The Use of Low Dose Metronidazole to Decrease Postoperative Pain After Endometriosis Surgery

The Use of Low Dose Metronidazole to Decrease Postoperative Pain After Endometriosis Surgery: A Prospective, Randomized, Placebo-Controlled Trial

The purpose of this study is to determine a difference in participant reported pain after endometriosis surgery in participants given oral metronidazole versus placebo.

Study Overview

• Status: Recruiting
• Conditions: Endometriosis; Endometriosis-related Pain
• Intervention / Treatment: Drug: Metronidazole Oral; Drug: Placebo

Detailed Description

The study is a prospective, randomized, placebo-controlled trial. Women scheduled for endometriosis surgery between 18-50 years of age will be invited to participate in the study.

Participants with surgically staged endometriosis will be randomized to the metronidazole plus routine postoperative care arm or the placebo plus routine postoperative care arm. Participants will take study or placebo drug for a total of 14 days.

Participants will complete surveys at baseline and postoperatively at 6 weeks, 6 months, 1 year, 2 years, 3 years, 4 years, and 5 years reporting intensity of endometriosis associated pain on a visual analog scale, pregnancy outcomes, quality of life, and sexual health.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Amira Quevedo, MD; Phone Number: 5025884400; Email: amira.quevedo@uoflhealth.org
• Study Contact Backup: Name: Resad Pasic, MD, PhD; Phone Number: 5025884400; Email: resad.pasic@louisville.edu

Study Locations

• United States
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Recruiting
      • University of Louisville Hospital
      • Contact: AMIRA QUEVEDO, MD; Phone Number: 502-588-4400; Email: amira.quevedo@uoflhealth.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Able to give informed consent
• Women aged 18-50 years old
• Scheduled to undergo excision of endometriosis
• Able to read and write in English and or Spanish
• Pain score > 2 on a 10 point visual analogue scale at baseline
• Negative screening by CAGE questionnaire

Exclusion Criteria:

• Refusal to surgery
• Contraindication to surgery
• Known allergy to metronidazole
• Known allergy to any component in gelatin placebo capsules
• Scheduled hysterectomy
• Endometriosis excision surgery within the last 3 months
• Elevated serum creatinine
• Abnormal liver function test greater than 2 times the normal
• Current pregnancy
• Breastfeeding
• Use of Disulfiram within the last 2 weeks
• History of Cockayne syndrome
• Inability to abstain from alcohol during the use of study drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Metronidazole	Drug: Metronidazole Oral; 250 mg oral three times a day for 14 days
Placebo Comparator: Placebo; Halal and Kosher certified gelatin placebo capsules	Drug: Placebo; Halal and Kosher certified gelatin placebo capsules oral three times a day for 14 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Self-reported pain persistence	The outcome of binary, subject pain persistence, assessed as yes or no, will be compared between groups using the Fisher exact test.	6 weeks postoperatively.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life scores	Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome	1 year postoperatively.
Quality of life scores	Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome	6 months postoperatively.
Quality of life scores	Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome	6 weeks postoperatively.
Quality of life scores	Endometriosis Health Profile-5 on scale of 1-100 with higher scores meaning worse outcome	5 years postoperatively.
Sexual health	Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction	6 weeks postoperatively.
Sexual health	Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction	6 months postoperatively.
Sexual health	Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction	1 year postoperatively.
Sexual health	Female sexual function index on a scale of 0-36 with higher scores meaning higher sexual dysfunction	5 year postoperatively.
Self-reported pain persistence	The outcome of binary, subject pain persistence, assessed as yes or no, will be compared between groups using the Fisher exact test.	1 year postoperatively.
Self-reported pain persistence	The outcome of binary, subject pain persistence, assessed as yes or no, will be compared between groups using the Fisher exact test.	6 months postoperatively.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fertility	Number of pregnancies and miscarriages postoperatively will be compared	6 months postoperatively
Fertility	Number of pregnancies and miscarriages postoperatively will be compared	1 year postoperatively
Fertility	Number of pregnancies and miscarriages postoperatively will be compared	5 years postoperatively

Collaborators and Investigators

• Sponsor: University of Louisville
• Investigators: Principal Investigator: Resad Pasic, MD, PhD, University of Louisville

Publications and helpful links

General Publications

• Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012 Sep;98(3):511-9. doi: 10.1016/j.fertnstert.2012.06.029. Epub 2012 Jul 20.
• Practice bulletin no. 114: management of endometriosis. Obstet Gynecol. 2010 Jul;116(1):223-236. doi: 10.1097/AOG.0b013e3181e8b073. No abstract available.
• Abbott J, Hawe J, Hunter D, Holmes M, Finn P, Garry R. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril. 2004 Oct;82(4):878-84. doi: 10.1016/j.fertnstert.2004.03.046.
• Sutton CJ, Ewen SP, Whitelaw N, Haines P. Prospective, randomized, double-blind, controlled trial of laser laparoscopy in the treatment of pelvic pain associated with minimal, mild, and moderate endometriosis. Fertil Steril. 1994 Oct;62(4):696-700. doi: 10.1016/s0015-0282(16)56990-8.
• Quaranta G, Sanguinetti M, Masucci L. Fecal Microbiota Transplantation: A Potential Tool for Treatment of Human Female Reproductive Tract Diseases. Front Immunol. 2019 Nov 26;10:2653. doi: 10.3389/fimmu.2019.02653. eCollection 2019.
• Leonardi M, Hicks C, El-Assaad F, El-Omar E, Condous G. Endometriosis and the microbiome: a systematic review. BJOG. 2020 Jan;127(2):239-249. doi: 10.1111/1471-0528.15916. Epub 2019 Sep 19.
• Chadchan SB, Cheng M, Parnell LA, Yin Y, Schriefer A, Mysorekar IU, Kommagani R. Antibiotic therapy with metronidazole reduces endometriosis disease progression in mice: a potential role for gut microbiota. Hum Reprod. 2019 Jun 4;34(6):1106-1116. doi: 10.1093/humrep/dez041.
• Simoens S, Hummelshoj L, D'Hooghe T. Endometriosis: cost estimates and methodological perspective. Hum Reprod Update. 2007 Jul-Aug;13(4):395-404. doi: 10.1093/humupd/dmm010.
• Nogueira F, Sharghi S, Kuchler K, Lion T. Pathogenetic Impact of Bacterial-Fungal Interactions. Microorganisms. 2019 Oct 16;7(10):459. doi: 10.3390/microorganisms7100459.
• Mert I, Walther-Antonio M, Mariani A. Case for a role of the microbiome in gynecologic cancers: Clinician's perspective. J Obstet Gynaecol Res. 2018 Sep;44(9):1693-1704. doi: 10.1111/jog.13701. Epub 2018 Aug 2.
• Moloney RD, Johnson AC, O'Mahony SM, Dinan TG, Greenwood-Van Meerveld B, Cryan JF. Stress and the Microbiota-Gut-Brain Axis in Visceral Pain: Relevance to Irritable Bowel Syndrome. CNS Neurosci Ther. 2016 Feb;22(2):102-17. doi: 10.1111/cns.12490. Epub 2015 Dec 10.
• Guo R, Chen LH, Xing C, Liu T. Pain regulation by gut microbiota: molecular mechanisms and therapeutic potential. Br J Anaesth. 2019 Nov;123(5):637-654. doi: 10.1016/j.bja.2019.07.026. Epub 2019 Sep 21.
• Glick LR, Sossenheimer PH, Ollech JE, Cohen RD, Hyman NH, Hurst RD, Rubin DT. Low-Dose Metronidazole is Associated With a Decreased Rate of Endoscopic Recurrence of Crohn's Disease After Ileal Resection: A Retrospective Cohort Study. J Crohns Colitis. 2019 Sep 19;13(9):1158-1162. doi: 10.1093/ecco-jcc/jjz047.
• Working group of ESGE, ESHRE and WES; Saridogan E, Becker CM, Feki A, Grimbizis GF, Hummelshoj L, Keckstein J, Nisolle M, Tanos V, Ulrich UA, Vermeulen N, De Wilde RL. Recommendations for the Surgical Treatment of Endometriosis. Part 1: Ovarian Endometrioma. Hum Reprod Open. 2017 Dec 19;2017(4):hox016. doi: 10.1093/hropen/hox016. eCollection 2017.

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2020
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: September 5, 2020
• First Submitted That Met QC Criteria: September 13, 2020
• First Posted (Actual): September 18, 2020

Study Record Updates

• Last Update Posted (Actual): October 27, 2023
• Last Update Submitted That Met QC Criteria: October 25, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Pain; Neurologic Manifestations; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Pain, Postoperative; Endometriosis; Anti-Infective Agents; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Metronidazole
• Other Study ID Numbers: 200544

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No