Methadone + Duloxetine for Peripheral Neuropathy

(METACIN Trial)

Recruiting at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University of British Columbia

Must not be taking: Methadone, Antidepressants, Thioridazine, CYP1A2 inhibitors

Disqualifiers: Peripheral neuropathy, Psychiatric illnesses, Medical illnesses, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: 5 weeks

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to compare the effectiveness of methadone and duloxetine in treating nerve pain caused by chemotherapy (CIPN). CIPN can make everyday activities difficult due to pain and weakness. The trial seeks participants who have experienced nerve pain for more than three months following chemotherapy and have a cancer diagnosis. Participants will receive either methadone (a pain medication) or duloxetine (an antidepressant that also treats nerve pain) in capsule form and will report their pain levels and any changes weekly for five weeks. The goal is to determine if methadone provides better relief for this painful condition. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop all current medications, but you cannot use methadone, other antidepressants, or certain other medications during the trial. Any pain medications you are already taking must be stable for more than 2 weeks before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that methadone is increasingly used for difficult nerve pain in cancer patients. It is considered safe and usually causes few side effects. While methadone is commonly used for severe pain and opioid addiction, it has not been specifically tested for nerve pain caused by chemotherapy.

Duloxetine, however, is well-known and recommended for this type of nerve pain. It is generally safe, but studies indicate it only slightly reduces pain. Both methadone and duloxetine are taken as pills, but methadone might help prevent tolerance, allowing it to remain effective over time without requiring a higher dose. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about methadone for peripheral neuropathy because it brings a unique approach compared to standard treatments like duloxetine. Unlike most treatments that primarily focus on serotonin and norepinephrine reuptake inhibition, methadone also acts as a μ-opioid receptor agonist and a N-methyl-D-aspartate (NMDA) antagonist. This combined action not only helps in managing neuropathic pain but also potentially prevents the development of opioid tolerance over time. This dual mechanism offers a promising alternative for patients who may not respond well to current options.

What evidence suggests that this trial's treatments could be effective for chemotherapy-induced peripheral neuropathy?

Research has shown that duloxetine, which participants in this trial may receive, is the only medication recommended by major health organizations to reduce pain from chemotherapy-induced peripheral neuropathy (CIPN). However, it only slightly lowers pain, by about 0.73 on a 10-point scale. Methadone, another treatment option in this trial, is a strong painkiller effective for nerve pain because it targets several pain pathways, and people tend to develop less tolerance to it over time. Although methadone has not been specifically studied for CIPN, its effectiveness for other types of nerve pain suggests it could be a useful option for treating CIPN, especially for those needing long-term pain relief. ^{1 2 3 5 6}

Are You a Good Fit for This Trial?

This trial is for adults over 18 with a life expectancy greater than 12 weeks, experiencing moderate to severe nerve pain from chemotherapy (CIPN) lasting more than 3 months after treatment. They must have had cancer treated with specific chemotherapies and be new to opioids or on low doses. Stable use of other pain medications for at least two weeks is required.

Inclusion Criteria

My doctor expects me to live more than 12 weeks.

I am older than 18 years.

I either don't use opioids or take less than 60 mg of morphine a day.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either methadone or duloxetine for 5 weeks, with weekly dose titration and monitoring.

5 weeks

5 visits (virtual or in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of dose tolerance of longer-term methadone use.

24 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Methadone

Trial Overview The study compares methadone and duloxetine's effectiveness in treating CIPN. Participants will randomly receive either drug in identical capsules, unaware of which one they're taking, and report their pain weekly for five weeks while the dose may increase until pain relief or study end.

How Is the Trial Designed?

Group I: methadone Experimental Treatment 1 Intervention

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.

Group II: duloxetine Active Control 1 Intervention

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.

Methadone is already approved in United States, European Union, Canada, Japan, Switzerland for the following indications:

Approved in United States as Dolophine for:

• Pain management
• Opioid use disorder

Approved in European Union as Methadose for:

• Pain management
• Opioid dependence

Approved in Canada as Physeptone for:

• Pain management
• Opioid use disorder

Approved in Japan as Heptadon for:

• Pain management

Approved in Switzerland as Heptanon for:

• Pain management
• Opioid dependence

Who Is Running the Clinical Trial?

University of British Columbia

Lead Sponsor

Trials

1,506

Recruited

2,528,000+

British Columbia Cancer Agency

Collaborator

Trials

181

Recruited

95,900+

Published Research Related to This Trial

A systematic review of seven randomized controlled trials involving 645 patients found that duloxetine was not significantly more effective than placebo for both the treatment and prevention of chemotherapy-induced peripheral neuropathy (CIPN).

The safety profile of duloxetine was also similar to that of placebo, indicating that there is currently limited evidence to support its use in CIPN, highlighting the need for more rigorous studies in this area.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duloxetine for prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN): systematic review and meta-analysis. Chow, R., Novosel, M., So, OW., et al.[2023]

Duloxetine has been shown to be effective in managing painful diabetic neuropathy (PDN), demonstrating significant benefits over placebo and pregabalin based on a systematic review of 23 studies, 8 of which were of high quality.

While duloxetine was effective compared to placebo, its superiority over amitriptyline and pregabalin needs further investigation, as current evidence is limited to only one trial for each comparison.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Duloxetine in Painful Diabetic Neuropathy: A Systematic Review. Hossain, SM., Hussain, SM., Ekram, AR.[2022]

Duloxetine significantly improves pain and quality of life in patients with painful diabetic peripheral neuropathy (PDPN) compared to placebo, based on a systematic review of 7 randomized controlled trials.

The treatment is generally safe, with severe adverse events being rare; however, common side effects like nausea and dizziness led to about 12.6% of patients discontinuing the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of duloxetine in painful diabetic peripheral neuropathy: a systematic review and meta-analysis of randomized controlled trials. Wu, CS., Huang, YJ., Ko, YC., et al.[2023]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40289780/

Methadone to treat chemotherapy-induced peripheral ... Outcomes: Primary outcome is the efficacy of methadone versus duloxetine in reducing average pain intensity from baseline to study end. Secondary outcomes ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05786599?intr=OXYPHENONIUM&aggFilters=studyType:int&viewType=Table&rank=1

Methadone to Treat Painful Chemotherapy Induced ... Outcomes: The primary outcome will be efficacy of methadone compared to duloxetine to reduce the average pain intensity between the baseline and end of ...

3. tandfonline.com tandfonline.com/doi/full/10.1080/17581869.2025.2494495?src=exp-la

Methadone to treat chemotherapy-induced peripheral ... 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 ...

4. trialx.com trialx.com/clinical-trials/listings/307035/methadone-to-treat-painful-chemotherapy-induced-peripheral-neuropathy/

Methadone to Treat Painful Chemotherapy Induced ... Outcomes: The primary outcome will be efficacy of methadone compared to duloxetine to reduce the average pain intensity between the baseline ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11674659/

Methadone in Cancer-Related Neuropathic Pain: A Narrative ... Retrospective cohort study. Methadone reduced pain intensity in 78% of patients; decreased need to address breakthrough pain in65%; and had ...

6. withpower.com withpower.com/trial/phase-2-peripheral-nervous-system-diseases-6-2023-843a9

Methadone + Duloxetine for Peripheral Neuropathy Is the combination of Methadone and Duloxetine safe for treating peripheral neuropathy? There is safety data available for Duloxetine, which has been studied ...