleep during jet lag2;9.

Melatonin* is not approved by the Food and Drug Administration (FDA) for any indication6. However, no major or consistent adverse events have been reported in the clinical trials that have been performed to date6. Waterhouse (2003) explains that ‘no pharmacological company wants to pay for the toxicological studies and the data assembly required to obtain a product license because it cannot have exclusivity’3. This is of concern given the likely benefits to many groups of people and professionals3.

Short acting hypnotics have also been found to reduce insomnia related to jet lag2;6. I will not to go into detail about these but you can enquire with your local medical practitioner.

With regard to daytime functioning, there is evidence that caffeine can temporarily alleviate fatigue from jet lag throughout the day2. The drug Modafinil may also be useful for alleviating fatigue during the day2;6 and seems to be without side effects2

Please refer to the table attached below, which is copied from the review by Sack (2010) for more detailed advice on how to minimize travel fatigue and jet lag6.

For the Jet Lag section

Delayed Sleep Phase Disorder (DSPD) (more common in adolescence)

Delayed sleep phase disorder represents a state where the sleep-wake cycle is delayed 3-6 hours relative to the most functional or ‘normal’ sleep-wake cycle1;10. When obliged to interrupt the sleep-wake cycle, due to work or school or other commitments, people will suffer from the usual symptoms of insomnia such as excessive sleepiness and have difficulty waking up in the morning1;10.

Although DSPD is not common in the general population, it is more common among adolescents (7-16%)1;10. Untreated DSPD is likely to negatively impact upon academic performance and psychological health among adolescents and underlying depression is often comorbid with DSPD10.

Effective treatments for DSPD include chronotherapy, timed bright light exposure and exogenous melatonin* 1;10.

Chronotherapy is a lengthy and demanding treatment and requires specialist guidance and the full support of family. It involves gradually delaying bedtimes by 3 hours every 2 days, until the bedtime has moved around the clock (by about 20 hours) to reach the desired bedtime1;10.

Bright light exposure in the early morning for example 6-8am for about 1 -3 hours is usually effective in advancing the sleep-wake cycle1;10. Bright natural light is ideal but if not available bright artificial light is a suitable substitution10.

In the treatment of DSPD, exogenous melatonin* should be given 4-6 hours before bedtime1;10. You may notice that the timing is earlier for the administration of melatonin in DSPD compared to the treatment of other sleep disturbances but this is shown to be the most effective timing for this condition1;10.

Regardless of the treatment regime, good sleep habits are still important, including limiting the use of technology at night (especially one hour or less before bedtime), establishing regular sleep and wake times, and avoiding caffeine (especially four hours or less before bedtime)10.

Specialist assessment and diagnosis is recommended so as not to be confused with people who have delayed sleep patterns without functional impairment or with other sleep disorders.

Circadian Rhythm Sleep Disorder, Shift Work Type (Shift Work Disorder)

Symptoms of shift work disorder (SWD) results when people are required to work and sleep at times at times that do not match their body clocks sleep-wake cycle causing insomnia and excessive sleepiness which may persist for several days even after returning to usual sleep-wake times1.

The prevalence of SWD is approximately 10% in night and rotating shift workers1.

Obviously there are Occupational Health and Safety risks involved with being excessively sleepy in the workplace and on the drive home from work. Shift work is associated with increased injuries and accidents11.

Effective treatments for SWD include bright light therapy and exogenous melatonin*1;11. This can help to adjust the body clocks sleep- wake cycle for shift workers on permanent night shift or slowly rotating shifts11. The body may not be able to adapt effectively to rapidly rotating schedules11.

Exposure to bright light during night shift work is recommended either a 3-6 hr continuous block or intermittently for 20 minutes every hour during the shift1. Light exposure during the morning should be avoided by wearing dark sunglasses when leaving work and blocking light entering bedroom windows11. It is recommended that shift workers try to sleep as soon as possible after their shift1;11.

When attempting to sleep during the day, good sleep habits such as having a quiet, dark sleeping environment are important1;11. Short acting hypnotic medications may also be useful1.

Melatonin* ingested early in the day can improve daytime sleep but does not improve night-time alertness1.

To increase alertness during the night, short scheduled naps during the night-time shift may be useful1. Caffeine during the first couple of hours of the night shift is also helpful1. Modafinil is a stimulant approved by the Food and Drug Administration (FDA) for the treatment of excessive sleepiness in SWD1.

Shift work is associated with many other health conditions such as depression and obesity, therefore it is recommended that shift workers receive appropriate medical assessment and support for SWD and other comorbidities1;11.

Autism Spectrum Disorder and Melatonin

As mentioned in my previous post on sleep, there is a higher rate of sleep disturbances among people with an ASD. Although behavioural treatments are generally considered the first step in treatment of sleep disturbances, exogenous melatonin* has a special role in people with an ASD who have sleep disturbances.

I also mentioned in my previous post on sleep that even with good sleep habits, my son Jeremy still had trouble going to sleep at night. On hearing about Jeremy’s difficulty going to sleep his pediatrician recommended trialing exogenous melatonin*. The pediatrician advised us to give melatonin* to Jeremy 30 minutes before bedtime. We commenced at the lower dose of 2mg of melatonin* and we were instructed to gradually increase the dose if needed.

It is safe to say that we did not need to increase the dose. Exogenous melatonin* has been a huge success in helping Jeremy to fall asleep within a much shorter time. Jeremy is very happy about finding it easier to go to sleep and is no longer excessively sleepy in the mornings either. Of course, all that is anecdotal and so now I will provide the compelling evidence regarding the effectiveness of exogenous melatonin* in managing sleep disturbances in children with ASD.

All studies on people with an ASD have shown differences in melatonin production compared to people without an ASD4;12. In particular, people with an ASD are much more likely to have a lower night- time secretion of melatonin4;12. The melatonin production differences of ASD appear to be genetic12;13 and heritable with parents without an ASD also showing reduced production of melatonin12.

Exogenous melatonin* has been more extensively studied in children with insomnia than any other sleep-promoting medication14;15. Exogneous melatonin* is shown to be effective with good tolerability in the short and long term for reductions in sleep latency and sleep duration in children with ASD with sleep disturbances when given prior to bedtime14;15.

Even though the administration of exogenous melatonin* is considered to be a Complementary and Alternative Therapy (CAT)* it is one of best studied CATS for ASD16. Lofthouse et al.(2012) reviewed the CATS most commonly used by people with an ASD and made recommendations for the use of only three CATS in specific circumstances, one of those was the use of exogenous melatonin*16. Lofthouse et al. (2012) determined melatonin* to be sensible, easy, cheap and safe and recommended it for trial for people with an ASD who experience sleep delay16.

More recently a review of the literature concluded that the administration of exogenous melatonin for people with an ASD, that have sleep disturbances related to abnormalities in endogenous melatonin secretion, is now evidence-based17.

Miano & Ferri (2010) recommends a combination of melatonin* and behavioural interventions as a first –choice treatment for children with an ASD with sleep disturbances because behavioural intervention alone may not be sufficient due to the low level of endogenous melatonin observed in children with ASDs15.

One recent well conducted study by Malow et al. (2012) demonstrated that exogenous melatonin* significantly improved sleep latency among children of 3-10 yrs of age with sleep onset delay. Melatonin* was effective at a dose of 1-3mg for the majority of children, when given 30 minutes before bedtime18. Daytime behaviour also significantly improved in all areas measured (hyperactivity, withdrawn and affective problems and stereotyped and compulsive subscales) and the side effects of melatonin* ingestion were minimal18.

Although melatonin* is safe and well tolerated, Malow et al.(2012) recommends that melatonin* is used under the guidance of an appropriate medical professional  ‘because of the importance of assessing children with ASD and insomnia for medical, neurological, and psychiatric comorbidities, which may cause or contribute to insomnia’18.

* In this blog ‘exogenous melatonin’ refers to melatonin that is artificially produced and ingested as a supplement. ‘Endogenous melatonin’ is melatonin that the body naturally produces.

Exogenous melatonin is not approved by the Food and Drug Administration because it has not undergone the appropriate testing to obtain a license. This contributes to its classification as a Complementary and Alternative Therapy (CAT).

Herxheimer and Petrie (2002) state that ‘The pharmacology and toxicology of melatonin and pharmaceutical aspects of its formulation have not been systematically studied, very likely because the drug cannot be patented and the cost of the work cannot readily be recouped from sales of the drug’9. Melatonin cannot be patented because it is a naturally occurring hormone. Waterhouse (2003) recommends that a cost-benefit analysis should be conducted and would likely indicate that it is in the public interest for public funding to be contributed to the relevant testing3.

Two categories of people should avoid exogenous melatonin until more is known: anyone taking Warfarin or another oral anticoagulant3;9 and people with epilepsy3 (Waterhouse 2003 BMJ).

Another concern regarding exogenous melatonin use is that no official standards of melatonin supplement purity exist3. In the US, Thailand and Singapore it is freely sold as a “dietary supplement” in health food stores and pharmacies3. Waterhouse (2003) recommends purchasing it from a ‘large reputable pharmacy chain’ and to ‘hope for the best’3. In Australia it can be purchased from compounding pharmacies via prescription and therefore may be more expensive but more regulated than over-the-counter versions in other countries.

References:

  1. Barion, A. & Zee, P. A clinical approach to circadian rhythm sleep disorders. Sleep Medicine 2007; 8(6):566-577
  2. Waterhouse, J. Jet lag: Trends and coping strategies. The Lancet 2007; 369: 1117-1129
  3. Waterhouse, J. The prevention and treatment of jet lag. BMJ 2003; 326:296-297
  4. Tordjman, S. Anderson, G. Bellissant, E. Botbol, M. Charbuy, H. Camus, F. Graignic, R. Kermarrec, S. Fougerou, C. Cohen, D. Touitou, Y. Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and young adults with autistic disorder. Psychoneuroendocrinology 2012; 37:1990-1987
  5. Czeisler, C. Perspective: Casting light on sleep deficiency. Nature 2013; S13 DOI: 10.1038/497S13a
  6. Sack, R. Clinical practice. Jet lag. The New England Journal of Medicine 2010; 362(5):440-447
  7. Cajochen, C. Frey, S. Anders, D. Spati, J. Bues, M. Pross, A. Mager, R. Wirz-Justice, A. Stefani, O. Evening exposure to a light-emitting diodes (LED)-backlit computer screen affects circadian physiology and cognitive performance. Journal of Applied Physiology 2011; 110:1432-1438
  8. West, K. Jablonski, M. Warfield, B. Cecil, K. James, M. Ayers, M. Maida, J. Bowen, C. Sliney, D. Rollag, M. Manifin, J. Brainard, G. Blue light from light-emitting diodes elicits a dose-dependent suppression of melatonin in humans. Journal of Applied Physiology 2011; 110:619-626
  9. Herxheimer, A. & Petrie, K. Melatonin for the prevention and treatment of jet lag (Review). Cochrane Database of Systematic Review 2002; Issue 2. Art. No.: CD001520.
  10. Bartlett, D. Biggs, S. Armstrong, S. Circadian rhythm disorders among adolescents: assessment and treatment options. Medical Journal of Australia 2013; 199(8):S16-S20
  11. Burgess, H. Sharkey, K. Eastman, C. Bright light, dark and melatonin can promote circadian adaptation in night shift workers. Sleep Medicine Reviews 2002; 6(5):407-420
  12. Melke, J. Goubran-Botros, H. Chaste, P. Betancur, C. Nygren, G. Anckarsater, H. Rastam, M. Stahlberg, O. Gillberg, C. Delorme, R. Chabane, N. Mouren-Simeoni, M-C. Fauchereau, F. Durand, C. Chevalier, F. Drouot, X. Collet, C. Launay, J-M. Leboyer, M. Gillberg, C. Bourgeron, T. and the PARIS study. Abnormal melatonin synthesis in autism spectrum disorders. Molecular Psychiatry 2008; 13(1): 90-98
  13. Jonsson, L. Ljunggern, E. Bremer, A. Pedersen, C. Landen, M. Thuresson, K. Giacobini, M. Melke, J. Mutation screening of melatonin-related genes in patients with autism spectrum disorders. BMC Medical Genomics 2010; 3(10):1-7
  14. Cortesi, F. Giannotti, F. Ivanenko, A. Johnson, K. Sleep in children with autistic spectrum disorder. Sleep Medicine 2010; 11:659-664
  15. Miano, S. & Ferri, R. Epidemiology and management of insomnia in children with autistic spectrum disorders. Pediatric Drugs 2010; 12(2):75-84
  16. Lofthouse,N. Hendren, R. Hurt, E. Arnold, LE. Butter, E. A Review of Complementary and Alternative Treatments for Autism Spectrum Disorders. Autism Research and Treatment 2012; Article ID 870391, 21pages
  17. Rossignol, D. & Frye, R. Melatonin in autism spectrum disorders. Current Clinical Pharmacology 2013; Ahead of print.
  18. Malow, B. Adkins, M. McGrew, S. Wang, L. Goldman, S. Fawkes, D. Burnette, C. Melatonin for sleep in children with autism: A controlled trial examining dose, tolerability, and outcomes. Journal of Autism and Developmental Disorders 2012; 42(8): 1729-1737
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