Methadone for 'Adenocarcinopathic' Pain Treatment

Adenocarcinoma Clinical Trial

— METHADOPT  

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT05325164
• Other study ID #: 638423678
• Status: Withdrawn
• Phase: Phase 3
• Start date: September 2022
• Est. completion date: September 2023

Study information

• Verified date: December 2022
• Source: Ottawa Hospital Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: September 2023
• Est. primary completion date: August 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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).

Related Conditions & MeSH terms

• Adenocarcinoma
• Cancer Pain

Intervention

Drug:
• Methadone
Methadone
• Morphine
Morphine

Locations

Country	Name	City	State
n/a

Sponsors (3)

Lead Sponsor	Collaborator
Ottawa Hospital Research Institute	Bruyere Research Institute, The Ottawa Hospital

References & Publications (6)

Bruera E, Palmer JL, Bosnjak S, Rico MA, Moyano J, Sweeney C, Strasser F, Willey J, Bertolino M, Mathias C, Spruyt O, Fisch MJ. Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study. J Clin Oncol. 2004 Jan 1;22(1):185-92. doi: 10.1200/JCO.2004.03.172. — View Citation

Gagnon B, Almahrezi A, Schreier G. Methadone in the treatment of neuropathic pain. Pain Res Manag. 2003 Fall;8(3):149-54. doi: 10.1155/2003/236718. — View Citation

Haumann J, Geurts JW, van Kuijk SM, Kremer B, Joosten EA, van den Beuken-van Everdingen MH. Methadone is superior to fentanyl in treating neuropathic pain in patients with head-and-neck cancer. Eur J Cancer. 2016 Sep;65:121-9. doi: 10.1016/j.ejca.2016.06.025. Epub 2016 Aug 3. — View Citation

Leppert W, Zajaczkowska R, Wordliczek J, Dobrogowski J, Woron J, Krzakowski M. Pathophysiology and clinical characteristics of pain in most common locations in cancer patients. J Physiol Pharmacol. 2016 Dec;67(6):787-799. — View Citation

Mercadante S, Bruera E. Methadone as a First-Line Opioid in Cancer Pain Management: A Systematic Review. J Pain Symptom Manage. 2018 Mar;55(3):998-1003. doi: 10.1016/j.jpainsymman.2017.10.017. Epub 2017 Nov 1. — View Citation

Slosky LM, BassiriRad NM, Symons AM, Thompson M, Doyle T, Forte BL, Staatz WD, Bui L, Neumann WL, Mantyh PW, Salvemini D, Largent-Milnes TM, Vanderah TW. The cystine/glutamate antiporter system xc- drives breast tumor cell glutamate release and cancer-induced bone pain. Pain. 2016 Nov;157(11):2605-2616. doi: 10.1097/j.pain.0000000000000681. — View Citation

Outcome

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