Summary of studies assessing the effects of the prolonged-release melatonin formulation (PRM) on sleep
| Study | Age | Diagnosis | Design + Number of Participants | Results | Adverse Events | Conclusion |
|---|---|---|---|---|---|---|
| Arbon et al. (2015) | 55–64 | Healthy participants | Double-blind, placebo-controlled, four-way crossover trial. PRM 2 mg vs. temazepam 20 mg vs. zolpidem (10 mg) vs. placebo. N = 16 | PRM has minor effects on stage N3 in comparison with those of temazepam and zolpidem. | 10 adverse events of mild intensity due to PRM. The most common reported were gastrointestinal disorders (constipation, dry mouth, flatulence, and nausea), nervous system disorders (balance disorder, somnolence, and headache), and general disorders (fatigue and feeling hot). | PRM does not significantly affect sleep parameters in elderly. |
| Dolev (2011) | See Mirtazapine section | |||||
| Lemoine et al. (2007) | 55+ | Primary insomnia | 2-wk single-blind placebo run-in period followed by a 3-wk RCT treatment period. PRM 2 mg/day vs. placebo. N = 170. | PRM improved QOS measured by LSEQ (−22.5 vs. −16.5, P = 0.047). | Nine patients in each treatment group reported AEs. The most common reported AEs were mild. Diarrhea occurred in one patient receiving PRM and one patient receiving placebo. | PRM is effective at reducing symptoms of insomnia in the elderly. |
| Lemoine et al. (2011) | 20–80 | Primary insomnia | 6–12 mo open-label continuation trial. PRM 2 mg/day. N = 244. | The mean (+S.E.M.) percentage of nights per week scored by the patients as “good” or “very good” increased progressively with treatment duration. At the plateau level, 54%–56% of nights per week were scored as “good” or “very good” (i.e., 3.8 nights/wk) compared with 26% (i.e., 1.8 nights/wk) at baseline (P < 0.001), which was maintained throughout trial. | PRM discontinuation even after 12 mo was not associated with AEs, withdrawal symptoms, or suppression of endogenous melatonin production. Most common reported events were pharyngitis (12.4%) and back pain (11.8%). | PRM is effective at reducing symptoms of insomnia as long-term treatment. |
| Lemoine and Zisapel (2012) | 55+ | Primary insomnia | Post hoc analysis of pooled antihypertensive drug-treated subpopulations from four randomized, double-blind trials of PRM and placebo for 3 wk. N = 589. | By the end of the 6-mo treatment period, means subjective improvement in patients’ evaluated SOL was significantly higher with PRM (25.89 minutes) than with placebo (7.54 minutes) P = 0.02. | Rate of AEs normalized per 100 patient-weeks was lower for PRM (3.66) than for placebo (8.53). | PRM is efficacious and safe in primary insomnia patients treated with antihypertensive drugs |
| Luthringer et al. (2009) | 55+ | Primary insomnia | 2-wk single-blind placebo run-in followed by 3-wk RCT of PRM 2 mg/day for 3 wk followed by a 3-wk withdrawal period. N = 40 | PRM group had significantly shorter SOL (9 min; P = 0.02) compared with the placebo group and scored significantly better in the Critical Flicker Fusion Test (P = 0.008) without negatively affecting sleep structure and architecture. Half of the patients reported substantial improvement in QOS at home with PRM compared with 15% with placebo (P = 0.018). No rebound effects were observed during withdrawal | AEs were reported by 11 patients in each treatment group. The most common AE was headache, reported by four patients in the PRM group and three in the placebo group. No significant difference in the incidence of AEs. | PRM was effective in reducing symptoms of insomnia. |
| Otmani et al. (2008) | 55+ | Healthy participants | RCT crossover study. PRM 2 mg, zolpidem 10 mg, PRM + zolpidem vs. placebo. Effects on psychomotor functions, memory recall, and driving skills were assessed at 1, 4 h and morning following administration. N = 16. | A main ‘‘treatment’’ effect was found for all variables (P < 0.05) Zolpidem significantly increased sedation compared with placebo at 1 hour (P = 0.0011, P < 0.0001, respectively) and 4 hours postdosing (P < 0.0001 for both) and compared with PRM at 1 hour (P = 0.03, P < 0.0001, respectively) and 4 hour (P = 0.015 for both). | N/A | PRM does not have significant cognitive adverse effects in the elderly. |
| Wade et al. (2007) | 55–80 | Primary insomnia | 2-wk single-blind placebo run-in period followed by a 3-wk RCT treatment period. PRM 2 mg/day vs. placebo. N = 354. | PRM improved quality of sleep measured by LSEQ (−22.5 vs. −16.5, P = 0.047). | 24% and 21% of patients in the respective PRM and placebo groups reported AEs. Most commonly reported effects were nasopharyngitis and headache or migraine. | PRM is effective at reducing symptoms of insomnia in the elderly. |
| Wade et al. (2010) | 18–80 | Primary insomnia | 2-wk single-blind placebo run-in period followed by 3-wk RCT of PRM 2 mg/day vs. placebo; 26-wk extension study with 2 wk of single-blind placebo run-out. N = 791 | PRM in patients with low endogenous melatonin regardless of age did not improve SOL compared with placebo, whereas PRM significantly reduced SOL compared with placebo in elderly patients regardless of melatonin levels (−19.1 vs. −1.7 min; P = 0.002). | AE rates were similar between PRM and placebo groups. 34.5% and 35.9% of respective PRM- and placebo-treated patients reported any AE during the treatment period. In extension period, 73.8% and 76.8% of PRM- and placebo-treated subjects reported any AE. Most common events were nasopharyngitis, arthralgia, diarrhea, respiratory tract infections, and headache. | PRM is effective at reducing symptoms of insomnia in the elderly. The results demonstrate short- and long-term efficacy and safety of PRM in elderly insomnia patients. Low melatonin production regardless of age is not useful in predicting responses to melatonin therapy in insomnia. |
| Wade et al. (2014) | 52–85 | Mild to moderate Alzheimer’s disease, with and without insomnia comorbidity | 2-wk single-blind placebo run-in followed by 24-wk RCT and 2-wk placebo run-out period. PRM 2 mg/day vs. placebo. N = 80. | Patients treated with PRM (24 wk) had significantly better cognitive performance than those treated with placebo, as measured by the IADL (P = 0.004) and MMSE (P = 0.044). Mean ADAS-Cog did not differ between the groups. The PSQI global score improved in PRM (−1.62 [2.74], P = 0.004) but not placebo group (0.74 [2.52], P = 0.139) | AE rates were similar between PRM and placebo groups. 82.1% of PRM patients reported AEs vs. 67.6% of placebo-treated patients. | Add-on PRM has positive effects on cognitive functioning and sleep maintenance in AD patients compared with placebo, particularly in those with insomnia comorbidity. |