PEA: A Novel Fatty Acid in the Treatment of Pain

The topic of peroxisome proliferator-activated receptor (PPAR) ligands typically involves a discussion of the lipid-lowering effects of fibrates and the blood sugar-lowering effects of thiazolidinedio- nes. However, more recent research has investigated the role of the endogenous PPAR-a ligand, palmitoylethanolamide (PEA) on inflammation, pain, neurodegenerative diseases, stroke, spinal cord injury, and neuropsychiatric disorders.¹ Palmitoylethanolamide is a naturally occurring fatty acid belonging to the A'-acyletlianolamine (NAE) class of signaling molecules and can be isolated from egg yolks, peanut meal, and lecithin. It is rapidly metabolized in the human body via fatty acid amide hydrolase (FAAH) and A'-acylethanolamine-hydrolyzing acid amidase (NAAA) to inactive metabolites palmitic acid and ethanolamide.²-’ Initial pharmacokinetic research by Lambert et al.² assumed a ligand-binding relationship between PEA and the endogenous cannabinoid 2 (CB2) receptor. However, these initial claims proved to be incorrect and were explained as the entourage effect, where PEA competes with the endocannabinoid anandamide (AEA) for FAAH, resulting in higher concentrations of AEA.⁴ Although it does have a structural relationship to AEA and other endocannabinoids, PEA was found to have pharmacologic activity at PPAR-a, PPAR-y, PPAR-5, G protein-coupled receptor (GPR) 55, GPR119, transient receptor potential channel type (TRP) VI, ATP-sensitive potassium channels, and calcium-activated potassium channels. Additionally, PEA appears to inhibit ceramidases, and potassium channels Kv4.3 and Kvl.5, as well as interacting with NF-кВ, cyclooxygenase (COX), TNFa, interleukin (IL)-4, IL-6, IL-8, nitric oxide (NO), and substance P mast cell activation. This variety of interactions has afforded PEA the title of being “promiscuous.”⁴⁵

Many of the receptors, channels, and cytokines that PEA interacts with are involved in inflammatory pain signaling (e.g., PPAR-a), immune systems (e.g., GPR55), and endocrine systems (e.g., GPR119). As discussed by Skaper et al.,¹ inflammation is a protective response in the human body that is initiated during the cellular healing process. However, when inflammation is prolonged it can cause damage and lead to pain, neurologic diseases, and other inflammatory disorders. Palmitoylethanolamide accomplishes its anti-inflammatory and anti-nociceptive effects by binding to and modulating PPAR-a, which is a regulator of the gene networks controlling pain and inflammation. This gene network switches NF-кВ off, which is involved in the pathology of peripheral neuropathies, carpal tunnel syndrome, sciatic pain, osteoarthritis, low-back pain, dental pain, multiple sclerosis, chronic pelvic pain, postherpetic neuralgia, and vaginal pain.⁵ The cannabinoid-like receptors GPR55 and GPR119 have been linked to inflammation in the gut related to immune system modulation and GLP-1 secretion from entero-endocrine cells, respectively.⁶ Additionally, PEA influences potassium channels involved in pain perception and desensitizes the TRPV1 channel on sensory neurons. These pharmacodynamic relationships are what gives PEA its anti-inflammatory, immune-modulatory, and anti-nociceptive properties.

Pain, Endometrial Pain, Fibromyalgia, and IBS-Related Pain

The interaction between PEA and PPAR-a has been demonstrated by comparing the observed effects of PEA on normal mice to those that have been genetically altered without PPAR-a. When exposed to PEA, the PPAR-a null mice did not experience the anti-nociceptive effects of PEA.⁷-⁸ Based on animal studies, the hypothesis that PPAR-a has anti-nociceptive and anti-inflammatory effects is supported by showing reduced edema and macrophage infiltration, and increased myelin sheath, axonal diameter, and number of fibers. PEA was also associated with a reduction of inflammatory markers (e.g., COX-2, inducible NO synthase, malondialdehyde). Consequently, it was determined that PEA not only exerts anti-inflammatory and anti-nociceptive effects, but also prevents neurotoxicity and neurodegeneration.¹⁷

PEA has been shown to be effective in a number of chronic pain conditions both as an adjunct therapy to other pain medication and as a monotherapy. Gatti et al.⁹ performed a prospective observational study on the effects of PEA in several chronic pain conditions including diabetic neuropathy, post-herpetic neuralgia, and osteoarthritis. This study consisted of 564 patients suffering from various pathological conditions who were either undergoing standard therapy with unsatisfactory results or who had discontinued therapy because of side effects. Adult patients greater than 18 years old, with chronic pain for more than 6 months, and a Numerical Rating Scale (NRS) score of 4 or greater were included in the study. Study participants were instructed to take 600 mg of PEA (Normast®) twice daily for 3 weeks followed by once daily dosing for 1 week. The NRS was used to evaluate changes in pain before and after the treatment period. Participants were separated into two groups based on whether they were taking concomitant medication with PEA or PEA alone. The researchers reported that the PEA treatment markedly decreased the mean score pain intensity from a baseline value of 6.4 to 2.5 for all study participants. Their analysis of the data using a mixed model repeated measure ruled out any other factors beside the PEA treatment for the improvement of pain. The study also highlighted the value of having a group that was taking the PEA as a monotherapy for pain by stating that there was a similar reduction in pain seen with this group as compared to the other group.

Human studies on the effects of PEA on endometrial pain have shown promising results. Keppel Hesselink¹⁰ observed a therapeutic response with the combination of PEA and trans-polydatin, as measured by the visual analogue scale (VAS) score within 1-4 weeks of treatment, of at least 50% when compared to baseline in patients with chronic pelvic pain related to endometriosis. Mast cells have been associated with endometrial pain, and PEA has been shown to be effective in reducing mast cell activation.¹⁵⁶

Another study was conducted in 2015 on the effects of PEA and trans-polydatin as a treatment for primary dysmenorrhea. This randomized placebo-controlled study investigated the effects of a PEA + trans-polydatin combination on 220 adolescent and young women (mean age 19 years) who experienced primary dysmenorrhea. The researchers found that an improvement in pelvic pain was seen in 98.18% of the cases in the group treated with the combination medication versus 56.36% in the placebo group. The average improvement in pain in the treatment group was 4 points based on the VAS as compared to only 1 point in the placebo group. While this was a small sample size, the researchers noted that this therapy would, at the very least, be a good adjunct treatment to the traditional use of NSAIDs or oral contraceptives for the relief of primary dysmenorrhea. Using this combination would lead to a decrease in side effects seen from the use of these traditional treatments.¹¹

Cobellis et al.¹² investigated the effectiveness of a PEA+ trans-polydatin combination in endometriosis through a randomized, double-blind, parallel-group, placebo-controlled clinical study. The 61 participants in this study were female between the ages of 24 and 41 who had a confirmed diagnosis of endometriosis. The participants were separated into three separate groups and were given the PEA + trans-polydatin combination (400 mg+40 mg twice daily for 3 months), placebo, or celecoxib (200 mg twice daily for 7 consecutive days). Study participants completed a questionnaire for pelvic pain assessment and rated their pelvic pain using the VAS both before and after treatment. The researchers reported that there was a larger reduction in pain with the PEA + trans-polydatin compared to placebo reported by the patients. Additionally, there was a reduction in pain seen in the celecoxib group. While NSAIDs are an effective symptomatic therapy for endometriosis, they have a number of side effects that can make them dangerous for long-term use. This study highlighted that the PEA + trans-polydatin combination would be a good option for patients suffering from endometriosis if they have absolute contraindications for NSAIDs. While this study was promising, more research needs to be done to establish the effectiveness of PEA on endometriosis.

Giugliano et al.¹³ performed a study investigating the effects of a PEA + trans-polydatin combination on endometriosis pain. This was a prospective cohort clinical study with 47 participants. They were separated into two groups based on where the endometriosis was located; group A had endometriosis located at the recto-vaginal septum and group В at the ovary. All patients were treated with estrogen-progestin therapy and anti-inflammatory therapy for at least 6 months prior to the start of the trial and continued that therapy for the duration of the trial. Every patient received the same treatment (PEA + trans-polydatin, 400 mg+40 mg twice daily) for 90 days. Patients rated the severity of dysmenorrhea, chronic pelvic pain, dyspareunia, and dyschezia using the VAS prior to the start of treatment and at 30 (Tl), 60 (T2), and 90 (T3) days after treatment. At the beginning of the trial the average mean scores for chronic pelvic pain, dysmenorrhea, dyspareunia, and dyschezia were 5.11, 6.7, 3.85, and 2.57, respectively. Except for dyschezia, there was a significant reduction in pain observed among the two groups over the period of 90 days. Specifically, reductions in chronic pelvic pain in the patients with recto-vaginal endometriosis and dysmenorrhea in patients with ovarian endometriosis were observed. This study demonstrated the efficacy of a PEA + trans-polydatin combination as an adjunct therapy in the treatment of endometriotic pain. The authors of this paper noted that the patients who participated in this study started out with moderate endometriotic pain; therefore, they cannot attest to the efficacy of PEA + trans-polydatin in patients with severe endometriotic pain.

Fibromyalgia is a complex disease state that encompasses many different pain disorders, making diagnosis and treatment difficult. The presence of inflammatory cytokines is key to the nociception, allodynia, and hyperalgesia seen in fibromyalgia patients. Del Giorno et al.¹⁴ investigated the efficacy of a combination therapy consisting of duloxetine, pregabalin, and PEA. The results of the study showed a significant reduction of painful tender points and global pain with the addition of PEA. This provides evidence for the PEA as an adjunct to pain management in fibromyalgia.

Irritable bowel syndrome (IBS) is a gastrointestinal disorder that typically presents with pain associated with the alteration of bowel function. Recent evidence has shown a link between endogenous cannabinoid receptors (e.g., CB,, CB₂), cannabinoid-like receptors (e.g., TRPV1, GPR55), and endogenous ligands (e.g., AEA, PEA) with attenuation of IBS-related pain.¹⁵ Irritable bowel syndrome can be divided into two main categories based on symptomatology. Type-D patients present with diarrhea, w'hereas type-C patients present with constipation. Fichna et al.¹⁵ found that patients with IBS-D have lower plasma levels of PEA, correlating with cramping pain, and patients with IBS-C have higher levels of endogenous cannabinoids combined with lower levels of FAAH. Russo et al.¹⁶ reported that PEA has been well-established as an effective anti-inflammatory, analgesic in inflammatory bowel disease (IBD), and their work in animal models showed a reduction in inflammation and pain in IBD pain animal models. Depending on the type and presentation, a

PEA agonist and/or antagonist may prove to be an effective treatment option for patients with IBS and IBD.

A study performed by Cremon et al.¹⁷ investigated the analgesic properties of a PEA/polydatin (200 mg/20 mg) combination and its effect on patients with IBS. This was a pilot, phase lib, randomized, double-blind, placebo-controlled, parallel-arm, multicenter trial that lasted for 12 weeks and included 54 patients. Irritable bowel syndrome can lead to alteration of the intestinal mucosal barrier that allows for the passage of immune mediators, including the recruitment of mast cells and their activation. This study reported the effects of the PEA/polydatin combination on mast cell count, mast cell/immune cell activation, and the effect of treatment on immune activation, the effect of treatment on the endocannabinoid system, and the effect of treatment on digestive symptoms associated with IBS. Based on tissue samples taken from the colon, those with IBS had a higher area occupied by mast cells than the tissue samples from healthy patients. The researchers found that the treatment and placebo groups did not have statistically significant differences in the area taken up by mast cells. Immune factor parameters did not differ significantly between the healthy patients and those with IBS, and there was no significant difference between the placebo and treatment groups over time. The researchers did observe a decrease in the severity of abdominal pain and discomfort over time with the treatment group compared to the placebo. They showed that 62.1% of the patients on the PEA/polydatin treatment responded versus 40% in the placebo group. Other symptoms of IBS, including bloating severity and frequency, bowel habits, and dyspeptic and gastro-esophageal reflux symptoms, were found to be unaffected by the interaction between treatment and duration of treatment. The lack of effect seen on the endocannabinoid receptors and endo- cannabinoid-like mediators suggests that, witli respect to IBS, PEA acts through a different pathway to exert its effects. This study suggested that PEA/polydatin was markedly effective in reducing the severity of abdominal pain and discomfort in IBS, and that it may act through an alternate pathway besides the endocannabinoid system. This study set a path for further study on this supplement and its use in the treatment of IBS symptoms.