Combination Melatonin, Palmitoylethanolamide Significantly Improves Pain, Insomnia in Patients with Fibromyalgia

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Results of a first-of-its-kind study revealed treatment with a combination of palmitoylethanolamide and melatonin as an adjunct therapy in fibromyalgia significantly reduced pain and improved insomnia, both commonly reported symptoms among this patient population.

The two endogenous mediators have previously demonstrated pain-relieving benefits in other chronic pain conditions and have boasted excellent safety profiles with very minimal adverse events. A randomized, double-blinded, placebo-controlled crossover trial conducted in 2022 showed palmitoylethanolamide was able to increase pain modulation and reduce both peripheral and central sensitization. Melatonin, a pleiotropic hormone produced by the pineal gland, plays an important role in contributing to quality and duration of sleep. This combination may be particularly important for treating conditions such as fibromyalgia, which currently has no universally acknowledged therapy, as data has shown a bidirectional relationship between pain and sleep. Not only can pain disrupt sleep, but a shortened sleep time can also lower the pain threshold and can increase bouts of spontaneous pain.

“International guidelines favor a multimodal approach based on physical therapy and physical exercise as the first line of treatment,” wrote lead investigator Riccardo Terribili, MD, of the Rheumatology Unit at Siena University Hospital in Italy. “Furthermore, patients with fibromyalgia frequently report a certain degree of intolerance to different kinds of medications (muscle relaxants, opioids, non-steroidal anti-inflammatory drugs), significantly narrowing down therapeutic alternatives. In this context, supplements and nutraceuticals could represent a useful tool as add-on therapy, especially due to their excellent safety profile.”

The open-label study evaluated the effects of 1200 mg of palmitoylethanolamide and 0.2 mg of melatonin on sleep, pain and quality of life in a cohort of 50 patients with fibromyalgia between June 2023 and March 2024. Patients were evaluated at baseline, month 1, month 3 and month 4. Investigators determined changes in the visual analog scale (VAS) for pain, Insomnia Severity Index (ISI) for insomnia, the Health Assessment Questionnaire (HAQ) for health assessments and an evaluation of tender points.

Among the cohort, 38 patients were female, 12 were male and the average age was 54.12 years. Approximately one quarter of patients had concomitant hypothyroidism and/or anxiety–depressive disorder.

Patients receiving the combination treatment had significant improvements in ISI, VAS and HAQ scores compared with their personal baseline assessments, as well as a reduction in tender points at both months 1 and 3, which was sustained through the end of the study period.

VAS pain scores improved by 1.6 points at month 1 and continued to improve another 1.18 points at month 3. However, these advancements worsened slightly during the withdrawal period. Similarly, ISI scores improved by 6.24 points at 1 month, 1.54 points at 3 months and .36 points at 4 months. HAQ scores also steadily improved throughout the study period before stabilizing at 4 months. No adverse events were observed among participants.

Investigators noted limitations of the study, including the lack of a control group and enrolling patients with secondary fibromyalgia, which could have confounded results. However, recruiting a large number of patients coupled with the originality of the research reinforced the findings.

“These results could strengthen the already existing body of evidence favoring the use of nutraceuticals in the management of chronic pain conditions and fibromyalgia, for which it is often challenging to reach adequate disease control with standard therapies, offering an alternative to pharmacological polytherapy, which tends to be scarcely tolerated in these patients,” investigators concluded.