Ramelteon for Chronic Insomnia in Adults: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

 ZHOU Junxiang ^1,2 , WU Fengbo ¹ , TANG Yao ¹

1. Department of Pharmacy, West China Hospital, Sichuan University, Chengdu 610041, China;2. West China School of Pharmacy, Sichuan University, Chengdu 610041, China;

Corresponding author：

ZHOU Junxiang, Email: tangyao@yahoo.cn

Keywords：

Ramelteon; Chronic insomnia; Adult; Safety; Systematic review; Meta-analysis

DOI：

10.7507/1672-2531.20120051

Video：

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Objective　 To evaluate the effectiveness and safety of ramelteon for chronic insomnia in adults.
Methods　 The following databases as CENTRAL, PubMed, EMbase, ISI, CNKI, CBMdisc, VIP and WanFang Data were searched from the date of their establishment to November 2010. The randomized controlled trials (RCTs) meeting the inclusion criteria were included. The data extraction and quality assessment were conducted according to the methods of Cochrane Reviewers’ Handbook recommend by The Cochrane Collaboration, and meta-analysis was performed with RevMan5.0 software.
Results　 A total of 5 RCTs involving 1 772 patients were included. The results of meta-analyses showed that: a) Effectiveness: In the effectiveness, ramelteon was superior to placebo in latency to persistent sleep (MD=18.36, 95%CI 11.55 to 25.18, P lt;0.000 01), total sleep time (MD= –15.47, 95%CI –22.50 to –8.43, P lt;0.000 1), sleep efficiency (MD= –3.39, 95%CI –5.32 to –1.46, P=0.000 6), sleep quality (MD=0.14, 95%CI 0.03 to 0.25, P=0.01) after one week treatment and latency to persistent sleep (MD=13.02, 95%CI 6.01 to 20.03, P=0.000 3) except for wake after sleep onset (MD= –8.79, 95%CI –17.24 to –0.35, P=0.04) after one month treatment. b) Safety: significant differences were only found in the female prolactin (MD=5.50, 95%CI 2.02 to 8.98, P=0.002) and male free testosterone (MD=15.30, 95%CI 0.62 to 29.98, P=0.04) between the two groups, rather than in all the other hormones concentration, rebound insomnia, withdrawal syndrome, next-day residual effects and incidence rate of adverse reactions.
Conclusion　 Ramelteon has marked effects on adults’ chronic insomnia after 1-week treatment, but its effect is not obvious after 1-month treatment. The adverse reactions are mostly the somnolence, rising of male free testosterone and female prolactin concentration.

Citation： ZHOU Junxiang,WU Fengbo,TANG Yao. Ramelteon for Chronic Insomnia in Adults: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2012, 12(3): 314-319. doi: 10.7507/1672-2531.20120051 Copy

1.	Ota A, Masue T, Yasuda N, et al. Association between psychosocial job characteristics and insomnia: an investigation using two relevant job stress models—the demand -control-support (DCS) model and the effort-reward imbalance (ERI) model. Sleep Medicine, 2005, 6(4): 353-358.
2.	Neubauer DN. A review of ramelteon in the treatment of sleep disorders. Neuropsychiatric Disease and Treatment, 2008, 4(1): 69-79.
3.	Daley M, Morin CM, Leblanc M, et al. The Economic Burden of Insomnia: Direct and Indirect Costs for Individuals with Insomnia Syndrome, Insomnia Symptoms, and Good Sleepers. Sleep, 2009, 32(1): 55-64.
4.	Higgins JPT, Green S. Cochrane Handbook for systematic Reviews of Interventions Version 5.0. The Cochrane Collaboration, 2008. Available at: www.Cochranehandbook.org.
5.	Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia. Sleep medicine, 2006, 7(1): 17-24.
6.	Richardson G, Wang-Weigand S. Effects of long-term exposure to ramelteon, a melatonin receptor agonist, on endocrine function in adults with chronic insomnia. Human Psychopharm acology, 2009, 24(2): 103-111.
7.	Zammit G, Erman M, Wang-Weigand S, et al. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. Journal of Clinical Sleep Medicine, 2007, 3(5): 495-504.
8.	Hajak G, Ferini-Strambi L, Wang-Weigand S, et al. Objective and subjective efficacy of ramelteon 4 mg in adults with chronic insomnia. Journal of Cancer Education, 2009, 24: S354-S355.
9.	Mayer G, Wang-Weigand S, Roth-Schechter B, et al. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep, 2009, 32(3): 351-360.
10.	Van der HeiJden KB, Smits MG, Van Someren EJ, et al. Prediction of melatonin efficacy by pretreatment dim light melatonin onset in children with idiopathic chronic sleep onset insomnia. J Sleep Res, 2005, 14(2): 187-194.
11.	Zhdanova IV, Wurtman RJ. Efficacy of melatonin as a sleep-promoting agent. J Biol Rhythms, 1997, 12: 644-650.
12.	Stone BM, Turner C, Mills SL, et al. Hypnotic activity of melatonin. Sleep, 2000, 23(5): 663-669.
13.	Srinivasan V, Pandi-Perumal SR, Trahkt I, et al. Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci, 2009, 119 (6): 821-846.
14.	Stimmel GL, Dopheide JA. Sleep disorders: focus on insomnia. US Pharmacist, 2000, 25: 69.
15.	Kato K, Hirai K, Nishiyama K, et al. Neurochemical properties of ramelteon(TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology, 2005, 48(2): 301-310.
16.	Stevenson S, Bryson S, Amakye D, et al. Study to investigate the absolute bioavailability of a single oral dose of ramelteon(TAK-375) in healthy male subjects. Clinical Pharmacology & Therapeutics, 2004, 75: 22.
17.	Pandi-Perumal SR, Srinivasan V, Spence DW, et al. Ramelteon: a review of its therapeutic potential in sleep disorders. Advances In Therapy, 2009, 26(6): 613-626.

1. Ota A, Masue T, Yasuda N, et al. Association between psychosocial job characteristics and insomnia: an investigation using two relevant job stress models—the demand -control-support (DCS) model and the effort-reward imbalance (ERI) model. Sleep Medicine, 2005, 6(4): 353-358.
2. Neubauer DN. A review of ramelteon in the treatment of sleep disorders. Neuropsychiatric Disease and Treatment, 2008, 4(1): 69-79.
3. Daley M, Morin CM, Leblanc M, et al. The Economic Burden of Insomnia: Direct and Indirect Costs for Individuals with Insomnia Syndrome, Insomnia Symptoms, and Good Sleepers. Sleep, 2009, 32(1): 55-64.
4. Higgins JPT, Green S. Cochrane Handbook for systematic Reviews of Interventions Version 5.0. The Cochrane Collaboration, 2008. Available at: www.Cochranehandbook.org.
5. Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia. Sleep medicine, 2006, 7(1): 17-24.
6. Richardson G, Wang-Weigand S. Effects of long-term exposure to ramelteon, a melatonin receptor agonist, on endocrine function in adults with chronic insomnia. Human Psychopharm acology, 2009, 24(2): 103-111.
7. Zammit G, Erman M, Wang-Weigand S, et al. Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia. Journal of Clinical Sleep Medicine, 2007, 3(5): 495-504.
8. Hajak G, Ferini-Strambi L, Wang-Weigand S, et al. Objective and subjective efficacy of ramelteon 4 mg in adults with chronic insomnia. Journal of Cancer Education, 2009, 24: S354-S355.
9. Mayer G, Wang-Weigand S, Roth-Schechter B, et al. Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep, 2009, 32(3): 351-360.
10. Van der HeiJden KB, Smits MG, Van Someren EJ, et al. Prediction of melatonin efficacy by pretreatment dim light melatonin onset in children with idiopathic chronic sleep onset insomnia. J Sleep Res, 2005, 14(2): 187-194.
11. Zhdanova IV, Wurtman RJ. Efficacy of melatonin as a sleep-promoting agent. J Biol Rhythms, 1997, 12: 644-650.
12. Stone BM, Turner C, Mills SL, et al. Hypnotic activity of melatonin. Sleep, 2000, 23(5): 663-669.
13. Srinivasan V, Pandi-Perumal SR, Trahkt I, et al. Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci, 2009, 119 (6): 821-846.
14. Stimmel GL, Dopheide JA. Sleep disorders: focus on insomnia. US Pharmacist, 2000, 25: 69.
15. Kato K, Hirai K, Nishiyama K, et al. Neurochemical properties of ramelteon(TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology, 2005, 48(2): 301-310.
16. Stevenson S, Bryson S, Amakye D, et al. Study to investigate the absolute bioavailability of a single oral dose of ramelteon(TAK-375) in healthy male subjects. Clinical Pharmacology & Therapeutics, 2004, 75: 22.
17. Pandi-Perumal SR, Srinivasan V, Spence DW, et al. Ramelteon: a review of its therapeutic potential in sleep disorders. Advances In Therapy, 2009, 26(6): 613-626.

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