Novel Use of Probenecid to Alleviate Symptoms of Opioid Withdrawal

NCT04939623 | Recruiting Phase 2 FDA Drug

• 1 other identifier: Probenacid 1.0
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Chronic Pain; Drug Dependence of Morphine Type; Symptom, Withdrawal

Outcome Measures

Primary Outcomes (3)

• To evaluate tolerability of oral probenecid in patients undergoing voluntary opioid tapering

  Tolerability will be assessed through use of the "SAFTEE-SI questionnaire recorded as a percentage for each of the three group assignments and again in two groups titled "probenecid" and "placebo". Statistical comparisons will be made between groups with regard to the percentage of participants experiencing any given adverse event. (example: rash occurred at a rate of 0% with placebo, 2% with probenecid 500 mg, and 4% with probenecid 1000 mg). Comparisons will also be made between the "probenecid group" and "placebo group" (Example: Blurred vision occurred at a rate of 2% with placebo compared to 4% with probenecid)

  12 weeks

• To evaluate acceptability of oral probenecid in patients undergoing voluntary opioid tapering

  Acceptability will be measured by assessing the Percent of patients achieving 80% compliance in each group as measured by returned supply in medication vials.

  12 weeks

• To evaluate safety of oral probenecid in patients undergoing voluntary

  Safety will be assessed by the clinical research team who have diagnosed the adverse events which will be recorded as a percentage for each of the three group assignments and again in two groups titled "probenecid" and "placebo". Statistical comparisons will be made between groups with regard to the percentage of participants experiencing any given adverse event. (example: rash occurred at a rate of 0% with placebo, 2% with probenecid 500 mg, and 4% with probenecid 1000 mg). Comparisons will also be made between the "probenecid group" and "placebo group" (Example: Blurred vision occurred at a rate of 2% with placebo compared to 4% with probenecid)

  12 weeks

Secondary Outcomes (2)

• To evaluate the feasibility of treatment with probenecid in a patient-directed opioid tapering protocol, in the setting of an interdisciplinary pain clinic

  3 years

• To evaluate whether Panx1 gene variants correlate with opioid withdrawal severity and response to probenecid by collecting salivary samples and performing DNA extraction in a small cohort.

  3 years

Study Arms (3)

Probenecid 500 mg PO BID

ACTIVE COMPARATOR

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

Drug: Probenecid

Probenecid 1000 mg PO BID

ACTIVE COMPARATOR

Probenecid 500mg X 2 PO BID

Drug: Probenecid

Placebo PO BID

PLACEBO COMPARATOR

Placebo X 2 PO BID

Drug: Probenecid

Interventions

Probenecid DRUG

The Investigators aim to recruit 40 participants who will be followed for 12 weeks in duration. Participants will be randomized in a 2:2:1 ratio to one of probenecid 500 mg, 1000 mg, or placebo PO BID for 12 weeks. Justification for use of a non-active placebo comparator includes the fact that this trial is meant to identify tolerability and safety of probenecid in a population of patients living with chronic pain, this will be best measured by comparing to a non-active placebo.

Also known as: 4-(Dipropylsulfamoyl)benzoic acid, Benemid, Probalan

Placebo PO BID; Probenecid 1000 mg PO BID; Probenecid 500 mg PO BID

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults with chronic pain. Age greater than or equal to 18 years on the day of enrolment.
• Subjects are currently taking a daily opioid pain medication and planning to taper the dose.
• Participants complete at least one voluntary opioid dose reduction in the twelve-week study period.
• Glomerular filtration rate (GFR) \> 50 mL/min
• Capable of providing informed consent

You may not qualify if:

• Allergy to probenecid or related drugs
• History of uric acid renal calculi, if known to be urate calculi. If unknown type, then any history of renal calculi.
• Known G6PD deficiency
• Active gout in any joint
• Current use of drugs whose exposure may be prolonged, or risk of toxicity increased when used in combination with probenecid:
• Penicillins, specifically ampicillin, penicillin G sodium, and piperacillin
• Carbapenems, specifically doripenem and meropenem
• Lorazepam, midazolam, nitrazepam
• Ketorolac
• Oseltamivir
• Methotrexate
• Mycophenolate
• Current use of drugs which may mask symptoms of withdrawal:
• a. Clonidine, lofexidine, tizanidine
• Current use of drugs which may diminish the effect of probenecid:

Sponsors & Collaborators

• University of Calgary: lead

Study Sites (1)

Richmond Road Diagnostic and Treatment Centre

Calgary, Alberta, T2T 5C7, Canada

RECRUITING

Related Publications (4)

• 1 Beyer, R. H., Wiebelhaus, V. D., Russe, H. F., Peck, H. M., & McKinney, S. E. (1950). Benemid: An anticatabolite; its phar- macological properties. Federation Proceedings, 9, 258.

  BACKGROUND

• Probenecid CPhA Monograph. RxTx. Date of Revision: November 2017. Accessed online at https://www.e-therapeutics.ca on February 21, 2018.

  BACKGROUND

• Robbins N, Koch SE, Tranter M, Rubinstein J. The history and future of probenecid. Cardiovasc Toxicol. 2012 Mar;12(1):1-9. doi: 10.1007/s12012-011-9145-8.

  PMID: 21938493 BACKGROUND

• Benuryl Tablets, Probenecid Tablets. Prescribing Information. Montreal, Quebec. Valeant Canada LP. Date of Revision: September 1, 2004.

  BACKGROUND

Related Links

• Probenecid CPhA Monograph. RxTx. Date of Revision: February 2014. Accessed online at https://www.e-therapeutics.ca on May 22, 2015.

MeSH Terms

Conditions

Chronic Pain; Substance Withdrawal Syndrome

Interventions

Probenecid

Condition Hierarchy (Ancestors)

Pain; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds

Study Officials

• Lori Montgomery, MD

  University of Calgary

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Tammy Eberle

CONTACT

403-943-9900; tammy.eberle@albertahealthservices.ca

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: Participants will be sequentially randomized. Allocation will be concealed through use of a computer-generated algorithm employing simple randomization without stratification. Participants and the research team will be blinded to group assignment. Randomization will utilize a 2:2:1 ratio (500 mg Probenecid:1000mg Probenecid: placebo).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 40 participants will be randomized in a 2:2:1 ratio to one of: 1. Probenecid 500 mg PO BID (16 participants) 2. Probenecid 1000 mg PO BID (16 participants) 3. Placebo PO BID (8 participants)

Study Record Dates

• First Submitted: September 11, 2020
• First Posted: June 25, 2021
• Study Start: October 31, 2023
• Primary Completion: December 31, 2025
• Study Completion: December 31, 2025
• Last Updated: March 30, 2025

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)