Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety

Abstract

BackgroundMelatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment.MethodsAdult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit.ResultsOn the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] ≤8 μg/night) regardless of age did not differ from the placebo, whereas PRM significantly reduced sleep latency compared to the placebo in elderly patients regardless of melatonin levels (-19.1 versus -1.7 min; P = 0.002). The effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over the 6-month period with no signs of tolerance. Most adverse events were mild in severity with no clinically relevant differences between PRM and placebo for any safety outcome.ConclusionsThe 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. The age cut-off for response warrants further investigation.

0395 Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults: An American Academy of Sleep Medicine Clinical Practice Guideline

“…Wade 146 found that the melatonin deficient group (including all ages) showed no improvement with melatonin versus placebo on SL at three weeks. However, the elder group (65-80 years) showed significant reduction of SL with melatonin, regardless of melatonin deficiency status (SL: −19.1 min; placebo −1.7 min).…”

“…[141][142][143][144][145][146][147] These investigations employed various dosages and combinations with other agents, rendering meaningful comparisons to the 2 mg RCTs impossible. Pertinent features of these studies are included within each outcome section.…”

Evidence for the efficacy of melatonin in the treatment of primary adult sleep disorders

“…[84] Wade et al [48] preformed a trial over six months of daily melatonin use and demonstrated no adverse effects or rebound withdrawal symptoms. Two studies [62,85] that arise from sleep restriction (e.g., jet lag, shift-work), [4] but the results of their review may be partly attributable to trial limitations similar to those discussed in the current paper.…”

Cognitive Behavioral Therapy in the Treatment of Insomnia

“…Four trials studied the general adult population with pain [80][81][82][83][84] and three assessed the efficacy of CBT-I in older adults with pain. 79,85,86 McCurry is a second publication of an earlier trial analyzing only a portion of the participants with pain.…”