Metronidazole for Postoperative Pain in Endometriosis

Overseen By Resad Pasic, MD, PhD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 4

Sponsor: University of Louisville

Must not be taking: Disulfiram

Disqualifiers: Pregnancy, Breastfeeding, Elevated creatinine, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 6

Duration: 2 weeks

90 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing if taking the antibiotic metronidazole can reduce pain after endometriosis surgery in women aged 18-50. The antibiotic works by killing bacteria to prevent infections, which might help with pain relief.

Do I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot use Disulfiram within the last 2 weeks before the trial.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications, but you cannot use Disulfiram within the last 2 weeks or consume alcohol during the study.

What data supports the idea that Metronidazole for Postoperative Pain in Endometriosis is an effective drug?

The available research shows that Metronidazole is effective in reducing postoperative pain, but the studies focus on its use after haemorrhoidectomy, not specifically for endometriosis. In these studies, Metronidazole was shown to reduce pain when compared to a placebo. However, there is no direct evidence from the provided information that supports its effectiveness for postoperative pain in endometriosis. ^{1 2 3 4 5}

Is the drug metronidazole effective for reducing postoperative pain?

Research shows that metronidazole can help reduce pain after surgery, such as haemorrhoidectomy, which suggests it might also be helpful for postoperative pain in endometriosis. ^{1 2 3 4 5}

What safety data exists for metronidazole?

Metronidazole is generally considered safe for short-term use, particularly for treating protozoal and anaerobic infections. It is well tolerated with common side effects including gastrointestinal symptoms like nausea and a metallic taste. Serious side effects such as peripheral neuropathy and encephalopathy are rare and usually associated with high doses or prolonged use. Metronidazole should be used cautiously in long-term treatments and in obstetric and pediatric patients due to unresolved toxicological concerns. It is contraindicated with alcohol due to a disulfiram-like reaction. While mutagenicity and carcinogenicity have been observed in some animal studies, these risks are considered low in humans. ^{4 6 7 8 9}

Is metronidazole generally safe for human use?

Metronidazole is generally considered safe for short-term use in treating infections, but it can cause side effects like nausea, headache, and a metallic taste. Long-term use should be approached with caution due to potential risks like nerve damage and rare cases of cancer in animals, although these risks are considered low in humans. ^{4 6 7 8 9}

Is the drug Metronidazole Oral a promising treatment for reducing pain after surgery in endometriosis?

Metronidazole has shown promise in reducing pain after surgeries like hemorrhoidectomy, which suggests it might help with postoperative pain in endometriosis too. It has been effective in reducing pain and preventing infections in other surgical contexts. ^{1 10 11 12 13}

How does the drug Metronidazole differ from other treatments for postoperative pain in endometriosis?

Metronidazole is unique because it is an antibiotic that can reduce postoperative pain, as seen in hemorrhoidectomy cases, and it may help prevent infections after surgery. This dual action of pain relief and infection prevention could make it a novel option for managing postoperative pain in endometriosis. ^{1 10 11 12 13}

Research Team

Resad Pasic, MD, PhD

Principal Investigator

University of Louisville

Eligibility Criteria

This trial is for women aged 18-50 who can consent, read and write in English or Spanish, have a pain score over 2 due to endometriosis, and are scheduled for excision surgery. It's not for those pregnant, breastfeeding, allergic to metronidazole, with recent endometriosis surgery or certain health issues like abnormal liver tests.

Inclusion Criteria

I am scheduled for surgery to remove endometriosis.

Able to give informed consent

I am a woman aged between 18 and 50.

Exclusion Criteria

You have high levels of creatinine in your blood.

I had surgery for endometriosis in the last 3 months.

Known allergy to any component in gelatin placebo capsules

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either metronidazole or placebo for 14 days as part of routine postoperative care

2 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, with surveys at multiple time points

5 years

Surveys at baseline, 6 weeks, 6 months, 1 year, 2 years, 3 years, 4 years, and 5 years

Treatment Details

Interventions

• Metronidazole Oral
• Placebo

Trial Overview The study aims to see if low dose oral Metronidazole reduces postoperative pain after endometriosis surgery compared to a placebo. Participants will report their pain levels after receiving either the medication or a placebo.

Participant Groups

Group I: Metronidazole Experimental Treatment 1 Intervention

Metronidazole

Group II: Placebo Placebo Group 1 Intervention

Halal and Kosher certified gelatin placebo capsules

Metronidazole Oral is already approved in United States, European Union, India, Canada for the following indications:

Approved in United States as Flagyl for:

• Pelvic inflammatory disease
• Endocarditis
• Bacterial vaginosis
• Dracunculiasis
• Giardiasis
• Trichomoniasis
• Amebiasis
• Clostridioides difficile colitis

Approved in European Union as Flagyl for:

• Pelvic inflammatory disease
• Endocarditis
• Bacterial vaginosis
• Dracunculiasis
• Giardiasis
• Trichomoniasis
• Amebiasis
• Clostridioides difficile colitis

Approved in India as Metrogyl for:

• Pelvic inflammatory disease
• Endocarditis
• Bacterial vaginosis
• Dracunculiasis
• Giardiasis
• Trichomoniasis
• Amebiasis
• Clostridioides difficile colitis

Approved in Canada as Flagyl for:

• Pelvic inflammatory disease
• Endocarditis
• Bacterial vaginosis
• Dracunculiasis
• Giardiasis
• Trichomoniasis
• Amebiasis
• Clostridioides difficile colitis

Who Is Running the Clinical Trial?

University of Louisville

Lead Sponsor

Trials

353

Recruited

76,400+

Findings from Research

A systematic review of nine randomized controlled trials involving 523 patients found that both oral and topical metronidazole significantly reduced post-operative pain after excisional haemorrhoidectomy, as measured by visual analogue scores (VAS).

Patients receiving metronidazole also experienced no increase in complications and returned to normal activities approximately 4.5 days earlier compared to those not receiving the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metronidazole following excisional haemorrhoidectomy: a systematic review and meta-analysis. Xia, W., Manning, JPR., Barazanchi, AWH., et al.[2019]

In a double-blind, randomized controlled trial involving 40 patients, oral metronidazole did not significantly reduce posthaemorrhoidectomy pain compared to placebo, indicating it may not be effective as an adjunct treatment.

Although there was a trend suggesting less pain in the metronidazole group on certain days, these differences were not statistically significant after applying correction methods, leading to the conclusion that metronidazole should not be routinely used for pain management after hemorrhoid surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of postoperative oral metronidazole for haemorrhoidectomy pain: a randomized double-blind, placebo-controlled trial. Wilkie, BD., Chandra, R., Chua, J., et al.[2021]

Inclusion of metronidazole in the treatment plan for acute appendicitis with local or diffuse peritonitis significantly reduced the occurrence of pus-related complications after surgery.

Patients receiving metronidazole experienced a shorter hospital stay, indicating improved recovery times associated with its use in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment of complicated appendicitis]. Tarshis, VE., Bronskaia, LK., Bogomolova, NS., et al.[2006]

Metronidazole is a preferred treatment for various infections, but certain conditions or medications can limit its use, leading to the need for alternative treatments.

For infections like trichomoniasis, bacterial vaginosis, giardiasis, and Clostridium difficile, there are effective alternatives available, such as clindamycin, paromomycin, and oral vancomycin, for patients who cannot take nitroimidazole antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What would we do without metronidazole? Stover, KR., Riche, DM., Gandy, CL., et al.[2020]

A meta-analysis of 8 randomized controlled trials involving 437 patients found that metronidazole significantly reduces postoperative pain after conventional haemorrhoidectomy, with notable pain reduction on days 1, 2, and 7 post-surgery.

Metronidazole is highlighted as a safe and cost-effective option for pain management following haemorrhoidectomy, making it a valuable addition to postoperative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic review and meta-analysis of the role of metronidazole in post-haemorrhoidectomy pain relief. Lyons, NJR., Cornille, JB., Pathak, S., et al.[2018]

Metronidazole and other nitroimidazoles are effective and cost-efficient treatments for protozoal infections and anaerobic infections, with oral and rectal administration preferred for safety and efficacy.

While these drugs are generally safe for short-term use, caution is advised for long-term use and in special populations like pregnant women and children until more is known about potential toxic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current clinical applications and dose regimens of metronidazole and related nitroimidazoles. McLean, AJ., Ioannides-Demos, LL., Spicer, WJ.[2013]

Metronidazole is an effective treatment for various infections, including Trichomonas, amebiasis, and anaerobic infections, and is well tolerated with minimal impact on colonic flora.

While there are some concerns about potential mutagenicity and carcinogenicity in animals, the overall risk is considered low, and no increased cancer incidence has been observed in treated patients, highlighting the importance of weighing benefits against risks in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metronidazole. Finegold, SM.[2019]

Nitroimidazoles, including metronidazole, tinidazole, and ornidazole, are well-absorbed from the gastrointestinal tract and can reach effective concentrations in various body fluids and tissues, including the central nervous system and female genital tract, with varying elimination half-lives (7-8 hours for metronidazole, 12 hours for tinidazole, and 14-15 hours for ornidazole).

Common side effects include gastrointestinal symptoms like nausea and vomiting, as well as neurological issues such as dizziness and headache; serious adverse reactions can occur with high doses, including encephalopathy and peripheral neuropathy, and a disulfiram-like reaction can happen if taken with alcohol.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of nitroimidazoles. Spectrum of adverse reactions. Andersson, KE.[2004]

Metamizole is effective for both short- and long-term pain relief and has a better safety profile compared to traditional NSAIDs, making it a useful option for pain management.

Despite its favorable safety profile, metamizole carries a risk of agranulocytosis, a potentially fatal side effect, with an estimated occurrence of less than one in a million prescriptions, as illustrated by a case of leukopenia in a 68-year-old patient.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chronic use of metamizole: not so safe after all? Vuik, FE., Koehestanie, P., Herbers, AH., et al.[2017]

In a study of 47 patients undergoing hemorrhoidectomy, topical metronidazole (10 percent) significantly reduced postoperative pain compared to a placebo, with effects lasting up to 14 days post-surgery.

Patients using metronidazole experienced less pain after defecation on day 2 and required fewer additional analgesics on days 2 and 7, indicating its efficacy in managing discomfort after the procedure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Topical metronidazole can reduce pain after surgery and pain on defecation in postoperative hemorrhoidectomy. Ala, S., Saeedi, M., Eshghi, F., et al.[2022]

In a study of 100 healthy women undergoing cesarean sections, intravenous metronidazole significantly reduced the incidence of endometritis (14% vs. 30%) and wound infections (2% vs. 8%) compared to a placebo, indicating its efficacy in preventing post-surgical infections.

Metronidazole was well tolerated by the mothers, and its administration did not expose the fetus to the drug, making it a safe option for reducing postcesarean section infectious complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prevention of postcesarean infectious morbidity with a single dose of intravenous metronidazole. Ruiz-Moreno, JA., Garcia-Rojas, JM., Lozada-Leon, JD.[2019]

In a systematic review of 14 randomized controlled trials involving 336 subjects, metronidazole significantly reduced postoperative pain scores after open haemorrhoidectomy, particularly on day 5 post-surgery.

Despite the pain reduction, there was no significant difference in postoperative complications between the metronidazole group and the control group, indicating that while metronidazole may help with pain management, its overall safety profile remains consistent with standard care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metronidazole in the Management of Post-Open Haemorrhoidectomy Pain: Systematic Review. Re, AD., Toh, JWT., Iredell, J., et al.[2020]

Oral metronidazole significantly reduced postoperative pain on the first and fourth days after hemorrhoidectomy, suggesting it may help improve early pain management for patients.

However, the overall benefits were inconsistent, and the positive effects diminished when accounting for potential biases in the studies, indicating that further well-designed trials are needed before making routine recommendations for its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Metronidazole May Not Reduce Posthemorrhoidectomy Pain: A Meta-Analysis of Randomized Controlled Trials. Wanis, KN., Emmerton-Coughlin, HM., Coughlin, S., et al.[2022]

References

1. Australia pubmed.ncbi.nlm.nih.gov

Metronidazole following excisional haemorrhoidectomy: a systematic review and meta-analysis. [2019]

2. England pubmed.ncbi.nlm.nih.gov

Efficacy of postoperative oral metronidazole for haemorrhoidectomy pain: a randomized double-blind, placebo-controlled trial. [2021]

3. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Treatment of complicated appendicitis]. [2006]

4. United States pubmed.ncbi.nlm.nih.gov

What would we do without metronidazole? [2020]

5. England pubmed.ncbi.nlm.nih.gov

Systematic review and meta-analysis of the role of metronidazole in post-haemorrhoidectomy pain relief. [2018]

6. Australia pubmed.ncbi.nlm.nih.gov

Current clinical applications and dose regimens of metronidazole and related nitroimidazoles. [2013]

7. United States pubmed.ncbi.nlm.nih.gov

Metronidazole. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of nitroimidazoles. Spectrum of adverse reactions. [2004]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Chronic use of metamizole: not so safe after all? [2017]

10. United States pubmed.ncbi.nlm.nih.gov

Topical metronidazole can reduce pain after surgery and pain on defecation in postoperative hemorrhoidectomy. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Prevention of postcesarean infectious morbidity with a single dose of intravenous metronidazole. [2019]

12. Korea (South) pubmed.ncbi.nlm.nih.gov

Metronidazole in the Management of Post-Open Haemorrhoidectomy Pain: Systematic Review. [2020]

13. United States pubmed.ncbi.nlm.nih.gov

Systemic Metronidazole May Not Reduce Posthemorrhoidectomy Pain: A Meta-Analysis of Randomized Controlled Trials. [2022]