What is the role of nonsteroidal anti-inflammatory drugs in the management of endometriosis? How do they work to alleviate the pain and symptoms associated with this condition?.

Understanding Endometriosis

Endometriosis is a chronic, estrogen-dependent gynecological condition characterized by the growth of endometrial-like tissue outside the uterus. This abnormal tissue can implant and grow on various organs within the pelvic cavity, including the ovaries, fallopian tubes, and the lining of the pelvic cavity (the peritoneum). The presence of this ectopic endometrial tissue can lead to inflammation, scarring, and the formation of adhesions, resulting in debilitating pelvic pain, dysmenorrhea (painful menstruation), dyspareunia (painful intercourse), and even infertility.

Pathogenesis of Endometriosis

The exact cause of endometriosis is not fully understood, but several theories have been proposed. The most widely accepted is Sampson’s theory of retrograde menstruation, which suggests that during menstruation, some of the endometrial tissue flows back through the fallopian tubes and implants on the pelvic organs, leading to the development of endometriotic lesions. Estrogen plays a crucial role in the pathogenesis of endometriosis, as it promotes the proliferation and growth of the ectopic endometrial tissue. Additionally, endometriosis is associated with an increase in inflammatory mediators, such as prostaglandins, interleukins, and tumor necrosis factor, which further contribute to the pain and progression of the disease.

Role of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a mainstay in the pharmacologic management of endometriosis-related pain. NSAIDs work by inhibiting the cyclooxygenase (COX) enzymes, which are responsible for the production of prostaglandins. Prostaglandins play a key role in the inflammatory process associated with endometriosis, contributing to pain, swelling, and menstrual cramps.

Mechanism of Action of NSAIDs in Endometriosis

NSAIDs, such as ibuprofen and naproxen, exert their analgesic (pain-relieving) and anti-inflammatory effects by blocking the COX-1 and COX-2 enzymes. This inhibition leads to a reduction in the production of prostaglandin E2 (PGE2), a key mediator of the inflammatory response in endometriosis. By reducing prostaglandin levels, NSAIDs can help alleviate the pain and discomfort associated with endometriosis, including pelvic pain, dysmenorrhea, and painful intercourse.

Dosing and Efficacy of NSAIDs in Endometriosis

For the management of endometriosis-related pain, NSAIDs should be administered several days before the start of menstruation to block the prostaglandin formation that leads to pain and swelling. The highest tolerable dose of an NSAID should be used, as this has been shown to be more effective in reducing endometriosis-related pain. If the first NSAID tried is not effective after 4-6 weeks, a different NSAID should be tried, as individual responses to these medications can vary. No single NSAID has been demonstrated to be superior to another for the treatment of endometriosis.

Combination Therapy with NSAIDs

In some cases, NSAIDs may be combined with other pharmacologic agents, such as hormonal therapies, to manage endometriosis more effectively. Hormonal treatments, including oral contraceptives, progestins, danazol, and gonadotropin-releasing hormone agonists, can help suppress estrogen levels and inhibit the growth of endometriotic lesions, thereby reducing pain and other symptoms. The combination of NSAIDs and hormonal therapy can provide a more comprehensive approach to the management of endometriosis.

Limitations and Considerations

While NSAIDs are a valuable tool in the management of endometriosis-related pain, they do not address the underlying cause of the condition or lead to its resolution. Their use is primarily aimed at symptom relief, and they do not cure endometriosis. Additionally, long-term use of NSAIDs can be associated with potential side effects, such as gastrointestinal bleeding, renal dysfunction, and cardiovascular complications. Patients should be closely monitored, and the lowest effective dose should be used to minimize these risks.

The Pharmacologic Management of Endometriosis

US Pharm. 2017;42(9):12-16.

ABSTRACT: Endometriosis is an estrogen-mediated growth of endometrial tissue outside the uterus. Patients with this gynecologic condition, for which there is no cure, experience debilitating pelvic pain during menstruation and have a greater chance of infertility. Endometriosis affects about 10% of women of childbearing age. Management of endometriosis involves the use of nonsteroidal anti-inflammatory drugs and hormonal therapies, which have been observed to reduce endometrial proliferation. Following an evaluation of patient-specific toxicities, oral contraceptives, progestins, danazol, or gonadotropin-releasing hormone agonists are used to suppress estrogen levels. Surgery is considered if a pelvic mass is detected or if the patient is planning a pregnancy.

Endometriosis, which is the estrogen-dependent growth of endometrial tissue outside the uterus, causes inflammation, pelvic pain, dysmenorrhea, painful intercourse, and infertility in approximately 10% of females of reproductive age. ¹ As of 2010, an estimated 176 million women of childbearing age worldwide were affected.² Although it is considered a benign disorder, endometriosis can affect the patient’s quality of life. In addition to causing debilitating pain, endometriosis results in worse clinical outcomes in women undergoing assisted reproductive technology, adding to the negative social and psychological impact of this chronic gynecologic condition.³ Endometriosis occurs rarely in postmenopausal women.⁴

Pathogenesis and Clinical Presentation

Several theories have been proposed for the pathogenesis of endometriosis. It was first hypothesized by Sampson that women with prolonged menses have an increased risk because of the retrograde flow of sloughed endometrial cells into the pelvic cavity from the fallopian tubes.⁵ The tissue implants onto the peritoneum, resulting in the growth of lesions. Estrogen plays a role in this process by promoting cellular proliferation. ⁶ Patients with endometriosis have higher concentrations of activated macrophages, interleukins, and tumor necrosis factor, as well as repressed natural killer cell formation, further promoting lesion growth in the area and preventing the elimination of endometrial debris.^7-9 The development of endometriosis is characterized by an increase in cyclooxygenase-2 (COX-2), which results in prostaglandin excess and inflammation and in enhanced aromatase activity that raises estrogen levels. Progesterone resistance also occurs.¹⁰ A genetic component should not be excluded because endometriosis has an estimated heritability of about 50%.¹¹

A patient with endometriosis experiences consistent premenstrual pelvic and lower back pain that may be alleviated following menstruation. Endometriosis-related infertility is thought to be caused by the aforementioned development of lesions accompanied by pelvic distortion or by the presence of an ovarian cyst known as an endometrioma, or “chocolate cyst. ” Endometriomas adhere to surrounding structures, such as the fallopian tubes, and are suggested to increase the risk of ovarian cancer.¹²

Diagnosis and Treatment

No individual markers have been identified that are specific to the diagnosis of endometriosis, and there are no detectable laboratory abnormalities. An experienced physician may be able to obtain a diagnosis during the patient history or palpation of the pelvic area. The most useful diagnostic technique remains laparoscopy, with suspicious lesions biopsied for histologic confirmation.¹³ There is no cure for endometriosis. Clinical management may be achieved through surgery or by using drugs that modify the abovementioned mechanisms of pathogenesis, including medication for the relief of pain.

Pharmacologic Management

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs should be administered several days before the start of menstruation in order to block the endometriosis-associated prostaglandin formation that leads to pain and swelling. ¹⁴ NSAIDs prevent prostaglandin E₂ (PGE₂) production through reversible blockade of COX-1 and COX-2. Nonprescription formulations (ibuprofen and naproxen) should be taken according to the manufacturer’s dosing instructions, and a prescription may be obtained from a physician if a higher dose is required. For the treatment of endometriosis, the highest NSAID dose tolerated by the patient should be administered. If the first NSAID is not effective after 4 to 6 weeks, another NSAID should be tried because of the variability in drug response among individuals. No NSAID has been observed to be superior to another.¹⁵ For the management of endometriosis, an NSAID may be combined with another pharmacologic agent, such as a hormonal preparation (discussed in upcoming sections).

Patients with a known aspirin allergy, bronchial asthma, and nasal polyps—often referred to as the aspirin triad—should avoid the use of NSAIDs, as cross-sensitivity reactions can occur. ¹⁶ NSAIDs should be administered with plenty of water and on a full stomach. This is to protect the gastrointestinal tract from the loss of cytoprotective PGE₂. Likewise, patients with a history of gastric irritation, ulceration, and bleeding should avoid COX-1 inhibitors. NSAIDs should not be administered on a chronic basis; renal injury can result from the loss of PGE₂-mediated vasodilation in the afferent arteriole of the kidney, leading to a reduction in glomerular filtration rate through reduced blood flow. NSAIDs can also negate the effects of antihypertensives and the antiplatelet action of aspirin while increasing the toxicity of the mood stabilizer lithium.

Hormones: Combined estrogen-progestin contraceptives and progestin-only preparations reduce endometrial proliferation, blocking the inflammation and pain associated with endometriosis. The decreased ovulation afforded by these agents is protective against epithelial ovarian and endometrial cancers, which are associated with endometriosis. ¹⁷ Gonadotropin-releasing hormone (GnRH) agonists, danazol, and aromatase inhibitors should also be considered.

Combined Estrogen-Progestin Contraceptives: These drugs, which are available in pill, transdermal patch, and vaginal ring formulations, are considered an appropriate treatment option for the pain of endometriosis until pregnancy is desired. Contraceptives reduce ovarian function by inhibiting the secretion of gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH]). These drugs downregulate cell proliferation and enhance apoptosis in the eutopic endometrium.¹⁸ Serious adverse effects of estrogen-progestin combinations are lower than in previous years because the formulations contain a lower estrogen dose. However, the risks of thromboembolism, cerebrovascular disease, and coronary artery disease, which are attributed to the estrogen component of the formulation, cannot be eliminated. Smoking, especially in women older than 35 years, remains a contraindication to the use of combined estrogen-progestin contraceptives. It is also inadvisable for patients with a history of estrogen-dependent cancer to use these formulations. For the treatment of endometriosis, hormonal birth control should be administered continuously (skipping the placebo tablets) for 3 months or more in order to achieve less-frequent menstrual periods and consequently less pain.¹⁹

Progestin-Only Preparations: This therapy is appropriate for patients who do not respond to or have a contraindication to estrogen-progestin contraceptives. Progestins bind to nuclear receptors, leading to enhanced gene transcription and suppression of gonadotropin synthesis. In addition, progestins prevent the implantation and growth of regurgitated endometrial cells by inhibiting angiogenesis and matrix metalloproteinases.²⁰ Norethindrone is started at 5 mg per day for 14 days and increased in increments of 2.5 mg per day to reach 15 mg per day, which is continued for 6 to 9 months or until the occurrence of breakthrough bleeding (when the uterine lining becomes thin). Medroxyprogesterone may be administered as an SC injection at a dosage of 150 mg every 3 months. In addition to breakthrough bleeding, progestin-only preparations can induce breast tenderness and acne. Weight gain is possible given the stimulation of insulin secretion and increased appetite.

 Although limited results are available on the use of the levonorgestrel-releasing intrauterine system to treat endometriosis, this device has improved patient compliance over the once-daily oral progestin formulations because there is no repeated administration. Levonorgestrel enhances endometrial glandular atrophy and promotes endometrial apoptosis, resulting in a decrease in proliferation.²¹

Danazol: This agent is a synthetic androgen with minimal estrogen or progesterone potential. Danazol suppresses the activity of the ovary by inhibiting steroidogenic enzymes and preventing midcycle FSH and LH release. Because it can bind to glucocorticoid receptors, danazol also has been observed to modulate immunologic function. ²² Danazol is administered orally in divided doses ranging from 400 mg to 800 mg daily for 6 to 9 months in mild cases; severe cases may require 800 mg per day in two divided doses. The increase in liver injury, masculinization, and risk of thromboembolism limits the use of danazol for endometriosis treatment. This drug is teratogenic and should be avoided in patients considering pregnancy. Abrupt discontinuation of danazol has been linked to idiopathic intracranial pressure (or pseudotumor cerebri), which may be due to a rebound phenomenon of cerebral vascular tone or prolonged effects of the drug’s metabolites.²³

GnRH Agonists: These drugs bind to and downregulate pituitary gland receptors. The initial surge of LH and FSH may exacerbate endometriosis pain because of the ovarian stimulation. However, 2 weeks after therapy initiation, an estrogen-deficient state occurs; this is the mechanism of leuprolide and goserelin for endometriosis management. GnRH agonists also enhance apoptosis and decrease cellular proliferation in the endometrial cells.²⁴ Some expected adverse effects are hot flashes, vaginal dryness, and atrophy. Since a hypoestrogenic state is induced, accelerated bone loss can occur in patients treated long-term with these agents. Therefore, an appropriate add-back regimen—the addition of a small amount of either estrogen and progesterone or progesterone alone—to lessen these toxicities should be considered. Leuprolide may be used in combination with norethindrone 3.75 mg per month for up to 6 months or norethindrone 11.25 mg every 3 months for up to two doses (total 6-month duration). Goserelin is administered at 3.6 mg every 28 days for 6 months.

Although further research is required, GnRH antagonists such as degarelix are being studied as possible management options for endometriosis. These drugs differ from GnRH agonists in that, instead of downregulation, there is a competitive blockade at the pituitary GnRH receptor. Gonadotropins are suppressed without the initial flare of estrogen.²⁵

Aromatase Inhibitors: Aromatase activity is absent in the normal endometrium but is increased in patients with endometriosis.²⁶ This enzyme is involved in the conversion of androstenedione to estrone and testosterone to estradiol. Increased estrogen production stimulates the synthesis of PGE₂, leading to inflammation. Although considered an off-label use, aromatase inhibitors have been found beneficial for patients with postmenopausal endometriosis given the competitive blockade offered by letrozole and anastrozole. Long-term treatment with aromatase inhibitors has been associated with bone loss, so vitamin D or bisphosphonates are sometimes added to the regimen to prevent this deleterious effect. For the management of endometriosis, aromatase inhibitors are taken orally once daily and may be given concurrently with combined estrogen-progestin contraceptives, progestins, or GnRH agonists.

TABLE 1 summarizes the pharmacologic options recommended for endometriosis management.

Surgical Treatment: Surgical evaluation and treatment via laparoscopy is considered if drug therapy is unsuccessful, a pelvic mass is detected, or the patient is considering pregnancy. Conservative surgery is considered first-line treatment, as it is less invasive and preserves fertility because much of the uterus and ovary are preserved.²⁷

Conclusion

Endometriosis is an estrogen-mediated growth of tissue outside the uterine lining that is characterized by recurring pain. The use of NSAIDs to manage inflammation and the administration of hormonal preparations to inhibit endometrial proliferation should be considered the main pharmacologic treatments for this condition. Pharmacists can play an important role in assessing the efficacy of these therapies, and they can evaluate endometriosis patients taking these medications for contraindications and adverse drug effects.

REFERENCES

1. Mettler L, Schmidt D, Maher P. The impact of endometriosis on the health of women 2016. Biomed Res Int. 2016;2016:1747280.
2. Slopien R, Meczekalski B. Aromatase inhibitors in the treatment of endometriosis. Prz Menopauzalny. 2016;15:43-47.
3. Culley L, Law C, Hudson N, et al. The social and psychological impact of endometriosis on women’s lives: a critical narrative review. Hum Reprod Update. 2013;19:625-639.
4. Streuli I, Gaitzsch H, Wenger JM, Petignat P. Endometriosis after menopause: physiopathology and management of an uncommon condition. Climacteric. 2017;20:138-143.
5. Sampson JA. Heterotopic or misplaced endometrial tissue. Am Obstet Gynecol. 1925;10:649-664.
6. Augoulea A, Alexandrou A, Creatsa M, et al. Pathogenesis of endometriosis: the role of genetics, inflammation and oxidative stress. Arch Gynecol Obstet. 2012;286:99-103.
7. Sikora J, Mielczarek-Palacz A, Kondera-Anasz Z. Role of natural killer cell activity in the pathogenesis of endometriosis. Curr Med Chem. 2011;18:200-208.
8. Osuga Y, Koga K, Hirota Y, et al. Lymphocytes in endometriosis. Am J Reprod Immunol. 2011;65:1-10.
9. Christodoulakos G, Augoulea A, Lambrinoudaki I, et al. Pathogenesis of endometriosis: the role of defective ‘immunosurveillance’. Eur J Contracept Reprod Health Care. 2007;12:194-202.
10. Burney RO, Talbi S, Hamilton AE, et al. Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology. 2007;148:3814-3826.
11. Borghese B, Zondervan KT, Abrao MS, et al. Recent insights on the genetics and epigenetics of endometriosis. Clin Genet. 2017;91:254-264.
12. King CM, Barbara C, Prentice A, et al. Models of endometriosis and their utility in studying progression to ovarian clear cell carcinoma. J Pathol. 2016;238:185-189.
13. Nisenblat V, Prentice L, Bossuyt PM, et al. Combination of the non-invasive tests for the diagnosis of endometriosis. Cochrane Database Syst Rev. 2016;(7):CD 012281.
14. Allen C, Hopewell S, Prentice A, Gregory D. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev. 2009;(2):CD004753.
15.  Brown J, Crawford TJ, Allen C, et al. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev. 2017;(1):CD004753.
16. Berkes EA. Anaphylactic and anaphylactoid reactions to aspirin and other NSAIDs. Clin Rev Allergy Immunol. 2003;24:137-148.
17. Vercellini P, Buggio L, Berlanda N, et al. Estrogen-progestins and progestins for the management of endometriosis. Fertil Steril. 2016;106:1552-1571.
18. Meresman GF, Augé L, Barañao RI, et al. Oral contraceptives suppress cell proliferation and enhance apoptosis of eutopic endometrial tissue from patients with endometriosis. Fertil Steril. 2002;77:1141-1147.
19. Davis L, Kennedy SS, Moore J, Prentice A. Oral contraceptives for pain associated with endometriosis. Cochrane Database Syst Rev. 2007;(3):CD001019.
20. Vercellini P, Fedele L, Pietropaolo G, et al. Progestogens for endometriosis: forward to the past. Hum Reprod Update. 2003;9:387-396.
21. Viganò P, Somigliana E, Vercellini P. Levonorgestrel-releasing intrauterine system for the treatment of endometriosis: biological and clinical evidence. Womens Health (Lond). 2007;3:207-214.
22. Barbieri RL, Ryan KJ. Danazol: endocrine pharmacology and therapeutic applications. Am J Obstet Gynecol. 1981;15;141:453-463.
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Nonsteroidal anti-inflammatory drugs for management of pain in women with endometriosis

What is the issue?

Endometriosis is a gynaecological condition that commonly affects women of childbearing age. It can lead to painful symptoms, including painful periods, pain during or after sexual intercourse, pelvic and lower abdominal pain and infertility. It can greatly affect women’s quality of life by impacting their careers, everyday activities, sexual and nonsexual relationships and fertility. Nonsteroidal anti-inflammatory drugs (NSAIDs) are most commonly used as first-line treatment for women with endometriosis because they have few side effects, and many are available over the counter.

Why is this important?

Endometriosis is very common, but the condition can be difficult to diagnose. In 2015, 1.8 billion women (aged 15 to 49 years) in the world had received a diagnosis of endometriosis. It is estimated that up to 60% of women with painful periods have endometriosis. Endometriosis greatly affects women’s quality of life, impacting their careers, everyday activities, sexual and nonsexual relationships and fertility. An unpublished survey conducted by a patient support organisation in the United Kingdom – Endometriosis UK (www.endometriosis-uk.org/) – found that 65% of women with endometriosis reported that their condition had negatively affected their employment. Ten per cent of women had to reduce their hours of work, and 30% had not been able to continue in the same employment. As many as 16% of women were unable to continue in any employment, and 6% needed to claim state benefits; thus, in addition to their feelings of loss as contributors to society, they became dependent upon others. This increased their feelings of low self-esteem. Endometriosis is seen as a significant public health issue because a large number of women are affected and illnesses associated with this disease are significant.

Nonsteroidal anti-inflammatory drugs are readily available without prescription for pain relief. They work by preventing or slowing down the production of prostaglandins, which helps to relieve the painful cramps associated with endometriosis. However, a Cochrane review on the use of NSAIDs for painful periods found greater risk of stomach upset (e.g. nausea, diarrhoea) or other side effects (e.g. headache, drowsiness, dizziness, dryness of the mouth). We conducted the present review to compare all NSAIDs used to treat women with painful symptoms caused by endometriosis versus placebo, other pain management drugs or no treatment, to evaluate their effectiveness and safety.

What evidence did we find?

We searched for new evidence in October 2016 and identified no new randomised controlled trials.

From previous updates, this review found limited evidence on the effectiveness of NSAIDs (specifically naproxen) for management of pain caused by endometriosis. This review is also limited in that it includes only one study with data suitable for analysis, and this study involved only 20 women. Available evidence is of very low quality, mainly owing to poor reporting of methods, lack of precision in findings for overall pain relief, unintended side effects of treatment and the need for extra pain relief. The included trial did not report on quality of life, effects on daily activities, absence from work or school or participant satisfaction with treatment.

What does this mean?

Available evidence does not allow us to conclude whether NSAIDs are effective for managing pain caused by endometriosis, or whether any individual NSAID is more effective than another. As has been shown in other Cochrane reviews, women who use NSAIDs must be aware that NSAIDs may cause adverse effects such as nausea, vomiting, headache and drowsiness. Unless we identify new evidence in the future, we will not update this review again.

Quality of evidence

Evidence was of very low quality owing to risk of bias and imprecision (findings were based on a single small trial).

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Authors’ conclusions: 

Owing to lack of high-quality evidence and lack of reporting of outcomes of interest for this review, we can make no judgement as to whether NSAIDs (naproxen) are effective in managing pain caused by endometriosis. There is no evidence that one NSAID is more effective than another. As shown in other Cochrane reviews, women taking NSAIDs must be aware that these drugs may cause unintended effects.

Read the full abstract…

Background: 

Endometriosis is a common gynaecological condition that affects women and can lead to painful symptoms and infertility. It greatly affects women’s quality of life, impacting their careers, everyday activities, sexual and nonsexual relationships and fertility. Nonsteroidal anti-inflammatory drugs (NSAIDs) are most commonly used as first-line treatment for women with pain associated with endometriosis.

Objectives: 

To assess effects of NSAIDs used for management of pain in women with endometriosis compared with placebo, other NSAIDs, other pain management drugs or no treatment.

Search strategy: 

We searched the Cochrane Gynaecology and Fertility Group Specialised Register of Controlled Trials (October 2016), published in the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, as well as MEDLINE (January 2008 to October 2016), Embase (date limited from 1 January 2016 to 19 October 2016, as all earlier references are included in CENTRAL output as a result of the Embase project), registers of ongoing trials and the reference lists of relevant publications. We identified no new randomised controlled trials. Unless we identify new evidence in the future, we will not update this review.

Selection criteria: 

We included all randomised controlled trials (RCTs) describing use of NSAIDs for management of pain associated with endometriosis in women of all ages.

Data collection and analysis: 

In the 2009 update of this review, two review authors (CA and SH) independently read and extracted data from each of the included studies. We analysed cross-over trials using the inverse variance method of RevMan to calculate odds ratios for binary outcomes.

Main results: 

We identified no new trials for the 2016 update. This review includes two trials, but we included only one trial, with 24 women, in the analyses.

The overall risk of bias was unclear owing to lack of methodological detail. Using the GRADE method, we judged the quality of the evidence to be very low. We downgraded evidence for risk of bias and for imprecision (wide confidence intervals and evidence based on a single small trial).

Comparison of NSAIDs (naproxen) versus placebo revealed no evidence of a positive effect on pain relief (odds ratio (OR) 3.27, 95% confidence interval (CI) 0.61 to 17.69; one trial, 24 women; very low-quality evidence) in women with endometriosis. Evidence indicating whether women taking NSAIDs (naproxen) were less likely to require additional analgesia (OR 0.12, 95% CI 0.01 to 1.29; one trial, 24 women; very low-quality evidence) or to experience side effects (OR 0.46, 95% CI 0.09 to 2.47; one trial, 24 women; very low-quality evidence) when compared with placebo was inconclusive.

Studies provided no data on quality of life, effects on daily activities, absence from work or school, need for more invasive treatment or participant satisfaction with treatment.

Non-steroidal anti-inflammatory drugs for pain relief in women with endometriosis

What is the problem?

Endometriosis is a gynecological condition that usually affects women of childbearing age. This can lead to painful symptoms, including painful menstruation, pain during or after intercourse, pelvic and lower abdominal pain, and infertility. This can significantly affect women’s quality of life, their careers, daily activities, sexual and non-sexual relationships, and fertility. Non-steroidal anti-inflammatory drugs (NSAIDs) are most commonly used as first-line therapy in women with endometriosis because they have few side effects and many are available over-the-counter.

Why is this important?

Endometriosis is a very common condition that can be difficult to diagnose. In 2015, 1.8 billion women (ages 15 to 49) worldwide were diagnosed with endometriosis. It is estimated that 60% of women have endometriosis with painful symptoms. Endometriosis can significantly affect women’s quality of life, affecting their careers, daily activities, sexual and non-sexual relationships, and fertility. An unpublished study by the UK patient support organization Endometriosis UK (www. endometriosis-uk.org/) found that 65% of women with endometriosis reported that their condition negatively affected their work. Ten percent of women were forced to reduce their hours of work, and 30% were unable to continue the same work. As many as 16% of women were unable to continue doing any work, and 6% had to claim government benefits; in addition to feelings of loss of contribution to society, they became dependent on others. This further lowers their low self-esteem. Endometriosis is considered a significant public health issue because it affects a large number of women and the conditions associated with this disease are important.

Non-steroidal anti-inflammatory drugs are available without a doctor’s prescription and are used to relieve pain. They work by preventing or slowing down the production of prostaglandins, which helps relieve the painful cramps associated with endometriosis. However, a Cochrane review of the use of NSAIDs for painful periods found that NSAIDs increased the risk of stomach upset (eg, nausea, diarrhea) or other side effects (eg, headache, drowsiness, dizziness, dry mouth). We conducted this review to compare all NSAIDs used to treat women with painful symptoms due to endometriosis versus placebo, other pain medications, or no treatment to evaluate their efficacy and safety.

What evidence did we find?

We searched for new evidence in October 2016 and identified no new randomized controlled trials.

Based on previous updates, this review found limited evidence for the effectiveness of NSAIDs (particularly naproxen) in the treatment of pain associated with endometriosis. This review is also limited in that it includes only one study with data suitable for analysis, and this study included only 20 women. The available evidence is of very low quality, mainly due to poor presentation of methods, lack of precision in conclusions on overall pain relief, unintended side effects from treatment, and the need for additional pain relief. The included trials did not report on quality of life, impact on daily activities, absence from work or school, or participant satisfaction with treatment.

What does this mean?

Evidence does not support the conclusion that NSAIDs are effective for treating endometriosis pain, or whether individual NSAIDs are more effective than others. As shown in other Cochrane reviews, women who use NSAIDs should be aware that NSAIDs can cause side effects such as nausea, vomiting, headache, and drowsiness. Unless we discover new evidence in the future, we will not update this review again.

Quality of evidence

The evidence was of very low quality due to the risk of bias and imprecision (results were based on one small trial).

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Translation notes:

Translation: Romanchenko Polina Igorevna. Editing: Alexandrova Elvira Grigorievna. Project coordination for translation into Russian: Cochrane Russia – Cochrane Russia (branch of the Northern Cochrane Center based at Kazan Federal University). For questions related to this translation, please contact us at: [email protected]; [email protected]

Medical treatment of endometriosis

Home » Information for patients » Medical treatment of endometriosis

Since there is still no universal medical therapy for endometriosis, all treatment is non-specific, aimed mainly at reducing the severity of existing symptoms and is selected individually, based on the characteristics and needs of each patient.

Endometriosis is often characterized by a persistent relapsing course, therefore, when choosing a treatment, special attention should be paid not only to its effectiveness, but also to long-term safety and tolerability, due to the fact that quite long-term therapy may be necessary. The cost-effectiveness of the treatment must also be taken into account.

It should be remembered that laparoscopy is not always necessary before initiating medical therapy for pelvic pain when endometriosis is suspected and there are no anatomical changes (with the exception of endometrioid ovarian cysts).

In the treatment of endometriosis, any methods of drug therapy should be used for 3 months in the absence of contraindications and side effects, after which its effectiveness is evaluated and, if necessary, the drug is changed or laparoscopy is performed.

With the complete removal of histologically verified endometrioid ovarian cysts (enucleation of the capsule or vaporization), as well as foci of endometriosis on the peritoneum of the small pelvis, sacro-uterine ligaments and other localizations, surgical treatment can be limited, but one should remember about the rather high incidence of relapses and persistence of the disease.

In general, the incidence of recurrence of endometriosis after surgical treatment after 1-2 years is 15-21%, after 5 years – 36-47%, after 5-7 years – 50-55% and is the highest with advanced endometriosis or if it is impossible to remove infiltrative foci while preserving the organs of the reproductive system (nodular forms of adenomyosis, retrocervical endometriosis with frequent internal or complete germination of the wall of the rectum or sigmoid colon, distal ureters, bladder). In these cases, it is advisable to qualify the clinical course as progression of the disease, and not relapse.

The frequency of recurrence of endometrioid ovarian cysts within 2-5 years after surgery varies from 12 to 15%. Reoperations on the ovary in women with infertility should be performed strictly according to indications, as there is evidence of a decrease in ovarian reserve after removal of endometrioid ovarian cysts. In this regard, in most cases, the treatment of endometriosis is complex and is carried out using various medications.

Non-selective NSAIDs inhibit the activity of both isoforms of the cyclooxygenase enzyme involved in the synthesis of prostaglandins, COX-1 and COX-2, although only the latter isoform is found to be overexpressed in the ectopic endometrium of endometriosis.

A just-published meta-analysis of data on the effects of the most widely used NSAIDs (naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib and lumiracoxib) suggests an increased cardiovascular risk with their use. In 2004, data were published on the effectiveness of the selective COX-2 inhibitor rofecoxib in the treatment of moderate manifestations of dysmenorrhea, dyspareunia and chronic pelvic pain, and a year later it was withdrawn from clinical practice due to an increased risk of myocardial infarction and stroke with long-term use of the drug in high doses. Thus, the efficacy and safety of the use of NSAIDs in long-term therapy of endometriosis is questionable, and the risk of long-term use of these drugs in high doses should be taken into account.

However, short-term treatment of pain associated with endometriosis with this class of drugs may be useful, including while waiting for symptom relief after targeted medical or surgical treatment is initiated.

Thus, non-steroidal anti-inflammatory drugs can be successfully used during therapy with GnRH-a, started in the luteal phase of the cycle or during menstruation, to relieve dysmenorrhea, which may increase during one cycle due to the initial effect of activation of the hypothalamic-pituitary-ovarian system observed against the background of these drugs.

Although hormonal therapy is not specific, its role in the complex treatment of patients with endometriosis can hardly be overestimated, since it is effective, safe enough, serves to prevent the recurrence and progression of the disease, and reduces the risk of repeat surgery.

The pathogenetic basis of hormonal therapy is a temporary suppression of ovarian function with modeling of the state of “pseudomenopause” using gonadotropin-releasing hormone (GnRH) agonists or GnRH antagonists (antGnRH), aromatase inhibitors or the initiation of a state of pseudodecidualization with subsequent atrophy of endometriosis foci due to the action of progestogens (with taken orally or intrauterine), selective progesterone receptor modulators or combined oral contraceptives.

There is a hypothesis that in some cases, the formation of endometrioid cysts can occur at the site of the ovulating follicle, so the suppression of ovulation, accompanied by inhibition of its characteristic “pro-inflammatory cascade”, can serve as a measure to prevent the recurrence of the disease.

Hormone therapy can be used as, firstly, empirical therapy in the treatment of patients with symptoms indicating a high probability of having endometriosis in the absence of cystic (ovarian) forms, and, secondly, adjuvant therapy for the prevention of recurrence after laparoscopic confirmation of endometriosis and / or removal of visible lesions, endometrioid cyst capsule or removal of endometriosis in infiltrate active form of the disease (retrocervical localization, bladder, intestines).

Hormone therapy helps to preserve fertility, increase working capacity, social activity and quality of life of women. Currently, there are direct indications for the treatment of endometriosis with aGn-RH, antGn-RH and some progestogens.

Before prescribing hormonal therapy, it is necessary to conduct a generally accepted examination, including:

1. collection of family and personal anamnesis with an emphasis on identifying hereditary forms of thrombophilia;
2. gynecological examination;
3. instrumental and laboratory studies to assess the state of the cardiovascular system, biochemical parameters of the liver and kidneys to exclude contraindications;
4. transvaginal ultrasound, breast ultrasound or mammography depending on age and family risk, cervical smears for oncocytology.

Then the complex of these examination methods should be repeated every 12 months. throughout the course of hormone therapy. According to the recommendations of the leading gynecological societies, combined oral contraceptives are the drugs of first choice (although without an approved indication) for the relief of endometriosis-related chronic pelvic pain in women who have no contraindications and are not planning a pregnancy at this point in time.

The potential advantages of combined oral contraceptives are low cost, few side effects, and the possibility of long-term treatment. The results of many studies indicate that the use of combined oral contraceptives significantly reduces the intensity of pain associated with endometriosis. The mechanism of their therapeutic action is due to the blockade of the synthesis of GnRH and, as a result, the suppression of the cyclic secretion of FSH and LH, which is accompanied by anovulation, decidualization of the stroma and atrophy of endometriosis foci.