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

Trial Summary

What is the purpose of this 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.

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.

What data supports the effectiveness of the drug Methadone + Duloxetine for Peripheral Neuropathy?

Research shows that duloxetine is effective in treating painful diabetic peripheral neuropathy and paclitaxel-induced peripheral neuropathy, suggesting it may help with other types of nerve pain. Methadone has been evaluated for neuropathic pain in HIV-associated polyneuropathies, indicating potential benefits when combined with duloxetine. ^{1 2 3 4 5}

Is the combination of Methadone and Duloxetine safe for treating peripheral neuropathy?

There is safety data available for Duloxetine, which has been studied for peripheral neuropathy in various conditions, showing it is generally safe for use in humans. However, there is no specific safety data available for the combination of Methadone and Duloxetine. ^{2 4 6 7 8}

How is the drug Methadone + Duloxetine unique for treating peripheral neuropathy?

The combination of Methadone and Duloxetine is unique because it combines an opioid (Methadone) with an antidepressant (Duloxetine) to potentially enhance pain relief for peripheral neuropathy, which is not commonly addressed by monotherapy. This dual approach may offer a novel way to manage pain by targeting different pain pathways. ^{1 3 4 8 9}

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Experience and challenges presented by a multicenter crossover study of combination analgesic therapy for the treatment of painful HIV-associated polyneuropathies. [2022]

2. England 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. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy. [2022]

4. China pubmed.ncbi.nlm.nih.gov

Efficacy and safety of duloxetine in Chinese breast cancer patients with paclitaxel-induced peripheral neuropathy. [2022]

5. United States pubmed.ncbi.nlm.nih.gov

Duloxetine in Painful Diabetic Neuropathy: A Systematic Review. [2022]

6. Germany pubmed.ncbi.nlm.nih.gov

Pregabalin for chemotherapy-induced neuropathy: background and rationale for further study. [2023]

7. Japan pubmed.ncbi.nlm.nih.gov

[A case of Paclitaxel-induced peripheral neuropathy successfully treated with duloxetine]. [2015]

8. Switzerland pubmed.ncbi.nlm.nih.gov

Comparative Efficacy of Tapentadol versus Tapentadol Plus Duloxetine in Patients with Chemotherapy-Induced Peripheral Neuropathy (CIPN): A Randomized Non-Inferiority Clinical Trial. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Duloxetine for prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN): systematic review and meta-analysis. [2023]