Feasibility of a randomised controlled trial comparing opioid dose escalation with low-dose methadone addition for refractory cancer pain: JORTC-PAL23/NCCH2309 – protocol

Abstract

Introduction

Methadone exerts analgesic effects through μ-opioid receptor affinity and N-methyl-D-aspartate receptor antagonism, which may benefit refractory cancer pain with neuropathic components. Methadone can be introduced by the ‘stop-and-go’ (SAG) method or the ‘add-on’ (AO) method, in which low-dose methadone is added to existing opioids. Observational studies suggest AO may improve pain control but no double-blind randomised controlled trial (RCT) has evaluated this approach. Therefore, the primary aim of this study is to assess the feasibility of conducting a double-blind RCT comparing methadone AO therapy with opioid dose escalation according to standard practice for refractory cancer pain while also exploring safety and preliminary efficacy signals.

Methods and analysis

A two-centre, randomised, double-blind, two-arm feasibility trial will enrol 22 patients with advanced or recurrent cancer and inadequately controlled pain (oral morphine equivalent daily dose 60–300 mg). Participants will be allocated 1:1 to the methadone AO or opioid-escalation group using a web-based randomisation system with the minimisation method. The primary endpoint is the completion rate of the 2-week study treatment. Secondary outcomes include pain intensity (Brief Pain Inventory), time to adequate pain control, achievement of a personalised pain goal, adverse events (Common Terminology Criteria for Adverse Events (CTCAE)/Patient-Reported Outcomes version of the CTCAE) and quality of life (European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire Core 15-PAL). Feasibility will be determined based on achieving a treatment completion rate of 70% or higher.

Ethics and dissemination

The protocol was approved by the Certified Review Board of the National Cancer Centre Hospital (CRB3180008). Written informed consent will be obtained from all participants. The trial is registered in the Japan Registry of Clinical Trials. Results will be published in peer-reviewed journals and presented at international conferences.

Trial registration number

jRCTs031240220.

STRENGTHS AND LIMITATIONS OF THE STUDY.

• A feasibility design is used to confirm the practicality of conducting a future large-scale multicentre confirmatory trial.

• The study employs a double-blind randomised controlled design to reduce assessment bias in pain-related outcomes.

• The study includes comprehensive and patient-centred outcome assessments, incorporating both physician-reported and patient-reported measures such as the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events and a personalised pain goal.

• The small sample size inherent to a feasibility study limits statistical precision and precludes definitive conclusions regarding comparative efficacy.

• The short follow-up duration and the clinical heterogeneity in cancer type, pain mechanisms and concomitant treatments may influence treatment response and interpretation of secondary outcomes.

Introduction

Cancer pain is broadly classified into nociceptive pain, including somatic and visceral pain, and neuropathic pain. The prevalence of cancer pain ranges from about 38% to 85% across all cancer types and is higher among patients with advanced disease.¹ Cancer pain that remains poorly controlled despite opioid therapy is often complex in nature, and frequently involves neuropathic components, in addition to nociceptive mechanisms.² Pain management based on the WHO analgesic ladder using non-opioid, opioid and adjuvant analgesics is the standard approach for cancer pain. Studies in the general cancer pain population have suggested no clinically meaningful differences in analgesic efficacy among commonly used opioids.³ However, a subset of patients has poorly controlled or refractory pain despite guideline-based opioid therapy. Such refractory cancer pain is frequently characterised by mixed nociceptive and neuropathic mechanisms, for which opioid dose escalation alone may be insufficient, indicating the need for alternative or adjunctive analgesic strategies.

Methadone exerts its analgesic effects through both μ-opioid receptor agonism and N-methyl-D-aspartate (NMDA) receptor antagonism.^4–6 Methadone can be introduced by the stop-and-go (SAG) method after a strong opioid is discontinued, or the add-on (AO) method, in which a small amount of methadone is added to the preceding opioid. Both methods are clinically effective, but the SAG method has been associated with a higher risk of adverse events (AEs), particularly during titration. In contrast, the AO method may be a safer and more practical approach for refractory cancer pain.

Several observational studies have suggested that adding low-dose methadone to ongoing opioid therapy may improve analgesia in patients with refractory cancer pain.^{7 8} In a 2020 observational study, Fürst et al reported that low-dose methadone supplementation of an existing opioid regimen may improve poorly controlled pain in patients with advanced cancer, particularly pain consisting of mixed nociceptive and neuropathic components.⁷ In addition, recent multicentre prospective data from France reported significant pain reduction with low-dose methadone supplementation while maintaining an acceptable safety profile.⁸ However, these studies did not include a control group.

To date, 12 randomised controlled trials (RCTs) have evaluated methadone for cancer pain (table 1).^9–20

Table 1. Previous RCTs of methadone.

Literature (author, year, journal)	Patient/population	Intervention	Comparison/control	Outcome
Mercadante, 2008, European Journal of Pain9	Patients with advanced cancer on strong opioids (n=108)	Oral methadone	Transdermal fentanyl or oral morphine	・Comparable efficacy. ・Cost is lower for methadone.
Bruera, 2004, Journal of Clinical Oncology10	Opioid-naive patients with cancer requiring strong opioids (n=103)	Oral methadone	Oral morphine	・Comparable efficacy.
Haumann, 2018, Pain Practice11	Opioid-naive patients with head and neck cancer with nociceptive pain due to radiation mucositis (n=82)	Oral methadone	Transdermal fentanyl	・Non-inferiority of methadone. ・Methadone effective after 3 weeks.
Haumann, 2016, European Journal of Cancer12	Opioid-naive patients with head and neck cancer with neuropathic pain (n=52)	Oral methadone	Transdermal fentanyl	・Decreased NRS in methadone group at 1, 3 and 5 weeks.
Mercadante, 1998, Journal of Clinical Oncology13	Opioid-naive patients with cancer requiring strong opioids (n=40)	Oral methadone	Oral morphine	・Less need for opioid escalation with methadone.
Ventafridda, 1986, Journal of Pain and Symptom Management14	Opioid-naive patients with cancer requiring strong opioids (n=66)	Oral methadone	Oral morphine	・Methadone provided better analgesia at lower doses.
Beaver, 1967, Clinical Pharmacology & Therapeutics15	Cancer pain (n=55)	Methadone (oral or intramuscular)	Oral morphine	・Comparable efficacy and safety.
Twycross, 1977, British Journal of Clinical Pharmacology16	Cancer pain (n=46)	Oral methadone	Diamorphine	・Poor prognosis in methadone group in hospice.
Poulain, 2016, Journal of Pain and Symptom Management17	Patients with advanced cancer on strong opioids (n=146)	Oral methadone	Oral morphine	・Reduction of pain. ・Equal effect at day 4.
Duarte, 2021, Clinical Journal of Pain18	Patients with advanced cancer receiving weak opioid (n=41)	Oral methadone+morphine	Oral morphine	・Decreased NRS in methadone add-on group at 2 weeks.
González-Barboteo, 2021, Journal of Palliative Medicine19	Patients with advanced cancer receiving parenteral methadone (n=39)	Parenteral-to-oral methadone conversion ratio of 1:1.2	Parenteral-to-oral methadone conversion ratio of 1:2	・Comparable analgesia with fewer adverse events using a 1:1.2 conversion ratio.
Sulistio, 2024, Supportive Care in Cancer20	Patients with cancer with refractory cancer-induced bone pain on strong opioids (n=38)	Methadone rotation	Other opioid rotation	・Comparable analgesia with lower OMEDD in the methadone group.

NRS, Numerical Rating Scale; OMEDD, oral morphine equivalent daily dose; RCTs, randomised controlled trials.

Most of these studies focused on opioid switching strategies, such as the SAG method, or on specific clinical settings. None have rigorously evaluated the efficacy and safety of the methadone AO approach. Consequently, no double-blind RCT investigating the AO strategy has been conducted worldwide.

Therefore, evaluation of the methadone AO strategy in patients with refractory cancer pain is warranted. The present study aimed to assess the feasibility and preliminary clinical outcomes of low-dose methadone AO therapy in a multicentre prospective setting as a preparatory step toward a future multicentre double-blind RCT.

Methods and analysis

Study design

The Standard Protocol Items for Randomised Trials statement and checklist were followed in preparing the protocol. A two-centre randomised, double-blind, two-parallel study will be conducted to examine the feasibility of a double-blind randomised RCT of opioid usage.

Study setting and participants

Participants will be recruited from inpatient and outpatient settings at our institutions, with a plan to enrol 22 patients. The inclusion and exclusion criteria are summarised in box 1. The key inclusion criteria are: (1) cancer pain with an unresectable advanced or recurrent malignant tumour, (2) Karnofsky Performance Status (KPS) >40, (3) worst pain intensity in the past 24 hours (Brief Pain Inventory (BPI) item 3) ≥4 at enrolment despite opioid use (oral morphine equivalent daily dose (OMEDD) ≥60–≤300 mg) and (4) no QT prolongation (QTcB<450 ms). Participants receiving any opioid analgesic were eligible, provided that the total OMEDD was between 60 and 300 mg/day. Patients with a history of cardiovascular disease such as myocardial infarction, heart failure, angina or acquired QT prolongation, and currently taking antiarrhythmic drugs will be excluded from the study. Those using drugs that strongly affect CYP3A4 will also be excluded to ensure a stable drug effect and prevent side effects, since CYP3A4 is involved in the metabolism of methadone and methadone itself is a CYP3A4 inducer.

Box 1. Inclusion and exclusion criteria.

Inclusion criteria

1. Unresectable advanced or recurrent malignancy.

2. Cancer pain (chest wall invasion, brachial plexus invasion, skull base invasion, sacral plexus invasion, malignant iliopsoas syndrome, bone metastatic pain, nerve root invasion, inflammatory breast cancer, etc).

3. Age >18 years.

4. Karnofsky Performance Status >40.

5. Have not used methadone within 28 days of enrolment.

6. Worst pain intensity (BPI item 3) is more than 4 in the past 24 hours.

7. On an appropriate dose of opioid analgesia (between 60 mg and 300 mg of oral morphine equivalent (OMED)).

8. Total bilirubin ≤1.5 mg/dL, AST ≤100 U/L and ALT ≤100 U/L; and creatinine clearance ≥40 mL/min or estimated glomerular filtration rate based on serum cystatin C ≥40 mL/min/1.73 m².

9. Serum potassium >3.5 mmol/L.

10. QTcB ≤450 ms measured using a simplified electrocardiographic device or QTcB ≤450 ms as measured by a cardiologist.

11. Written consent to participate in the study obtained from the patient.

Exclusion criteria

1. History of myocardial infarction^I, heart failure classified as New York Heart Association class III or IV, angina requiring ongoing treatment, or QT prolongation with QTc >450 ms^II.

2. Current use of antiarrhythmic drugs.

3. Presence of nausea or somnolence of CTCAE V.5.0-JCOG Grade ≥2 at the time of enrolment.

4. Presence of constipation of CTCAE V.5.0-JCOG Grade ≥3 at the time of enrolment.

5. Participation in another clinical trial or investigational study, or plans to participate in one.

6. Initiation of regularly scheduled administration of analgesics or adjuvant analgesics within 48 hours prior to enrolment.

7. Initiation of the following medications (new chemotherapy, molecular targeted agents or immune checkpoint inhibitors) or treatments (nerve block) within 7 days prior to enrolment, or plans to initiate them within 7 days after enrolment.

8. Contraindications to methadone, including: patients with severe respiratory depression; severe chronic obstructive pulmonary disease; acute bronchial asthma attack; paralytic ileus; acute alcohol intoxication; a history of hypersensitivity to components of methadone; haemorrhagic colitis; or current treatment with nalmefene or within 1 week after discontinuation.

9. Known allergy or a history of hypersensitivity to opioid compounds.

10. Use of medications that strongly affect CYP3A4 within 7 days prior to enrolment (including supplements and foods containing St. John’s wort, a CYP3A4 inducer), or plans to use such medications.

11. Pregnancy or breastfeeding, continued need for breastfeeding after initiation of the study drug or possible pregnancy.

12. Presence of psychosis or psychiatric symptoms that interfere with activities of daily living and are judged to make participation in the study difficult.

13. Any other condition judged by the principal investigator or sub-investigator to make the patient unsuitable for participation in the study.

^IPatients with a remote history of myocardial infarction are eligible for enrolment.

^IIPatients with acquired long QT syndrome may be enrolled if the underlying cause has been resolved and QTc has improved to ≤450 ms.

ALT, alanine aminotransferase; AST, aspartate transferase; BPI, Brief Pain Inventory; CTCAE, Common Terminology Criteria for Adverse Events; JCOG, Japanese Clinical Oncology Group; OMED, oral morphine equivalent daily dose.

Recruitment

Eligible patients satisfying the screening inclusion and exclusion criteria will be invited to participate in the study by experienced investigators trained in palliative care, and informed consent will be obtained.

Randomisation

Eligible patients will be randomly assigned to the methadone AO group or the opioid escalation group (control) in a 1:1 ratio using an electronic data capture system (Viedoc 4, Viedoc Technologies, Uppsala, Sweden). Allocation will be performed using a minimisation method to balance: (1) worst pain intensity on a Numerical Rating Scale (NRS) in the last 24 hours (4–6 vs 7–10), and (2) OMEDD (low dose 60–159 mg vs high dose 160–300 mg).

Masking

Patients and clinicians responsible for treatment will be blinded to administration of methadone or oxycodone. Only a clinical trial pharmacist who generates capsules, but is not involved in patient care, will know the allocation and outcomes. All study drugs will be packaged by this pharmacist. If a serious AE occurs and there is strong suspicion of a causal relationship with the study drug, unblinding will be performed.

Data management and central monitoring

Evaluations will be performed at four time points: baseline (within 3 days of randomisation), the day before the start of treatment (day 1) and day 8 and day 15 after initiation of treatment. If the study is discontinued, the evaluation will also be done on the date of discontinuation. The timing and details of evaluations are given in table 2.

Table 2. Evaluation schedule.

Measurement	Baseline	Day 1	Day 8	Day 15
Background	❍
KPS	❍			❍
Blood examination	❍			❍
ECG	❍			❍
BPI-SF	❍		❍	❍
Worst pain (BPI-Item 3)
Average pain (BPI-Item 5)
SF-MPQ-2	❍
EORTC-QLQ-C15-PAL	❍
CTCAE	❍			❍
PRO-CTCAE	❍		❍	❍
HADS	❍			❍
PPG	❍			❍

BPI-SF, Brief Pain Inventory-Short Form; CTCAE, the Common Terminology Criteria for Adverse Events; EORTC-QLQ, European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire; HADS, Hospital Anxiety and Depression Scale; KPS, Karnofsky Performance Status; PPG, Personal Pain Goal; PRO-CTCAE, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; SF-MPQ-2, Short Form McGill Pain Questionnaire 2.

Once a patient is enrolled or randomised, the study site will make every reasonable effort to follow the patient for the entire study period. Patients will not be allowed to cross over from one group to the other until the end of the study (day 15). However, they can choose to leave the study for any reason at any time without detriment to the provision or quality of their clinical care. Investigators will maintain individual records for each patient as source data, including a copy of informed consent, medical records, laboratory data and other relevant notes. All data will be collected by the data centre. Clinical data entry, data management and central monitoring will be conducted using Viedoc 4. To ensure data quality, all assessors will receive standardised training, and data checks for completeness and consistency will be performed centrally. Laboratory tests and other instruments used are validated and standardised according to institutional protocols. Data collection forms are available from the study data centre on request. Every effort will be made to retain participants for the full study period. Participants who discontinue or deviate from the intervention protocol will still be followed for safety and key outcome data, including clinical assessments and laboratory results at the time of discontinuation. An interim analysis will not be performed. Auditing is not planned in the study.

Assessment tools

Karnofsky Performance Status

KPS will be evaluated by primary physicians.

Blood examination

Blood examinations will be performed to assess liver function, renal function and other risks of cardiovascular events, including arrhythmia. Laboratory items include: white blood cell count, haemoglobin, platelet count, total bilirubin, aspartate transferase, alanine aminotransferase, serum creatinine, urea nitrogen (blood urea nitrogen) and electrolytes (Na, K, Cl).

ECG

Methadone has a side effect of QT prolongation. Therefore, to ensure patient safety, the eligibility criteria include the presence or absence of arrhythmia and treatment history. After the study period, ECG will be performed to check for arrhythmia or QT prolongation.

Brief Pain Inventory-Short Form

The BPI-SF provides a simple assessment of the severity of pain using a NRS, and is used both clinically and for research.²¹ In this study, BPI-SF will be used for patient-described assessment of pain. Item 3, the worst pain within 24 hours, and item 5, the average pain over 24 hours, of the BPI-SF will be reported daily by the patients themselves.

Short-Form McGill Pain Questionnaire 2

Short-Form McGill Pain Questionnaire 2 (SF-MPQ-2) will be used to investigate differing effects based on pain mechanisms. SF-MPQ-2²² and its Japanese version²³ are validated for cancer neuropathic pain, as a 22-item questionnaire that covers superficial and deep spontaneous pain, paroxysmal pain and paraesthesia/dysesthesia.

EORTC-QLQ-C15

The European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ)-C15-PAL will be used for evaluation of quality of life.²⁴ The reliability and validity of the Japanese version of this scale have been confirmed.²⁵

Common Terminology Criteria for Adverse Events/Patient-Reported Outcomes version of the CTCAE

AEs during the study period will be assessed using the Common Terminology Criteria for Adverse Events (CTCAE) V.5.0,²⁶ Japanese Clinical Oncology Group version by physicians and the Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE) by patients.²⁷ PRO-CTCAE was developed by the National Cancer Institute for AE assessment of subjective symptoms.^{28 29} The Japanese version of the PRO-CTCAE has acceptable reliability³⁰ and linguistic³¹ and psychometric validity for common and clinically important symptoms. Four AEs, somnolence, nausea, vomiting and constipation, are common with opioids and ECG abnormalities can occur as a side effect of methadone. Thus, it is necessary to evaluate a causal relationship with the study drug.

Hospital Anxiety and Depression Scale

The Hospital Anxiety and Depression Scale (HADS) will be used for measurement of psychiatric symptoms (anxiety and depression) of patients with a physical disease. HADS is a screening tool that allows assessment based on a small number of items.^{32 33}

Personalized Pain Goal

The Personalized Pain Goal (PPG) is used to tailor pain management. As for pain intensity evaluation, the PPG uses a NRS, on which patients use a 0–10 scale to describe the level/intensity of pain that will allow comfort in physical, functional and psychosocial domains.³⁴ This scale was chosen after the study group concluded that neither the between-group differences in mean values nor changes in pain intensity (eg, absolute or relative values) correctly evaluated patient discomfort.

Interventions

Participants will be randomly assigned to one of the following two groups. The intervention schedule and dose allocation according to baseline OMEDD are shown in figure 1 and 2.

Figure 1. Participants will be randomised (1:1 allocation ratio) into the opioid escalation group or the methadone add-on group. BPI-SF, Brief Pain Inventory-Short Form; CTCAE, the Common Terminology Criteria for Adverse Events; EORTC-QLQ, European Organisation for Research and Treatment of Cancer-Quality of Life Questionnaire; HADS, Hospital Anxiety and Depression Scale; KPS, Karnofsky Performance Status; PPG, Personal Pain Goal; PRO-CTCAE, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; SF-MPQ-2, Short Form McGill Pain Questionnaire 2.

Figure 2. Oxycodone, methadone and placebo should all be overencapsulated and administered two times per day. Participants will be administered daily from days 1–14, and a symptom diary (BPI item 3, 5) will be kept. BPI, Brief Pain Inventory; OMEDD, oral morphine equivalent daily dose.

Control group (opioid escalation method)

Cases with OMEDD ≥60–<160 mg will be administered an additional 20 mg of oxycodone, and those with OMEDD ≥160–≤300 mg will receive an additional 40 mg of oxycodone. Use of adjuvant analgesics at the start of treatment is not a factor. If AEs such as somnolence occur, the dose of adjuvant analgesics or opioid may be reduced. On the treatment start date, it will be confirmed that the regular opioid dose currently being administered is OMEDD ≥60–≤300 mg (regardless of the number of rescue doses). In cases with OMEDD ≥60–<160 mg, the oxycodone dose will be increased by 10 mg in the morning and evening. In those with OMEDD ≥160–≤300 mg, the oxycodone dose will be increased by 20 mg in the morning and evening. The dose of adjuvant analgesic drugs will not be increased. The opioid dose will not be changed from the start date until the 2-week evaluation, but with no limit on the number of rescue doses. After 2 weeks, after evaluation items have been assessed and an ECG has been performed, the protocol treatment will be discontinued. The attending physician will select the next treatment, and dose changes or new analgesics and adjuvant analgesics will be permitted.

Methadone add-on group

As above, use of adjuvant analgesics at the start of treatment is not a factor. If AEs such as somnolence occur, the dose of adjuvant analgesics and opioid analgesics can be reduced. On the treatment start date, it will be confirmed that the current regular opioid dose is OMEDD ≥60–≤300 mg (regardless of the number of rescue doses). Cases with OMEDD ≥60–<160 mg will receive a placebo capsule in the morning and 5 mg of methadone in the evening. In cases with OMEDD ≥160–≤300 mg, 5 mg of methadone will be added in the morning and evening. The dose of adjuvant analgesics will not be increased. The opioid dose will not be changed from the start date until the 2-week evaluation, but with no limit on the number of rescue doses. After 2 weeks, after the evaluation items are assessed and an ECG is performed, the protocol treatment will be discontinued. The attending physician will select the next treatment, and dose changes or new analgesics and adjuvant analgesics will be permitted.

During the study period, symptomatic therapy other than pain relief is permitted as appropriate, but if AEs are not improved by this therapy, or if Grade 3 or higher AEs occur, the adjuvant analgesic drug will be reduced or discontinued in the control and AO groups. If AEs persist after this drug is discontinued, the study treatment will be discontinued. Participants will receive appropriate medical care for any AEs related to trial participation.

Compensation will be provided in accordance with institutional policies and applicable regulations.

Endpoints

Primary endpoint

The primary endpoint is the completion rate of the 2-week study treatment. This is defined as the percentage of patients who were able to take the study drug for 2 weeks.

Secondary endpoints

The secondary endpoints are defined to assess the feasibility of the sample size, efficacy and safety. These endpoints are the number of participants enrolled in the study at 12 months; change in worst pain NRS (BPI item 3) in the last 24 hours between study entry (baseline) and weeks 1 and 2; change in mean pain intensity (BPI item 5) between baseline and weeks 1 and 2; % reduction in BPI items 3 and 5 from baseline to 1, 2, 3 and ≥4 at 1 and 2 weeks; % of BPI items 3 and 5 reduced by at least 30% and 50% from baseline at 1 and 2 weeks; number of days to achieve good pain control; number of days from baseline until BPI items 3 and 5 decrease by at least 2, at least 3, at least 30% and at least 50%; % of patients requiring a reduction in the dose of analgesics and an increase or decrease in the dose of opioids and methadone by 2 weeks compared with baseline; % effectiveness for each intervention group at 1 and 2 weeks in patients with neuropathic pain (International Association for the Study of Pain (IASP) criteria); SF-MPQ-2 score; % of patients able to achieve PPG; CTCAE; frequency of unscheduled visits, tests, hospitalisations and medical costs; EORTC QLQ-C15-PAL; and HADS.

Statistical considerations

The timing of each analysis will be after the data have been fixed. Details will be described separately in a statistical analysis plan, which will be created after discussion of inclusion or exclusion of data for analysis and missing-data handling, prior to data fixing.

The clinical hypothesis of the study is that a randomised trial comparing an increase in opioid dose with addition of methadone is feasible in patients with cancer pain that is poorly controlled by other opioids. Therefore, the primary endpoint evaluates the feasibility of conducting a randomised trial, and the number of planned enrolments is calculated based on the hypothesis for the CI, which is the main criterion for judgement. The purpose of each analysis is not to detect statistical significance, but the significance level used in statistical hypothesis testing or CI estimation will be set at 5% on both sides for convenience. No adjustment for multiple testing will be made.

To ascertain the comparability of the groups, all registered cases will undergo a comprehensive analysis, including calculation of numerical variables, such as the number of cases, mean values, SD and minimum, median and maximum values. The frequency and proportion of each level will be determined for categorical variables. The 95% CI (Wilson’s score CI) will be calculated for the rate of completion of the test treatment (proportion of patients able to take the test drug for 2 weeks) when the groups are combined. Feasibility will be defined based on a treatment completion rate of ≥70%. Subgroup analysis will be performed to evaluate differences between neuropathic pain and other pain, and those undergoing anticancer treatment and other treatment.

Based on similar studies^{16 35 36} and clinical practice, we hypothesise that the primary endpoint, the rate of completion of the study treatment at 2 weeks, will be ≥70%. To obtain a 70% completion rate with a 95% CI of ±20%, 10 participants are needed in each group. To allow for some dropouts, a total of 22 participants will be enrolled.

Protocol version and amendments

The current protocol is version 1.4 (5 January 2026). Any important protocol modifications will be communicated to the certified review board (CRB) and updated in the trial registry.

Patient and public involvement

Patients and the public were not involved in the design of this study protocol.

Ethics

All patients will be required to provide written informed consent. An English translation of the participant information sheet, informed consent form and consent withdrawal form is provided in online supplemental file 1. The protocol was approved by National Cancer Center Hospital CRB (CRB3180008), and modifications in the study protocol will be communicated to the CRB. The trial has been registered with the clinical trials registry of Japan (jRCTs031240220). If any adverse health effects related to the study treatment occur unexpectedly and cannot be ruled out as causally related during or after the study, medical expenses and allowances required for treatment will be compensated based on the payment conditions of the clinical research insurance. Adverse health effects arising from routine medical care unrelated to the study will be addressed through standard insurance-covered medical treatment.

Dissemination

The results of the trial will be submitted for publication in international peer-reviewed journals and the key findings presented at conferences. Patients will be informed of the results by the investigators. Authorship will be ascribed in accordance with the International Committee of Medical Journal Editors guidance.

Discussion

To our knowledge, there are no RCTs of the efficacy and safety of the methadone AO method. Thus, several issues related to the content of the trial require discussion, including: (1) the rationale for evaluating methadone AO therapy, (2) the choice of the comparator drug, (3) the oral morphine equivalent ratio for methadone, (4) the primary endpoint and (5) the study duration. These issues are addressed in the following paragraphs.

In addition to methadone AO therapy, complete opioid rotation to methadone is an established strategy for refractory cancer pain.^{20 37} Methadone’s unique pharmacological properties, including NMDA receptor antagonism,^4–6 may be particularly relevant in patients with neuropathic pain components. However, the objective of the present study was not to compare methadone AO therapy with methadone rotation, but rather to evaluate whether the addition of low-dose methadone provides analgesic benefit beyond that achievable through conventional opioid dose escalation. Consequently, the present study is not designed to determine the comparative effectiveness of methadone AO therapy versus complete methadone rotation. For this reason, the comparator was designed to reflect standard clinical practice for patients with persistent cancer pain despite ongoing opioid therapy.

Second, oxycodone was selected as the comparator drug for both clinical and practical reasons. It is one of the most commonly used strong opioids for cancer pain and is widely used in clinical practice, particularly in Japan. Its dose conversion to morphine is well established (eg, oral oxycodone 20 mg is nearly equal to oral morphine 30 mg), which enables consistent interpretation of the methadone conversion ratio based on morphine equivalents. The oxycodone doses in the study (20 or 40 mg) also represent clinically reasonable escalation levels that are commonly used in daily practice. From a practical standpoint, the design also considered ease of administration and blinding feasibility. We aimed to encapsulate the study drug, placebo and comparator in capsules that are not too large or difficult for patients to swallow. Among available strong opioids, oxycodone capsules were the only formulation that could be encapsulated similarly to methadone or placebo in capsules of similar size and appearance, allowing the medications to be taken easily while maintaining blinding. Therefore, oxycodone was selected as the comparator from both pharmaceutical and practical perspectives.

The third concern is the morphine equivalence ratio for methadone, since the conversion ratio between methadone and other opioids is uncertain. Previous studies have suggested ratios from 4:1 to 20:1, depending on the amount of previous opioids administered. For instance, Mercadante et al suggested a conversion ratio of oral morphine to oral methadone of 3:1 to 5:1.³⁵ A ratio of 4:1 may be appropriate at low doses,³⁶ while a 10:1 ratio may be better in patients receiving OMEDD 60–160 mg,³⁸ with no established consensus. We discussed this issue in our study group and set the morphine equivalent ratio for methadone at 6:1 based on the dose in the study and with reference to Ripamonti et al.³⁹ This is not as safe as the 8:1 ratio suggested by the National Comprehensive Cancer Network (NCCN), but less favourable in the methadone group than 3:1 and 4:1 ratios, thus avoiding overestimation of the effectiveness of methadone. Furthermore, to ensure that the 6:1 conversion ratio would adequately cover the practical dosing range, we limited the eligible baseline opioid dose to an OMEDD of 60–300 mg prior to study treatment. Clinically, for patients receiving a baseline opioid dose of OMEDD 60–160 mg/day, an AO of 20 mg oral oxycodone is generally regarded as reasonable and practicable. Since 20 mg of oxycodone corresponds to about 30 mg of oral morphine, applying the 6:1 morphine-to-methadone conversion ratio results in 5 mg of methadone, which is a feasible low-dose AO regimen. At the higher end of the range (OMEDD 160–300 mg/day), an AO of 40 mg oral oxycodone is clinically appropriate. As 40 mg of oxycodone is roughly equivalent to 60 mg of oral morphine, the same 6:1 conversion ratio gives 10 mg of methadone, supporting the upper-dose setting in this protocol. Thus, the 5 mg and 10 mg methadone AO regimens both correspond to realistic oxycodone escalation scenarios frequently encountered in clinical practice, supporting the external validity of our dose setting.

The fourth concern is the determination of the primary endpoint. Although methadone has potential efficacy for refractory cancer pain, there are few RCTs due to the lack of established conversion ratios (oral morphine equivalents), which made it necessary to evaluate the feasibility in a validation study. Our primary endpoint was defined as a study treatment completion rate of at least 70%. There are no prospective clinical trials, but a Canadian cohort study (n=146) reported a continuation rate of 78.1% at day 15 with a mean methadone dose of 6 mg.⁴⁰ In light of these results and our internal discussion, a treatment completion rate of 70% was determined to be a realistic and meaningful target.

Finally, the choice of a 2-week study period was based on evidence from previous studies. Mercadante et al (n=108) showed that the dose of methadone was almost unchanged over 4 weeks⁹ and Bruera et al (n=103) found that about 75% of patients had >20% pain relief by day 8, with no difference in analgesic dose between days 14 and 28.¹⁰ Furthermore, in an opioid use study conducted in Japan, 83.1% of patients achieved pain symptom relief goals within 7 days of intervention, with an average of 3 days to achieve treatment goals. Given these findings, we concluded that 2 weeks of treatment was sufficient to assess the efficacy and safety of methadone.

The results of this feasibility study suggest that it is possible to conduct a larger, multicentre, double-blind RCT to establish methadone as a standard treatment option for refractory cancer pain. This study will help integrate methadone into clinical practice for better cancer pain management to improve the quality of life of patients with cancer with severe pain.

Patient and public involvement

Patients and the public were not involved in the design of this study protocol.

Trial status

The trial opened in November 2024. At the time of manuscript writing (March 2026), 11 patients have been randomised. We expect to complete the recruitment by March 2028 and to finish the trial by November 2028.

Confidentiality

Data will be managed in accordance with the Japanese Clinical Research Act. Participants will be assigned a unique identification (ID) number at randomisation. The participant ID number list linking the ID number to the participant’s identity will be kept confidential and stored securely at each institution. All data analyses will be performed using ID numbers only. Study records will be retained for 5 years after study completion and then appropriately disposed of at each institution.