Probenecid for Opioid Withdrawal

Overseen By Tammy Eberle

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Calgary

Must be taking: Opioids

Must not be taking: Penicillins, Carbapenems, Benzodiazepines, others

Disqualifiers: G6PD deficiency, Active gout, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

40 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to help people with chronic pain reduce their use of opioid medications. It will test probenecid, a drug that may ease withdrawal symptoms by targeting a specific protein. Participants will receive either probenecid or a placebo to assess probenecid's effectiveness. Ideal candidates are those currently using opioids for chronic pain relief and planning to reduce their dosage. As a Phase 2 trial, this research measures probenecid's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial requires you to stop taking certain medications that could interact with probenecid or affect withdrawal symptoms. These include specific antibiotics, sedatives, pain relievers, and other drugs like clonidine and high-dose aspirin. If you're on any of these, you'll need to discuss alternatives with your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that probenecid, a drug already used for other health issues, might alleviate symptoms of opioid withdrawal. In animal studies, probenecid reduced withdrawal symptoms by blocking a protein called pannexin-1 (Panx1), which contributes to these symptoms. Probenecid is considered safe for humans, as it is already approved for other uses.

In its approved use, probenecid is generally well-tolerated, with common side effects being mild, such as nausea and a mild skin rash. Given its established use and safety record, probenecid is a promising option for treating opioid withdrawal symptoms. The ongoing trial aims to confirm its safety specifically for this new purpose. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for opioid withdrawal?

Researchers are excited about Probenecid for opioid withdrawal because it offers a new approach to managing symptoms. Unlike the standard treatments, which often involve opioid agonists like methadone or buprenorphine, Probenecid works as a uricosuric agent traditionally used for gout. This unique mechanism may help reduce withdrawal symptoms without the risk of addiction associated with opioid-based therapies. Additionally, Probenecid's oral administration could provide an easier and more accessible option for patients compared to current treatments that require strict medical supervision.

What evidence suggests that probenecid might be an effective treatment for opioid withdrawal?

Research suggests that probenecid might help ease opioid withdrawal symptoms. Animal studies have shown that probenecid blocks a protein called pannexin-1, which is linked to these symptoms. Specifically, probenecid reduced withdrawal symptoms in rats and mice dependent on opioids like fentanyl and morphine. In this trial, participants will receive either probenecid at different dosages or a placebo to evaluate its effectiveness in humans. Although probenecid has not been tested for opioid withdrawal in humans yet, it is already known as a safe and well-tolerated drug. This makes it a promising option for helping people dealing with opioid withdrawal symptoms. ^{1 3 4 6 7}

Who Is on the Research Team?

Lori Montgomery, MD

Principal Investigator

University of Calgary

Are You a Good Fit for This Trial?

Adults over 18 with chronic pain, currently on daily opioid medication and planning to reduce their dose. They must have a kidney function test (GFR) above 50 mL/min and be able to give informed consent. The trial is not suitable for those who cannot voluntarily decrease their opioid use or have other health issues that the study doesn't list.

Inclusion Criteria

I am an adult experiencing chronic pain.

I have voluntarily reduced my opioid dose at least once in the last 12 weeks.

I am currently on daily opioid pain medication and plan to reduce the dose.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive probenecid or placebo for opioid withdrawal management during a 12-week tapering protocol

12 weeks

Regular visits for monitoring and medication compliance

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Long-term follow-up

Evaluation of feasibility and genetic correlation over a 3-year period

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Probenecid

Trial Overview The trial tests Probenecid's effectiveness in easing symptoms of opioid withdrawal in patients dependent on opioids due to chronic pain management. It explores whether this already approved drug can block certain proteins involved in withdrawal symptoms.

How Is the Trial Designed?

Group I: Probenecid 500 mg PO BID Active Control 1 Intervention

Probenecid 500 mg X 1 PO BID and Placebo X 1 PO BID

Group II: Probenecid 1000 mg PO BID Active Control 1 Intervention

Probenecid 500mg X 2 PO BID

Group III: Placebo PO BID Placebo Group 1 Intervention

Placebo X 2 PO BID

Probenecid is already approved in United States, Canada, European Union for the following indications:

Approved in United States as Benemid for:

• Gout
• Hyperuricemia

Approved in Canada as Probecid for:

• Gout
• Hyperuricemia

Approved in European Union as Probenecid for:

• Gout
• Hyperuricemia

Who Is Running the Clinical Trial?

University of Calgary

Lead Sponsor

Trials

827

Recruited

902,000+

Published Research Related to This Trial

In a study of 225 participants with opioid dependence, sublingual dexmedetomidine (BXCL501) showed preliminary efficacy in reducing withdrawal symptoms, particularly at higher doses (120, 180, and 240 μg), as indicated by significant reductions in Clinical Opiate Withdrawal Scale (COWS) and Subjective Opiate Withdrawal Scale (SOWS) scores.

While higher doses of BXCL501 were associated with mild to moderate adverse effects like hypotension and somnolence, the overall safety profile was acceptable, supporting further development of BXCL501 for opioid withdrawal management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sublingual dexmedetomidine (BXCL501) reduces opioid withdrawal symptoms: findings from a multi-site, phase 1b/2, randomized, double-blind, placebo-controlled trial. Jones, JD., Rajachandran, L., Yocca, F., et al.[2023]

In a study with morphine-dependent rats, the peripheral opioid receptor antagonist methylnaloxone significantly reduced the severity of withdrawal symptoms when administered at a dose of 2 mg/kg for 3 days after morphine withdrawal.

The treatment notably decreased symptoms such as wet dog shakes and limb and head shakes, suggesting that targeting peripheral opioid receptors can help alleviate some aspects of opioid withdrawal, although it did not affect diarrhea or writhing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Methylnaloxone suppresses the development of withdrawal syndrome in morphine-dependent rats. Sudakov, SK., Rusakova, IV., Trigub, MM., et al.[2019]

Current treatment standards for opioid withdrawal include μ-opioid receptor agonists like methadone and partial agonists like buprenorphine, which are effective in managing withdrawal symptoms in patients with opioid use disorder.

Future research is needed to explore strategies for stabilizing patients on extended-release naltrexone and transitioning between different medications, which could improve treatment outcomes for those with opioid use disorder.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New directions in the treatment of opioid withdrawal. Srivastava, AB., Mariani, JJ., Levin, FR.[2021]

Phentonium bromide, an anti-muscarinic agent, was effective in reducing withdrawal symptoms in rats that were undergoing opioid withdrawal after chronic morphine treatment, indicating its potential efficacy in managing withdrawal signs.

The drug's effects may be due to its ability to interfere with the mechanisms regulating withdrawal symptoms, suggesting it could be a useful treatment option for controlling acute opioid withdrawal in humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of administration of phentonium bromide on opioid withdrawal syndrome in rats. Pinelli, A., Trivulzio, S., Tomasoni, L.[2019]

Chronic morphine exposure leads to physical dependence and withdrawal symptoms, but increasing levels of proenkephalin in the spinal cord can significantly reduce these withdrawal symptoms in rats.

In a study involving rats with neuropathic pain, overexpressing proenkephalin through a viral vector reduced withdrawal symptoms like jumps and diarrhea after naloxone administration, suggesting that spinal opioid peptides play a crucial role in managing morphine withdrawal responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transgene-mediated enkephalin expression attenuates signs of naloxone-precipitated morphine withdrawal in rats with neuropathic pain. Hao, S., Hu, J., Fink, DJ.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04939623

Novel Use of Probenecid to Alleviate Symptoms of Opioid ... The study is a single centre, randomized, double blind, placebo-controlled, 12-week clinical trial meant to study probenecid use among adult participants living ...

2. news-medical.net news-medical.net/news/20240829/Probenecid-shows-promise-for-easing-opioid-withdrawal-symptoms-in-new-study-A-Deep.aspx

Probenecid shows promise for easing opioid withdrawal ... "Probenecid has not been tested for opioid withdrawal before, but we know it is a safe and well tolerated drug. Headache and nausea are the ...

3. ctv.veeva.com ctv.veeva.com/study/novel-use-of-probenecid-to-alleviate-symptoms-of-opioid-withdrawal

Novel Use of Probenecid to Alleviate Symptoms of Opioid ... The proposed clinical trial will address the problem of opioid withdrawal. Opioids are essential for pain-relief in the short term, but their continued use is ...

4. ucalgary.ca ucalgary.ca/news/new-insights-brain-spinal-communication-opioid-withdrawal-lead-clinical-trial

New insights on brain-spinal communication in opioid ... “Probenecid has not been tested for opioid withdrawal before, but we know it is a safe and well tolerated drug. Headache and nausea are the most ...

5. withpower.com withpower.com/trial/phase-2-and-3-chronic-pain-8-2021-e751b

Probenecid for Opioid Withdrawal Phentonium bromide, an anti-muscarinic agent, was effective in reducing withdrawal symptoms in rats that were undergoing opioid withdrawal after chronic ...

6. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04939623/novel-use-of-probenecid-to-alleviate-symptoms-of-opioid-withdrawal

Novel Use of Probenecid to Alleviate Symptoms of Opioid ... The proposed clinical trial will address the problem of opioid withdrawal. Opioids are essential for pain-relief in the short term, ...

7. nature.com nature.com/articles/s41467-024-50657-7

Pannexin-1 channel inhibition alleviates opioid withdrawal ... We show here that pannexin-1 (Panx1) channels expressed on microglia critically modulate LC activity during opioid withdrawal.