Melatonin as add-on treatment for epilepsy

Epilepsy is one of the most common chronic neurologic disorders. Despite the plethora of antiepileptic drugs (AEDs) currently available, 30% of patients continue having seizures. This group of patients requires a more aggressive treatment, since monotherapy, the first choice scheme, fails to control seizures. Nevertheless, polytherapy often results in a number of unwanted effects, including neurologic disturbances (somnolence, ataxia, dizziness), psychiatric and behavioral symptoms, and metabolic alteration (osteoporosis, inducement or inhibition of hepatic enzymes, etc.). The need for better tolerated AEDs is even more urgent in this group of patients. Reports have suggested an antiepileptic role of melatonin with a good safety profile.

To assess the efficacy and tolerability of melatonin as add-on treatment for epilepsy.

We searched the Cochrane Epilepsy Group Specialized Register (May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL Issue 4 of 12, The Cochrane Library 2012), and MEDLINE (1946 to April 2012). The bibliographies of any identified study were searched for further references. We handsearched selected journals and conference proceedings. No language restrictions were imposed. In addition, we contacted melatonin manufacturers (i.e. Nathura) and original investigators to identify any unpublished study.

Randomized controlled trials; double, single, or unblinded trials; parallel group or cross-over studies. People with epilepsy regardless of age and sex, including children and adults with disabilities. Administration of melatonin as add-on treatment to any AED(s) compared to add-on placebo or no add-on treatment.

Review authors independently selected trials for inclusion according to predefined criteria, extracted relevant data, and evaluated the methodologic quality of trials. The following outcomes were assessed: at least 50% seizure reduction, seizure freedom, adverse events, and quality of life.

Four publications, with a total of 102 participants (90 aged under 18 years), were included. Two different comparisons were available: 1. melatonin versus placebo and 2. melatonin 5 mg versus melatonin 10 mg. Despite our primary intention, due to insufficient information on outcomes, we were unable to perform any meta-analysis, but summarized data narratively. Two studies were randomized, double-blind, cross-over, placebo-controlled trials and two were randomized, double-blind, parallel, placebo-controlled trials. Only one study provided the exact number of seizures during the trial compared to the baseline: none of the patients with seizures during the trial had a change in seizure frequency compared with the baseline. Adverse events were systematically evaluated in only one study (no adverse events observed). Only one study systematically evaluated quality of life, showing no statistically significant improvement in quality of life in the add-on melatonin group.

Included studies were of poor methodologic quality, and did not systematically evaluate seizure frequency and adverse events, so that it was impossible to summarize data in a meta-analysis. It is not possible to draw any conclusion about the role of melatonin in reducing seizure frequency or improving quality of life in patients with epilepsy.