Summary of studies assessing the effects of ramelteon (RMT) on sleep
| Study | Age | Diagnosis | Design + Number of Participants | Results | Adverse Events | Conclusion |
|---|---|---|---|---|---|---|
| Erman et al. (2006) | 18–64 | Chronic primary insomnia | Five-period crossover RCT. RMT 4 vs. 8 vs. 16 vs. 32 mg/day vs. placebo. N = 107. | PSG LPS (minute) was 37.7 for placebo vs. 24.0 for RMT 4 mg/day, P < 0.001, vs. 24.3 for RMT 8 mg/day, P < 0.001, vs. 24.0 for RMT 16 mg/day, P < 0.001, vs. 22.9 for RMT 32 mg/day, P < 0.001. P < 0.001 for overall effect. | No difference in number or type of AEs between active treatment and placebo group. | RMT is effective at reducing symptoms of insomnia. |
| Gooneratne et al. (2010) | ≤60 | Obstructive sleep apnea | 4-wk RCT. RMT 8 mg/day vs. placebo. N = 21. | Objective polysomnographic SOL (minute) was 20.4 ± 23.2 at baseline in the RMT group and 9.7 ± 10.3 after treatment. In the placebo group, objective SOL was 16.6 ± 17.5 at baseline and 34.4 ± 30.7 after treatment. For between groups comparison: P = 0.008. Subjective SOL was not significantly improved. | Four AEs occurred in RMT arm and two in placebo arm; none judged related to treatment. | RMT may be effective at reducing symptoms of insomnia in older adults. |
| Kohsaka et al. (2011) | 20–65 | Chronic primary insomnia | Crossover RCT (five periods of 2 nights each). RMT 4 vs. 8 vs. 16 vs. 32 mg/day vs. placebo. N = 65. | LPS (minute) was 29.02 ± 28.55 for RMT 4 mg/day, 22.12 ± 18.16 for RMT 8 mg/day, 28.17 ± 29.40 for RMT 16 mg/day, 24.37 ± 32.79 for RMT 32 mg/day, and 35.27 ± 40.68 for placebo. Differences between treatment and placebo were only significant for RMT 8 and 32 mg/day. However, the linear P value trend was: P = 0.0046. | The number of patients with an AE was higher in the 16 and 32 mg/day than with placebo and the 4 and 8 mg/day doses. The most common AEs were somnolence, headache, malaise, and dizziness. | RMT 8 and 32 mg/day are effective at reducing symptoms of insomnia. |
| Kuriyama et al. (2014) | 18–93 | Chronic, primary, or psychophysiological insomnia; bipolar disorder; insomnia associated with obstructive sleep apnea | Systematic review and meta-analysis of placebo-controlled RCTs. N = 5812. | RMT was significantly associated with reduced subjective SOL and improved QOS. It was not associated with increased subjective total sleep time. | Only significant AE was somnolence. No difference in occurrence of other AEs between RMT and placebo. | RMT is effective at reducing symptoms of insomnia. |
| Liu and Wang (2012) | 18 and over | DSM-IV primary chronic insomnia | Systematic review and meta-analysis of placebo-controlled RCTs. N = 4055 | Significant improvements in self-reported and polysomnographic SOL, TST, latency to REM. No improvement in percentage of REM. | RMT was not associated with a high risk ratio of any frequent AEs compared with placebo. However, there were significantly more subjective reports of at least one AE with RMT. | RMT is effective at reducing symptoms of insomnia. |
| Mayer et al. (2009) | 18–79 | Chronic primary insomnia | 6-mo RCT. RMT 8 mg/day vs. placebo. N = 451. | RMT consistently reduced LPS compared with baseline and compared with placebo as measured by objective polysomnography. RMT reduced LPS (minute) from 70.75 at baseline to 32.02 at week 1. Similar effects were observed at each follow up. | Incidence of AEs was similar between RMT (51.8%) and placebo (50.7%) groups. Eight patients in RMT and 10 patients in placebo discontinued due to an AE. Leukopenia occurred in one RMT-treated subject and was judged as possibly treatment related. | RMT is effective at reducing symptoms of insomnia over the course of 6 mo. |
| McElroy et al. (2011) | 18–65 | Bipolar I disorder | 8-wk RCT. 8 mg/day RMT vs. placebo. N = 21. | RMT and placebo and similar rates of reduction in symptoms of insomnia, mania, and global severity of illness. RMT was associated with improved depressive symptoms. Pittsburgh Insomnia Rating Scale total score difference from baseline to final visit: placebo, −69.3 vs. RMT, −54.2, P = 0.46. | One patient of 21 who were randomized withdrew due to sedation (RMT group). No participant experienced a serious AE. Small sample size limits ability to detect meaningful differences in the occurrence of AEs. | RMT may not be effective at reducing symptoms of insomnia in bipolar I disorder. |
| NCT#00755495 | 18–80 | Primary insomnia by DSM-IV-TR | 5-wk RCT. RMT 8 mg/day + doxepin 3 mg/day vs. RMT 8 mg/day vs. doxepin 3 mg/day vs. placebo. N = 472. | RMT 8 mg/day + doxepin 3 mg/day was significantly superior to placebo at reducing LPS at week 1, P < 0.001. However, at week 3, P = 0.400, and at week 5, P = 0.122. RMT 8 mg/day + doxepin 3 mg/d was significantly superior to placebo at increasing TST at all time points: P < 0.001 at week 1, P = 0.017 at week 3, and 0.036 and week 5. | The rates of AEs were similar among all treatment groups: 28.1% of RMT + doxepin, 30.8% for doxepin, 35.9% for RMT, 36.6% for placebo. Most reported AEs were somnolence (4.9%) and headache (4.5%), with somnolence occurring with the greatest incidence in the RMT + doxepin group (8.8%). | RMT + doxepin is effective at reducing symptoms of insomnia. Subjective sleep quality improved more with RMT + doxepin than with RMT alone over 5 wk of treatment. |
| Roth et al. (2006) | 64–93 | Primary insomnia | 35-night RCT. RMT 4 mg/day vs. 8 mg/day vs. placebo. N = 829. | LPS (minute) at week 1 was 70.2 for RMT 4 mg/day vs. 78.5 min for placebo, P = 0.008; it was 70.2 for RMT 8 mg/day vs. 78.5 for placebo, P = 0.008. RMT also significantly increased TST and rebound insomnia or withdrawal effects were not observed following discontinuation. | Incidence of AEs was similar among all treatment groups. Incidence of any AE: 51.5% of placebo group, 54.8% of RMT 4 mg/day, 58.0% of RMT 8 mg/day. | RMT is effective at reducing symptoms of insomnia. |
| Roth et al. (2007) | 65–83 | Chronic primary insomnia | 9-wk, three-period crossover RCT trial with treatment administered for 2 nights per treatment. RMT 4 vs. 8 mg/day vs. placebo. N = 100. | SOL (minute) was 28.7 for RMT 4 mg/day vs. 38.4 for placebo, P < 0.001; 30.8 for RMT 8 mg/day vs. 38.4 for placebo, P = 0.005. TST and SE were also significantly improved. | Incidence of AEs considered treatment-related was placebo 7%, RMT 4 mg/day 11%, and RMT 8 mg/day 5%. No evidence of next-day psychomotor or cognitive effects. | RMT is effective at reducing symptoms of insomnia. |
| Uchimura et al. (2011) | Mean: 48.8; S.D.: 17.2 | Chronic insomnia | RCT. RMT 4 vs. 8 mg/day vs. placebo for 2 wk followed by dose escalation to 8 vs. 16 vs. 4 mg/day, respectively, for 2 wk. N = 1143. | LS mean weekly subjective SOL (minute) at week 1: RMT 4 mg/day was not significantly superior to placebo, P = 0.9315. RMT 8 mg/day was not significantly superior to placebo, P = 0.0905. | 42.1% in the placebo/4 mg/day group, 42.5% in the 4/8 mg/day group and 41.8% in the 8/16 mg/day group reported at least one treatment-emergent AE The incidences of AEs among the treatment groups were comparable, and no dose–response relationships were observed. | RMT may not be effective at reducing symptoms of insomnia. |
| Uchiyama et al. (2011) | 20–85 | Chronic insomnia | 4-wk RCT. RMT 8 mg/day vs. placebo for 2 wk followed by 2-wk placebo run-out period to monitor rebound insomnia. N = 987. | RMT was significantly superior to placebo at reducing SOL at week 1 but insignificantly superior to placebo at week 2. LS mean (in minute) for RMT was 61.15 ± 0.97 at week 1 vs. 65.69 ± 0.97 for placebo. | No evidence of rebound insomnia. 2.7% of RMT group and 2.3% of placebo group discontinued due to AEs. The most common reason in both groups was nasopharyngitis. One serious adverse effect occurred in RMT group, a road accident >15 h after taking drug. | RMT is effective at reducing symptoms of insomnia after 1 wk of treatment. |
| Wang-Weigand et al. (2011) | 18–64 | Chronic insomnia | 3-wk RCT. RMT 8 mg/day vs. placebo. N = 556. | For mean subjective SOL relative to placebo: week 1 - reduction of 4.1 min, P = 0.088. Week 2: reduction of 2.8 min, P = 0.258. Week 3: reduction of 4.9 min, P = 0.060. No significant difference from placebo. | Somnolence occurred in 1.8% of placebo group and 4.4% of RMT group. The proportion of subjects with any treatment-related AEs was similar between groups (placebo 15.4%, ramelteon 16.5%). | RMT 8 mg/day may not be effective at reducing symptoms of insomnia. |
| Zammit et al. (2007) | 18–64 | Primary insomnia | 5-wk RCT. RMT 8 vs. 16 mg/day vs. placebo. N = 405. | LPS (minute) at week 1 was 32.2 for RMT 8 mg/day vs. 28.9 for RMT 16 mg/day vs. 47.9 for placebo, P < 0.001; significant improvements were maintained at weeks 3 and 5. | No evidence of next-day pharmacologic residual effects. No evidence of rebound insomnia following discontinuation of RMT. Most common AE in all groups was headache. | RMT is effective at reducing symptoms of insomnia. |
| Zammit et al. (2009) | ≥65 | Insomnia | Three-way crossover RCT. RMT 8 mg/day vs. zolpidem 10 mg/day vs. placebo. N = 33. | While zolpidem significantly impaired performance on the sensory organization test, turn time, and turn sway (P < 0.001 for all), RMT did not produce any differences from placebo. Immediate recall declined significantly with zolpidem (P = 0.002) while it was similar to placebo for RMT. | N/A | RMT did not impair middle-of-the-night balance, mobility, or memory in older adults relative to placebo |