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Natural Pain Management for Endometriosis

What is endometriosis?

Endometriosis is defined as the presence of endometrial glands or stroma in locations outside the uterine cavity, such as the ovaries, pelvic peritoneum, and the rectovaginal septum. (1) It affects approximately 5-20% of women of reproductive age, and can cause a reduction in quality of life due to the presence of severe pain, sometimes also causing infertility. (1, 2) More than 95% of patients who suffer from deep infiltrated endometriosis (DIE) experience severe pain. Current medical treatment focuses on hormonal therapy, painkillers or nonsteroidal anti-inflammatory drugs (NSAIDs), and/or surgery, but these are far from perfect treatments due to increased side-effects and increased contraindications. (1) Up until recently, surgery was viewed as the best option for treatment due to its effectiveness on symptoms and lesion eradications, however, recent data shows that there is a high recurrence rate of lesions after surgery, and this, coupled with the possible complications of extensive surgery, particularly on the ovarian reserve, has encouraged medical professionals to seek better options for the chronic and severe pain that often presents in endometriosis. (2)

What causes the pain in endometriosis?

Endometriosis has come to be recognised as an inflammatory condition. (2) Recent research has uncovered an important role for mast cells in the pathogenesis, and subsequent pain, of endometriosis. (2) Mast cells are fundamental participants of immune system response, especially during primary allergic reaction, and also play a role in several normal female processes including reproduction, pregnancy and labour. (3) Numerous studies have shown an increased number of mast cells in endometriotic tissue, compared to unaffected tissue. Furthermore, these endometriotic lesions showed significantly more activated mast cells situated less than 25 mm from nerve structures than unaffected tissue, particularly in deep-infiltrating lesions. (3) This has a direct impact on neurons and may contribute to the development of pain and hyperalgesia in endometriosis. (3) When mast cells are activated they release histamine, leukotrienes, tryptase, TNF-a, PGs, serotonin, IL-1 and IL-8, which directly contributes to neuropathic pain. (3)

Palmitoylethanolamide (PEA) – What is it?

Palmitoylethanolamide (PEA) is an endogenous fatty acid amide with the ability to stabilize mast cells and therefore limit the inflammation related to mast cell activation. (3) When taken as a supplement, PEA is often micronized, or ultra-micronized, which improves the distribution and diffusion. (2) There is increasing evidence to support the use of ultra-micronized PEA (um-PEA) by itself, or a co-micronized combination of PEA and polydatin m(PEA/PLD) to help reduce chronic pelvic pain in women with endometriosis. (2) One double-blind study showed that the favourable effects of m(PEA/PLD) were comparable to those of anti-inflammatory drugs, and were more effective than placebo in pain reduction. (2)

Although the main pain-relieving properties of PEA lie in its ability to downregulate mast cell activity, there is also evidence to suggest that PEA works directly on pain inhibition through an as-yet undefined cannabinoid CB2-like receptor, or the nuclear receptor peroxisome proliferator-activated receptor-alpha. (2) PEA may also help enhance the anti-inflammatory and anti-nociceptive effects of anandamide, a fatty acid neurotransmitter. (2)

PEA treatment, either as um-PEA or m(PEA/PLD), has also been shown to significantly improve overall quality of life for women suffering from endometriosis, particularly for scores relating to physical functioning, body pain, role limitations due to physical health, personal or emotional problems, emotional well-being, social functioning, energy levels, and general perceptions of their health. (2) Although some of the more psychological improvements may be a result of reduced pain, there is also a link between inflammatory diseases and mood disorders that should not be overlooked. (2) Some research indicates a role for mast cells in peripheral and central coordination of the inflammatory processes of neuropsychiatric diseases. (2)

Treatment with PEA for endometriosis patients has demonstrated a range of positive outcomes, from improving symptoms of neuropsychiatric disorders commonly present in endometriosis patients, through to pain reduction. This broad spectrum of beneficial outcomes, coupled with its relatively high safety profile and lack of adverse side effects, supports the rationality of including PEA as a potential treatment in patients with endometriosis.


1. Bouaziz J, Bar On A, Seidman DS, Soriano D. The clinical significance of endocannabinoids in endometriosis pain management. Cannabis and Cannabinoid Research. 2017 Apr 1;2(1):72-80.

2. Loi ES, Pontis A, Cofelice V, Pirarba S, Fais MF, Daniilidis A, Melis I, Paoletti AM, Angioni S. Effect of ultramicronized-palmitoylethanolamide and co-micronized palmitoylethanolamide/polydatin on chronic pelvic pain and quality of life in endometriosis patients: An open-label pilot study. International journal of women's health. 2019;11:443.

3. Binda MM, Donnez J, Dolmans MM. Targeting mast cells: a new way to treat endometriosis. Expert opinion on therapeutic targets. 2017 Jan 2;21(1):67-75.

Written by Clare Carrick as part of her 2020 internship with Wholefood Healing.

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