PEA: A Novel Anti-Neuroinflammatory Compound

PEA: A Novel Anti-Neuroinflammatory Compound

KEY LEARNINGS

Palmitoylethanolamide

• PEA, or palmitoylethanolamide, is an endogenously produced cannabimimetic compound
• PEA contains analgesic, anti-inflammatory and neuroprotective effects

Mechanisms of action

• PEA exerts its analgesic and anti-inflammatory effects through a broad range of physiological pathways, which include modulation of mast cells, transcription factors, pain sensitisation, cannabinoid receptors, and other endogenous anti-inflammatory and neuroprotective compounds

Neuropathic pain

• Neuropathic pain is one of the most difficult chronic pain conditions to treat
• The compression of nerves induces inflammation within the nerve and nerve root
• PEA’s ability to inhibit mast cell migration and activation, and the over-activation of glia and astrocytes, has led to it being extensively studied in neuropathic pain, where it is particularly effective in trapped nerve pain such as sciatica and carpal tunnel syndrome

Further indications

• PEA's anti-inflammatory activity has led to positive results in clinical trials for a broad range of conditions including; osteoarthritis, shingles, peripheral neuropathy, low back pain, fibromyalgia, depression, autism and cold and flu.

For a list of PEA products available at HealthMasters, CLICK HERE

Palmitoylethanolamide

PEA or palmitoylethanolamide, is an endogenously produced cannabimimetic compound1 that has been extensively studied in clinical and preclinical trials for its analgesic, anti-inflammatory and neuroprotective effects.2 It belongs to a group of endogenously produced bioactive lipids called N-acylethanolamines (NAEs), which contribute to the regulation of pain and inflammation,3 and include various cannabinoid receptor ligands and satiety factors. PEA is ubiquitous in mammals, being produced on demand from the lipid bilayer, and was identified as an active anti-inflammatory agent in the 1950s.4 It is particularly abundant in the central nervous system (CNS), where it is produced by neurons and glial cells, and also in immune cells.5

PEA was first isolated from soy lecithin in 1957, however from as early as 1939 it was recognised that feeding dried egg yolk (equivalent to 4–6 eggs) to undernourished children reduced the occurrence of rheumatic fever despite repeated infections with haemolytic streptococcus. This was attributed to an antiinflammatory component of the yolk, now understood to be PEA.6

PEA is found in a number of common foods including cow’s milk, breast milk, beans, peas, tomato, alfalfa, corn, soy lecithin and peanuts.2

Figure 1: Palmitoylethanolamide

Figure 2: PEA Indications

PEA and its known mechanisms of action

Models of chronic inflammation and chronic or neuropathic pain have confirmed the anti-inflammatory and analgesic effects of PEA. Chronic treatment with PEA has been shown in these models to reduce pain and preserve peripheral nerve morphology while reducing endoneural oedema, the recruitment and activation of mast cells, and the production of pro-inflammatory mediators at the site of injury.7 It has recently been discovered that certain families with inherited pain insensitivity (feel no physical pain) have a polymorphism in the enzyme that breaks down PEA and other amides.8

PPAR-α

The primary route by which PEA exerts its effects is through the activation of peroxisome proliferator-activated receptor (PPAR)-α. PPAR-α is a transcription factor that is activated by endogenous fatty acid derivatives including PEA. PPARs control pain and inflammation by switching off the nuclear factor-κB (NF-κB) signalling cascade which leads to the synthesis of proinflammatory mediators.5 By activating PPAR-α, PEA is also able to stimulate de novo neurosteroid synthesis and may modulate GABA(A) receptors.5

Sensitisation

PEA’s significant anti-inflammatory effects contribute to the reduction of peripheral and central sensitisation, a type of pain hypersensitivity. Neuronal and non-neuronal cells, including glia and peripheral and central mast cells, mediate this process. PEA is known to regulate the activity of microglial cells and inhibit mast cell activation in both the CNS and periphery, thereby reducing sustained inflammatory nociceptive insults, which contribute to the development of peripheral and central sensitisation.5

Microglia and Cannabinoid receptors

Microglia are the primary immune cell in the CNS, and are the first defence against injury or disease of the CNS. The phenotype of the microglia, which is marked by the expression of surface receptors, determines whether an activated microglia will have a cytotoxic, pro-inflammatory effect, or a neuroprotective effect through the reduction of inflammation and by engaging in phagocytosis to remove dying cells, bacteria and myelin debris.9 Cannabinoid type 2 (CB2) receptors are almost exclusively expressed in glia;9 selective stimulation of these receptors downregulates microglial reactivity and promotes neuroprotection, promoting analgesia and the release of anti-inflammatory cytokines. While PEA does not have an ability to bind to cannabinoid receptors and is therefore not strictly an endocannabinoid, it has been shown to enhance CB2 receptor expression in microglia by increasing CB2 mRNA and protein expression via a PPAR-α-mediated mechanism.10

Mast Cells

Mast cells in the CNS play a significant role in inflammatory and neurodegenerative diseases by sending pro-inflammatory signals to microglia.5 Additionally, mast cells in the peripheral nerves degranulate at the site of nerve damage, releasing histamine and TNF-α, which sensitise nociceptors and increase recruitment of neutrophils and macrophages.11 PEA downregulates mast cell recruitment and degranulation.12 Nerve growth factor (NGF) is a neurotrophic factor released by mast cells, which sensitises and activates nociceptors; PEA has been shown to significantly reduce the release of nerve growth factor (NGF) from mast cells,11 thereby modulating nociception.

Ion channels and endogenous compounds

PEA is also able to activate various receptors and inhibit some of the ion channels involved in the rapid response to neuronal firing, including vanilloid receptor and K+ channels.5 It also reduces the activity of COX, eNOS and iNOS thereby exerting anti-inflammatory and neuroprotective effects.13 Oral supplementation with PEA has also been shown to increase plasma levels of other endogenous anti-inflammatory, neuroprotective and analgesic NAEs, including oleoylethanolamide (OEA) and the endocannabinoid anandamide (AEA).14

PEA as a neuroprotective compound

PEA accumulates in brain tissue following injury, leading researchers to hypothesise that it may have neuroprotective properties and several preclinical studies support this proposition.5 Daily dosing

of PEA reduces experimentally produced memory deficit in a mouse model of Alzheimer’s disease, via a PPAR-α – dependent mechanism.15 Animal models also demonstrate that chronic administration of PEA is able to reduce some Parkinson’s diseaserelated motor deficits,16 and to ameliorate behavioural, biochemical and functional changes triggered by traumatic brain injury.17

Figure 3: PEA Mechanisms of Action

Neuropathic and chronic pain

Neuropathic pain, caused by the damage or dysfunction of nerves, is often experienced as shooting, radiating, tingling, stabbing or burning pain. The compression of nerves, as found in sciatica or carpal tunnel syndrome, is a common cause of neuropathic pain. Other common causes include post-herpetic neuralgia (shingles), persistent postsurgical pain, diabetic neuropathy, pelvic pain, fibromyalgia and complex regional pain syndrome.18,19

Neuropathic pain is one of the most difficult chronic pain conditions to treat. The dynamic nature of the nervous system means that changes to its structure — for example damage caused by longterm compression or inflammation of the nerves – allow the nerves to continue to send pain signals to the brain long after the original cause of the pressure on the nerves has been removed. This “pain memory” can lead to “pain sensitisation” where the threshold of pain receptors to stimuli is reduced, allowing even light touch of the affected area to induce the sensation of pain.19

The compression of nerves induces inflammation within the nerve and nerve root; this is largely mediated by inflammatory cells such as mast cells, which release pro-inflammatory prostaglandins and cytokines, which in turn trigger the synthesis of nitrogen monoxide13 which causes vasodilation, promoting the infiltration of immune cells.20 Metalloproteinases and other pro-inflammatory compounds are then produced, inducing the expansion and hyperactivation of connective tissue surrounding the nerves. This triggers the release of cytokines and other pro-inflammatory molecules13 which act on receptors on the nociceptor nerve terminals, enhancing their responsiveness and leading to sensitisation. Microglia in the CNS may then be activated, propagating neuroinflammation through the recruitment of other microglia and astrocytes, thereby leading to chronic pain.20

PEA’s ability to inhibit mast cell migration and activation, and the over-activation of glia and astrocytes, has led to it being extensively studied in neuropathic pain, where it is particularly effective in trapped nerve pain such as sciatica and carpal tunnel syndrome, as well as chronic pelvic pain, arthritis of the TMJ, and pain from molar surgery. A 2015 review of eight published clinical trials on the use of PEA in nerve entrapment syndromes in 1366 patients found PEA to be effective and safe in these conditions.13

Clinical Research

Chronic pain of various aetiologies

A 2012 study on chronic pain20 included 610 patients with ineffectively controlled chronic pain (NRS score ≥4) of various aetiologies: 331 with radiculopathy (including sciatica), 76 with failed back surgery syndrome, 54 with osteoarthritis, and the rest with herpes zoster infection (acute, persistent, and post-herpetic neuralgia), diabetic neuropathy, oncologic or other diseases. Apart from those with acute herpes zoster, all subjects had experienced pain for more than 6 months. 515 of the patients had poor pain control, but continued with their conventional analgesic therapies (antidepressants, anticonvulsants, opioids and NSAIDs) throughout the trial, while 95 had ceased use of conventional therapy due to side effects and so were using PEA alone; these two groups were distributed evenly according to aetiology and severity of pain. 564 subjects completed the study, and 46 dropped out; 16 due to good pain control, 20 for unspecified personal reasons, and 10 due to poor adherence to therapy.

Patients took 600mg of PEA twice daily for 3 weeks, and then 600mg once daily for the following 4 weeks, in addition to their previously established analgesic therapy, which was taken as fixed doses throughout the study period. The mean baseline NRS was 6.4 ± 1.4, and by the end of treatment the mean NRS had reduced to 2.5 ± 1.3 across all patient groups by aetiology or use of concomitant medication. This result was analysed to show that PEA treatment was the only variable to significantly affect the difference between baseline and end means (p = 0.0001). None of the concomitant therapies were found to impact the efficacy of PEA.

Although all of the conditions have at least some degree of neuropathic pain, these results demonstrate that, unlike standard analgesics that only control single components of systemic pain, PEA can be applied to pain resulting from a diverse range of pathological conditions. This study also shows that PEA is safe and effective when taken concomitantly with standard analgesic medications.

PAIN ASSESSMENT IN CLINICAL PRACTICE

The most common method of measuring pain clinically is the visual analog scale (VAS) to assess pain intensity. This is a simple 100mm line with no markings (numbers or descriptions) on which patients can mark their level of pain from 0 (no pain) to 10 (worst pain possible). The distance between the “no pain” end and the patient’s mark is then measured in centimetres to give a score from 1–10. These are generally then interpreted according to the following: no pain (0–4mm), mild pain (5–44mm), moderate pain (45–74mm), and severe pain (75–100mm).21

The numeric rating scale (NRS) also rates pain from 0 (no pain) to 10 (worst possible pain) and results are highly comparable to VAS scores.22

A score of three is often considered the maximum rating to qualify as tolerable pain.

Knee Osteoarthritis

It has been shown that 26% of pain from knee osteoarthritis is neuropathic.24 In a double-blind, placebo-controlled trial, 111 non-obese patients aged 38–76 years old with mild to moderate osteoarthritis were randomised to a daily dose of 300mg PEA, 600mg PEA, or placebo for 8 weeks in two separate doses with meals. Patients were only permitted paracetamol as a rescue medication, ceased use of all other osteoarthritis medications (pharmaceutical or complementary), and were excluded from the trial if they had used supplements including fish oil, glucosamine, chondroitin, or green-lipped mussel in the last 30 days. Pain, stiffness and function (assessed by WOMAC) improved in both PEA groups compared to placebo within 8 weeks (300mg PEA group p = 0.037, 600mg PEA group p = 0.001). Worst daily pain score measured by NRS reduced by 19.1% at week 1, 32.2% at week 4 and 40% by week 8 in the 300mg group. Pain score in the 600mg group was reduced by 21.5% at week 1, 32.2% at week 4 and 49.5% at week 8. Pain in the placebo group reduced by 12.7% at week 4 but returned to baseline at week 8. Pain reduction was significant in both the 300mg and 600mg groups (p < 0.001 for both).25 (See Figure 5).

Sciatica

A double-blind, placebo-controlled study published in 2010 assessed the efficacy of PEA in 636 patients with lumbosciatica over a period of three weeks. All patients had a VAS pain score of ≥5 at initial assessment, and were allowed to continue their usual treatments. On day 21, patients were assessed for pain using the VAS score, and quality of life using the 24 point Roland-Morris disability questionnaire (RDQ), and both patients and physicians gave a subjective analysis of treatment efficacy. Patients were assigned to either 300mg, 600mg or placebo. At the end of 3 weeks, patients taking 600mg had more than a 50% reduction in pain, from an average 7.1 to 2.1 on the VAS scale, while the reduction in pain in the placebo and 300mg groups was similar (6.6 to 4.6, and 6.5 to 3.6 respectively); the VAS difference between the groups had a p-value of <0.05. After 3 weeks of treatment, the NNT for the 600mg group was calculated as 1.5 (See Figure 4). At the 3 week point, RDQ scores had improved by an average of 3 points in the placebo group, 5 points in the 300mg group, and 9.2 points in the 600mg group to finish with an average score of 3.5 (p<0.001).13 The 600mg dose was concluded to be significantly more effective than the 300mg dose (p<0.05).23

Figure 4: Number needed to treat (NNT) to reach a 50% reduction in pain on the
visual analogue scale (VAS)

Figure 5: Pain reduction in osteoarthritis after PEA supplementation

Diabetic Neuropathy

More than 50% of diabetic patients have some degree of peripheral neuropathy. This can significantly affect quality of life, with a particular impact on sleep and daily activities. A clinical trial in 30 patients with moderate symptoms of painful peripheral neuropathy resulting from compensated Type II diabetes mellitus (ie T2DM with blood glucose levels which are close to normal values) were given PEA at a dose of 300mg twice daily for 60 days. At the 60-day mark, significant improvements were measured in the patients’ Michigan Neuropathy Screening Instrument, Total Symptoms Score, and Neuropathic Pain Symptoms Inventory scores (p < 0.0001). Furthermore, when assessed 30 days after ceasing use of PEA, there was no significant difference (p>0.05) between the 60 and 90 day results, demonstrating that the effects of PEA persisted after treatment was withdrawn.26

Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-Induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy for which there is no established effective treatment. It has a complex, poorly understood pathophysiology, and causes pain, sensory changes and weakness, and occurs in as many as 68% of patients within the first month of chemotherapy treatment. In some cases, it is sufficiently severe to warrant a reduction in dose or cessation of chemotherapy treatment, and can significantly affect quality of life and a patient’s ability to perform activities of daily living independently on an ongoing basis.27

A small clinical trial of PEA was run in 20 patients who had developed CIPN while undergoing treatment with bortezomib and thalidomide for multiple myeloma. After two months of treatment with PEA (300mg bd), patients had lower pain scores (p<0.002), and showed a partial improvement of all myelinated fibre groups as shown by neurophysiological measures. Both bortezomib and thalidomide are known to inhibit the activation of NF-κB, which in turn blocks transcription of NGF.28 As NGF is known to modulate sensory and nociceptive nerve physiology,29 the results of this study suggest that PEA has a normalising effect on NF-κB and NGF, rather than simply inhibitory.11,28

Fibromyalgia

Fibromyalgia is a common condition affecting 2–5% of the population and is primarily seen in young and middle-aged women. It is characterised by widespread musculoskeletal pain and tenderness, poor quality sleep and significant fatigue, in addition to cognitive disturbances including poor concentration and memory, and high levels of distress. The underlying pathophysiology involves the development of “central sensitisation” changes in the CNS which result in usually non-painful stimuli being experienced as painful.30

A clinical trial in 35 patients who had undergone standard treatment with duloxetine and pregabalin for three months demonstrated that the addition of PEA to standard treatment for an additional three months (600mg bd for one month, then 300mg bd for two months) significantly improved VAS ratings from 3.7 to 1.9 (p<0.0001), and significantly reduced the number of Tender Points (p<0.0001).31

Depression

Emerging data demonstrates that the pathogenesis of major depression involves immuno-inflammatory markers including interleukin (IL)-1, IL-6 and TNF-α. Impairment of endocannabinoid signalling is also implicated in mood disturbances and other neuropsychiatric disorders. Due to PEA’s anti-inflammatory and neuroprotective effects and its influence on cannabinoid receptor expression, it has been proposed as a beneficial adjunct to the treatment of depression.32

In a double blind, placebo controlled clinical trial, 58 patients with major depression (HAM-D score ≥19) were randomly assigned to either citalopram plus placebo, or citalopram plus PEA (600mg bd) for 6 weeks. At the two-week mark, the PEA group had a significantly greater reduction in HAM-D score than the placebo group, and at the end of the trial, response rate (measured as a ≥50% reduction in HAM-D score) in the PEA group was 100%, compared to 74% of patients taking citalopram alone (p= 0.01). Adverse events were similar between groups, with no serious adverse events and no related dropouts.32

Autism

PEA has been proposed as a potential adjunct to the treatment of autism, due to its anti-inflammatory effects and its role in protecting neurons against glutamate toxicity, two of the proposed key mechanisms in the aetiology of autism. In a placebo-controlled clinical trial, 62 children aged 4–12 years old were randomised to receive either Risperidone and PEA (600mg bd) or Risperidone and placebo for 10 weeks. The PEA group showed a significantly greater reduction in hyperactivity than the placebo group (p < 0.001), and also in irritability (p = 0.002).33

Cold & Flu

Prior to the discovery of PEA’s role in neuropathic pain, it was well known as a treatment for cold and flu. Six double blind, placebo controlled clinical trials in a total of almost 4000 subjects were published between 1969 and 1979. A daily dose of 1.8g (600mg tds) for 12 days was found to be an effective treatment for fever and pain (reduced by 45.5% compared to placebo). As a prophylactic, a loading dose of 1.8g per day (600mg tds) for 3 weeks then 600mg per day for 6 weeks, was found to significantly reduce the total number of sick days. PEA was shown to significantly reduce instances of serologically verified influenza infection (p < 0.0002).6

Further clinical research

Emerging evidence suggests that the anti-inflammatory effects of PEA may also be effective in conditions characterised by inflammatory intestinal hyper-permeability,34 glaucoma,35 and even in slowing down disease progression in Parkinson’s disease.36

Dosage safety and clinical tips

Dosing – The daily dosage of PEA in clinical trials has ranged from 300mg–1200mg daily for chronic pain and up to 1800mg daily for acute colds and flu. Clinical trial data would suggest that a loading dose of 600–1200mg for 3–4 weeks followed by a maintenance dose of 300–600mg may be the most appropriate dosing strategy for chronic pain conditions. Individual requirements will vary.

Timing – Considering that PEA is a fat soluble compound, consumption with a fat-containing meal may enhance absorption.

Contraindications and adverse effects – There are no known contraindications. PEA has been clinically studied across a broad population group and has been found to be highly tolerable, with aside effect profile similar to placebo.

For a list of PEA products available at HealthMasters, CLICK HERE

Selected references:

5. Raso, G.M., Russo, R., Calignano, A. and Meli, R., 2014. Palmitoylethanolamide in CNS health and disease. Pharmacological Research, 86, pp.32-41.
6. Hesselink, J.M.K. and Kopsky, D.J., 2015. Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome. Journal of pain research, 8, p.729.
7. Gatti, A., Lazzari, M., Gianfelice, V., Di Paolo, A., Sabato, E. and Sabato, A.F., 2012. Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis. Pain Medicine, 13(9), pp.1121-1130.
8. Steels, E., Venkatesh, R., Steels, E., Vitetta, G. and Vitetta, L., 2019. A doubleblind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis. Inflammopharmacology, pp.1-11.
9. Schifilliti, C., Cucinotta, L., Fedele, V., Ingegnosi, C., Luca, S. and Leotta, C., 2014. Micronized palmitoylethanolamide reduces the symptoms of neuropathic pain in diabetic patients. Pain research and treatment, 2014.
10. Truini, A., Biasiotta, A., Di Stefano, G., La Cesa, S., Leone, C., Cartoni, C., Federico, V., T Petrucci, M. and Cruccu, G., 2011. Palmitoylethanolamide restores myelinated-fibre function in patients with chemotherapy-induced painful neuropathy. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders), 10(8), pp.916-920.
11. Del Giorno, R., Skaper, S., Paladini, A., Varrassi, G. and Coaccioli, S., 2015. Palmitoylethanolamide in fibromyalgia: results from prospective and retrospective observational studies. Pain and therapy, 4(2), pp.169-178.
12. Ghazizadeh-Hashemi, M., Ghajar, A., Shalbafan, M.R., Ghazizadeh-Hashemi, F., Afarideh, M., Malekpour, F., Ghaleiha, A., Ardebili, M.E. and Akhondzadeh, S., 2018. Palmitoylethanolamide as adjunctive therapy in major depressive disorder: A double-blind, randomized and placebo-controlled trial. Journal of affective disorders, 232, pp.127-133.

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Additional References and Resources

[1] Wang J. Glial endocannabinoid system in pain modulation. Int J Neurosci. 2019 Jan;129(1):94-100. doi: 10.1080/00207454.2018.1503178.

[2] Steels E, Venkatesh R, Steels E, Vitetta G, Vitetta L. A double-blind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis. Inflammopharmacology. 2019 Jun;27(3):475-485. doi: 10.1007/s10787-019-00582-9.

[3] Gatti A, Lazzari M, Gianfelice V, Di Paolo A, Sabato E, Sabato AF. Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis. Pain Med. 2012 Sep;13(9):1121-30. doi:10.1111/j.1526-4637.2012.01432.x.

[4] Wang J. Glial endocannabinoid system in pain modulation. Int J Neurosci. 2019 Jan;129(1):94-100. doi: 10.1080/00207454.2018.1503178.

[5] Skaper SD, Facci L, Fusco M, Della Valle MF, Zusso M, Costa B, et al. Palmitoylethanolamide, a naturally occurring disease-modifying agent in neuropathic pain. Inflammopharmacology. 2014 Apr;22(2):79-94. doi:10.1007/s10787-013-0191-7.

[6] Barrie N, Manolios N. The endocannabinoid system in pain and inflammation: its relevance to rheumatic disease. Eur J Rheumatol. 2017 Sep;4(3):210-218. doi:10.5152/eurjrheum.2017.17025.

[7] Grotenhermen F. Cannabinoids and the endocannabinoid system. Cannabinoids. 2006;1(1):10-4.

[8] Wang J. Glial endocannabinoid system in pain modulation. Int J Neurosci. 2019 Jan;129(1):94-100. doi: 10.1080/00207454.2018.1503178.

[9] Barrie N, Manolios N. The endocannabinoid system in pain and inflammation: its relevance to rheumatic disease. Eur J Rheumatol. 2017 Sep;4(3):210-218. doi:10.5152/eurjrheum.2017.17025.

[10] Lu HC, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016 Apr 1;79(7):516-25. doi: 10.1016/j.biopsych.2015.07.028.

[11] Wang J. Glial endocannabinoid system in pain modulation. Int J Neurosci. 2019 Jan;129(1):94-100. doi: 10.1080/00207454.2018.1503178.

[12] Wang J. Glial endocannabinoid system in pain modulation. Int J Neurosci. 2019 Jan;129(1):94-100. doi: 10.1080/00207454.2018.1503178.

[13] Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Feb;14(2):162-73. doi: 10.1016/S1474-4422(14)70251-0.

[14] Schifilliti C, Cucinotta L, Fedele V, Ingegnosi C, Luca S, Leotta C. Micronized palmitoylethanolamide reduces the symptoms of neuropathic pain in diabetic patients. Pain Res Treat. 2014;2014:849623. doi: 10.1155/2014/849623.

[15] Skaper SD, Facci L, Fusco M, Della Valle MF, Zusso M, Costa B, et al. Palmitoylethanolamide, a naturally occurring disease-modifying agent in neuropathic pain. Inflammopharmacology. 2014 Apr;22(2):79-94. doi:10.1007/s10787-013-0191-7.

[16] Steels E, Venkatesh R, Steels E, Vitetta G, Vitetta L. A double-blind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis. Inflammopharmacology. 2019 Jun;27(3):475-485. doi: 10.1007/s10787-019-00582-9.

[17] Del Giorno R, Skaper S, Paladini A, Varrassi G, Coaccioli S. Palmitoylethanolamide in fibromyalgia: results from prospective and retrospective observational studies. Pain Ther. 2015 Dec;4(2):169-78. doi:10.1007/s40122-015-0038-6.

[18] Marcucci M, Germini F, Coerezza A, Andreinetti L, Bellintani L, Nobili A, et al. Efficacy of ultra-micronized palmitoylethanolamide (um-PEA) in geriatric patients with chronic pain: study protocol for a series of N-of-1randomized trials. Trials. 2016 Jul 29;17:369. doi: 10.1186/s13063-016-1496-9.

[19] Donvito G, Wilkerson JL, Damaj MI, Lichtman AH. Palmitoylethanolamide reverses paclitaxel-induced allodynia in mice. J Pharmacol Exp Ther. 2016 Nov;359(2):310-318. PMID: 27608657.

[20] Gatti A, Lazzari M, Gianfelice V, Di Paolo A, Sabato E, Sabato AF. Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis. Pain Med. 2012 Sep;13(9):1121-30. doi:10.1111/j.1526-4637.2012.01432.x.

[21] Schifilliti C, Cucinotta L, Fedele V, Ingegnosi C, Luca S, Leotta C. Micronized palmitoylethanolamide reduces the symptoms of neuropathic pain in diabetic patients. Pain Res Treat. 2014;2014:849623. doi: 10.1155/2014/849623.

[22] Cocito D, Peci E, Ciaramitaro P, Merola A, Lopiano L. Short-term efficacy of ultramicronized palmitoylethanolamide in peripheral neuropathic pain. Pain Res Treat. 2014;2014:854560. doi: 10.1155/2014/854560.

[23] Truini A, Biasiotta A, Di Stefano G, La Cesa S, Leone C, Cartoni C. Palmitoylethanolamide restores myelinated-fibre function in patients with chemotherapy-induced painful neuropathy. CNS Neurol Disord Drug Targets. 2011 Dec;10(8):916-20. PMID: 22229320.

[24] Hesselink JM, Hekker TA. Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series. J Pain Res. 2012;5:437-42. doi: 10.2147/JPR.S32143.

[25] Assini A, Laricchia D, Pizzo R, Pandolfini L, Belletti M, Colucci M, et al. The carpal tunnel syndrome in diabetes: clinical and electrophysiological improvement after treatment with palmitoylethanolamide: P1577. Eur J Neurol. 2010 Sep 17;12(3):295-295.

[26] Guida G, De Martino M, De Fabiani A, Canterieri L, Alexandre A, Vassallo GM, et al. Palmitoylethanolamide (Normast®) in chronic neuropathic pain due to compression lumbociatalgia: a multicenter clinical study. DOLOR. 2010:25(1):35-42.

[27] Del Giorno R, Skaper S, Paladini A, Varrassi G, Coaccioli S. Palmitoylethanolamide in fibromyalgia: results from prospective and retrospective observational studies. Pain Ther. 2015 Dec;4(2):169-78. doi:10.1007/s40122-015-0038-6.

[28] Gatti A, Lazzari M, Gianfelice V, Di Paolo A, Sabato E, Sabato AF. Palmitoylethanolamide in the treatment of chronic pain caused by different etiopathogenesis. Pain Med. 2012 Sep;13(9):1121-30. doi:10.1111/j.1526-4637.2012.01432.x.

[29] Steels E, Venkatesh R, Steels E, Vitetta G, Vitetta L. A double-blind randomized placebo controlled study assessing safety, tolerability and efficacy of palmitoylethanolamide for symptoms of knee osteoarthritis. Inflammopharmacology. 2019 Jun;27(3):475-485. doi: 10.1007/s10787-019-00582-9.

[30] Marini I, Lavinia Bartolucci M, Bortolotti F, Rosaria Gatto M, Alessandri Bonetti G. Palmitoylethanolamide versus a nonsteroidal anti-inflammatory drug in the treatment of temporomandibular joint inflammatory pain. J Orofac Pain. 2012 Apr 1;26(2):99.

[31] Cobellis L, Castaldi MA, Giordano V, Trabucco E, De Franciscis P, Torella M, et al. Effectiveness of the association micronized N-palmitoylethanolamine (PEA)-transpolydatin in the treatment of chronic pelvic pain related to endometriosis after laparoscopic assessment: a pilot study. Eur J Obstet Gynecol Reprod Biol. 2011 Sep;158(1):82-6. doi: 10.1016/j.ejogrb.2011.04.011.

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