How cannabis could help manage the unmet need in endometriosis

Endometriosis is a chronic inflammatory disorder that affects 10% of all women between the ages of 12 and 80 years old and for which there is an urgent need for new treatment options. Here, experts at Peak Pharm Labs and SOMAÍ Pharmaceuticals explore how cannabis could be part of the solution.

Approximately 1 in 10 women of the reproductive age are diagnosed with endometriosis. These women suffer from debilitating symptoms such as chronic pelvic pain, pain on intercourse, dysmenorrhea, and infertility, all of which severely impact quality of life.

Endometriosis is diagnosed when endometrial tissue, similar to the endometrial wall is found outside of the uterus. These tissues are called endometrial implants which are usually found in the peritoneum, ovaries, fallopian tubes, uterus, bladder, ureters, intestines, and rectum. The growth of the implants proliferate and bleed like the endometrium throughout a woman’s menstrual cycle.

Pain in endometriosis is caused by increased inflammatory markers, including prostaglandins, increased nerve endings, and pro-inflammatory cytokines. Prostaglandin F2α induces vasoconstriction and can cause uterine contractions, a component of dysmenorrhea, while prostaglandin E2 can induce pain through direct actions on nerves. The cytokines involved, TNFa and interleukins, promote lesion formation, adhesion, and infiltration and induce pain through pelvic nerve stimulation leading to central sensitisation.

Current traditional management

The current treatment goal is to manage symptom and minimise endometriotic lesions. This is done via hormone therapies which puts the patient in a pseudo-menopausal state. However these treatments do not remove the lesions or improve fertility. In fact, traditional treatment does not cause full resolution of symptoms and other adjunctive pharmacotherapy such as analgesics, like NSAIDs, are needed to control endometriosis related pain.

First line pharmacotherapy includes oral combined hormonal contraceptives, progestins, or depot progestin medroxyprogesterone acetate (DMPA).1  The choice of initial therapy thus depends on factors such as the patient’s primary complaint, the location and extent of disease, desire for future fertility, cost of therapy, contraindications to therapy, and potential side effects. If a patient’s primary symptom is dysmenorrhea, NSAIDs are often used as first-line treatment.

Alternative pharmacotherapy includes gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, danazol and aromatase inhibitors. These are often reserved for patients who fail conventional therapy due to the lack of efficacy data, adverse effects or uncertain long-term safety information.

Surgery is another option for patients, however it is usually reserved for patients who experienced medication failure, or are suffering from infertility. Women with persistent symptoms may elect for a hysterectomy but even such a major procedure does not guarantee freedom from endometriosis symptoms.

The role for cannabinoids in management of endometriosis

The endocannabinoid system (ECS) has recently been implicated in the pathophysiology of endometriosis progression and endometriosis related pain. In endometriosis, it is thought that the ECS interacts with mechanisms involved in inflammation, cell proliferation and survival, which all contribute to pain establishment. CB1 receptors are a main receptor of the ECS and are abundant in the uterus, along with non-reproductive tissue like the CNS. CB2 receptors are found in abundance throughout the immune system, in addition to the uterus and other body tissues. During oocyte maturation, previous literature has found that CB1 and CB2 expression varies throughout the maturation stages. In the secretory phase of normal endometrial tissue, progesterone increases CB1 receptor expression. This mechanism controls inflammation caused by the release of nitric oxide (NO) during endometrial tissue damage by preventing degranulation of pro-inflammatory markers from mast cells.

Anandamide (AEA), an endogenous cannabinoid is found in the ovaries as well as the reproductive fluid. Anandamide has an integral role in follicle and oocyte maturation. High levels of anandamide are found during ovulation while low levels of anandamide are found during implantation. Changes to endocannabinoid signaling is implicated with lower success rates of pregnancy and subsequently appears important in women’s reproductive health.

In patients with endometriosis, they found that these women had decreased levels of CB1 receptors in endometrial tissue, which may contribute to inflammation and pain. While CB1 receptors are abundant in the uterus, they are more concentrated in the cysts in patients with endometriosis. This alludes to the possibility of CB1 agonists being more effective in cyst tissue versus normal endometrial tissue. When comparing CB1 antagonists to CB2 antagonists, studies found that CB1 antagonists increased hyperalgesia and treatment with CB1/CB2 agonists reduced pain in a CB1 receptor dependent mechanism.

Synthetic cannabinoid receptor agonists and natural delta-9-THC have been found to modulate cytokine production, via upregulation of CB2 receptors.  By binding CB2 receptors, the cannabinoids can prevent the degranulation and release of pro-inflammatory mediators. Current literature has agreed that cannabinoids have an antiproliferative effect, however it appears that THC has a biphasic effect on proliferation. Only at high doses of THC will it reduce proliferation whereas at lower concentrations, it increases proliferation of cells.

Many of the clinical trials have focused on PEA and its effect on pain. N-palmitoylethanolamine, or PEA, is an endogenous fatty acid that acts on the peroxisome proliferator-activated receptor. Although PEA does not have a strong affinity for CB1 or CB2 receptors, it can potentiate endogenous cannabinoid activity, also known as the entourage effect. This effect is described where it increases anandamide’s affinity towards receptors or prevents the degradation of anandamide. The clinical trials found that PEA could help improve pelvic pain, dysmenorrhea, and dyspareunia. Another point of interest is the clinical trials did not report any significant side effects from the PEA treatment arms.

Alternative treatment of endometriosis

Patients suffering from hyperalgesia due to endometriosis have noticed improvement of symptoms using 1:1 THC/CBD vaginal suppositories and have found it to be well tolerated. THC appears to be the cannabinoid of choice for its affinity towards CB1 receptors to control pain, and its antiproliferative effect.

However, its side effect profile such as impaired concentration, drowsiness, etc and fear of dependence may caution its use. The transvaginal route using vaginal suppositories is a good option for endometriosis and other vaginal dysfunctions. This route provides local effect, avoids first pass metabolism, has high bioavailability, and has rapid absorption.

Also, this route is not affected by gastrointestinal disturbances and can be offered to almost all patients. Vaginal administration allows less than daily administration, lower daily doses, and fewer side effects. It could allow for selective local administration with minimal to no systemic changes.

The article was written by Rahim Dhalla, Antuanette Gomez, Natasha Jacob of Peak Farm Labs and Michael Sassano of SOMAÍ Pharmaceuticals.

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