Improving adaptation to simulated night shift: timed exposure to bright light versus daytime melatonin administration.

Chronic circadian disturbance is thought to cause many of the health and social problems reported by shift workers. In recent years, appropriately timed exposure to bright light and exogenous melatonin have been used to accelerate adaptation to phase shifts of the circadian system. In this study we compared adaptation to night shift in three groups of subjects. The first treatment group received timed exposure to bright light (4-7,000 lux between 2400 and 0400 hours on each of three night shifts). The second treatment group received exogenous melatonin by capsule (2 mg at 0800 hours then 1 mg at 1100 and 1400 hours). The placebo control groups received either dim red light at less than 50 lux or placebo (sucrose) in identical capsules at the same time. Results indicated that all groups shifted significantly from baseline. Using the dim-light melatonin onset as a circadian marker, the bright-light group shifted the furthest, whereas there was no significant difference between the melatonin and placebo groups. Sleep quality as determined by wrist actigraphy was most improved in the light-treatment group, although the melatonin group also showed significant improvements. Cognitive psychomotor performance was most improved in the light-treatment group and the melatonin group again showed little difference from the control group. Although melatonin was unable to increase the amount of the phase shift following transition to night shift, it is likely that the intermediate levels of improvement in sleep reflect the hypothermic effects of melatonin. By lowering core temperature across the sleep period, sleep may be enhanced. This improvement in sleep quality did not produce concomitant improvements in shift performance for the melatonin group. This suggests that the enhanced performance in the light-treatment group may reflect more direct "energizing" effects. On the basis of these results, bright light is clearly superior in its ability ot phase shift the circadian system and thereby improve sleep and performance. However, melatonin may permit shift workers to override the circadian system for short periods and avoid the potential toxicity due to overzealous manipulations of the circadian pacemaker. In rapidly rotating shift schedules, melatonin may be preferable because it would not require workers to reverse the large phase shift induced by light.

Urinary 6-sulfatoxymelatonin cycle-to-cycle variability.

For either clinical or research purposes, the timing of the nocturnal onset in production of the urinary melatonin metabolite 6-sulfatoxymelatonin (UaMT6s-onset), has been proposed as a reliable and robust marker of circadian phase. However, given that most circadian rhythms show cycle-to-cycle variability, the statistical reliability of phase estimates obtained from a single study using UaMT6s-onset remains to be determined. Following 2 weeks of sleep diary and wrist actigraphy, 15 young, healthy good sleepers participated in four UaMT6s sampling sessions spaced 1 day apart. During the sampling sessions subjects remained indoors under low light conditions and hourly urine samples were collected from 19:00 to 02:00 h. Samples were subsequently assayed for UaMT6s using standard radioimmunographic techniques. UaMT6s-onset was determined by the time at which melatonin production exceeded the average of three proceeding trials by 100%. Sleep onset times were derived from sleep diary and actigraphic measures taken before the melatonin collection nights. We found that there was no significant variation between nights in group mean UaMT6s-onset times, and intraindividual variability was small. In addition, UaMT6s-onset times were highly and significantly correlated between nights (grand mean r = 0.804). Our results suggest that within 95% confidence interval limits, individual UaMT6s-onset estimates obtained from a single night UaMT6s-onset study can be used to predict subsequent UaMT6s-onset times within +/- 97 min. A close temporal relationship was also found between the timing of UaMT6s-onset and sleep onset. Overall, our results suggest that under entrained conditions single-session UaMT6s-onset studies can provide reliable individual UaMT6s-onset phase estimates and that the protocol described in this study is a practical and noninvasive methodology.

Melatonin and sleep in humans.

Early studies on the physiological effects of melatonin typically reported hypnotic 'side-effects'. Later studies, specifically addressing this action, failed to reliably replicate hypnotic effects using standard polysomnography. This difference may be related to differences in the basic physiological action of melatonin compared with more conventional hypnotics. It is suggested that melatonin exerts a hypnotic effect through thermoregulatory mechanisms. By lowering core body temperature, melatonin reduces arousal and increases sleep-propensity. Thus, in humans, one role of melatonin is to transduce the light-dark cycle and define a window-of-opportunity in which sleep-propensity is enhanced. As such, melatonin is likely to be an effective hypnotic agent for sleep disruption associated with elevated temperature due to low circulating melatonin levels. The combined circadian and hypnotic effects of melatonin suggest a synergistic action in the treatment of sleep disorders related to the inappropriate timing of sleep and wakefulness. Adjuvant melatonin may also improve sleep disruption caused by drugs known to alter normal melatonin production (e.g., beta-blockers and benzodiazepines). If melatonin is to be developed as a successful clinical treatment, differences between the pharmacological profile following exogenous administration and the normal endogenous rhythm should be minimized. Continued development as a useful clinical tool requires control of both the amplitude and duration of the exogenous melatonin pulse. There is a need to develop novel drug delivery systems that can reliably produce a square-wave pulse of melatonin at physiological levels for 8-10 hr duration.