Review
Medical therapy options for endometriosis related pain, which is better? A systematic review and network meta-analysis of randomized controlled trials

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Abstract

Our objective was to assess and rank different pharmacological interventions for relieving endometriosis-related pain. We conducted an online bibliographic search in different databases from their inception until March 2019. We included randomized controlled trials (RCTs) that assessed different medical therapies in the management of endometriosis-related pain. We applied this network meta-analysis (NMA) based on the frequentist approach using statistical package “netmeta” (version 1.0−1) in R software. Our main outcomes were the change in severity of pelvic pain, dysmenorrhea score, non-menstrual pelvic pain score, and dyspareunia score. Overall, 36 RCTs were included in this study (patients no. = 7942). Dienogest (0.94), combined hormonal contraceptives (CHCs) (0.782), and elagolix (0.38) were the highest-ranked interventions for reducing the severity of pelvic pain at three months, while at six months, gonadotropin-releasing hormone (GnRH) analogues (0.75), levonorgestrel-releasing intrauterine system (LNG-IUS) (0.73), and dienogest (0.65) were linked to more reduction in pelvic pain. The ranking p-score showed that GnRH analogues was the highest-ranked treatment for reducing dysmenorrhea at 3 months (1.00), while CHCs were the highest-ranked treatment at 6 months (0.97), followed by GnRH analogues (0.89). GnRH analogues (0.63) and elagolix (0.54) at three months while desogestrel (0.94) and CHCs (0.91) at six months were the highest-ranked treatment to reduce non-menstrual pelvic pain. GnRH analogues and elagolix were the highest-ranked pharmacologic therapies for reducing dyspareunia. In conclusion, CHCs, GnRH analogues, progesterone, and elagolix were the best approaches in reducing the pain of endometriosis.

Introduction

Endometriosis is a common gynecological disorder that usually affects adolescents and women in their reproductive age. The condition is characterized by the presence of functioning endometrial-like tissue or gland outside the uterine cavity, mainly in the ovary or peritoneal cavity [1]. According to previous epidemiological figures, the prevalence of endometriosis ranges between 10–15% among women aged 18–45 years; moreover, endometriosis accounted for about one-third of the causes of chronic pelvic pain [2]. Although endometriosis can be asymptomatic and discovered accidentally, the majority of the affected women present mainly with irregular menstrual bleeding, as well as menstrual and non-menstrual pelvic pain [3].

Endometriosis-related pain is a distressing chronic condition that can lead to disability and impaired quality of life (QoL); recent reports showed that chronic pain is a leading cause of hospitalization, impairment of different aspects of health-related QoL, and high economic burden in women with endometriosis [4,5]. Endometriosis pain usually arises from tissue damage at the site of lesions, and its severity may be correlated with the depth of infiltration of endometriosis; less likely, the pain can arise from nerve injury leading to neuropathic pain [6]. Different approaches have been proposed for relieving endometriosis-associated pain, including medical therapy, surgical interventions, and acupuncture [7,8].

The medical treatment represents the cornerstone for the management of endometriosis-related pain [9]; non-steroidal anti-inflammatory drugs (NSAIDs) are widely used as first-line options in mild-to-moderate cases [10]. On the other hand, low-dose combined hormonal contraceptives (CHCs) and progestins are effective options for relieving chronic pelvic pain through inhibition of gonadal estrogen production and induction of pseudo-pregnancy state [9]. Both gonadotropin-releasing hormone (GnRH) agonists and antagonists exhibited an acceptable efficacy in reducing moderate to severe pain of endometriosis [11]. Nevertheless, there is scarcity in the published evidence that directly compares the efficacy of those different pharmacological interventions.

Therefore, the present network meta-analysis aimed to synthesize evidence regarding the most effective pharmacological interventions for relieving endometriosis-related pain.

Section snippets

Materials and methods

We run the present systematic review and network meta-analysis according to the recommended standards of the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0 [12]. The manuscript was prepared in adherence to the recommendations of Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions (PRISMA-NMA) [13]. Because this study was a systematic review and network meta-analysis, formal ethical approval was not required.

Literature search results

We retrieved 9143 unique citations from the online bibliographic search. From which, 205 full texts were retained for full-text screening. Finally, 36 RCTs (patients no. = 7942) were included in the present systematic review and network meta-analysis.

Fig. 1 shows the PRISMA chart. The network plots illustrating direct evidence between interventions are shown in Supplementary Figs. 1 and 2.

Summary characteristics of included studies

All included studies recruited adult women with chronic pelvic pain due to endometriosis. The sample size

Discussion

There is a plethora of published literature regarding the safety and effectiveness of a wide range of pharmacological interventions for treating endometriosis-related pain. However, evidence that directly compares those different interventions is lacking. In the present network meta-analysis, dienogest, combined hormonal contraceptives (CHCs), and elagolix were the highest-ranked interventions for reducing the severity of pelvic pain at three months, while at six months, GnRH analogues,

Conclusions

The present network meta-analysis showed that CHCs, GnRH analogues, progesterone, and elagolix were the highest-ranked medical options for the management of endometriosis-related pain. Moreover, the pooled analysis did not support the use of NSAIDs, despite their current widespread use. The current published literature is limited by the small number of RCTs in some of the treatment arms, which may limit the confidence in our findings.

Authors contributions

Study Design and Concepts: Ahmed Samy, Ayman Taher, and Sileem A.Sileem.

Data Collection: Ahmed Mohamed Abdelhakim, Mohamed Fathi, Hisham Haggag, Moutaz Elsherbini, Khaled Ashour, and Shady Abdelsattar Ahmed,

Drafting of manuscript: Ahmed Samy, Mohammad Abrar Shareef, Abdulhadi A. AlAmodi, Nawal Hamdy Ahmed Keshta, Hanan Barakat Abu Elyazid Shatat, Doaa M Salah, Ahmed Said Ali, and Eman Abdel Monem El Kattan.

Revision and critical appraisal: Ahmed Samy, Ayman Taher, Sileem A.Sileem, Ahmed Mohamed

Conflict of interest

All authors confirm no financial or personal relationship with a third party whose interests could be positively or negatively influenced by the article’s content.

Funding source

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgments

We thank Mrs. Yasmin Samir Negm (Teacher at Om El Momineen Primary School, Helwan, Egypt) for her invaluable efforts in recording and organizing study data and proofreading of this article. Her remarks enriched this study.

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