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. 2025 May;15(5):235-243.
doi: 10.1080/17581869.2025.2494495. Epub 2025 Apr 28.

Methadone to treat chemotherapy-induced peripheral neuropathy (METACIN): study protocol

Mathieos Belayneh  1   2 , Samar Hejazi  3 , Bruno Gagnon  4   5 , Philippa Hawley  1   2
Affiliations

Methadone to treat chemotherapy-induced peripheral neuropathy (METACIN): study protocol

Mathieos Belayneh et al. Pain Manag. 2025 May.

Abstract

Rationale: Chronic chemotherapy-induced peripheral neuropathy (CIPN) affects 70% of cancer patients, causing neuropathic pain. Duloxetine is the most recommended treatment for CIPN per most guidelines. However, Methadone, an alternative and effective treatment for refractory neuropathic cancer pain has been under-recognized and under-studied in patients with CIPN.

Participants: Adult patients with cancer and life expectancy greater than 12 weeks who have >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: A triple-blind, double-dummy randomized controlled trial, participants randomized to either methadone or duloxetine, followed weekly over 5 weeks with dose titration.

Outcomes: Primary outcome is the efficacy of methadone versus duloxetine in reducing average pain intensity from baseline to study end. Secondary outcomes include improvements in functional and quality-of-life interference. Exploratory outcomes include proportion of participants achieving ≥30% or ≥50% pain reduction, patient-reported global impression of change, incidence of adverse events, and methadone dose escalation over a 24-week follow up period.

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.

Clinical trial registration: www.clinicaltrials.gov identifier is NCT05786599.

Keywords: Methadone; NMDA antagonist; SNRI; cancer pain; chemotherapy; duloxetine; neuropathic; peripheral neuropathy.

Plain language summary

Up to 70% of chemotherapy patients develop a painful nerve condition that can dramatically affect their daily lives. This nerve damage typically affects the hands, feet, arms, and legs, causing not just pain, but also weakness, reduced mobility, and lower quality of life.Doctors recommend an antidepressant medication called duloxetine for this condition, but research shows it provides only modest relief. This leaves many patients struggling with inadequate treatment options.Methadone, a well-studied opioid effective for nerve pain might offer new hope. It works particularly well for nerve pain and may be more effective than similar medications. Patients might also be less likely to develop tolerance to methadone over time, making it potentially valuable for long-term use. These qualities make it an appealing option for patients who suffer from long-term nerve pain from chemotherapy. Unfortunately, methadone is understudied for this condition, which means doctors are less likely to prescribe it.Our new study will directly compare these two medications by providing participants with either methadone or duloxetine for five weeks. Researchers will adjust doses weekly based on each person’s response and track results through questionnaires. By the end of the study, we hope to determine whether methadone could provide better relief for this challenging side effect of cancer treatment.This research addresses a critical need for more effective treatments, potentially improving the lives of thousands of cancer survivors dealing with persistent nerve pain from chemotherapy.

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References

    1. Kim PY, Johnson CE.. Chemotherapy-induced peripheral neuropathy: a review of recent findings. Curr Opin Anaesthesiol. 2017. Oct;30(5):570–576. doi: 10.1097/ACO.0000000000000500 - DOI - PubMed
    1. Zhang S. Chemotherapy-induced peripheral neuropathy and rehabilitation: a review. Semin Oncol. 2021. Jun;48(3):193–207. doi: 10.1053/j.seminoncol.2021.09.004 - DOI - PubMed
    1. Loprinzi CL, Lacchetti C, Bleeker J, et al. Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: ASCO guideline update. J Clin Oncol. 2020. Oct 1;38(28):3325–3348. doi: 10.1200/JCO.20.01399 - DOI - PubMed

    2. • This reference represents the American Society of Clinical Oncology (ASCO) guidelines for CIPN management. We note that these guidelines recommend duloxetine as the only evidence-based medication for CIPN. This reference establishes the current treatment landscape and highlights the gap the proposed study aims to fill by potentially offering methadone as another evidence-based option.

    1. Smith EM, Pang H, Cirrione C, et al. Alliance for clinical trials in oncology. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA. 2013. Apr 3;309(13):1359–1367. doi: 10.1001/jama.2013.2813 - DOI - PMC - PubMed

    2. • This describes the key randomized clinical trial of duloxetine for CIPN. We frequently reference this study when discussing the current standard of care and the modest efficacy of duloxetine. It provides the benchmark (pain reduction of 0.73/10 compared to placebo) that the current protocol aims to improve upon with methadone. The study is essential for justifying the need for alternative treatments and providing comparative data.

    1. Zanville NR, Nudelman KN, Smith DJ, et al. Evaluating the impact of chemotherapy-induced peripheral neuropathy symptoms (CIPN-sx) on perceived ability to work in breast cancer survivors during the first year post-treatment. Support Care Cancer. 2016;24(11):4779–4789. doi: 10.1007/s00520-016-3329-5 - DOI - PMC - PubMed

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