Methadone to Treat Painful Chemotherapy Induced Peripheral Neuropathy

NCT05786599 | Recruiting Phase 2

• 1 other identifier: H22-01702
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 4

Brief Summary

Chemotherapy induced peripheral neuropathy (CIPN) or nerve pain, is a painful and debilitating complication which can chronically affect up to 70% of patients who receive chemotherapy. It causes "glove-and-stocking" distribution of nerve-pain, weakness, and other debilitating symptoms. This can affect patient's quality of life, function, ability to tolerate chemotherapy, and return to work. Duloxetine is the only recommended medication to reduce the painful symptoms and consequences of CIPN by national and international groups such as the American Society of Clinical Oncology. However, studies indicate it only has modest effect; for example, the largest study shows it only reduces pain by 0.73/10 points compared to placebo. Another promising medication in theory and practice is methadone. It is a commonly used and well-studied opioid with unique attributes which allows it to treat non-cancer and cancer associated nerve-pain with better efficacy when compared to other opioids. Furthermore, patients appear to develop less tolerance to methadone over time when compared to other opioids; this is helpful as many develop long-term CIPN and may greatly benefit from long-term pain medication. Therefore, if a patient requires chronic opioids to reduce the painful symptoms of CIPN, one that develops less tolerance is invaluable. Despite the promising role for methadone to treat CIPN, it has not been studied to treat this condition. Therefore, methadone may never be considered by prescribers to reduce the painful symptoms of CIPN. This study is a randomized controlled trial to assess the efficacy of methadone compared to duloxetine to treat painful CIPN. Participants will be randomized to receive either methadone or duloxetine regularly for 5 weeks. Methadone and duloxetine will be placed in indistinguishable capsules, so the participant and assessor are not aware of their treatment. They will be followed virtually or in-person weekly for 5 weeks where they will answer brief questionnaires detailing the effect of their treatment on their pain and their dose will increase weekly as tolerated until their pain is controlled or its the end of the study. This study would be critical in assessing the efficacy of a very promising medication to reduce the painful symptoms of CIPN: a debilitating disorder with otherwise few treatment options.

Conditions

Chemotherapy-induced Peripheral Neuropathy

Outcome Measures

Primary Outcomes (1)

• Efficacy of methadone compared to duloxetine to reduce the reported average pain intensity using the Brief Pain Inventory-Short Form questionnaire.

  This is a well validated tool that is independently completed by participants. It measures pain intensity and the functional interference caused by pain via four items assessing average, worse, least, and immediate pain intensity in the last 24 hours. Pain intensity is measured using an 11-point numeric rating scale (0=no pain; 10=worst you can imagine). The participant's "average" pain intensity will be the primary end-point; this will be aligned with other clinical trials on chemotherapy-induced peripheral neuropathy (CIPN) and will facilitate comparison across studies.

  5 weeks

Secondary Outcomes (2)

• Efficacy of methadone compared to duloxetine to improve the functional interference of CIPN using the Brief Pain Inventory-Short Form questionnaire.

  5 weeks

• Efficacy of methadone compared to duloxetine to improve the quality-of-life interference of CIPN using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group - Neurotoxicity 4 Item version.

  5 weeks

Other Outcomes (4)

• Difference between the proportion of participants treated with methadone compared to duloxetine that have a 30% and a 50% reduction in average pain intensity.

  5 weeks

• Efficacy of methadone compared to duloxetine to improve the Patients' Global Impression of Change (PGIC) using the PGIC questionnaire.

  5 weeks

• Incidence of adverse events with methadone compared to duloxetine using the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.

  5 weeks

Study Arms (2)

methadone

EXPERIMENTAL

Methadone is a strong opioid that is μ-opioid receptor agonist like other opioids; however, it is additionally a N-methyl-D- aspartate antagonist with serotonin and norepinephrine reuptake inhibition; these attributes enable its efficacy in neuropathic pain and may prevent opioid tolerance over time. It is commonly used to treat opioid use disorder, as well as to treat severe pain. This medication is taken orally every 8 hours when used to treat pain. It has not been studied to treat chemotherapy-induced peripheral neuropathy.

Drug: methadone

duloxetine

ACTIVE COMPARATOR

Duloxetine is a serotonin and norepinephrine reuptake inhibitor that is commonly used to treat major depressive disorder, generalized anxiety disorder, and neuropathic pain. This medication is taken orally once daily for all of its indications. It is the only well-studied medication that is recommended internationally to treat chemotherapy-induced peripheral neuropathy.

Drug: duloxetine

Interventions

methadone DRUG

The treatment arm will take methadone 2 mg PO q8h and a placebo called "placeboD" PO qdaily. PlaceboD and duloxetine will be placed in capsules to be virtually indistinguishable. Participants will be followed (televisit or in-person) by assessors every week; this will take approximately 15 minutes. This includes review of questionnaire(s), adverse events (and any potential management), and recommendations on dose titration. To maintain blinding and ensure standardization across assessors, titration protocols will be provided. If pain is not controlled, the assessors will instruct the participant to increase their methadone/placeboM drug by 1 capsule PO q8h and their duloxetine/placeboD drug to 2 capsules PO qdaily (the study maximum). If there are poorly tolerated adverse events the dose will be reduced to the previously tolerated dose, and then the following week they may attempt to titrate up again per the above protocol.

Also known as: metadol

methadone

duloxetine DRUG

The control arm will receive duloxetine 30 mg PO qdaily, and a placebo called "placeboM" PO q8h. PlaceboM and methadone will be placed in capsules to be virtually indistinguishable. Participants will be followed (televisit or in-person) by assessors every week; this will take approximately 15 minutes. This includes review of questionnaire(s), adverse events (and any potential management), and recommendations on dose titration. To maintain blinding and ensure standardization across assessors, titration protocols will be provided. If pain is not controlled, the assessors will instruct the participant to increase their methadone/placeboM drug by 1 capsule PO q8h and their duloxetine/placeboD drug to 2 capsules PO qdaily (the study maximum). If there are poorly tolerated adverse events the dose will be reduced to the previously tolerated dose, and then the following week they may attempt to titrate up again per the above protocol.

Also known as: cymbalta

duloxetine

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>18 years old.
• Estimated life expectancy greater than 12 weeks.
• Opioid naïve or oral morphine equivalent use \<60 mg/day.
• Greater than grade 1 CIPN based on CTCAE.
• \>3/10 average CIPN-related neuropathic pain lasting ≥3 months beyond chemotherapy completion.
• A cancer diagnosis.
• Treatment with one of the following neurotoxic chemotherapies: platinums, taxanes, vinca alkaloids, bortezomib, or thalidomide.

You may not qualify if:

• Other causes of peripheral neuropathy.
• The following psychiatric illnesses: severe depression, suicidality, bipolar disease or psychotic disorder, alcohol or substance use disorder, DSM V criteria eating disorder.
• The following medical illnesses: known or suspected mechanical gastrointestinal obstruction or any disease/conditions that affect bowel transit, suspected surgical abdomen, acute or severe asthma, COPD, acute respiratory depression, elevated serum CO2 and cor pulmonale, delirium tremens, convulsive disorders, severe CNS depression such as from cerebrospinal or intracranial pressure and head injury, diarrhea from pseudomembranous colitis, leptomeningeal disease.
• Liver or renal dysfunction within the last 90 days as defined by MELD-Na score ≥17 and GFR ≤30 ml/min respectively.
• QTC \>499ms within last 90 days.
• Current pregnancy or lactation.
• Inability to take oral medications.
• Positive CAGE and/or Opioid Risk Tool - Revised questionnaire
• Known allergy or hypersensitivity to opioids, duloxetine, or any ingredient in their formulation.
• Concomitant use of excluded medications: methadone, other antidepressants (including within 14 days of discontinuing monoamine oxidase inhibitors), thioridazine, potent CYP1A2 inhibitors (such as fluvoxamine and some quinolone antibiotics).
• Uncontrolled narrow-angle glaucoma.
• If women of child-bearing potential (i.e. Menstruation within \<2 years) are unable or unwilling to use Health Canada approved highly effective methods of contraception (hormonal contraceptives, intrauterine device or system, vasectomy, tubal ligation, or double barrier method), or abstinence during the treatment period.
• Note: Any use of prior co-analgesics will be continued (and must have been stable for more than 2 weeks), but the use of new co-analgesics or titration of current co-analgesics will not be permitted during the trial.

Sponsors & Collaborators

• University of British Columbia: lead
• British Columbia Cancer Agency: collaborator

Study Sites (4)

Nanaimo Regional Hospital

Nanaimo, British Columbia, Canada

NOT YET RECRUITING

BC Cancer Surrey

Surrey, British Columbia, Canada

RECRUITING

BC Cancer Vancouver

Vancouver, British Columbia, V5Z 4E6, Canada

NOT YET RECRUITING

BC Cancer Victoria

Victoria, British Columbia, Canada

NOT YET RECRUITING

Related Publications (1)

• Belayneh M, Hejazi S, Gagnon B, Hawley P. Methadone to treat chemotherapy-induced peripheral neuropathy (METACIN): study protocol. Pain Manag. 2025 May;15(5):235-243. doi: 10.1080/17581869.2025.2494495. Epub 2025 Apr 28.

  PMID: 40289780 DERIVED

MeSH Terms

Interventions

Methadone; Duloxetine Hydrochloride

Intervention Hierarchy (Ancestors)

Ketones; Organic Chemicals; Thiophenes; Sulfur Compounds; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Clinician Researcher

Study Record Dates

• First Submitted: March 9, 2023
• First Posted: March 27, 2023
• Study Start: March 21, 2025
• Primary Completion: March 1, 2026
• Study Completion: March 1, 2026
• Last Updated: March 27, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

CA (4)