Methadone for 'Adenocarcinopathic' Pain Treatment (METHADOPT)

December 1, 2022 updated by: Ottawa Hospital Research Institute

Methadone for 'Adenocarcinopathic' Pain Treatment: Methadone vs. Morphine Vanguard RCT

Methadone is an opioid that has been used for over 80 years to treat various types of pain, including cancer pain. Despite its increasing popularity as a co-analgesic and first-line treatment for cancer pain, there remain some outstanding questions regarding its use in treating cancer pain, such as its efficacy compared to other opioids and its appropriateness as a first-line treatment. The investigators will conduct a Vanguard Randomized Clinical Trial (RCT) to estimate the efficacy of methadone compared to morphine for the treatment of a newly defined type of cancer pain, which the investigators have termed 'adenocarcinopathic' pain (ACPP).

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Background:

Methadone is an opioid that has been used for over 80 years to treat various types of pain, including cancer pain. Its use as a co-analgesic and first-line treatment for cancer pain is becoming more widespread. Despite its increasing popularity, there remain some outstanding questions regarding its use in treating cancer pain, such as its efficacy compared to other opioids and its appropriateness as a first-line treatment.

Traditional classifications of cancer related chronic pain is classified as neuropathic and nociceptive (somatic or visceral). This classification is based on clinical descriptors as opposed to pathophysiologic mechanisms. The investigators propose a new mechanism, called 'adenocarcinopathic' pain (ACPP), which can be defined as pain caused by an adenocarcinoma that is in 'proximity' to or invading a nerve or nerve plexus. The suggested mechanism of ACPP is that the tumour excretes excess glutamate, which activates NMDA receptors on nearby sensory nerves, causing the pain sensation. As methadone is an NMDA antagonist (and mu receptor agonist), it becomes an interesting molecule for ACPP in comparison to other opioids (such as morphine) that are unable to suppress NMDA receptors.

Study Hypothesis:

Methadone will demonstrate superior efficacy to morphine for the treatment of ACPP, and physicians will demonstrate satisfactory confidence in its use.

Study Objectives:

  1. Monitor safety and response to treatment
  2. Evaluate the confidence of physicians

Study Design:

Participants will be randomized to receive either methadone or morphine. Patients will be observed for a period of 14 days, plus one physician follow-up after 28 days.

Sample Size & Study Population:

The investigators will aim to enrol n=40 patients total across all sites. Eligible outpatients are those for whom a strong opioid is being initiated or escalated for the treatment of ACPP.

Intervention:

For patients previously taking 0-30mg morphine equivalent daily dose (MEDD), starting dose is 0.5mg Q4H for methadone, 2.5mg for morphine. For those previously taking 31-60 mg MEDD, starting dose is 1.0mg Q4H for methadone, 5.0mg for morphine. Up to 4 breakthrough analgesia doses allowed per day. Dose escalations can be made at each patient encounter according to a standard dosing schedule.

Study Outcome Measures:

Using validated questionnaires, the patient's degree of pain control & relief, degree of satisfaction, global impression of change, and any side effects will be assessed. In addition, physicians will be asked to rate their confidence in treating each patient.

Expected Outcomes:

Positive results should provide justification to prolong the study to complete a phase III trial.

Study Type

Interventional

Phase

  • Phase 3

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years to 73 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Cancer type is adenocarcinoma;
  • In the physician's opinion, mechanism of pain is most likely linked to an adenocarcinoma 'in proximity to' or invading a nerve or nerve plexus (i.e., 'adenocarcinopathic' pain; ACPP);
  • Experiencing poorly controlled pain (defined as pain of 4 or higher on a 10-point visual analogue scale) despite the use of non-opioid analgesics or despite the regular use of up to 60 mg morphine equivalent daily dose (MEDD);
  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 2;
  • Estimated prognosis of at least 3 months;
  • Able to fill out questionnaires and understand procedures in English and/or French;
  • Able to provide first person informed consent;
  • Physician deems it appropriate to start the patient on the opioid.

Exclusion Criteria:

  • Known QTc prolongation (QTc greater than 500ms, QRS less than 120ms) or known congenital QTc prolongation syndrome;
  • Taking at least one medication that increases risk of Torsades de Pointes (TdP): cisapride, disopyramide, dofetilide, flecainide, procainamide, propafenone, quinidine, quinine, sotalol;
  • History of opioid abuse or dependence using Edmonton Pain Classification;
  • Has geographic difficulties with follow-up in person;
  • Has any of the following comorbidities: documented class 3 or 4 New York Heart Association (NYHA) heart failure, myocardial infarction in the last 3 months, unstable angina, pericardial disease, oxygen dependent pulmonary diseases, Parkinson's disease, suspected or diagnosed dementia, bipolar disorder, poorly managed major depression (current or treated) or anxiety disorder;
  • Taking medication known to have clinically significant interactions with the CYP450 enzyme: carbamazepine, efavirenz, phenobarbital, rifampicin, azole antifungals, antiretrovirals, grapefruit juice, clarithromycin, erythromycin;
  • Diagnosed with Child-Pugh class B and/or C cirrhosis;
  • Has hepatic insufficiency, defined as jaundice with irreversible hyperbilirubinemia of at least 34 micromol/L despite biliary tract stents (severity criteria in Child-Pugh-Turcotte score);
  • Received radiation or any nerve block or plexus block on the same side as the pain in the past 14 days or PLANNED within the next 14 days;
  • PLANNED prescription for daily co-analgesia with pregabalin, gabapentin, or dexamethasone during the next 14 days (not including dexamethasone with chemotherapy);
  • Taking medication associated with major risk of serotonin syndrome (monoamine oxidase inhibitors; MAOIs): linezolid, moclobemide, rasagiline, selegiline;
  • Taking medication known to be an opioid agonist, antagonist, or partial agonist: naltrexone, buprenorphine, tapentadol, tramadol;
  • Other negative characteristic as per physician discretion (e.g., reduced renal function).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Methadone

DESCRIPTION:

Blinded methadone 1mg tablets PO

--

DOSAGE:

A) For patients initially taking 0-30 mg MEDD:

Starting dose: 0.5mg Q4H x 4 doses + 1.0mg QHS + 0.5mg Q2H PRN (max 4 doses)

First increase: 1.0 mg Q4H x 4 doses + 2.0mg QHS + 0.5mg Q2H PRN (max 4 doses)

Second increase: 1.5mg Q4H x 4 doses + 3.0mg QHS + 0.5mg Q2H PRN (max 4 doses)

Third increase: 2.0mg Q4H x 4 doses + 4.0mg QHS + 1.0mg Q2H PRN (max 4 doses)

Fourth increase: 2.5mg Q4H x 4 doses + 5.0mg QHS + 1.0mg Q2H PRN (max 4 doses)

B) For patients initially taking 31-60 mg MEDD:

Starting dose: 1.0mg Q4H x 4 doses + 2.0mg QHS + 0.5mg Q2H PRN (max 4 doses)

First increase: 1.5mg Q4H x 4 doses + 3.0mg QHS + 1.0mg Q2H PRN (max 4 doses)

Second increase: 2.0mg Q4H x 4 doses + 4.0mg QHS + 1.0mg Q2H PRN (max 4 doses)

Third increase: 2.5mg Q4H x 4 doses + 5.0mg QHS + 1.5mg Q2H PRN (max 4 doses)

Fourth increase: 3.0mg Q4H x 4 doses + 6.0mg QHS + 1.5mg Q2H PRN (max 4 doses)
Drug: Methadone
Methadone
Other Names:
  • Dolophine
  • Methadose
Active Comparator: Morphine

DESCRIPTION:

Blinded morphine 5mg tablets PO

--

DOSAGE:

A) For patients initially taking 0-30 mg MEDD:

Starting dose: 2.5mg Q4H x 4 doses + 5.0mg QHS + 2.5mg Q2H PRN (max 4 doses)

First increase: 5.0 mg Q4H x 4 doses + 10.0mg QHS + 2.5mg Q2H PRN (max 4 doses)

Second increase: 7.5mg Q4H x 4 doses + 15.0mg QHS + 2.5mg Q2H PRN (max 4 doses)

Third increase: 10.0mg Q4H x 4 doses + 20.0mg QHS + 5.0mg Q2H PRN (max 4 doses)

Fourth increase: 12.5mg Q4H x 4 doses + 25.0mg QHS + 5.0mg Q2H PRN (max 4 doses)

B) For patients initially taking 31-60 mg MEDD:

Starting dose: 5.0mg Q4H x 4 doses + 10.0mg QHS + 2.5mg Q2H PRN (max 4 doses)

First increase: 7.5mg Q4H x 4 doses + 15.0mg QHS + 5.0mg Q2H PRN (max 4 doses)

Second increase: 10.0mg Q4H x 4 doses + 20.0mg QHS + 5.0mg Q2H PRN (max 4 doses)

Third increase: 12.5mg Q4H x 4 doses + 25.0mg QHS + 12.5mg Q2H PRN (max 4 doses)

Fourth increase: 15.0mg Q4H x 4 doses + 30.0mg QHS + 12.5mg Q2H PRN (max 4 doses)
Drug: Morphine
Morphine
Other Names:
  • Kadian
  • MS Contin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pain control
Time Frame: 2 weeks
Proportion of patients reporting pain of 3 or less on a 10-point scale
2 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pain control
Time Frame: 1 week
Proportion of patients reporting pain of 3 or less on a 10-point scale
1 week
Pain relief
Time Frame: 1 week
Proportion of patients reporting at least 50% pain relief since start of treatment
1 week
Pain relief
Time Frame: 2 weeks
Proportion of patients reporting at least 50% pain relief since start of treatment
2 weeks
Patient satisfaction
Time Frame: 1 week
Proportion of patients who are satisfied (yes or no) with their current level of pain control
1 week
Patient satisfaction
Time Frame: 2 weeks
Proportion of patients who are satisfied (yes or no) with their current level of pain control
2 weeks
Physician confidence
Time Frame: 2 weeks
Proportion of patients for whom physicians felt confident in treating with methadone or morphine
2 weeks
Global change
Time Frame: 2 weeks
Patient's global impression of change (PGIC)
2 weeks
Side effects
Time Frame: 2 weeks
Proportion of patients who experienced or had worsening opioid side effects
2 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Ottawa Hospital Research Institute

Collaborators

The Ottawa Hospital
Bruyere Research Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

September 1, 2022

Primary Completion (Anticipated)

August 1, 2023

Study Completion (Anticipated)

September 1, 2023

Study Registration Dates

First Submitted

April 5, 2022

First Submitted That Met QC Criteria

April 5, 2022

First Posted (Actual)

April 13, 2022

Study Record Updates

Last Update Posted (Actual)

December 5, 2022

Last Update Submitted That Met QC Criteria

December 1, 2022

Last Verified

December 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 638423678

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Adenocarcinoma

Clinical Trials on Morphine

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Rwanda

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe