Prolonged release melatonin in the treatment of primary insomnia: evaluation of the age cut-off for short- and long-term response

Abstract

Objectives:

The authors recently reported on efficacy and safety of prolonged-release melatonin formulation (PRM; Circadin 2 mg) in elderly insomnia patients. The age cut-off for response to PRM and the long-term maintenance of efficacy and safety were further evaluated by looking at the total cohort (age 18–80 years) from that study and subsets of patients aged 18–54 and 55–80 years (for whom the drug is currently indicated).

Design:

Randomised, double-blind, placebo controlled trial.

Setting:

Multicentre, outpatients, primary care setting.

Methods:

A total of 930 males and females aged 18–80 years with primary insomnia who reported mean nightly sleep latency (SL) >20 min were enrolled and 791 entered the active phase of the study. The study comprised a 2-week, single-blind placebo run-in period followed by 3 week’s double-blind treatment with PRM or placebo, one tablet per day at 2 hours before bedtime. PRM patients continued whereas placebo completers were re-randomised 1:1 to PRM or placebo for 26 weeks followed by 2-weeks run-out on placebo.

Main outcome measures:

SL and other sleep variables derived from sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of life (WHO-5), Clinical Global Impression of Improvement (CGI-I) and adverse effects, recorded each visit, withdrawal and rebound effects during run-out.

Results:

In all, 746 patients completed the 3-week and 555 (421 PRM, 134 placebo) completed the 6-month period. The principal reason for drop-out was patient decision. At 3 weeks, significant differences in SL (diary, primary variable) in favour of PRM vs. placebo treatment were found for the 55–80-year group (−15.4 vs. −5.5 min, p = 0.014) but not the 18–80-year cut-off which included younger patients. Other variables (SL-PSQI, PSQI, WHO-5, CGI-I scores) improved significantly with PRM in the 18–80-year population, more so than in the 55–80-year age group. Improvements were maintained or enhanced over the 6–month period with no signs of tolerance. No withdrawal symptoms or rebound insomnia were detected. Most adverse events were mild with no significant differences between PRM and placebo groups in any safety outcome.

Conclusions:

The results demonstrate short- and long-term efficacy of PRM in insomnia patients aged 18–80 years, particularly those aged 55 and over. PRM was well-tolerated over the entire 6-month period with no rebound or withdrawal symptoms following discontinuation.

Trial registration: ClinicalTrials.gov identifier: NCT00397189.

Key words::

• Melatonin insomnia
• Long-term
• Prolonged-release
• Sleep latency

Transparency

Declaration of funding

The study was funded by Neurim Pharmaceuticals, Tel-Aviv, Israel.

Declaration of financial/other relationships

A.G.W. and I.F. have disclosed that they have acted as paid consultants to Neurim. T.N., M.L. and N.Z. have disclosed that they are employees of Neurim.

Acknowledgement

The authors thank Dr G. Crawford and partners, Dr R. Lesley and partners, Dr D. Campbell and partners, Dr M. MacRae and partner, Dr M. Angus and partners and Dr S. Connolly and partners who managed the patients so admirably. The authors are also indebted to the research nurses and management staff of CPS Research without whom the study would not have taken place.