Rapid Responses to:
|
|
Rapid Responses: Rapid Responses published:
-
![[Read Rapid Response]](/icons/misc/sectionDOWN.gif)
Melatonin use in children and adolescents
- Alka S Ahuja (10 February 2006)
-
Efficacy of melatonin
- Josephine Arendt (12 February 2006)
-
Research on selected groups is still needed
- Maybelle Wallis (17 February 2006)
-
Re: Research on selected groups is still needed
- Peter J Miles (18 February 2006)
-
Muddles with Melatonin
- M E Jan Wise (20 February 2006)
-
More muddles with melatonin
- Josephine Arendt (24 February 2006)
-
More research on melatonin clinical efficacy is urgently needed.
- Santiago Perez-Lloret, Daniel P. Cardinali (24 February 2006)
-
Melatonin and Sleep
- Amnon Brzezinski, Richard J. Wurtman, Mark Vangel (27 February 2006)
-
Elucidation, not noise – melatonin is effective for certain sleep disorders
- Timo Partonen, Outi Saarenpää-Heikkilä, and Markku Partinen (3 May 2006)
-
Experience of a travelling doctor
- Giuseppe P. Mazzarello (2 August 2006)
|
|
|||
|
Alka S Ahuja, Consultant Child & Adolescent Psychiatrist Gwent Healthcare NHS Trust
Send response to journal:
|
Melatonin is increasingly being used in children with sleep difficulties secondary to behaviour disorders such as Hyperkinetic disorders, Pervasive developmental disorders etc. Although till date there was very little research to prove its efficacy in theses conditions melatonin was being pescribed on a regular basis and was found to be clinically effective in this group of children. This meta-analysis by Buscemi et al has highlights the limited evidence for its use in children and adolescents with sleep difficulties secondary to developmental delays and pervasive developmental disorders and will prove to be a warning for clinicans who are currently using the drug in children with similar difficulties. Competing interests: None declared |
|||
|
|
|||
|
Josephine Arendt, Professor of Endocrinology, Emeritus School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, GU2 7XH, UK
Send response to journal:
|
This meta-analysis reports that melatonin is ineffective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction such as jet lag or shift work. There is certainly some inconsistency in the published reports in this domain and now inconsistency in the meta-analyses. Numerous published studies, mostly with a significant positive result, have not been included (see references below), even the first controlled jet lag trial, published in the BMJ. This publication may have done a disservice to those who do benefit from melatonin and may in consequence be denied access (in the UK) to this prescription-only medication. For example the report does not mention the importance of melatonin in blind sleep disorder and delayed sleep phase syndrome. Some of the data have appeared previously in a report from the Agency for Healthcare Research and Quality, Rockville, MD, USA (http://www.ahrq.gov/news/press/pr2004/melatnpr.htm) where benefits for delayed sleep phase syndrome were identified, but not mentioned here. Successful use of melatonin to counter the effects of time zone change or shift work requires correct timing of treatment relative to internal ‘circadian’ rhythms. Incorrect timing can lead to undesirable effects. It is difficult to time melatonin correctly in field studies. Uncontrolled exposure to natural light (which shifts internal timing), individual differences, unscheduled sleep times all contribute to the problems. If a reliable and rapid method for assessing the timing of the human internal clock (and hence the timing of treatment) were available no doubt the efficacy of melatonin would be enhanced. A more helpful approach to assessing the usefulness of melatonin would be to evaluate those few studies where circadian timing was either measured or accurately predicted prior to treatment. Josephine Arendt, PhD, FRCPath, Professor of Endocrinology, Emeritus Director Emeritus, Centre for Chronobiology, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey, GUI2 7XH Competing interests: Sleep Advisory Board Member, Alliance Pharmaceuticals Studies not cited Meta analysis: Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben-Shushan A, Ford I. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev 2005;9:41-50. Jet lag studies: Arendt J, Aldhous M, Marks V. Alleviation of jet-lag by melatonin: preliminary results of controlled double-blind trial. Br Med J. 1986;292:1170. Arendt I, Aldhous M, Marks M, et al. Some effects of jet-lag and their treatment by melatonin. Ergonomics. 1987;30:1379-1393. Nickelsen T, Lang A, Bergau L. The effect of 6-, 9- and 11-hour time shifts on circadian rhythms: adaptation of sleep parameters and hormonal patterns following the intake of melatonin or placebo. Adv Pineal Res. 1991;5:30J-306. Comperatore CA, Lieberman HR, Kirby AW, et al. Melatonin efficiency in aviation missions requiring rapid deployment and night operations. Aviat Space Environ Med. 1996;67:520-524. Spitzer RL, Terman M, Williams IBW, et al. Jet lag: clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomized double-blind trial. Am J Psychiatry. 1999;156:1392-1396. Takahashi T, Sasaki M, Itoh H et al. Melatonin alleviates jet lag symptoms caused by an 11-hour eastward flight. Psychiatry Clin Neurosci. 2002; 56: 301-2. Paul MA, Brown G, Buguet A, et al. Melatonin and zopiclone as pharmacologic aids to facilitate crew rest. Aviation, Space and Environmental Medicine. 2001; 72: 974-984. Skene DJ, Aldhous M, Arendt J. Melatonin, jet-lag and the sleep- wake cycle. In: Horne J, ed. Sleep ‘88. Basel, Switzerland: Karger;1989:39-41. Simulation studies: Samel A, Wegman HM, Vejvoda M, et al. Influence of melatonin treatment on human circadian rhythmicity before and after a simulated 9 hour time shift. J Biol Rhythms. 1991;6;235-248. Deacon S, Arendt J. Adapting to phase.shifts, II: effects of melatonin and conflicting light treatment. Physiol Behav. 1995;39:675- 682. Revell VL, Burgess HJ, Gazda CJ, Smith MR, Fogg LF, Eastman CI. Advancing Human Circadian Rhythms with Afternoon Melatonin and Morning Intermittent Bright Light . J Clin Endocrinol Metab 2005;91:54-59. Melatonin for blind sleep disorder: Arendt J, Aldhous M, Wright J. Synchronisation of a disturbed sleep-wake cycle in a blind man by melatonin treatment. Lancet. 1988;1:772-773. Folkard S, Arendt I, Aldhous M, et al. Melatonin stabilises sleep onset time in a blind man without entrainment of cortisol or temperature rhythms. Neurosci Lett. 1990;113:193-198. Sack RL, Lewy AJ, Blood ML, et al. Melatonin administration to blind people: phase advances and entrainment. J Biol Rhythms. 1991;6:249-261. Aldhous ME, Arendt J. Melatonin rhythms and the sleep wake cycle in blind subjects. J Interdisciplin Cycle Res. 1991;22:84-85. Lockley S W, Skene D J, James K et al. Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol 2000; 164: R1-6 Sack R L, Brandes R W, Kendall A R et al. Entrainment of free-running circadian rhythms by melatonin in blind people. N Engl J Med 2000; 343: 1070-7 Hack L M, Lockley S W, Arendt J, et al. The effects of low-dose 0.5-mg melatonin on the free-running circadian rhythms of blind subjects. J Biol Rhythms 2003; 18: 420-9. (NB several more studies in the blind) Melatonin for shift work: Sack RL, Blood ML, Lewy AJ. Melatonin administration promotes circadian adaptation to shift work. Sleep Res. 1994;23:509. Dawson D, Encel N, Lushington K. Improving adaptation to simulated night-shift: timed exposure to bright light versus day- time melatonin administration. Sleep. 1995;18:11-21. Burgess H J, Sharkey K M & Eastman C I. Bright light, dark and melatonin can promote circadian adaptation in night shift workers. Sleep Med Rev 2002; 6: 407-20. (NB several more studies in simulated shift work) Reviews which might be helpful: Arendt J, Deacon S. Treatment of circadian rhythm disorders-melatonin. Chronobiol Int. 1997;14:185-204. Arendt J, Stone B, Skene D. Sleep disruption in jet lag and other circadian rhythm disturbances. Principles and Practice of Sleep Medicine, 4th Edition, Eds Kryger, Roth, Dement, WB Saunders and Co. Philadelphia, 2005, Ch 55, pp 659-672. ISBN 1416003207. Arendt J, Skene DJ. Melatonin as a chronobiotic. Sleep Medicine Reviews, 2004; 9:25-39. Arendt J. Melatonin: characteristics, concerns and prospects. J Biol Rhythms, 2005;20:291-313 Editorial: Arendt J. Melatonin, sleep and circadian rhythms. Editorial. The New England Journal of Medicine, 000;343:1114-1116. |
|||
|
|
|||
|
Maybelle Wallis, Consultant Paediatrician Sandwell General Hospital B71 4HJ
Send response to journal:
|
My personal experience, as a neurodevelopmental paediatrician, of prescribing melatonin over the last five years has been that some patients benefit and others do not. It seems to be more successful in children with either visual impairment or autism and less so in children with other forms of developmental disability. There is a lack of research specific to these groups of patients. I am not surprised that this meta analysis, looking at all causes of secondary sleep disorder, did not identify an effect. Competing interests: None declared |
|||
|
|
|||
|
Peter J Miles, Project Management Guelph, Canada, N1K 1A5
Send response to journal:
|
I must certainly concur with Dr. Wallis. As a parent of an autistic child the effects of melatonin cannot be understated. When we first began using melatonin it was not permitted for sale in Canada, but you were allowed to bring some across the border from the US where it was sold over the counter. At the time, our's son's sleep pattern, or more often lack of pattern, was causing significant stress for the whole family. I recall a particularly bad period when he would rise at about 6:00 a.m. but fall asleep somewhere between 3:00 and 5:00 p.m. . . .and so well asleep that he was almost impossible to wake. But around 6:00 to 7:00 p.m. he would wake and then stay awake until around 1:00 or 2:00 a.m. This went on for over six months. At other times he would go to sleep at a normal 8:00 p.m. but would wake sometime near midnight and be awake for two, or four hours or even be awake the whole night. My wife and I often slept separately in two hour shifts. As well, during his waking hours our son could be screaming, or becoming very agitated to the point of violence, or simply be getting into danger (e.g. he learned at an early age how to open windows and doors and get outside, and he often turned on electric or gas appliances, etc.). The sleep deprivation for the family, parents and siblings was causing profound problems. At around six years old we began using melatonin and found it transformational. We could give him melatonin at around 8:00 p.m. and he would be asleep by 9:00, and would sleep until around 6:00 to 7:00 a.m. It wasn't 100%, there were times when it didn't seem to work. Some I think were related to the quality of the product, I do suspect that some of the melatonin sold in the US OTC at the time was very poor quality and possibly even downright fraudulent. And at other times his sleep habits were disturbed by some quite normal problems, dental problems, food related problems, and other health related issues. However, the effects of melatonin were very real for our family. We still give him melatonin at the age of 14, and have tried to withdraw it from time to time, but it seems he is unable to get into a circadian rhythm without it. Fortunately, melatonin is now available in Canada OTC. We don't have to travel to the US for supplies nor buy it UTC, Under-The- Counter, from a sympathetic health food store owner. I would certainly suggest when a family is showing signs of distress as a result of an autistic child's sleep behaviour that melatonin be tried. If the continued stress of sleep deprivation can be very easily remedied by this substance the improvement for all in the family will be profound. Competing interests: None declared |
|||
|
|
|||
|
M E Jan Wise, Consultant Psychiatrist 13-15 Brondesbury Rd, London NW6 6BX
Send response to journal:
|
Editor - Buscemi et al (1)assert that there is no evidence base for exogenous melatonin for secondary sleep disorder. Lewy et al (2) have shown that low levels of melatonin, 0.5mg, reset circadian rythm but not high doses, 2mg. The prolonged half-life of melatonin and the sensitivity of the circadian rythm to its presence mean that in trying to achieve phase advancement (bringing sleep forward when flying west) or phase delay (for flying east) melatonin has a limited window of opportunity. Too low a dose and no effect, too high and the chronobiologic effects are lost and only the direct somnolent action is experienced. Until very recently there have been no commercially available preparations of the correct dose, substantially hindering research. As melatonin is of most use where there is circadian rythm dysregulation it is essential that the correct dose is used at the right time. It would be a shame if a potentially useful treatment for a limitted range of disorders was discarded due to excess expectations and premature disappointment. N Buscemi ,B Vandermmer, N Hooton et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 2006;332:385-8 (2)AJ Lewy, JS Emens, RL Sack, BP Hasler, RA Bernert. Low, but not high doses of melatonin entrained a free running blind person with a long circadian rythm. Chronobiol Intl 2002; 19(3): 649-658. Competing interests: The author uses Melatonin and Bright Light to reduce recovery time from intercontinental jetlag (personal use only) |
|||
|
|
|||
|
Josephine Arendt, Professor of Endocrinology Emeritus, Emeritus Director, Centre for Chronobiology School of Biomedical and Molecular Sciences, University of Surrey, Guildford, GU2 7XH
Send response to journal:
|
I am surprised that your correspondent 'Muddles with melatonin' finds melatonin a useful treatment for jet lag, since when going west a delay of the rhythm is required, whereas going East the rhythm must normally be advanced. Over 12 time zones there is no data that I know of addressing the question of whether it is better to advance or to delay. I would also like to point out that synchronisation of free running sleep rhythms in the blind and subsequently full entrainment of the circadian system was first achieved by my group, using 5 mg melatonin (Arendt et al., Lancet, 1988, Lockley et al., J Endocrinol, 2000). It is true, however, that 0.5 mg and sometimes lower doses may be more efficacious in some circumstances, than higher doses. Josephine Arendt Competing interests: Sleep Advisory Board Alliance Pharmaceuticals |
|||
|
|
|||
|
Santiago Perez-Lloret, Graduated Student Dto de Fisiología, Facultad de Medicina, Universidad de Buenos Aires, Argentina, Daniel P. Cardinali
Send response to journal:
|
EDITOR- The meta-analysis from Buscemi et al [1] appears to be generally methodologically-sound. However, some relevant studies about the subject are surprinsingly not been included [2]. Nonetheless, we believe that the claim that “…melatonin does not have a significant effect on sleep onset latency…” is not supported by the results of that work. An statistically non-significant finding indicates that the alternative hypothesis (e.g melatonin is effective on sleep onset latency) is not likely to be true, rather than that the null hypothesis is true (which in this case would be that melatonin is not effective on sleep onset latency) because of the possibility of a type II error [3]. By combining several studies, meta-analyses provide better size effect estimates and reduce the probability of a type II error [4], making less likely false-negative results. Nonetheless, this may not have been the case in the present case. Firstly, sample size was constituted by less than 300 subjects. Reviewed papers showed significant variations in the route of administration of melatonin, the dose administered and the way in which outcomes were measured. All of these drawbacks resulted in a significant heterogeneity index and in a low quality size effect estimation (shown by the wide 95% confidence intervals reported) [5]. All these facts make the type II error a living threaten, which would subtract credibility to the results, making impossible to drawn the conclusion stated by the authors. There is a lot evidence suggesting that melatonin is a physiologically important sleep-wake rhythm regulator in humans [6]. Therefore it is feasible that pharmacological manipulation of the system may be a good strategy to treat sleep disorders. Ramelteon, a selective MT1/MT2 receptor agonist has been shown to reduce sleep onset latency in 375 healthy subjects in a recent methodologically-sound randomized controlled trial [7]. In summary, the conclusions drawn by Buscemy et al [1] are not supported by their results. On the contrary, we believe that they clearly show that more methodologically-sound randomized controlled trial are needed for the assessment of melatonin clinical efficacy. It appears that no corporative interest in the study of melatonin is feasible. Therefore, we strongly recommend that public sources be sought as sponsors for these trials. References 1. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta- analysis. BMJ 2006; 332:385-393. 2. Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben- Shushan A, Ford I. Effects of exogenous melatonin on sleep: a meta- analysis. Sleep Med Rev 2005; 9:41-50. 3. Altman DG, Bland JM. Absence of evidence is not evidence of absence. BMJ 1995; 311:485. 4. Jenicek M. Meta-analysis in medicine. Where we are and where we want to go. J Clin Epidemiol 1989; 42:35-44. 5. Altman D, Bland JM. Confidence intervals illuminate absence of evidence. BMJ 2004; 328:1016-1017. 6. Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336:186-195. 7. Roth T, Stubbs C, Walsh JK. Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep 2005; 28:303-307. Competing interests: None declared |
|||
|
|
|||
|
Amnon Brzezinski, Prof. of Obstetrics and Gynecology Hadassah-Hebrew University Medical Center Jerusalem Israel, Richard J. Wurtman, Mark Vangel
Send response to journal:
|
Editor - The Buscemi et al meta-analysis (1) concluded that there is no evidence that melatonin is effective in treating sleep disorders. Quite surprisingly, Buscemi et al (and, presumably, the British Medical Journal’s editors and reviewers) ignored our similar, 2005 meta-analysis (2) in their review. Our conclusions differed markedly from theirs: data from 17 controlled clinical trials indicated that melatonin significantly reduced sleep onset latency, and increased sleep efficiency and total sleep duration. Several additional comments: 1. The authors describe melatonin as a "popular complementary and alternative treatment…". Melatonin is a hormone (secreted by the pineal gland) and can no more be regarded as an “alternative therapy” than estrogen for menopausal women or insulin for diabetics. 2. The authors dismiss as “clinically unimportant” their own finding that melatonin produced a statistically significant increase (1.9%) in sleep efficiency. Sleep efficiency, normally is 90–95%; small increases usually reflect decreased number of awakenings during sleep or shortened periods of wakefulness, both of which certainly are significant for insomniacs (e.g., the FDA recently approved a new, melatonin-analog hypnotic drug, ramelteon, which increases sleep efficiency by 2.5% and total sleep time by 8-10 minutes). 3. Exogenous melatonin activates brain M1 and M2 receptors, thereby promoting sleep onset and maintenance and providing time cues for circadian rhythms. Large doses of melatonin (e.g., 3 mg, which raises its plasma levels to 900-2500 pg/ml) down-regulate these receptors (3), suppressing melatonin’s hypnotic and Zeitgeber effects (4). Almost all the studies included in the Buscemi, et al meta-analysis used such excessive doses. The correct, lower dose, which raises plasma melatonin levels to what they would be in a young person at nighttime (i.e., about 150-250 pg/ml) are highly effective, both in melatonin-deficient older people (5) and to treat jet lag or help shift workers. REFERENCES 1. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, Vohra S, Klassen TP, and Baker G. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 2006; 332: 385-393. 2. Brzezinski A, Vangel MG, Wurtman RJ, Norrie G, Zhdanova I, Ben- Shushan A,Ford I. Effects of exogenous melatonin on sleep: a meta- analysis. Sleep Med Rev. 2005 Feb; 9(1):41-50. 3. Dubocovich ML, Markowska M. Functional MT1 and MT2 melatonin receptors in mammals. Endocrine. 2005; 27(2):101-110. 4. Lewy AJ, Emens JS, Sack RL, Hasler BP, Bernert RA. Low, but not high, doses of melatonin entrained a free running blind person with a long circadian rythm. Chronobiol Intl 2002; 19(3): 649-658. 5. Zhdanova V I, Wurtman RJ, Regan MM, Taylor JA, Shi JP, Leclair OU. Melatonin treatment for age-related insomnia. J Clin Endocrinol Metab 2001; 86(10): 4727—4730. Competing interests: Dr. Wurtman's university, MIT, owns a United States patent on the use of melatonin to promote sleep. |
|||
|
|
|||
|
Timo Partonen, academy research fellow National Public Health Institute, Mannerheimintie 166, FI-00300 Helsinki, Finland, Outi Saarenpää-Heikkilä, and Markku Partinen
Send response to journal:
|
Editor - The Buscemi and colleagues meta-analysis (1) concludes that there is no evidence that melatonin is effective in treating secondary sleep disorders or sleep disorders accompanying sleep restriction. Here, readers need to recall that there is another meta-analysis by these colleagues, pointing at the efficacy and safety of melatonin in the management of chronic or primary insomnia (2). Sleep onset latency was reduced on average by 16.5 min with benzodiazepines, 18.1 min with non- benzodiazepines and 8.3 min with melatonin. Wakefulness after sleep onset was reduced on average by 23.1, 12.6 and 9.7 min respectively. All these were of statistical significance, except the last one, and may have relevance to clinical practice. A meta-analysis may contain errors, thereby increasing noise instead of providing elucidation. The quality of information makes the difference. This particular meta-analysis did have limitations in its methods. For example, insomnia was considered to be secondary to a range of disorders from developmental disability to chronic whiplash syndrome, induced insomnia was considered as a medical condition in healthy volunteers, etc. Treatment of insomnia needs to be based on the identification of its cause. It is not surprising that melatonin is not effective for the treatment of secondary insomnia. A key to the treatment is then the principal disorder. Melatonin may or may not be of help. However, it is effective for primary insomnia and jet lag as pointed out earlier in responses to the meta-analysis in question. REFERENCES 1. Buscemi N, Vandermeer B, Hooton N, Pandya R, Tjosvold L, Hartling L, et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta- analysis. BMJ 2006; 332: 385-393. 2. Buscemi N, Vandermeer B, Friesen C, Bialy L, Tubman M, Ospina M, et al. Manifestations and management of chronic insomnia in adults. Evidence report/Technology assessment No. 125 (prepared by the University of Alberta Evidence-based Practice Center, under Contract No. C400000021). AHRQ Publication No. 05-E021-2. Rockville, Md: Agency for Healthcare Research and Quality, June 2005. Timo Partonen, MD, National Public Health Institute, Helsinki, Finland Outi Saarenpää-Heikkilä, MD, Tampere University Hospital, Tampere, Finland Markku Partinen, MD, Skogby Sleep Disorders Centre, Espoo, Finland Competing interests: None declared |
|||
|
|
|||
|
Giuseppe P. Mazzarello, General Practioner 16127 Genoa (Italy)
Send response to journal:
|
Sir, I am a medical doctor, healthy, 46 years old and usually have not insomnia. I had to go on a transatlantic flight and fortunately I knew about your research. For insomnia I took melatonin 3 mg once the first night and once the second after my arrival at New York from Rome. My insonnia disappeared in a few minutes and I slept well for 8 hours or more. When I was back in Italy I repeated the same treatment with the same result. Maybe I am very sensitive to melatonin. In the same occasions I think I shall prescribe melatonin to my patients. Yours respectfully, Giuseppe P. Mazzarello Competing interests: None declared |
|||