MetAddon: Methadone as co-analgesic for patients with metastatic bone pain: a double-blind randomized controlled trial

This study evaluates the comparative efficacy of methadone versus morphine as adjunctive analgesic therapy in patients with metastatic bone pain. The primary objective is to determine whether methadone administered as add-on treatment to existing primary opioid therapy achieves superior pain reduction compared to morphine in this patient population. This comparison is clinically relevant as it addresses the optimization of pain management strategies in patients with cancer-related bone metastases who experience inadequate analgesia despite ongoing opioid treatment.

The secondary objectives assess multiple clinical parameters comparing methadone and morphine as adjunctive therapy:

• Time to analgesic response
• Changes in mean and worst pain intensity
• Global perceived effect
• Rescue medication utilization
• Opioid dose escalation ratio
• Adverse effects profile
• Treatment-related complications
• Health-related quality of life
• Healthcare costs

The sponsor did not provide information regarding the total number of participants enrolled in this clinical trial. The study population included both **male** and **female** adult and elderly subjects aged 18 years and older. Participants were patients diagnosed with **cancer** presenting with **bone metastasis** and experiencing associated **pain**. Eligible subjects demonstrated metastatic bone pain with a mean pain intensity score of at least 5 on an 11-point scale. All participants were required to be receiving stable doses of strong **opioids** for a minimum of seven days prior to enrollment, with a daily dose equivalent to at least 60 mg **morphine milligram equivalence** (such as oxycodone sustained-release 40 mg, fentanyl transdermal 25 mcg/hr, or hydromorphone sustained-release 12 mg). Female participants of childbearing potential were required to use contraceptive methods during the study period. The trial did not involve vulnerable populations.

This study is designed as a double-blind randomized controlled trial to evaluate the efficacy of methadone hydrochloride as an add-on analgesic compared to morphine sulfate in patients with metastatic bone pain. The trial is classified as a phase IV study investigating two existing treatments within their approved indication. Participants will be randomized to receive either methadone capsules for oral use at a maximum daily dose of 10 mg or morphine sulfate capsules for oral use at a maximum daily dose of 80 mg, both administered as co-analgesics in addition to their existing opioid therapy. The maximum total dose for methadone is 175 mg and for morphine sulfate is 1400 mg over a treatment period of 3 weeks. Eligible participants must be adults aged 18 years or older with metastatic bone pain reflected by a mean pain intensity score of at least 5 on an 11-point scale, currently using strong opioids at a stable dose for at least seven days with a minimum daily dose of 60 mg morphine milligram equivalence. Female participants of childbearing potential are required to use contraceptives during the study period.

The primary endpoint is the difference in proportion of patients achieving at least 30% reduction in mean pain between both groups, based on average scores from days 5, 6, and 7 using an 11-point scale. Secondary endpoints include mean and worst pain intensity after each week, time in days to reach at least 30% pain reduction, mean pain intensity on day 21 compared to baseline, global perceived effect after three weeks, frequency of rescue medication use, self-reported side effects assessed on days 1, 7, 8, 14, and 21 using a 7-point scale, health-related quality of life measured with EQ-5D-5L and FACT-BP questionnaires at baseline and after 7, 14, and 21 days, health-care costs and cost-effectiveness at three weeks, and opioid dose increase ratio comparing daily opioid dose on day 21 to baseline.

The total duration of participant involvement in the trial is 21 days. Study visits include a screening visit for assessment of eligibility criteria, followed by baseline assessment and randomization. Participants will complete daily pain and medication diaries throughout the study period. Follow-up assessments are conducted at days 7, 14, and 21, with the end-of-study visit occurring on day 21. Safety monitoring includes assessment of adverse events and serious adverse events throughout the trial. The estimated recruitment period is scheduled to begin on January 1, 2026, with the estimated study completion date of December 31, 2027. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, participant withdrawal of consent, or protocol violations as determined by the investigator.

The experimental treatment in this clinical trial consists of **Methadon**, which contains **methadone hydrochloride** as the active substance. The medicinal product is formulated as a **capsule** for **oral use**. The maximum daily dose is 10 mg, with a maximum total dose of 175 mg administered over a treatment period of 3 weeks. Methadone hydrochloride is a chemical substance that functions as an **analgesic** and serves as add-on therapy to already used primary opioids in patients with **metastatic bone pain**.

The comparator treatment used in this study is **Morphine sulfate**, which contains **morphine sulfate** as the active substance. This medicinal product is also formulated as a capsule for oral use. The maximum daily dose is 80 mg, with a maximum total dose of 1400 mg administered over a treatment period of 3 weeks. Morphine sulfate is a chemical substance that functions as an analgesic and serves as the comparator to assess the relative efficacy of methadone as co-analgesic therapy.

Both investigational products are administered orally in capsule form according to the specified **dosing schedules** over the 3-week treatment period. The trial employs a **double-blind** design to ensure objective assessment of treatment efficacy and safety outcomes. The study aims to evaluate whether methadone as add-on therapy to existing opioid treatment is more effective in achieving pain reduction compared to morphine in the target patient population.

Efficacy will be assessed using pain intensity measurements on an 11-point scale. The primary endpoint is the difference in proportion of patients achieving at least 30% reduction in mean pain between both groups, based on average scores of day 5, 6 and 7. Secondary endpoints include mean and worst **pain intensity** after each week using an 11-point scale, time in days between start of study medication and reaching at least 30% reduction in mean pain score, and mean pain intensity on day 21 compared to baseline. Additional secondary endpoints comprise global perceived effect after three weeks, frequency of rescue medication use throughout the study, and self-reported side effects on day 1, 7, 8, 14 and 21 using medication and pain diary on a 7-point scale. **Health-related quality of life** will be assessed at baseline and after 7, 14 and 21 days using EQ-5D-5L and FACT-BP questionnaires. Healthcare costs and cost-effectiveness will be evaluated at three weeks. The opioid increased ratio, defined as the difference in daily opioid dose on day 21 compared to baseline, will also be measured.