Efficacy of Palmitoylethanolamide (Levagen+<sup>TM</sup>) Compared to Ibuprofen for Reducing Headache Pain Severity and Duration in Healthy Adults: A Double-Blind, Parallel, Randomized Clinical Trial

Background: Palmitoylethanolamide (PEA) has shown promise as an analgesic for those with chronic pain pathologies. With recently increased bioavailability, PEA may also be a treatment for acute pain presentations such as tension-type headaches. Aim: To assess the efficacy of a bioavailable PEA formulation (Levagen+TM) for reducing the severity and duration of acute episodes of tension-type headaches when compared to a standard treatment, nonsteroidal anti-inflammatory drug (NSAID) (the comparator). Methods: The study was a double-blind, randomized, single site, comparator controlled clinical study, with the cohort consisting of otherwise healthy adults, aged between 18 and 71, who experienced regular tension-type headaches. 94 adults experiencing headaches were randomised to receive either PEA (n = 47) or Ibuprofen comparator (n = 47). Upon headache onset, participants consumed their allocated product, recorded pain levels using a visual analogue scale (VAS) and continued to log their pain scores at 30-minute intervals for up to 4-hours. Results: Eighty-six participants (44 active treatment and 42 comparator) recorded at least one headache with a total of 271 tension-type headaches recorded (120 active treatment and 151 comparator). Most headaches were reduced in both treatment arms by 2 hours and almost all by 4 hours; 90% in the PEA group, and 97% in comparator group, p > 0.5. For moderate at onset headaches, the comparator group had a greater percentage of pain-free events at 2-hours. However, the time taken to resolve severe headaches was significantly lower in the PEA group than the comparator group (p Conclusions: These results place PEA as a potential treatment option for tension-type headaches.