Methadone to Treat Painful Chemotherapy-induced Peripheral Neuropathy

Study Overview
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Brief Summary
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Chemotherapy induced peripheral neuropathy (CIPN) is a painful and disabling nerve pain that can be caused from common types of chemotherapy used to treat cancer. It can affect up to 70% of people who receive chemotherapy for months or even life-long. CIPN causes glove-and-stocking distribution of nerve-pain, weakness, lower quality of life, lower ability to do day to day tasks such as walking and writing, and other symptoms. Duloxetine is the only recommended medication by national and international groups such as the American Society of Oncology to treat painful CIPN. However, studies show it only has small benefit; for example, the largest study showed it only reduces pain by 0.73 out of 10 points compared to placebo. Another promising medication in theory and practice is methadone. It is a very well studied and commonly used pain medication from a class called opioids. However, it does have unique qualities that make it more effective to treat nerve pain when compared to other opioids like morphine and fentanyl. Furthermore, studies show it may develop less tolerance in the body over time when compared to other opioids; this is helpful as many develop lifelong CIPN and therefore may benefit from lifelong pain medication. Methadone has not been studied in CIPN. This study is a pilot clinical trial to assess the ability of methadone to lower the pain caused by CIPN. It will help determine if it is feasible (ie. a good idea) to conduct a much larger study to absolutely determine if methadone is able to treat painful CIPN. In this pilot study, participants will receive methadone three times a day for 5 weeks. They will be followed virtually or in-person weekly for 5 weeks where they will answer brief questionnaires which will help determine the effect of their treatment on their pain and their dose will increase until their pain is hopefully controlled.

Official Title
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Methadone to Treat Painful Chemotherapy-induced Peripheral Neuropathy (METACIN): A Pilot Clinical Trial

Conditions
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Chemotherapy-induced Peripheral Neuropathy

Intervention / Treatment
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* Drug: Methadone


Participation Criteria
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Eligibility Criteria
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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 at least one of the following neurotoxic chemotherapies: oxaliplatin, carboplatin, cisplatin, paclitaxel, docetaxel, or nab-paclitaxel. 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 methadone.

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: methadone<br> | Drug: Methadone<br>* The intervention begins with methadone 2 mg orally q8h; this dose and interval reflect other prospective trials on the efficacy of methadone in neuropathic cancer pain. If there is a history of opioid sensitivity or severe frailty the investigator may choose to start with only 1 mg orally q8h. Participants will receive hydromorphone 1 mg tablets to take orally q2h PRN as well. Participants will be followed by assessors every week. Each week their methadone will be increased by 1 mg orally q8h until pain controlled (e.g., pain intensity <4/10) or until the end of the 5-week study duration. If there are poorly tolerated adverse events the dose will be reduced to the previously tolerated dose, and then the following week will re-attempt to titrate up again per the above protocol.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of methadone 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 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 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 |