Efficacy and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia
Geert Mayer, Sherry Wang-Weigand, Barbara Roth-Schechter, Reiner Lehmann, Corinne Staner, Markku Partinen, Geert Mayer, Sherry Wang-Weigand, Barbara Roth-Schechter, Reiner Lehmann, Corinne Staner, Markku Partinen
Abstract
Study objectives: Long-duration (> or = 6 months) polysomnographic studies of insomnia medications are lacking. This study evaluated the long-term efficacy of ramelteon, a selective MT1/MT2 melatonin-receptor agonist used for insomnia treatment.
Design: Six-month, randomized, double-blind, placebo-controlled study.
Setting: Forty-six investigative sites in the United States, Europe, Russia, and Australia.
Participants: Four hundred fifty-one adults (age > or = 18 years) with chronic primary insomnia.
Interventions: Ramelteon, 8 mg, or placebo 30 minutes before bedtime nightly for 6 months.
Measurements: Sleep was evaluated by polysomnography and morning questionnaires on the first 2 nights of Week 1; the last 2 nights of Months 1, 3, 5, and 6; and Nights 1 and 2 of the placebo run-out. Next-morning residual effects as well as adverse effects and vital signs were recorded at each visit. Rebound insomnia and withdrawal effects were evaluated during placebo run-out.
Results: Over the 6 months of treatment, ramelteon consistently reduced latency to persistent sleep compared with baseline and with placebo; significant decreases were observed at Week 1 and Months 1, 3, 5, and 6 (P < 0.05). Ramelteon significantly reduced subjective sleep latency relative to placebo at Week 1, Month 1, and Month 5 (P < 0.05), with reductions nearing statistical significance at Months 3 and 6 (P < or = 0.08). No significant next-morning residual effects were detected during ramelteon treatment. No withdrawal symptoms or rebound insomnia were detected after ramelteon discontinuation. Most adverse events were mild or moderate in severity.
Conclusions: In adults with chronic insomnia, long-term ramelteon treatment consistently reduced sleep onset, with no next-morning residual effects or rebound insomnia or withdrawal symptoms upon discontinuation.
Figures
![Figure 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2647789/bin/aasm.32.3.351a.jpg)
![Figure 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2647789/bin/aasm.32.3.351b.jpg)
Figure 3
Subjective sleep latency measured over…
Figure 3
Subjective sleep latency measured over 6 months of nightly ramelteon, 8 mg, or…
- Hypnotics cause insomnia: evidence from clinical trials.Kripke DF. Kripke DF. Sleep Med. 2014 Sep;15(9):1168-9. doi: 10.1016/j.sleep.2014.08.001. Sleep Med. 2014. PMID: 25152199 No abstract available.
- Response to Dr. Kripke's letter.Mayer G, Rodenbeck A. Mayer G, et al. Sleep Med. 2014 Sep;15(9):1169-71. doi: 10.1016/j.sleep.2014.08.002. Sleep Med. 2014. PMID: 25152200 No abstract available.
- Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia.Roth T, Seiden D, Sainati S, Wang-Weigand S, Zhang J, Zee P. Roth T, et al. Sleep Med. 2006 Jun;7(4):312-8. doi: 10.1016/j.sleep.2006.01.003. Epub 2006 May 18. Sleep Med. 2006. PMID: 16709464 Clinical Trial.
- Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia.Zammit G, Erman M, Wang-Weigand S, Sainati S, Zhang J, Roth T. Zammit G, et al. J Clin Sleep Med. 2007 Aug 15;3(5):495-504. J Clin Sleep Med. 2007. PMID: 17803013 Free PMC article. Clinical Trial.
- Self-reported efficacy and tolerability of ramelteon 8 mg in older adults experiencing severe sleep-onset difficulty.Mini LJ, Wang-Weigand S, Zhang J. Mini LJ, et al. Am J Geriatr Pharmacother. 2007 Sep;5(3):177-84. doi: 10.1016/j.amjopharm.2007.09.004. Am J Geriatr Pharmacother. 2007. PMID: 17996657 Clinical Trial.
- Ramelteon: a novel approach in the treatment of insomnia.Reynoldson JN, Elliott E Sr, Nelson LA. Reynoldson JN, et al. Ann Pharmacother. 2008 Sep;42(9):1262-71. doi: 10.1345/aph.1K676. Epub 2008 Jul 23. Ann Pharmacother. 2008. PMID: 18648020 Review.
- Ramelteon for the treatment of insomnia.Borja NL, Daniel KL. Borja NL, et al. Clin Ther. 2006 Oct;28(10):1540-55. doi: 10.1016/j.clinthera.2006.10.016. Clin Ther. 2006. PMID: 17157111 Review.
- The Comparative Effectiveness and Safety of Insomnia Drugs: A Systematic Review and Network Meta-Analysis of 153 Randomized Trials.Pan B, Ge L, Lai H, Hou L, Tian C, Wang Q, Yang K, Lu Y, Zhu H, Li M, Wang D, Li X, Zhang Y, Gao Y, Liu M, Ding G, Tian J, Yang K. Pan B, et al. Drugs. 2023 Mar 22. doi: 10.1007/s40265-023-01859-8. Online ahead of print. Drugs. 2023. PMID: 36947394
- Physicians' attitudes toward hypnotics for insomnia: A questionnaire-based study.Takeshima M, Aoki Y, Ie K, Katsumoto E, Tsuru E, Tsuboi T, Inada K, Kise M, Watanabe K, Mishima K, Takaesu Y. Takeshima M, et al. Front Psychiatry. 2023 Feb 14;14:1071962. doi: 10.3389/fpsyt.2023.1071962. eCollection 2023. Front Psychiatry. 2023. PMID: 36865069 Free PMC article.
- Long-Term Use of Insomnia Medications: An Appraisal of the Current Clinical and Scientific Evidence.Zee PC, Bertisch SM, Morin CM, Pelayo R, Watson NF, Winkelman JW, Krystal AD. Zee PC, et al. J Clin Med. 2023 Feb 17;12(4):1629. doi: 10.3390/jcm12041629. J Clin Med. 2023. PMID: 36836164 Free PMC article. Review.
- Melatonin for Insomnia in Medical Inpatients: A Narrative Review.Salahub C, Wu PE, Burry LD, Soong C, Sheehan KA, MacMillan TE, Lapointe-Shaw L. Salahub C, et al. J Clin Med. 2022 Dec 29;12(1):256. doi: 10.3390/jcm12010256. J Clin Med. 2022. PMID: 36615056 Free PMC article. Review.
- Effectiveness of low-dose amitriptyline and mirtazapine for insomnia disorder: study protocol of a randomised, double-blind, placebo-controlled trial in general practice (the DREAMING study).Bakker MH, Hugtenburg JG, van Straten A, van der Horst HE, Slottje P. Bakker MH, et al. BMJ Open. 2021 Sep 2;11(9):e047142. doi: 10.1136/bmjopen-2020-047142. BMJ Open. 2021. PMID: 34475156 Free PMC article.
- Multicenter Study
- Randomized Controlled Trial
- Research Support, Non-U.S. Gov't
- Adolescent
- Adult
- Aged
- Attention / drug effects
- Double-Blind Method
- Drug-Related Side Effects and Adverse Reactions
- Female
- Humans
- Hypnotics and Sedatives / adverse effects
- Hypnotics and Sedatives / therapeutic use*
- Indenes / adverse effects
- Indenes / therapeutic use*
- Male
- Memory, Short-Term / drug effects
- Middle Aged
- Polysomnography / drug effects
- Prospective Studies
- Retention, Psychology / drug effects
- Sleep Initiation and Maintenance Disorders / drug therapy*
- Substance Withdrawal Syndrome / diagnosis
- Treatment Outcome
- Wakefulness / drug effects
- Young Adult
- Hypnotics and Sedatives
- Indenes
- ramelteon
![Figure 3](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/2647789/bin/aasm.32.3.351c.jpg)
Source: PubMed