Methadone to Treat Painful Chemotherapy Induced Peripheral Neuropathy (METACIN)

Methadone to Treat Painful Chemotherapy Induced Peripheral Neuropathy (METACIN): A Randomized Double-blind Controlled Trial

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Chemotherapy-induced Peripheral Neuropathy
• Intervention / Treatment: Drug: methadone; Drug: duloxetine

Detailed Description

Rationale: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating consequence of chemotherapy that causes chronic neuropathic pain in up to 70% of cancer patients. Duloxetine is the only pharmacotherapy recommended by international guidelines, and its effects are modest. Methadone is increasingly used to treat refractory neuropathic pain in cancer patients and has not been studied in CIPN.

Question: Is methadone more effective than duloxetine for the treatment of CIPN? Participants: Adult cancer patients with life expectancy greater than 12 weeks who have greater than grade 1 CIPN based on National Cancer Institute Common Toxicity Criteria for Adverse Events version 5.0 grading scale lasting ≥3 months beyond chemotherapy completion.

Intervention: This trial will follow a double-blind double-dummy randomized controlled trial design where participants will be randomized to either treatment arm (methadone) or control arm (duloxetine). They will be followed weekly over a 5-week period and undergo dose titration.

Outcomes: The primary outcome will be efficacy of methadone compared to duloxetine to reduce the average pain intensity between the baseline and end of study for patients with painful CIPN. Secondary outcomes include i) Determine the effect of methadone compared to duloxetine to improve functional interference using the Brief Pain Inventory-Short Form; ii) Determine the effect 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. Exploratory outcomes include i) Determine the difference between the proportion of participants treated with methadone compared to duloxetine that have a 30% and a 50% reduction in average pain intensity; ii) Assess the efficacy of methadone compared to duloxetine to improve the patients' global impression of change (PGIC) using the PGIC questionnaire; and iii) Assess the incidence of adverse events with methadone compared to duloxetine using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Anticipated Impact: This study will determine if methadone is a viable treatment for CIPN: a very common, distressing, and debilitating condition that otherwise has limited treatment options.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2; Phase 3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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 NCI Common Toxicity Criteria for Adverse Events version 5.0 grading scale
• >3/10 average CIPN-related neuropathic pain lasting ≥3 months beyond chemotherapy completion. Furthermore, participants require
• Any cancer diagnosis
• Treatment with one of the following neurotoxic chemotherapies: platinums, taxanes, vinca alkaloids, bortezomib, or thalidomide.
• Co-analgesics have been stable for >2 weeks.

Exclusion Criteria:

Participants with a documented history:

• Other causes of peripheral neuropathy
• Leptomeningeal disease
• Severe depression
• Suicidality
• Bipolar disease or psychotic disorder
• Alcohol or substance abuse
• Major eating disorder
• Markedly abnormal renal or liver function tests within last 90 days
• Elevated QTC within last 90 days
• Pregnant or lactating patients
• Inability to take oral medications
• Known allergy to or already taking: methadone and/or duloxetine.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: methadone; 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; 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.; Other Names: metadol
Active Comparator: duloxetine; 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; 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.; Other Names: cymbalta

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy of methadone compared to duloxetine to improve the functional interference of CIPN using the Brief Pain Inventory-Short Form questionnaire.	This tool additionally measures seven items assessing the interference of pain on daily activities/function (0=does not interfere; 10=completely interferes), which will be summed to obtain a total interference score out of 70.	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.	This is another well validated tool that evaluates quality of life affected by peripheral neuropathy and was, in part, created for clinical trials specifically including CIPN. It contains 11 questions ultimately assessing joint pain or muscle cramps, discomfort, numbness or tingling in hands or feet, weakness all over, trouble hearing, tinnitus, trouble buttoning buttons, feeling small shapes when placed in the hand. Items are scored from 0-4 (0=not at all; 4=very much) and summed (total score range=0-44).	5 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference between the proportion of participants treated with methadone compared to duloxetine that have a 30% and a 50% reduction in average pain intensity.	This will help differentiate if there are "methadone-responders". This will detect if there is a significant proportion of patients with 30% and 50% pain reduction in the methadone group compared to placebo even if the reduction in average pain intensity is only modest.	5 weeks
Efficacy of methadone compared to duloxetine to improve the Patients' Global Impression of Change (PGIC) using the PGIC questionnaire.	This again is a well validated tool designed specifically to assess patients' perception of changes following treatment. It is a 7-point verbal scale with the options "very much improved," "much improved," "minimally improved," "no change," "minimally worsened," "much worsened," and "very much worsened." The PGIC is commonly used in clinical studies involving pain including peripheral neuropathy.	5 weeks
Incidence of adverse events with methadone compared to duloxetine using the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0.	This ubiquitous system will be used to classify the severity and incidence of adverse events as reported by participants.	5 weeks

Collaborators and Investigators

• Sponsor: University of British Columbia
• Collaborators: British Columbia Cancer Agency

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2024
• Primary Completion (Estimated): February 1, 2026
• Study Completion (Estimated): February 1, 2026

Study Registration Dates

• First Submitted: March 9, 2023
• First Submitted That Met QC Criteria: March 25, 2023
• First Posted (Actual): March 27, 2023

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 11, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neuromuscular Diseases; Peripheral Nervous System Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Opioid; Narcotics; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Serotonin and Noradrenaline Reuptake Inhibitors; Respiratory System Agents; Antitussive Agents; Duloxetine Hydrochloride; Methadone
• Other Study ID Numbers: H22-01702

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No