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

Trial Summary

What is the purpose of this trial?

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 associated with a host of adverse effects. People living with chronic pain who were initiated on opioid therapy now find themselves with a major life-changing problem - dependence on opioid medications. Opioid withdrawal symptoms are a key barrier to decreasing or stopping their opioid medication. Currently, there are few medications that ameliorate the symptoms of opioid withdrawal. This problem is a major part of the opioid crisis in Canada, and impacts people across all demographics and socioeconomic status. A misconception is that only individuals with opioid use disorder are susceptible to opioid withdrawal; on the contrary, appropriate use of prescription opioids to manage pain can lead to significant symptoms of opioid withdrawal when it is reduced or stopped. Patients in Alberta who are at risk for opioid withdrawal, either from prescribed use or misuse will be primarily impacted by this trial. The investigators have recently explored the underlying causes of opioid withdrawal and identified an important target in the spinal cord that is responsible for producing withdrawal symptoms in rats and mice. The target, a protein called pannexin-1 (Panx1), is located throughout the body, specifically in the brain and spinal cord. Using sophisticated biochemical, genetic, and pharmacological techniques, the investigators demonstrated how Panx1 on immune cells is implicated in the production of opioid withdrawal symptoms after cessation of fentanyl and morphine in opioid dependent rodents. The investigators then attenuated these symptoms of withdrawal using probenecid, a drug which inherently blocks Panx1 activity. Because probenecid is a safe and clinically available drug, the findings could be immediately translated into clinical therapy to support people who are struggling with the symptoms of opioid withdrawal and provide clinicians with a safe and effective option for caring for this population.

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.

How does the drug Probenecid differ from other treatments for opioid withdrawal?

Probenecid is unique in the context of opioid withdrawal treatment because it is traditionally used to treat gout by increasing uric acid excretion, and its application for opioid withdrawal is novel compared to standard treatments like methadone or buprenorphine, which directly target opioid receptors. ^{1 2 3 4 5}

Research Team

Lori Montgomery, MD

Principal Investigator

University of Calgary

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

New directions in the treatment of opioid withdrawal. [2021]

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

Effects of administration of phentonium bromide on opioid withdrawal syndrome in rats. [2019]

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

Methylnaloxone suppresses the development of withdrawal syndrome in morphine-dependent rats. [2019]

4. England 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. [2023]

5. Netherlands pubmed.ncbi.nlm.nih.gov

Transgene-mediated enkephalin expression attenuates signs of naloxone-precipitated morphine withdrawal in rats with neuropathic pain. [2021]