Headaches are broadly separated into two categories: primary and secondary. Primary includes tension-type headaches, migraines and cluster headaches while secondary refers to headaches caused by infection, injury or tumour [1] [2] [3]. The pathophysiology of primary headaches is a complex process involving neuronal dysfunction [2] [4], activation of pain pathways [4], upregulation of inflammatory processes in vascular structures [2] [5] [6], sensitization to pain stimuli [5] and musculoskeletal abnormalities [7]. Treatment for headaches usually incorporates over the counter pain relieving medication and lifestyle management [1] [2] [3].

The primary treatment for headaches is pharmaceuticals such as Ibuprofen and aspirin [1] [2]. Prolonged use of these medications has been shown to lead to potential adverse health outcomes including gastrointestinal upset [8] [9] and cardiovascular [8] [9], renal and hepatic effects [8]. Additionally, tolerance to some medications can occur [10], which can increase the incidence of medication over-use headaches (MOH) [11]. These reasons identify the need for other treatment options with a good safety and tolerability profiles.

Palmitoylethanolamide (PEA) is a locally acting endogenous fatty acid derivative that is ubiquitously expressed in body tissues including the brain [12] [13]. PEA is produced on-demand from cell membranes as a protective response to noxious stimuli [14] [15]. PEA’s analgesic and anti-inflammatory effects have been documented for over 50 years [14] and confirmed in several chronic pain studies [7] [9] [15] [16] [17] [18]. Along with down-regulating multiple proinflammatory and nociceptive pathways [19], PEA is known to inhibit mast and glial cell activity [9] [20], both of which are involved in the pathogenesis of pain and inflammation [9] [18].

PEA is of particular interest as a treatment for chronic tension-type headaches. Research has demonstrated that PEA is safe and well tolerated when taken daily (from 300 mg to up to 1200 mg per day) for management of chronic pain conditions [13]. Previously, pilot studies have found that ultra-micronized PEA improved the frequency, duration, and severity of migraine headaches as either a standalone treatment or in combination with standard NSAIDs [15] [16]. While PEA has been previously compared to Ibuprofen for treating osteoarthritis symptoms [9], this is the first study to compare PEA to an Ibuprofen comparator for headache treatment.

The aim of this study was to assess the efficacy of a bioavailable PEA formulation utilising LipiSperse^® dispersion technology (Levagen+^TM) compared to a traditional therapy, Ibuprofen, in reducing the pain/severity and duration of tension-type headaches. We hypothesize that PEA supplementation will reduce the perceived pain/severity and duration of headaches comparatively to that of Ibuprofen.

Both the PEA and comparator groups were normally distributed with no significant differences between groups at baseline (Table 1). 94 participants enrolled in the study, of which 86 recorded at least one headache, with a total of 269 headaches recorded (Table 1; Figure 1). There were fewer headache events recorded by the PEA group compared to the comparator group, which was not significant. Differences in headaches recorded did not unbalance any statistical test performed.

No significant differences were found for visual analogue scale (VAS) for pain scores at the onset of headache between groups (p ~ 0.10) (Table 2). There was no significant difference between groups for severity of headache at onset (Table 2).

The comparator group had a greater percentage of pain free events (p < 0.05) at 2-hours for moderate at onset headaches compared to the PEA group (Table 3). Headaches that were mild at onset were not statistically analyzed due to the small sample size (comparator n = 14, PEA n = 12).

Results are mean (SD); PEA = palmitoylethanolamide; SD = standard deviation.

PEA = palmitoylethanolamide; VAS = Visual Analogue Scale; SD = Standard deviation.

*significant difference between groups p < 0.05; PEA = palmitoylethanolamide.

For those reporting headache resolution (i.e. pain free), there was no difference for resolution time between groups for all headache events (Figure 2). Mean resolution time for severe headaches was significantly reduced for the PEA (95.5 minutes) group compared with the Comparator (116.9 minutes) group (p < 0.05; Figure 2). There was no significant difference in mean resolution time for moderate headaches between groups (Table 4).

The majority of headaches were reduced in both treatment groups by 2 hours and almost all by 4 hours (Table 5). There was no significant difference for VAS pain score reduction (PSR) between groups for all headache events or headache severity subgroups (Table 6, Figure 3).

Rescue medication use was significantly greater overall for the PEA group compared with the Comparator group (p < 0.01; Table 7). Rescue medication use was significantly less in the comparator group for the moderate headache categories (p < 0.05) with no difference in the mild or severe categories (Table 7).

There were no serious treatment related adverse events reported in this study. The incidence of mild gastrointestinal symptoms was similar in both groups (~12%).

Results are presented as mean (SD); PEA = palmitoylethanolamide; * P < 0.05.

^ excludes headaches that were mild at onset; PEA = palmitoylethanolamide.

Data presented as mean (SD); PEA = palmitoylethanolamide.

*p < 0.05.

While no differences were observed between groups for participant characteristics, there was a higher ratio of females to males in both groups. This may be due to females being more prone to suffering from headaches [19] and therefore, more likely to enroll in the study than males. Other factors may include differences in genetic factors, sex hormone fluctuations, receptor binding, stress responsiveness and pain perception between males and females [19].

For total headache episodes, there was no difference between groups for reduction in pain (VAS) at onset of headache episodes (p = 0.10; Table 2). Pain scores reduced by at least 85% of the starting pain score over four hours for both products. While the pathophysiology of tension-type headaches is unknown, it is proposed that the primary mechanism is sensitization of central and peripheral nervous systems involved in pain processing [5] [15] [16] [21] [22] [23]. Two key molecules identified in the development of pathological pain are mast and glial cells, which when activated, release a host of immune mediators that can sensitize nociceptors, thus reducing pain threshold [3] [5] [15] [16] [24] [25] [26] [27] [28]. PEA acts by down regulating mast cell degranulation at local sites and therefore exerts an antagonistic action against inflammation and pain receptor stimulation [9]. Further, PEA has been shown to have a dose-dependent analgesic action and is thought to be related to its ability to inhibit mast and glial cell activation [3] [15] [25]. Through suppressing immune modulators of pain, PEA may effectively target the root of pathological pain, instead of solely alleviating symptomatology [15] [16] [29]. At headache onset following pain receptor activation, PEA may help to target and downregulate mast cells associated with headache pain resulting in an alternative treatment to current first-line therapies such as NSAIDs [9] [30].

According to International Headache Society (IHS) guidelines [31], the primary measure for efficacy of treatment is the proportion of headache events pain free at two hours after treatment and before the use of any rescue medication [31]. When headaches were separated into severity classes (mild, moderate and severe), analysis identified that both products were effective at reducing pain scores over two and four hours. However, after 2-hours, the comparator was shown to reduce pain more effectively for moderate intensity headaches compared to PEA (p < 0.05).

When evaluating the mean resolution time of resolved headaches, it was shown that time taken for severe headache events to resolve following PEA (95.5 min) supplementation, was significantly less compared to the Comparator group (116.9 min). This result suggests PEA may be more effective against more severe headaches rather than mild or moderate headaches. It may therefore be that PEA may be a suitable for treating severe headaches and migraines rather than mild headache.

Pain and headache resolution data is supported by rescue medication use. Rescue medication use was significantly lower in the comparator group (p < 0.05) for total and moderate headache episodes. Therefore, the comparator, known to reduce tension headaches [32] [33], may be a better option for mild and moderate headaches, while PEA may be better suited to more severe headaches. However, one factor difficult to assess, is the mechanism/cause of the headache. Ibuprofen and PEA may both act better for headaches with a particular aetiology. Future studies would benefit by determining the aetiology of a person’s headache and assessing the efficacy of the treatment on the different mechanisms.

This study showed good gastrointestinal tolerance for both treatment groups. The lack of side effects for both treatments may however be due to the periodic use. Past studies reporting adverse effects associated with the use of Ibuprofen, are typically from long term use rather than that used here [34] [35].

A limitation of this study is that it relied on participants’ perception of headache severity. Therefore, the subjective data collected could be influenced by environmental and psychological factors that impact the individual’s pain threshold. However, without using highly expensive imaging technology there is no other means to obtain headache pain data. Future studies might benefit by including a cross-over design to account to the different levels of pain thresholds that may be experienced by different individuals.

Other future directions for PEA research may benefit from including participants experiencing migraines. This would enable the assessment of PEA as a potentially effective treatment of a more severe class of headache. Although limited in this study due to COVID-19, pathology would also provide valuable information to future studies. By looking at changes in pathology, it might help answer why PEA is more effective in some headaches and not others.

As far as we are aware, this is the first study to directly compare the efficacy of the PEA to a traditional NSAID, in improving primary headache symptoms. Overall, while the comparator was shown to result in less rescue medication used, PEA may be a viable option for treating headaches of moderate or severe intensity. PEA reduced headache pain at 2 and 4 hours to equivalent levels to the comparator. Furthermore, PEA was able to resolve severe headaches faster than the standard treatment.

The results of this study potentially make PEA a treatment option for acute headache episodes. However, this calls for further clinical studies comparing PEA to traditional analgesic treatments in different headache models including migraines. Additionally, long-term prospective studies could serve to give an accurate depiction of product efficacy and tolerability after prolonged usage.

The authors declare no conflicts of interest regarding the publication of this paper.

Briskey, D., Ebelt, P., Steels, E., Subah, S., Bogoda, N. and Rao, A. (2022) Efficacy of Palmitoylethanolamide (Levagen+^TM) Compared to Ibuprofen for Reducing Headache Pain Severity and Duration in Healthy Adults: A Double-Blind, Parallel, Randomized Clinical Trial. Food and Nutrition Sciences, 13, 690-701. https://doi.org/10.4236/fns.2022.137050