Which drugs reduce endometriosis-related pain most effectively?

Leuprolide plus combined OCP best for overall pelvic pain; elagolix for dysmenorrhea; vitamin C+E for dyspareunia; gestrinone for nonmenstrual pelvic pain.

Background

Comparative effectiveness of pharmacologic options for endometriosis-related pain is unclear due to few head-to-head trials.

Patients

31 RCTs; 8,665 women with surgically/histologically confirmed stage I–IV or deep endometriosis.

Intervention

  • GnRH agonists/antagonists: leuprolide, goserelin, triptorelin; elagolix, relugolix, linzagolix (± add-back)
  • Progestins/OCPs: dienogest, etonogestrel; combined OCPs (± letrozole or leuprolide)
  • Others: letrozole, gestrinone, ASP1707, eliapixant
  • Antioxidants/vitamins: vitamin C+E, vitamin D, omega-3

Control

Placebo or active comparators.

Outcome

Primary: Change in endometriosis-associated pelvic pain. Secondary: Dysmenorrhea, dyspareunia, nonmenstrual pelvic pain. Assessed via VAS/NRS; effect size as SMD (95% CI).

Study Design and Level of Evidence

Systematic review and network meta-analysis of RCTs (PRISMA/AMSTAR 2 compliant); Level 1a (2011 OCEBM).

Follow up period

End of treatment across trials; durations varied by study.

Results

  • Primary outcome (pelvic pain): vs placebo, leuprolide+OCP (SMD −1.40, 95% CI −2.41 to −0.38), dienogest (−1.20, −1.78 to −0.61), leuprolide (−1.05, −1.64 to −0.45), combined OCP (−0.67, −1.25 to −0.09). Best rank: leuprolide+OCP (SUCRA 89.1%).
  • Secondary—dysmenorrhea: Elagolix superior to placebo (SMD −2.89, −5.28 to −0.50); best rank (SUCRA 79.8%).
  • Secondary—dyspareunia: Best rank vitamin C+E; elagolix better than placebo (SMD −1.32, −2.55 to −0.08).
  • Secondary—nonmenstrual pelvic pain: Gestrinone significantly better than placebo and multiple agents; relugolix and leuprolide also superior to placebo; triptorelin and ASP1707 showed benefits versus placebo. Best rank: gestrinone (SUCRA 98.9%).
  • Combinations with add-back/OCP: Relugolix+OCP and elagolix+add-back tended to be less efficacious than monotherapy across several pain domains.

Limitations

  • Many comparisons indirect; several small trials.
  • Blinding/allocation concealment often unclear.
  • Limited and inconsistent safety/adherence data.

Funding

Government

Citation

Kou L, Huang C, Xiao D, Liao S, Li Y, Wang Q. Pharmacologic Interventions for Endometriosis-Related Pain: A Systematic Review and Meta-analysis. Obstet Gynecol. 2025;146:e23–e35. doi:10.1097/AOG.0000000000005923.