Pain Med. 2014 Aug;15(8):1379-89. doi: 10.1111/pme.12486. Epub 2014 Jul 4.

Effects of two different specific neck exercise interventions on palmitoylethanolamide and stearoylethanolamide concentrations in the interstitium of the trapezius muscle in women with chronic neck shoulder pain.

Ghafouri N¹, Ghafouri B, Fowler CJ, Larsson B, Turkina MV, Karlsson L, Gerdle B.

Author information

Abstract

PURPOSE:

Chronic neck/shoulder pain (CNSP) is one of the most common pain conditions. The understanding of mechanisms, including the peripheral balance between nociceptive and antinociceptive processes, is incomplete. N-acylethanolamines (NAEs) are a class of endogenous compounds that regulate inflammation and pain. The aim of this study was to investigate the levels of two NAEs: the peroxisome proliferator-activated receptor type-α ligand palmitoylethanolamide (PEA) and stearoylethanolamide (SEA) in the muscle interstitium of the trapezius muscle in women with CNSP randomized to two different neck specific training programs and in a healthy pain-free control group (CON).

MATERIALS AND METHODS:

Fifty-seven women with CNSP were randomized to strength + stretch or stretch alone exercise programs. Twenty-nine subjects underwent microdialysis procedure before and after 4-6 months of exercise. Twenty-four CON subjects underwent microdialysis procedure before and after 4-6 months without any intervention in between. Microdialysate samples were collected from the trapezius muscle and analyzed by mass spectrometry for PEA and SEA levels.

RESULTS:

PEA and SEA levels were significantly higher in CNSP patients compared with CON. PEA was significantly higher in CNSP than in CON after both training programs. SEA was significantly higher in CNSP than in CON after stretch alone but not after strength + stretch training. A significant positive correlation was found between changes in pain intensity and in SEA levels in the strength + stretch group, but not in the stretch alone group.

CONCLUSION:

Our results indicate that exercise interventions differentially affect the levels of the bioactive lipids PEA and SEA in the interstitium of the trapezius muscle in women with CNSP.

International Journal of Neurology & Brain Disorders

Giorgio Dalla Volta*, Paola Zavarize, Gaelle FK Ngonga, Daniela Carli

Abstract

The aim of this open study is to verify whether treatment with ultra-micronized palmitoylethanolamide can reduce headache frequency and intensity in patients suffering from migraine when used in migraine prevention.

Fifty patients, suffering from migraine without aura, for at least 6 months with a frequency of monthly crises from 3 to 8 and with presence of headache from 4 to12 days per month, were treated sublingually with ultra-micronized palmitoylethanolamide microgranules 600 mg bid for 3 months. The primary endpoint was reduction

in headache days per month; secondary endpoint was duration and intensity of pain crisis and number of analgesics taken per month and changes of thermographic pat- terns.

 All the considered parameters significantly improved at the end of treatment.The mean number of days per month with migraine significantly decreased (p< 0.0001); pain intensity was significantly (p <0.0001) mitigated; the number

of analgesics taken significantly decreased and the thermographic patterns showed a reduction of hypothermia as well as the response to trigger factors. No serious adverse events have been observed.

Despite the limitations of the study due to its open-label nature it would be

desirable to confirm with further clinical trials the ultra-micronized Palmitoyletha-

nolamide effect in migraine prevention.

J Pain Res. 2015 Oct 23;8:729-34. doi: 10.2147/JPR.S93106. eCollection 2015.

Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome.

Keppel Hesselink JM¹, Kopsky DJ¹.

Author information

Abstract

Palmitoylethanolamide (PEA) is an endogenous lipid modulator in animals and humans, and has been evaluated since the 1970s as an anti-inflammatory and analgesic drug in more than 30 clinical trials, in a total of ~6,000 patients. PEA is currently available worldwide as a nutraceutical in different formulations, with and without excipients. Here we describe the results of all clinical trials evaluating PEA's efficacy and safety in nerve compression syndromes: sciatic pain and pain due to carpal tunnel syndrome, and review preclinical evidence in nerve impingement models. Both the pharmacological studies as well as the clinical trials supported PEA's action as an analgesic compound. In total, eight clinical trials have been published in such entrapment syndromes, and 1,366 patients have been included in these trials. PEA proved to be effective and safe in nerve compression syndromes. In one pivotal, double blind, placebo controlled trial in 636 sciatic pain patients, the number needed to treat to reach 50% pain reduction compared to baseline was 1.5 after 3 weeks of treatment. Furthermore, no drug interactions or troublesome side effects have been described so far. Physicians are not always aware of PEA as a relevant and safe alternative to opioids and co-analgesics in the treatment of neuropathic pain. Especially since the often prescribed co-analgesic pregabaline has been proven to be ineffective in sciatic pain in a double blind enrichment trial, PEA should be considered as a new and safe treatment option for nerve compression syndromes.

KEYWORDS:

PPAR alpha; analgesics; anti-inflammatory agents; nerve compression; palmidrol; palmitoylethanolamide; sciatic

PMID:

 

26604814

 

PMCID:

 

PMC4631430

 

DOI:

 

10.2147/JPR.S93106

CONCLUSIONS:

The palmitoylethanolamide-polydatin combination seems to be very useful in controlling chronic pelvic pain associated with endometriosis. As a result of these findings we have initiated a multi-centre pilot study to verify the effectiveness of this treatment in controlling the chronic pelvic pain associated with endometriosis.

J Pain Res. 2012; 5: 437–442.

Published online 2012 Oct 26. doi:  10.2147/JPR.S32143

PMCID: PMC3500919

PMID: 23166447

Therapeutic utility of palmitoylethanolamide in the treatment of neuropathic pain associated with various pathological conditions: a case series

Jan M Keppel Hesselink and Thecla AM Hekker

Abstract

Palmitoylethanolamide (PEA), an endogenous fatty acid amide, has been demonstrated to bind to a receptor in the cell nucleus – the peroxisome proliferator–activated receptor – and performs a great variety of biological functions related to chronic and neuropathic pain and inflammation, as has been demonstrated in clinical trials. These include peripheral neuropathies such as diabetic neuropathy, chemotherapy-induced peripheral neuropathy, carpal tunnel syndrome, sciatic pain, osteoarthritis, low-back pain, failed back surgery syndrome, dental pains, neuropathic pain in stroke and multiple sclerosis, chronic pelvic pain, postherpetic neuralgia, and vaginal pains. Probably due to the fact that PEA is an endogenous modulator as well as a compound in food, such as eggs and milk, no serious side effects have been reported, nor have drug–drug interactions. This article presents a case series describing the application and potential efficacy and safety of PEA in the treatment of various syndromes associated with chronic pain that is poorly responsive to standard therapies.  (Full Article)

BMC Vet Res. 2017; 13: 229.

Published online 2017 Aug 2. doi:  10.1186/s12917-017-1151-z

PMCID: PMC5541643

PMID: 28768536

A novel composite formulation of palmitoylethanolamide and quercetin decreases inflammation and relieves pain in inflammatory and osteoarthritic pain models

Domenico Britti,¹ Rosalia Crupi,² Daniela Impellizzeri,² Enrico Gugliandolo,²Roberta Fusco,² Carlo Schievano,³ Valeria Maria Morittu,¹ Maurizio Evangelista,⁴Rosanna Di Paola,² and Salvatore Cuzzocrea^2,5

Author information ► Article notes ► Copyright and License information ► Disclaimer

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Abstract

Go to:

Background

Osteoarthritis (OA) is a common progressive joint disease in dogs and cats. The goal of OA treatment is to reduce inflammation, minimize pain, and maintain joint function. Currently, non-steroidal anti-inflammatory drugs (e.g., meloxicam) are the cornerstone of treatment for OA pain, but side effects with long-term use pose important challenges to veterinary practitioners when dealing with OA pain. Palmitoylethanolamide (PEA) is a naturally-occurring fatty acid amide, locally produced on demand by tissues in response to stress. PEA endogenous levels change during inflammatory and painful conditions, including OA, i.e., they are typically increased during acute conditions and decreased in chronic inflammation. Systemic treatment with PEA has anti-inflammatory and pain-relieving effects in several disorders, yet data are lacking in OA. Here we tested a new composite, i.e., PEA co-ultramicronized with the natural antioxidant quercetin (PEA-Q), administered orally in two different rat models of inflammatory and OA pain, namely carrageenan paw oedema and sodium monoiodoacetate (MIA)-induced OA. Oral treatment with meloxicam was used as benchmark.  (Full Article)

CONCLUSIONS:

The palmitoylethanolamide-polydatin combination seems to be very useful in controlling chronic pelvic pain associated with endometriosis. As a result of these findings we have initiated a multi-centre pilot study to verify the effectiveness of this treatment in controlling the chronic pelvic pain associated with endometriosis. (Full Article)

RESULTS:

The intensity of endometriotic pain decreased significantly for both groups (p<0.0001). The efficacy of drug treatment was significant after 30 days. Pain intensity decreased equally in the two groups except for dysmenorrhea, which was reduced more rapidly in group B.

CONCLUSIONS:

The combination of N-palmitoylethanolamine and transpolydatin reduced pain related to endometriosis irrespective of lesion site. It had a marked effect on chronic pelvic pain determined by deep endometriosis and on dysmenorrhea correlated to ovarian endometriosis.  (Full Article)

Full Article

Br J Clin Pharmacol. 2016 Oct; 82(4): 932–942.

Published online 2016 Jun 29. doi:  10.1111/bcp.13020

PMCID: PMC5094513

PMID: 27220803

Palmitoylethanolamide for the treatment of pain: pharmacokinetics, safety and efficacy

Linda Gabrielsson, ¹ Sofia Mattsson, ¹ and Christopher J. Fowler ¹

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Abstract

Palmitoylethanolamide (PEA) has been suggested to have useful analgesic properties and to be devoid of unwanted effects. Here, we have examined critically this contention, and discussed available data concerning the pharmacokinetics of PEA and its formulation. Sixteen clinical trials, six case reports/pilot studies and a meta‐analysis of PEA as an analgesic have been published in the literature. For treatment times up to 49 days, the current clinical data argue against serious adverse drug reactions (ADRs) at an incidence of 1/200 or greater. For treatment lasting more than 60 days, the number of patients is insufficient to rule out a frequency of ADRs of less than 1/100. The six published randomized clinical trials are of variable quality. Presentation of data without information on data spread and nonreporting of data at times other than the final measurement were among issues that were identified. Further, there are no head‐to‐head clinical comparisons of unmicronized vs. micronized formulations of PEA, and so evidence for superiority of one formulation over the other is currently lacking. Nevertheless, the available clinical data support the contention that PEA has analgesic actions and motivate further study of this compound, particularly with respect to head‐to‐head comparisons of unmicronized vs.micronized formulations of PEA and comparisons with currently recommended treatments.  (Full Article)

J Pain Res. 2015 Oct 23;8:729-34. doi: 10.2147/JPR.S93106. eCollection 2015.

Palmitoylethanolamide, a neutraceutical, in nerve compression syndromes: efficacy and safety in sciatic pain and carpal tunnel syndrome.

Keppel Hesselink JM¹, Kopsky DJ¹.

Author information

Abstract

Palmitoylethanolamide (PEA) is an endogenous lipid modulator in animals and humans, and has been evaluated since the 1970s as an anti-inflammatory and analgesic drug in more than 30 clinical trials, in a total of ~6,000 patients. PEA is currently available worldwide as a nutraceutical in different formulations, with and without excipients. Here we describe the results of all clinical trials evaluating PEA's efficacy and safety in nerve compression syndromes: sciatic pain and pain due to carpal tunnel syndrome, and review preclinical evidence in nerve impingement models. Both the pharmacological studies as well as the clinical trials supported PEA's action as an analgesic compound. In total, eight clinical trials have been published in such entrapment syndromes, and 1,366 patients have been included in these trials. PEA proved to be effective and safe in nerve compression syndromes. In one pivotal, double blind, placebo controlled trial in 636 sciatic pain patients, the number needed to treat to reach 50% pain reduction compared to baseline was 1.5 after 3 weeks of treatment. Furthermore, no drug interactions or troublesome side effects have been described so far. Physicians are not always aware of PEA as a relevant and safe alternative to opioids and co-analgesics in the treatment of neuropathic pain. Especially since the often prescribed co-analgesic pregabaline has been proven to be ineffective in sciatic pain in a double blind enrichment trial, PEA should be considered as a new and safe treatment option for nerve compression syndromes.

KEYWORDS:

PPAR alpha; analgesics; anti-inflammatory agents; nerve compression; palmidrol; palmitoylethanolamide; sciatic

PMID:

 

26604814

 

PMCID:

 

PMC4631430

 

DOI:

 

10.2147/JPR.S93106

CNS Neurol Disord Drug Targets. 2011 Dec;10(8):916-20.

Palmitoylethanolamide restores myelinated-fibre function in patients with chemotherapy-induced painful neuropathy.

Truini A¹, Biasiotta A, Di Stefano G, La Cesa S, Leone C, Cartoni C, Federico V, Petrucci MT, Cruccu G.

Author information

Abstract

We assessed the effect of palmitoylethanolamide (PEA) on pain and nerve function in patients with chemotherapy-induced painful neuropathy, in 20 patients undergoing thalidomide and bortezomib treatment for multiple myeloma. All patients were evaluated before and after a two-month treatment with PEA 300 mg BID using pain and warmth thresholds; blinded examiners measured motor and sensory nerve fibre function and laser-evoked potentials. Although no variables returned to normal values, pain and all neurophysiological measures � assessing Aα, Aβ, and Aδ fibres � significantly improved (P < 0.05). In contrast, warmth thresholds, assessing unmyelinated afferents, remained unchanged (P > 0.50). Although a placebo effect might play a role in the reported pain relief, the changes in neurophysiological measures indicate that PEA exerted a positive action on myelinated fibre groups. PEA, possibly by moderating mast cell hyperactivity, relieved conduction blocks secondary to endoneural edema. In a severe condition such as painful neuropathy associated with multiple myeloma and chemotherapy, a safe substance such as PEA provides significant restoration of nerve function.

PMID:   22229320   Full article

Neurotherapeutics. 2016 Apr;13(2):428-38. doi: 10.1007/s13311-016-0420-z.

Oral Palmitoylethanolamide Treatment Is Associated with Reduced Cutaneous Adverse Effects of Interferon-β1a and Circulating Proinflammatory Cytokines in Relapsing-Remitting Multiple Sclerosis.

Orefice NS¹, Alhouayek M², Carotenuto A³, Montella S³, Barbato F³, Comelli A⁴, Calignano A¹, Muccioli GG², Orefice G⁵.

Author information

Abstract

Palmitoylethanolamide (PEA) is an endogenous lipid mediator known to reduce pain and inflammation. However, only limited clinical studies have evaluated the effects of PEA in neuroinflammatory and neurodegenerative diseases. Multiple sclerosis (MS) is a chronic autoimmune and inflammatory disease of the central nervous system. Although subcutaneous administration of interferon (IFN)-β1a is approved as first-line therapy for the treatment of relapsing-remitting MS (RR-MS), its commonly reported adverse events (AEs) such as pain, myalgia, and erythema at the injection site, deeply affect the quality of life (QoL) of patients with MS. In this randomized, double-blind, placebo-controlled study, we tested the effect of ultramicronized PEA (um-PEA) added to IFN-β1a in the treatment of clinically defined RR-MS. The primary objectives were to estimate whether, with um-PEA treatment, patients with MS perceived an improvement in pain and a decrease of the erythema width at the IFN-β1a injection site in addition to an improvement in their QoL. The secondary objectives were to evaluate the effects of um-PEA on circulating interferon-γ, tumor necrosis factor-α, and interleukin-17 serum levels, N-acylethanolamine plasma levels, Expanded Disability Status Scale (EDSS) progression, and safety and tolerability after 1 year of treatment. Patients with MS receiving um-PEA perceived an improvement in pain sensation without a reduction of the erythema at the injection site. A significant improvement in QoL was observed. No significant difference was reported in EDSS score, and um-PEA was well tolerated. We found a significant increase of palmitoylethanolamide, anandamide and oleoylethanolamide plasma levels, and a significant reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile compared with the placebo group. Our results suggest that um-PEA may be considered as an appropriate add-on therapy for the treatment of IFN-β1a-related adverse effects in RR-MS.

KEYWORDS:

Anandamide; FAAH; N-acylethanolamines; NAAA; Neuroinflammation; Oleoylethanolamide; Pain

PMID:

 

26857391

 

PMCID:

 

PMC4824021

 

DOI:

 

10.1007/s13311-016-0420-z

Full Article

Mol Pharmacol. 2016 Nov;90(5):549-561. Epub 2016 Sep 13.

Adelmidrol, a Palmitoylethanolamide Analogue, as a New Pharmacological Treatment for the Management of Inflammatory Bowel Disease.

Cordaro M¹, Impellizzeri D¹, Gugliandolo E¹, Siracusa R¹, Crupi R¹, Esposito E¹, Cuzzocrea S².

Author information

Abstract

Leukocyte infiltration, improved levels of intercellular adhesion molecule 1 (ICAM-1), and oxidative stress in the colon are the principal factors in inflammatory bowel disease. The goal of the current study was to explore the effects of adelmidrol, an analog of the anti-inflammatory fatty acid amide signaling molecule palmitoylethanolamide, in mice subjected to experimental colitis. Additionally, to clarify whether the protective action of adelmidrol is dependent on the activation of peroxisome proliferator-activated receptors (PPARs), we investigated the effects of a PPARγ antagonist, GW9662, on adelmidrol action. Adelmidrol (10 mg/kg daily, o.s.) was tested in a murine experimental model of colitis induced by intracolonic administration of dinitrobenzene sulfonic acid. Nuclear factor-κB translocation, cyclooxygenase-2, and phosphoextracellular signal-regulated kinase, as well as tumor necrosis factor-α and interleukin-1β, were significantly increased in colon tissues after dinitrobenzene sulfonic acid administration. Immunohistochemical staining for ICAM-1, P-selectin, nitrotyrosine, and poly(ADP)ribose showed a positive staining in the inflamed colon. Treatment with adelmidrol decreased diarrhea, body weight loss, and myeloperoxidase activity. Adelmidrol treatment, moreover, reduced nuclear factor-κB translocation, cyclooxygenase-2, and phosphoextracellular signal-regulated kinase expression; proinflammatory cytokine release; and the incidence of nitrotyrosine and poly(ADP)ribose in the colon. It also decreased the upregulation of ICAM-1 and P-selectin. Adelmidrol treatment produced a reduction of Bax and an intensification of Bcl-2 expression. This study clearly demonstrates that adelmidrol exerts important anti-inflammatory effects that are partly dependent on PPARγ, suggesting that this molecule may represent a new pharmacologic approach for inflammatory bowel disease treatment.

PMID:

 

27625036

 

DOI:

 

10.1124/mol.116.105668

Full article