Clin Interv Aging. 2014; 9: 1163–1169.

Published online 2014 Jul 17. doi: 10.2147/CIA.S65448

PMCID: PMC4111646

PMID: 25071367

N-palmitoylethanolamine and N-acetylethanolamine are effective in asteatotic eczema: results of a randomized, double-blind, controlled study in 60 patients

Chao Yuan,^1,* Xue-Min Wang,^1,* Alexandre Guichard,² Yi-Mei Tan,¹ Chun-Yan Qian,¹Li-Jie Yang,¹ and Philippe Humbert²

Author information Copyright and License information Disclaimer

Go to:

Abstract

Background

Asteatotic eczema (AE) is characterized by itchy, dry, rough, and scaling skin. The treatments for AE are mainly emollients, usually containing urea, lactic acid, or a lactate salt. N-palmitoylethanolamine (PEA) and N-acetylethanolamine (AEA) are both endogenous lipids used as novel therapeutic tools in the treatment of many skin diseases. The purpose of this study was to compare a PEA/AEA emollient with a traditional emollient in the treatment of AE.

Methods

A monocentric, randomized, double-blind, comparative trial was conducted in 60 AE patients to evaluate and compare the efficacy of the two emollients. The level of skin dryness among the subjects ranged from mild to moderate. The subjects’ skin barrier function and the current perception threshold were tested for 28 days by clinical scoring and bioengineering technology.

Results

The results showed that, although some aspects were improved in both groups, the group using the emollient containing PEA/AEA presented a better skin surface change in capacitance. However, the most impressive finding was the ability of the PEA/AEA emollient to increase the 5 Hz current perception threshold to a normal level after 7 days, with a significant difference between values at baseline and after 14 days. A current perception threshold of 5 Hz was positively and significantly correlated with skin surface hydration and negatively correlated with transepidermal water loss in the PEA/AEA emollient group.

Conclusion

Compared with traditional emollients, regular application of a topical PEA/AEA emollient could improve both passive and active skin functions simultaneously.

Keywords: N-palmitoylethanolamine, N-acetylethanolamine, current perception threshold, skin barrier, pruritus, asteatotic eczema

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111646/ - Full Study Here.

Introduction

Asteatotic eczema (AE) is characterized by itchy, dry, rough, and scaling skin, and is often aggravated during the dry winter season as a result of the interaction between environmental agents such as soap and other detergents,1 especially for the elderly. Some researchers suggest that the itchy sensation can be persistent in its effects.2 The itchy sensation is produced via a complex process that involves stimulation of free nerve endings very close to the surface of the skin. The sensation is transmitted through the C-fibers in the skin to the dorsal horn of the spinal cord, and finally to the cerebral cortex for processing via the spinothalamic tract.3 An increasing number of studies have shown that daily use of emollients is a vital part of the management of patients with dry skin conditions.4,5

Endogenous phospholipids are universal among mammalian organisms. Among them, phospholipids like N-palmitoylethanolamine (PEA) and N-acetylethanolamine (AEA), which both belong to the functional endocannabinoid system, are present in high amounts in the stratum granulosum of the skin.6 A number of researchers have shown in recent years that the endocannabinoid system could play a role in providing substantial relief for objective and subjective symptoms of some skin diseases, including atopic eczema,7,8 facial postherpetic neuralgia,9 and contact allergic dermatitis.10 It has also been documented that the endocannabinoid system has the ability to prevent skin damage as a result of exposure to ultraviolet rays.11 Its main physiological function is to constitutively control and balance the proliferation, differentiation, and survival of skin cells.12

Considering that the endocannabinoid system could be used as a novel therapeutic tool to remedy dry skin by enhancing lipid production in the stratum granulosum, the scope of this clinical trial was to evaluate the advantages of using an emollient containing PEA/AEA over a traditional emollient. The neuroselective transcutaneous electrical stimulator, Neurometer^® CPT (Neurotron Inc., Baltimore, MD, USA), is a useful tool that was recently created to assess the threshold for itch sensation noninvasively.13 To investigate the differences between the PEA/AEA emollient and a traditional emollient, we measured and compared the difference in skin barrier function and current perception threshold (CPT) in AE patients.

Skin barrier function

After application of the emollients, the skin surface hydration was increased in both groups. There were significant differences on day 1 and days 3, 7, 14, and 28 in both groups (P<0.05). Comparing the change in capacitance of the skin surface (minus the baseline) between the two groups, product P was better than product A in treating AE (Figure 1).

Figure 1

Changes in skin surface hydration over 28 days.

Notes: In each group, 30 subjects completed the study. Measurements were performed three times on each test area of the skin at each visit. The error bars for product A were 3.86 (day 3), 5.23 (day 7), 5.54 (day 14), and 4.81 (day 28). The error bars for product P were 4.55 (day 3), 4.47 (day 7), 5.59 (day 14), and 5.61 (day 28). Comparing the change in capacitance of the skin surface (minus the baseline) between the two groups, product P resulted in a greater change in capacitance of the skin surface than product A. *P<0.05, **P<0.01. A refers to the emollient without PEA, and P refers to the emollient that contains PEA/AEA.

Abbreviations: AU, arbitrary units; D, day; PEA, N-palmitoylethanolamine; AEA, N-acetylethanolamine.

The TEWL values were decreased in both groups after application of emollient. There was a significant difference between baseline values for the two groups and the values on days 3, 7, 14, and 28 (P<0.05). However, we found no statistically significant difference between the two products (P>0.05) with regard to change in TEWL (Figure 2).

Figure 2

Changes in TEWL over the 28 recorded days.

Notes: There were no significant differences between products A and P. A refers to the emollient without PEA and P refers to the emollient that contains PEA/AEA.

Abbreviations: TEWL, transepidermal water loss; D, day; PEA, N-palmitoylethanolamine; AEA, N-acetylethanolamine.

Discussion

In recent years, more evidence has emerged suggesting that the skin and its appendages are active neuroimmunoendocrine organs.17 Skin has both a “passive” function (as a physicochemical barrier) and an “active” function (as a neuroimmunoendocrine barrier). The use of traditional emollients over a long time would help to restore the lipid lamellae, improve skin hydration and elasticity, and support epidermal differentiation.18 These elements are all skin physicochemical barrier functions.

The endocannabinoid system is believed to be actively involved in endogenous protective mechanisms in skin barrier function; application of PEA/AEA could augment local production of lipids and inhibit their degradation (via fatty acid amide hydrolase) in the stratum granulosum, and could therefore serve as another therapeutic method for combating dry skin and reducing itching. PEA could markedly augment the effect of AEA at cannabinoid receptor type 1 and/or 2, as well as directly activate peroxisome proliferator-activated receptor alpha constitutively, and simultaneously control both “passive” and “active” skin functions, including regeneration of skin and restoration of lipid lamellae, skin sensation, and immune competence.19–21 Activation of cannabinoid receptor type 2 in the sebaceous glands by AEA could markedly enhance lipid synthesis. The literature indicates that the endocannabinoid system is a good treatment for uremic pruritus. It was not only the result of dry skin improvement but also addition of endocannabinoids that may have played a role in affecting the sensation nerves.22In a model of passive immunoglobulin E-induced cutaneous anaphylaxis, researchers found that PEA and AEA are both bioactive signaling lipids capable of downregulating inflammation in the skin.23 In the immune system, PEA could downmodulate activation of skin mast cells and inhibit release of histamine, prostaglandin D2, and tumor necrosis factor alpha.24

Compared with the traditional emollient, the main physiological function of the cutaneous endocannabinoid system is to constitutively control and balance the proliferation, differentiation, and survival of immune cells and tolerance of skin cells (Figure 5).

Figure 5

Comparing the traditional emollient and PEA/AEA emollient.

Note: Compared with the traditional emollient, the PEA/AEA emollient could simultaneously control both “passive” and “active” skin functions, including regeneration of skin and restoration of lipid lamellae, skin sensation, and immune competence.

Abbreviations: ECS, endocannabinoid system; CB, cannabinoid receptor; PEA, N-palmitoylethanolamine; AEA, N-acetylethanolamine.

AE is characterized by itchy, dry, rough, and scaling skin. With aging, the activity of the sebaceous and sweat glands decreases, and the elderly are at increased risk of AE.25 There is evidence that AE is associated with a defect in skin barrier function, and this dysfunction results in increased permeability, ultimately causing inflammation and pruritus.26 The rational treatment of AE is the use of a complete emollient therapy. The aim of this study was to determine whether an emollient cream containing PEA/AEA is more efficient than a traditional emollient in treating AE. The results show that both emollient creams could restore the skin barrier function, improve skin surface hydration, and decrease TEWL values, but the emollient containing PEA/AEA performed better than its traditional counterpart in terms of change in capacitance at the skin surface.

However, the most impressive finding was that application of PEA/AEA emollient could increase 5 Hz CPT to normal levels after 7 days, with a significant difference between baseline values and those after 14 days. This is the remarkable “active” function of PEA/AEA in rebuilding the skin neuroimmunoendocrine barrier. The commercially available neuroselective stimulator can provoke itch in healthy individuals and there are body area-specific differences in the itch perception induced by this device. C-fibers are the sensory nerves that transmit the sensation of pruritus. CPT decreases when hydration levels in the stratum corneum are low, suggesting that sensitivity to itching is amplified when the skin is dryer. When the emollient containing PEA/AEA was applied to the skin, there was an inverse relationship between CPT and TEWL values. In contrast, these relationships were absent in the group using the emollient without PEA/AEA, suggesting that even though the traditional emollient may be an acceptable substitute for maintaining healthy skin, it cannot be relied on to increase 5 Hz CPT values or alleviate itching in the short term.

Go to:

Conclusion

This study shows that, compared with a traditional emollient, regular application of a topical PEA/AEA emollient in individuals with mild or moderate AE can significantly improve skin barrier function, increase 5 Hz CPT values, and reduce itching. Topical application of an emollient containing PEA/AEA is an effective tool that could guide prophylactic and therapeutic measures for AE, along with dry and itchy skin, in the elderly, in the future. However, this study was carried out only in female Shanghainese patients, and without checking their immunoglobulin E levels.

Go to:

Acknowledgments

The authors thank all the subjects who participated in this study. We appreciate the concern and support provided by the staff of our department. Our deepest gratitude goes to Ms PL Wu and Ms J Li.

Go to:

Footnotes

Disclosure

This research was supported by GlaxoSmithKline (China) Investment Co Ltd. The authors report no other conflicts of interest in this work.

Go to:

References

1. Cork MJ, Danby S. Skin barrier breakdown: a renaissance in emollient therapy. Br J Nurs. 2009;18(14):872–874. 876–877. [PubMed]

2. Kini SP, DeLong LK, Veledar E, McKenzie-Brown AM, Schaufele M, Chen SC. The impact of pruritus on quality of life: the skin equivalent of pain. Arch Dermatol. 2011;147(10):1153–1156. [PubMed]

3. Ikoma A, Cevikbas F, Kempkes C, Steinhoff M. Anatomy and neurophysiology of pruritus. Semin Cutan Med Surg. 2011;30(2):64–70. [PMC free article][PubMed]

4. Lodén M. Effect of moisturizers on epidermal barrier function. Clin Dermatol. 2012;30(3):286–296. [PubMed]

5. Chandar P, Nole G, Johnson AW. Understanding natural moisturizing mechanisms: implications for moisturizer technology. Cutis. 2009;84(1 Suppl):2–15. [PubMed]

6. Lo Verme J, Fu J, Astarita G, et al. The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol. 2005;67(1):15–19. [PubMed]

7. Kircik L. A nonsteroidal lamellar matrix cream containing palmitoylethanolamide for the treatment of atopic dermatitis. J Drugs Dermatol. 2010;9(4):334–338. [PubMed]

8. Eberlein B, Eicke C, Reinhardt HW, Ring J. Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study) J Eur Acad Dermatol Venereol. 2008;22(1):73–82. [PubMed]

9. Phan NQ, Siepmann D, Gralow I, Ständer S. Adjuvant topical therapy with a cannabinoid receptor agonist in facial postherpetic neuralgia. J Dtsch Dermatol Ges. 2010;8(2):88–91. [PubMed]

10. Petrosino S, Cristino L, Karsak M, et al. Protective role of palmitoylethanolamide in contact allergic dermatitis. Allergy. 2010;65(6):698–711.[PubMed]

11. Kemenv L, Koreck A, Kis K, et al. Endogenous phospholipid metabolite containing topical product inhibits ultraviolet light-induced inflammation and DNA damage in human skin. Skin Pharmacol Physiol. 2007;20(3):155–161.[PubMed]

12. Bíró T, Tóth BI, Haskó G, Paus R, Pacher P. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol Sci. 2009;30(8):411–420. [PMC free article] [PubMed]

13. Ozawa M, Tsuchiyama K, Gomi R, Kurosaki F, Kawamoto Y, Aiba S. Neuroselective transcutaneous electric stimulation reveals body area-specific differences in itch perception. J Am Acad Dermatol. 2006;55(6):996–1002.[PubMed]

14. Kobayashi H, Kikuchi K, Tsubono Y, Tagami H. Measurement of electrical current perception threshold of sensory nerves for pruritus in atopic dermatitis patients and normal individuals with various degrees of mild damage to the stratum corneum. Dermatology. 2003;206(3):204–211. [PubMed]

15. Mori T, Ishida K, Mukumoto S, et al. Comparison of skin barrier function and sensory nerve electric current perception threshold between IgE-high extrinsic and IgE-normal intrinsic types of atopic dermatitis. Br J Dermatol. 2010;162(1):83–90.[PubMed]

16. Koga K, Furue H, Rashid M, Takaki A, Katafuchi T, Yoshimura M. Selective activation of primary afferent fibers evaluated by sine-wave electrical stimulation. Mol Pain. 2005;25:1–13. [PMC free article] [PubMed]

17. Roosterman D, Goerge T, Schneider SW, Bunnett NW, Steinhoff M. Neuronal control of skin function: the skin as a neuroimmunoendocrine organ. Physiol Rev. 2006;86(4):1309–1379. [PubMed]

18. Proksch E, Lachapelle JM. The management of dry skin with topical emollients – recent perspectives. J Dtsch Dermatol Ges. 2005;3(10):768–774.[PubMed]

19. Lo Verme J, La Rana G, Russo R, Calignano A, Piomelli D. The search for the palmitoylethanolamide receptor. Life Sci. 2005;77(14):1685–1698. [PubMed]

20. Hesselink JM. Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-α agonist and effective nutraceutical. J Pain Res. 2013;6:625–634. [PMC free article][PubMed]

21. Costa B, Comelli F, Bettoni I, Colleoni M, Giagnoni G. The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB (1), TRPV1 and PPARgamma receptors and neurotrophic factors. Pain. 2008;139(3):541–550.[PubMed]

22. Szepietowski JC, Szepietowski T, Reich A. Efficacy and tolerance of the cream containing structured physiological lipids with endocannabinoids in the treatment of uremic pruritus: a preliminary study. Acta Dermatovenerol Croat. 2005;13(2):97–103. [PubMed]

23. Dalle Carbonare M, Del Giudice E, Stecca A, et al. A saturated N-acylethanolamine other than N-palmitoyl ethanolamine with anti-inflammatory properties: a neglected story. J Neuroendocrinol. 2008;20(Suppl 1):26–34.[PubMed]

24. Cerrato S, Brazis P, della Valle MF, Miolo A, Puigdemont A. Effects of palmitoylethanolamide on immunologically induced histamine, PGD2 and TNFalpha release from canine skin mast cells. Vet Immunol Immunopathol. 2010;133(1):9–15. [PubMed]

25. Norman RA. Xerosis and pruritus in the elderly: recognition and management. Dermatol Ther. 2003;16(3):254–259. [PubMed]

26. Elias PM, Choi EH. Interactions among stratum corneum defensive functions. Exp Dermatol. 2005;14(10):719–726. [PubMed]

J Eur Acad Dermatol Venereol. 2008 Jan;22(1):73-82. doi: 10.1111/j.1468-3083.2007.02351.x.

https://www.ncbi.nlm.nih.gov/pubmed/18181976

Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study).

Eberlein B¹, Eicke C, Reinhardt HW, Ring J.

Author information

Abstract

BACKGROUND:

For long-term management of atopic eczema, the use of skin care creams is recommended, but effectiveness of this treatment is not well established.

OBJECTIVE:

The objective of this study was to yield data on the skin care properties of a cream with a unique lamellar matrix containing N-palmitoylethanolamine (PEA) and to assess quality-of-life variables in patients with mild to moderate atopic eczema.

SETTING:

In this multinational, multicentre, observational, non-controlled, prospective cohort study, patients between 2 and 70 years of age were enrolled. All patients were supplied with the study product sufficient for treatment over the entire study period. Outcome was followed in periods between 3 and 7 days and 4 and 6 weeks after study start. Data were gathered from doctor reports and patient self-assessments via patient questionnaires.

RESULTS:

Data from 2456 patients entered the database. The mean examination intervals were 6 days for the 3- to 7-day period and 38 days for the 4- to 6-week period. At study end, intensities of erythema, pruritus, excoriation, scaling, lichenification and dryness were significantly reduced with a combined score reduction of 58.6% in the entire population (57.7% in adults > 12 years and 60.5% in children </= 12 years) according to doctors' reports. Patients reported a reduction of pruritus on visual analogue scales from 4.9 +/- 2.6 to 2.7 +/- 2.4 6 days after treatment start and a further reduction to 2.0 +/- 2.3 at study end (P < 0.001 each). Likewise, sleep quality improved significantly during the study period. Earlier-used topical corticosteroids were omitted by 56% of all patients (53.4% in adults and 62.5% in children) at study end, and the average weekly application rate decreased by 62% from 7.9 +/- 6.0 to 3.0 +/- 5.1 (P < 0.001). The tolerance was assessed as very good or good in 92% of cases by both patients and doctors.

CONCLUSION:

This study showed substantial relief of objective and subjective symptoms of atopic eczema after regular skin care with the study cream. The patient-related effectiveness (decline of pruritus and loss of sleep) indicated a gain in quality of life in these patients. The reduced use of topical corticosteroids is important in view of safety and pharmacoeconomic implications in the treatment of atopic eczema.

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

Go to:

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

Go to:

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