Ramelteon: a review of its therapeutic potential in sleep disorders Authors
Ramelteon is a tricyclic synthetic analog of melatonin that acts specifically on MT
1 and MT 2 melatonin receptors. Ramelteon’s half-life is longer than that of melatonin, being metabolized in the body to four main metabolites, M-I, M-II, M-III, and M-IV. M-II has an affinity to MT 1 and MT 2 of about one-tenth of the parent compound, but its concentration in the circulation exceeds that of ramelteon by more than an order of magnitude. Ramelteon is effective in decreasing latency to persistent sleep and increasing total sleep time in freely moving monkeys. A number of clinical studies have been undertaken to study the efficacy of ramelteon in subjects with chronic insomnia. In almost all of these studies, ramelteon, in various doses of 4, 8, or 16 mg most commonly, significantly reduced sleep latency and increased sleep duration. Its primary action in sleep promotion is not a generalized gamma-aminobutyric (GABA)-ergic central nervous system depression, but rather it acts as a melatonergic agonist in the suprachiasmatic nucleus (and at other central nervous system sites), from where downstream processes, including GABA-ergic effects, are controlled via the hypothalamic sleep switch. Unlike other commonly prescribed hypnotic drugs, ramelteon is not associated with next morning hangover effects or reductions in alertness, nor has it been shown to cause withdrawal symptoms. The adverse symptoms reported with ramelteon are mild. All long-term investigations that have been carried out support the conclusion that ramelteon is a well tolerated and effective drug for the treatment of insomnia.
Dijk DJ, Cajochen C. Melatonin and the circadian regulation of sleep initiation, consolidation, structure, and the sleep EEG. J Biol Rhythms. 1997;12:627–635.
Reiter RJ, Tan DX, Manchester LC, Qi W. Biochemical reactivity of melatonin with reactive oxygen and nitrogen species: a review of the evidence. Cell Biochem Biophys. 2001;34:237–256.
Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species? J Pineal Res. 2007;42:28–42.
Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine. 2005;27:119–130.
Srinivasan V, Maestroni GJM, Cardinali DP, Esquifino AI, Perumal SR, Miller SC. Melatonin, immune function and aging. Immun Aging. 2005;2:17.
Cardinali DP, Esquifino AI, Srinivasan V, et al. Melatonin and the immune system in aging. Neuroimmunomodulation. 2008;15:272–278.
Reiter RJ. Pineal control of reproduction. Prog Clin Biol Res. 1981;59B:349–355.
Brzezinski A, Wurtman RJ. The pineal gland: its possible roles in human reproduction. Obstet Gynecol Surv. 1988;43:197–207.
Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Therapeutic actions of melatonin in cancer: possible mechanisms. Integr Cancer Ther. 2008;7:189–203.
Cos S, Gonzalez A, Martinez-Campa C, Mediavilla MD, Alonso-González C, Sánchez-Barceló EJ. Melatonin as a selective estrogen enzyme modulator. Curr Cancer Drug Targets. 2008;8:691–702.
Bartness TJ, Goldman BD. Mammalian pineal melatonin: a clock for all seasons. Experientia. 1989;45:939–945.
Armstrong SM. Melatonin and circadian control in mammals. Experientia. 1989;45:932–938.
Chase JE, Gidal BE. Melatonin: therapeutic use in sleep disorders. Ann Pharmacother. 1997;31:1218–1226.
Cajochen C, Jewett ME, Dijk DJ. Human circadian melatonin rhythm phase delay during a fixed sleep-wake schedule interspersed with nights of sleep deprivation. J Pineal Res. 2003;35:149–157.
Pandi-Perumal SR, Smits M, Spence W et al. Dim light melatonin onset (DLMO): a tool for the analysis of circadian phase in human sleep and chronobiological disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1–11.
Pandi-Perumal SR, Trakht I, Spence DW, Srinivasan V, Dagan Y, Cardinali DP. The roles of melatonin and light in the pathophysiology and treatment of circadian rhythm sleep disorders. Nat Clin Pract Neurol. 2008;4:436–447.
Lieberman HR. Behavior, sleep and melatonin. J Neural Transm Suppl. 1986;21:233–241.
Attenburrow ME, Cowen PJ, Sharpley AL. Low dose melatonin improves sleep in healthy middleaged subjects. Psychopharmacology (Berl). 1996;126:179–181.
Sack RL, Lewy AJ, Hughes RJ. Use of melatonin for sleep and circadian rhythm disorders. Ann Med. 1998;30:115–121.
Vollrath L, Semm P, Gammel G. Sleep induction by intranasal administration of melatonin. Adv Biosci. 1981;29:327–329.
Buysse DJ, Germain A, Moul DE. Diagnosis, epidemiology and consequences of insomnia. Prim Psychiatry. 2005;12:37–44.
Foley DJ, Monjan AA, Brown SL, Simonsick EM, Wallace RB, Blazer DG. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep. 1995;18:425–432.
Ancoli-Israel S, Cooke JR. Prevalence and comorbidity of insomnia and effect on functioning in elderly populations. J Am Geriatr Soc. 2005;53:S264–S271.
Jindal RD, Thase ME. Treatment of insomnia associated with clinical depression. Sleep Med Rev. 2004;8:19–30.
Foley D, Ancoli-Israel S, Britz P, Walsh J. Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America Survey. J Psychosom Res. 2004;56:497–502.
Engle-Friedman M, Bootzin RR, Hazlewood L, Tsao C. An evaluation of behavioral treatments for insomnia in the older adult. J Clin Psychol. 1992;48:77–90.
Silber MH. Clinical practice. Chronic insomnia. N Engl J Med. 2005;353:803–810.
Kirkwood CK. Management of insomnia. J Am Pharm Assoc (Wash). 1999;39:688–696.
O’Hanlon J. Residual effects on memory and psychomotor performance of zaleplon and other hypnotic drugs. Primary Care Companion. J Clin Psychiatry. 2002;4:38–44.
Mendelson WB. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry. 2005;66:469–476.
Leger D, Laudon M, Zisapel N. Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy. Am J Med. 2004;116:91–95.
Zhdanova IV, Wurtman RJ, Lynch HJ, et al. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Ther. 1995;57:552–558.
Zhdanova IV, Wurtman RJ, Morabito C, Piotrovska VR, Lynch HJ. Effects of low oral doses of melatonin, given 2-4 hours before habitual bedtime, on sleep in normal young humans. Sleep. 1996;19:423–431.
Gorfine T, Assaf Y, Goshen-Gottstein Y, Yeshurun Y, Zisapel N. Sleep-anticipating effects of melatonin in the human brain. Neuroimage. 2006;31:410–418.
MacFarlane JG, Cleghorn JM, Brown GM, Streiner DL. The effects of exogenous melatonin on the total sleep time and daytime alertness of chronic insomniacs: a preliminary study. Biol Psychiatry. 1991;30:371–376.
James SP, Sack DA, Rosenthal NE, Mendelson WB. Mela-tonin administration in insomnia. Neuropsycho-pharmacology. 1990;3:19–23.
Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia. J Sleep Res. 1996;5:61–65.
Haimov I, Lavie P, Laudon M, Herer P, Vigder C, Zisapel N. Melatonin replacement therapy of elderly insomniacs. Sleep. 1995;18:598–603.
Garfinkel D, Laudon M, Nof D, Zisapel N. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet. 1995;346:541–544.
Nagtegaal JE, Kerkhof GA, Smits MG, Swart AC, Van Der Meer YG. Delayed sleep phase syndrome: a placebo-controlled cross-over study on the effects of melatonin administered five hours before the individual dim light melatonin onset. J Sleep Res. 1998;7:135–143.
Kayumov L, Brown G, Jindal R, Buttoo K, Shapiro CM. A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome. Psychosom Med. 2001;63:40–48.
Brzezinski A, Vangel MG, Wurtman RJ, et al. Effects of exogenous melatonin on sleep: a meta-analysis. Sleep Med Rev. 2005;9:41–50.
von Gall C, Stehle JH, Weaver DR. Mammalian melatonin receptors: molecular biology and signal transduction. Cell Tissue Res. 2002;309:151–162.
Dubocovich ML, Rivera-Bermudez MA, Gerdin MJ, Masana MI. Molecular pharmacology, regulation and function of mammalian melatonin receptors. Front Biosci. 2003;8:d1093–d1108.
Pandi-Perumal SR, Trakht I, Srinivasan V, et al. Physiological effects of melatonin: role of melatonin receptors and signal transduction pathways. Prog Neurobiol. 2008;85:335–353.
McArthur AJ, Hunt AE, Gillette MU. Melatonin action and signal transduction in the rat suprachiasmatic circadian clock: activation of protein kinase C at dusk and dawn. Endocrinology. 1997;138:627–634.
Hunt AE, Al Ghoul WM, Gillette MU, Dubocovich ML. Activation of MT(2) melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock. Am J Physiol Cell Physiol. 2001;280:C110–C118.
Liu C, Weaver DR, Jin X, et al. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron. 1997;19:91–102.
Jin X, von Gall C, Pieschl RL, et al. Targeted disruption of the mouse Mel1b melatonin receptor. Mol Cell Biol. 2003;23:1054–1060.
Edgar DM, Dement WC, Fuller CA. Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J Neurosci. 1993;13:1065–1079.
Krauchi K, Wirz-Justice A. Circadian clues to sleep onset mechanisms. Neuropsychopharmacology. 2001;25:S92–S96.
Stone BM, Turner C, Mills SL, Nicholson AN. Hypnotic activity of melatonin. Sleep. 2000;23:663–669.
Skinner DC, Malpaux B. High melatonin concentrations in third ventricular cerebrospinal fluid are not due to Galen vein blood recirculating through the choroid plexus. Endocrinology. 1999;140:4399–4405.
Turek FW, Gillette MU. Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med. 2004;5:523–532.
Mendelson WB. A critical evaluation of the hypnotic efficacy of melatonin. Sleep. 1997;20:916–919.
Kato K, Hirai K, Nishiyama K et al. Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology. 2005;48:301–310.
Miyamoto M. Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther. 2009;15:32–51.
Hardeland R, Poeggeler B, Srinivasan V, Trakht I, Pandi-Perumal SR, Cardinali DP. Melatonergic drugs in clinical practice. Arzneimittelforschung. 2008;58:1–10.
Stevenson S, Bryson S, Amayke D, Hibberd M. Study to investigate the absolute bioavailability of a single oral dose of ramelteon (TAK-375) in healthy male subjects. Clin Pharmacol Ther. 2004;75:P22.
Greenblatt DJ, Harmatz JS, Karim A. Age and gender effects on the pharmacokinetics and pharmacodynamics of ramelteon, a hypnotic agent acting via melatonin receptors MT1 and MT2. J Clin Pharmacol. 2007;47:485–496.
Yukuhiro N, Kimura H, Nishikawa H, Ohkawa S, Yoshikubo S, Miyamoto M. Effects of ramelteon (TAK-375) on nocturnal sleep in freely moving monkeys. Brain Res. 2004;1027:59–66.
France CP, Weltman RH, Koek W, Cruz CM, McMahon LR. Acute and chronic effects of ramelteon in rhesus monkeys (Macaca mulatta): dependence liability studies. Behav Neurosci. 2006;120:535–541.
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.
Roth T, Seiden D, Sainati S, Wang-Weigand S, Zhang J, Zee P. Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia. Sleep Med. 2006;7:312–318.
Roth T, Seiden D, Wang-Weigand S, Zhang J. A 2-night, 3-period, crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin. 2007;23:1005–1014.
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.
Zammit G, Schwartz H, Roth T, Wang-Weigand S, Sainati S, Zhang J. The effects of ramelteon in a first-night model of transient insomnia. Sleep Med. 2009;10:55–59.
Mini L, Wang-Weigand S, Zhang J. Ramelteon 8 mg/d versus placebo in patients with chronic insomnia: post hoc analysis of a 5-week trial using 50% or greater reduction in latency to persistent sleep as a measure of treatment effect. Clin Ther. 2008;30:1316–1323.
Simpson D, Curran MP. Ramelteon: a review of its use in insomnia. Drugs. 2008;68:1901–1919.
Wang-Weigand S, McCue M, Ogrinc F, Mini L. Effects of ramelteon 8 mg on objective sleep latency in adults with chronic insomnia on nights 1 and 2: pooled analysis. Curr Med Res Opin. 2009;25:1209–1213.
Gross PK, Nourse R, Wasser TE. Ramelteon for insomnia symptoms in a community sample of adults with generalized anxiety disorder: an open label study. J Clin Sleep Med. 2009;5:28–33.
Mayer G, Wang-Weigand S, Roth-Schechter B, Lehmann R, Staner C, Partinen M. Efficacy and safety of 6-month nightly ramelteon administra tion in adults with chronic primary insomnia. Sleep. 2009;32:351–360.
Dobkin RD, Menza M, Bienfait KL, Allen LA, Marin H, Gara MA. Ramelteon for the treatment of insomnia in menopausal women. Menopause Int. 2009;15:13–18.
Regestein QR, Monk TH. Delayed sleep phase syndrome: a review of its clinical aspects. Am J Psychiatry. 1995;152:602–608.
Dahlitz M, Alvarez B, Vignau J, English J, Arendt J, Parkes JD. Delayed sleep phase syndrome response to melatonin. Lancet. 1991;337:1121–1124.
Richardson GS, Zee PC, Wang-Weigand S, Rodriguez L, Peng X. Circadian phase-shifting effects of repeated ramelteon administration in healthy adults. J Clin Sleep Med. 2008;4:456–461.
Richardson G, Wang-Weigand S. Effects of longterm exposure to ramelteon, a melatonin receptor agonist, on endocrine function in adults with chronic insomnia. Hum Psychopharmacol. 2009;24:103–111.
Zammit G, Wang-Weigand S, Rosenthal M, Peng X. Effect of ramelteon on middle-of-the-night balance in older adults with chronic insomnia. J Clin Sleep Med. 2009;5:34–40.
Richardson GS, Zammit G, Wang-Weigand S, Zhang J. Safety and subjective sleep effects of ramelteon administration in adults and older adults with chronic primary insomnia: a 1-year, open-label study. J Clin Psychiatry. 2009;70:467–476.
Srinivasan V, Pandi-Perumal SR, Trahkt I et al. Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci. 2009;119:821–846.
Kryger M, Wang-Weigand S, Roth T. Safety of ramelteon in individuals with mild to moderate obstructive sleep apnea. Sleep Breath. 2007;11:159–164.
Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437:1257–1263.
Fuller PM, Gooley JJ, Saper CB. Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms. 2006;21:482–493.
Wurtman R. Ramelteon: a novel treatment for the treatment of insomnia. Expert Rev Neurother. 2006;6:957–964.
Gerdin MJ, Masana MI, Ren D, Miller RJ, Dubocovich ML. Short-term exposure to melatonin differentially affects the functional sensitivity and trafficking of the hMT1 and hMT2 melatonin receptors. J Pharmacol Exp Ther. 2003;304:931–939.
Gerdin MJ, Masana MI, Rivera-Bermudez MA, et al. Melatonin desensitizes endogenous MT2 melatonin receptors in the rat suprachiasmatic nucleus: relevance for defining the periods of sensitivity of the mammalian circadian clock to melatonin. FASEB J. 2004;18:1646–1656.
Borja NL, Daniel KL. Ramelteon for the treatment of insomnia. Clin Ther. 2006;28:1540–1555.
Bellon A. Searching for new options for treating insomnia: are melatonin and ramelteon beneficial? J Psychiatr Pract. 2006;12:229–243.
Cardinali DP, Golombek DA. Let there be sleep-on time. Lancet. 2009;373:439–441.
CrossRef PubMed Copyright information
© Springer Healthcare Communications 2009