Methadone to Treat Painful Chemotherapy Induced Peripheral Neuropathy

Chemotherapy-induced Peripheral Neuropathy Clinical Trial

— METACIN  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT05786599
• Other study ID #: H22-01702
• Status: Not yet recruiting
• Phase: Phase 2/Phase 3
• Start date: May 2024
• Est. completion date: February 2026

Study information

• Verified date: February 2024
• Source: University of British Columbia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 50
• Est. completion date: February 2026
• Est. primary completion date: February 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 19 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chemotherapy-induced Peripheral Neuropathy
• Peripheral Nervous System Diseases

Intervention

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.
• 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.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
University of British Columbia	British Columbia Cancer Agency

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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