Methadone for 'Adenocarcinopathic' Pain Treatment: Methadone vs. Morphine Vanguard RCT
试验速览
- 阶段
- 3 期
- 状态
- 撤回
- 主要终点
- Pain control
研究概览
简要总结
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).
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Care Provider)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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).
研究组 & 干预措施
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)
干预措施: Methadone (Drug)
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)
干预措施: Morphine (Drug)
结局指标
主要结局
Pain control
时间窗: 2 weeks
Proportion of patients reporting pain of 3 or less on a 10-point scale
次要结局
- Physician confidence(2 weeks)
- Global change(2 weeks)
- Side effects(2 weeks)
- Pain control(1 week)
- Pain relief(2 weeks)
- Patient satisfaction(2 weeks)