Circadian Rhythmicity and the Pharmacologic Management of Insomnia

The circadian clock modulates timing of sleep and wakefulness. In certain situations, the circadian potentiation of wakefulness may interfere with desired sleep-scheduling,

The human circadian clock modulates the timing of sleep and wakefulness through direct effects on sleep tendency (sleepiness/alertness) and on the neurophysiologic processes governing sleep state expression.⁷ Under normal conditions, this modulation reinforces the diurnal sleepwake schedule, with wakefulness during the daylight hours and sleep during the night. In other situations, however, the circadian potentiation of wakefulness may interfere with desired sleep-scheduling. Particularly affected are the elderly, shift workers, and other individuals who must live on a schedule which conflicts with the normal circadian cycle. In these patients, insomnia and consequent impairment of waking function result from desynchrony between the endogenous circadian rhythm of sleep and wakefulness, and the externally imposed sleep-wake schedule. Even in patients with more common nocturnal insomnia, the persistence of clock-mediated arousal in the evening hours may contribute to difficulty with sleep in the first half of the night. Due to its prominent role in the pathogenesis of insomnia, the circadian clock has long been an attractive target for insomnia treatments.

Circadian Physiology

Melatonin (N-acetyl-5-methoxytryptamine),the primary secretory product of the pineal gland, plays a fundamental role in circadian rhythmicity.^7,9,10 The pineal gland is a sympathetic efferent of the SCN that secretes melatonin into the general circulation in response to signals from the SCN.¹¹ These signals relay both circadian phase information and transmit light and dark information received from the retina. Melatonin secretion peaks during the night when SCN activity is minimal and inhibitory light is absent.

There are 3 types of melatonin receptors found in most mammalian species, including humans. MT1 and MT2 are g-protein coupled receptors, whereas MT3 is a binding site that appears to be linked to quinone reductase. Autoradiographic studies of human brains suggest that the majority of specific melatonin binding (MT1 and MT2) in the brain is located in the SCN. Animal studies demonstrate that MT1 and MT2 receptors in the SCN mediate the important effects of melatonin on circadian organization, including the modulation of SCN potentiation of wakefulness. The MT3 binding site is less well characterized, and little is known about its function.

Types of Circadian Rhythm Sleep Disorders

Melatonin receptor agonists, like ramelteon, are not controlled substances and have a positive longterm safety profile. Ramelteon is a melatonin MT1/MT2 receptor agonist indicated for the treatment of sleep-onset insomnia. In persons with chronic insomnia, ramelteon has been shown to reduce latency to persistent sleep and increase total sleep time when compared with placebo.^17-19 Unlike other sedative-hypnotics, ramelteon is not associated with addiction, rebound, next-day residual effects, or dependence.²⁰ Comparative trials are lacking, so it is not yet possible to determine ramelteon's efficacy or cost-effectiveness relative to other available insomnia treatments.

Cost Comparison of Available Therapies

agonist class has 1 US Food and Drug Administration— approved agent, ramelteon. There are limited and conflicting data comparing insomnia treatments, particularly with simultaneous assessments of efficacy, safety, and cost. In a systematic review, newer BzRAs were compared with older benzodiazepines.²¹ The review concluded that the medications were equally effective; however, due to the absence of trials, a cost-effectiveness analysis and comparative analysis were not conducted.

In a nonscientific, consumer-oriented comparison, zolpidem 5 mg to 10 mg orally at bedtime was considered the most cost-effective insomnia treatment,²² specifically because of its pending generic availability. The article recommends switching to generic zolpidem, asserting that only “weak†evidence exists that the controlled-release formulation has better efficacy or tolerability than the immediate-release product. In this review, ramelteon was considered less effective than the comparators; however, the rationale was not specifically stated. The authors did indicate that ramelteon exhibited a relatively longer sleep onset of 75 minutes. However, in clinical trials, ramelteon demonstrated a mean latency to persistent sleep time of approximately 25 minutes.^17-19,23

Cost Implications of Adverse Events, Dependence,Tolerance

Effective insomnia treatment holds promise as a cost-effective healthcare intervention. The importance of the circadian clock to normal function is particularly apparent in the expression of sleep and wakefulness and many sleep disorders can be traced to abnormalities in the circadian system. Practice guidelines are needed to lead appropriate therapy selection and further research is needed to determine the role of melatonin and melatonin receptor agonists in the management of chronic insomnia in specific patient populations. Randomized controlled clinical trials comparing ramelteon to shortacting BzRAs for short- and long-term management of insomnia are needed to determine the relative efficacy, toxicity, and treatment adherence. Healthrelated quality-of-life (QOL) data still needed to include overall QOL, incidence of daytime drowsiness, frequency and rate of development of dependency, impact on work productivity, incidence of accidents, and cost-effectiveness.

Preston Street, Salt Lake City, UT 84108. E-mail: tommy.bramley@xcenda.com.1. Winkelman J, Pies R. Current patterns and future directions in the treatment of insomnia. Ann Clin Psychiatry. 2005;17:31-40.

3.Walsh JK. Insights into the public health burden of insomnia. Sleep. 2006;29:142-143.

5. Martin SA, Aikens JE, Chervin RD. Toward cost-effectiveness analysis in the diagnosis and treatment of insomnia. Sleep Med Rev. 2004;8:63-72.

7. Richardson GS. The human circadian system in normal and disordered sleep. J Clin Psychiatry. 2005;66(suppl 9):3-9.

9. Arendt J. Melatonin and human rhythms. Chronobiol Int. 2006;23:21-37.

11. Brzezinski A. Melatonin in humans. N Engl J Med. 1997;336:186-195.

13. Richardson GS. Shift work sleep disorder. Sleep: A Comprehensive Handbook. Lee-Chiong T, ed. Hoboken, NJ: John Wiley & Sons, Inc; 2006:395-399.

15. Hajak G, Rodenbeck A, Staedt J, Bandelow B, Huether G, Rüther E. Nocturnal plasma melatonin levels in patients suffering from chronic primary insomnia. J Pineal Res. 1995;19:116-122.

17. Erman M, Seiden D, Zammit G, Sainati S, Zhang J. An efficacy, safety, and dose-response study of ramelteon in patients with chronic primary insomnia. Sleep Med. 2006;7:17-24.

19. Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. J Clin Sleep Med. 2007;3:495-504.

21. Dündar Y, Boland A, Strobl J, et al. Newer hypnotic drugs for the short-term management of insomnia: a systematic review and economic evaluation. Health Technol Assess. 2004;8:iii-x, 1-125.

23. 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.

25. Johnson MW, Suess PE, Griffiths RR. Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry. 2006;63:1149-1157.

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