In this prospective open-label study, we determined the efficacy and safety of low-dose methadone as an add-on to ongoing opioid therapy for patients with uncontrolled cancer pain.
During 15-day study periods, 68.4% participants were categorized as responders, with ≥33% pain reduction; the mean reduction in the average numerical rating score was 2.6 points.
Although more research on combination strategies of methadone with another opioid is needed, this study describes a promising algorithm for introducing low-dose methadone as an add-on to another ongoing opioid therapy that has been demonstrated to be safe and effective during the follow-up period.
Trial information
| Trial information | |
| Disease | Refractory cancer pain, regardless of conventional opioid therapy |
| Stage of disease/Treatment | Advanced or recurrent |
| Prior therapy | Adequate dose titration and current treatment with oral morphine equivalent of 60 mg/day or more |
| Type of study | Prospective, single-arm observational study |
| Primary endpoints | Proportion of pain reduction from baseline |
| Secondary endpoints | Pain intensity, frequency of daily breakthrough opioid use, and safety |
| Additional details of endpoints or study design The primary endpoint was the percentage of patients with ≥33% average pain reduction from baseline. The proportion of pain reduction was calculated using the following formula: (pain intensity at baseline − pain intensity on day 15)/(pain intensity at baseline) × 100. Single institution, single arm study |
Drug information
| Drug information | |
| Generic/Working name | Methadone |
| Company name | TEIKOKU SEIYAKU |
| Drug type | Analgesic |
| Drug class | Opioid |
| Dose | 5 or 10 mg/day |
| Route | Oral |
| Schedule of administration Oral methadone has been introduced as an add-on medication to ongoing opioid therapy. After day 7, the physicians increased the methadone dose. Scheduled intervention: see Figure 1 . |
Dose table
| Dose table | |||
| Dose of drug | Number enrolled | Number evaluable for toxicity | |
| Ongoing opioids with oral morphine equivalents less than 120 mg/day | 5 mg/day | 12 | 12 |
| Ongoing opioids with oral morphine equivalents 120 mg/day or more | 10 mg/day | 7 | 7 |
Patient characteristics
a Multiple-choice responses were available. Abbreviations: ECOG, Eastern Cooperative Oncology Group; IQR, interquartile range.
| Patient characteristics | |
| Age | |
| median (IQR), years | 69 (55-71) |
| range, years | 39-75 |
| Sex | |
| Female | 8 (42.1%) |
| Primary cancer | |
| Gastrointestinal | 6 (31.6%) |
| Head and neck | 6 (31.6%) |
| Breast | 2 (10.5%) |
| Multiple myeloma | 2 (10.5%) |
| Lung | 1 (5.3%) |
| Prostate | 1 (5.3%) |
| Unknown | 1 (5.3%) |
| Tumor stage | |
| Advanced or recurrent | 19 (100%) |
| Comorbidity of heart disease | |
| Yes | 1 (5.3%) |
| Comorbidity of lung disease | |
| Yes | 2 (10.5%) |
| History of gastrointestinal surgery | |
| Yes | 3 (15.8%) |
| Performance status (ECOG) | |
| 1 | 1 (5.3%) |
| 2 | 10 (52.6%) |
| 3 | 7 (36.8%) |
| 4 | 1 (5.3%) |
| Pain a | |
| Neuropathic pain | 11 (57.9%) |
| Multiple bone metastasis | 9 (47.4%) |
| Spinal cord invasion | 2 (10.5%) |
| Cancer skin ulcer | 2 (10.5%) |
| Visceral pain | 2 (10.5%) |
| Pleural invasion | 1 (5.3%) |
| Duration of opioid therapy | |
| Within 1 month | 4 (21.1%) |
| 1-3 months | 5 (26.3%) |
| 3-6 months | 2 (10.5%) |
| More than 6 months | 8 (42.1%) |
| Ongoing opioid therapy | |
| Oxycodone | 9 (47.4%) |
| Morphine | 5 (26.3%) |
| Fentanyl | 5 (26.3%) |
| Background oral morphine equivalent daily doses (mg) | |
| Median (IQR) | 90 (80-120) |
| Range | 60-216 |
| Concomitant medication a | |
| Nonsteroidal anti-inflammatory drugs | 13 (68.4%) |
| Acetaminophen | 8 (42.1%) |
| Anticonvulsants (pregabalin, all) | 8 (42.1%) |
| Steroids | 2 (10.5%) |
| Antidepressants | 1 (5.3%) |
| Primary assessment method | |
| Title | The proportion of responders (defined as ≥33% reduction in average pain intensity on the numerical rating scale [NRS]) on day 15 |
| Number of patients screened | 27 |
| Number of patients enrolled | 19 |
| Number of patients evaluable for toxicity | 19 |
| Number of patients evaluated for efficacy | 19 |
| Evaluation method | The proportion of pain reduction was calculated using the following formula: (pain intensity at baseline − pain intensity on day 15)/(pain intensity at baseline) × 100. |
| Outcome notes Response assessment: see Table 1 . |
Adverse events (AEs)
| Adverse events | ||||||||
| Baseline | During study period | New or worse than at baseline | ||||||
| Grade 1-2 | Grade 3 | Grade 4 | Grade 1-2 | Grade 3 | Grade 4 | ≥1 Grade | ≥2 Grade | |
| Nausea | 8 (42.2%) | 3 (15.8%) | 1 (5.3%) | 7 (36.8%) | 4 (21.1%) | 0 (0%) | 5 (26.3%) | 2 (10.5%) |
| Vomiting | 6 (31.6%) | 0 (0%) | 1 (5.3%) | 9 (46.8%) | 0 (0%) | 0 (0%) | 5 (26.3%) | 2 (10.5%) |
| Constipation | 12 (63.2%) | 2 (10.5%) | 0 (0%) | 8 (42.1%) | 2 (10.5%) | 0 (0%) | 1 (5.3%) | 0 (0%) |
| Somnolence | 16 (84.2%) | 3 (15.8%) | 0 (0%) | 16 (84.2%) | 2 (10.5%) | 1 (5.3%) | 5 (26.3%) | 0 (0%) |
Adverse events were evaluated using the Patient-Reported Outcome (PRO) Common Terminology Criteria for Adverse Events (CTCAE) at baseline, on days 8 and 15.
Discussion
In this prospective open-label study of patients with advanced cancer, we assessed the efficacy and safety of oral methadone in combination with ongoing opioid treatment. Few studies have investigated the combination of low-dose methadone for refractory cancer pain 1–3 ; moreover, to our knowledge, this is the first study to use a pre-planned approach to assess the efficacy and safety of low-dose methadone as a co-analgesic to another ongoing opioid therapy.
In this study, 68.4% participants were categorized as responders, with ≥33% pain reduction; the mean reduction in the average numerical rating score was 2.6 points. These findings are consistent with those of previous retrospective studies examining the use of low-dose methadone as a coanalgesic 1–3 and a prospective study of opioid switching to methadone as a second-line opioid. 4 In addition, the analgesic effects in this study appeared to be greater than those of switching to another opioid. 5 , 6 To date, switching to opioids other than methadone is generally recommended for refractory cancer pain, despite titrated opioid doses 7–9 ; however, low-dose methadone combined with other opioids might also be an option. In addition, because conversion ratios between methadone and other opioids have not been definitively established, there is a concern that opioid switching to methadone may increase pain 10 ; however, few patients on methadone combination therapy in the present study experienced worsening cancer pain.
Furthermore, adverse events in the present study were measured using the PRO-CTCAE, and the most common new adverse events or those that were worse than baseline were nausea/vomiting and somnolence. The safety of methadone has been questioned, and careful consideration when switching from opioids to methadone is essential. 11 Intensive monitoring of sedation caused methadone to be administered when it was titrated. Adverse events were also evaluated during intensive monitoring. With the exception of 5 cases in which methadone could not be continued due to difficulty in taking oral medication owing to tumor progression, no patients discontinued methadone treatment because of adverse effects. Accordingly, the combined use of low-dose methadone and ongoing opioid therapy appears to be safe. Two patients experienced QTc prolongation > 500 ms. Therefore, if low-dose methadone is initiated, caution should be exercised with the combined use of QTc-prolonging drugs, which are frequently used in palliative medicine and medical oncology.
This study has several limitations that should be considered. First, it was a prospective cohort study and did not include a comparison group. The observed reduction in pain intensity may be due to spontaneous improvement, regression to the mean, or obsequiousness bias. Therefore, the efficacy of the combined use of low-dose methadone and ongoing opioid treatment revealed in this study should be confirmed in randomized controlled trials. Second, this study was conducted at a single institution, and thus the findings cannot necessarily be generalized to other situations, such as other populations or clinical settings. Third, the participants did not receive high-dose opioids at baseline, and the appropriate dose of methadone for combination use remains unknown (especially in oral morphine equivalents of 300 mg/day or more). Fourth, the small sample size may have led to an underestimation of serious adverse events.
Background
Cancer pain is a common symptom that negatively affects the quality of life of patients with cancer. 12 Several clinical guidelines for cancer pain have shown that the use of strong opioids (morphine, oxycodone, fentanyl, or hydromorphone) is the mainstream approach to alleviate cancer pain. 7–9 Although opioids generally provide an analgesic effect in the majority of patients, a certain proportion of patients experience refractory pain despite adequate use of opioids. 13–16
Pharmacological options for refractory cancer pain are limited and consist of opioid switching and adjuvant analgesics, such as gabapentinoids. 17 , 18 However, these analgesics are often unsuccessful, and the development of effective analgesic treatments for refractory cancer pain is urgently needed. Among these, the use of methadone as a part of opioid switching is controversial. 11 Methadone has several unique profiles, not just as a synthetic mu-opioid agonist, but also as an N -methyl- d -aspartate receptor antagonist. 19 The conversion ratios from other opioids have not been well established, and there is a concern that switching to methadone may increase pain. Although its analgesic effects are promising, 4 the safety of switching to methadone has been a growing concern. 10 , 11 Owing to the long and unpredictable half-life of methadone, there are concerns regarding impaired consciousness and respiratory depression associated with overdose, forcing methadone initiation to be introduced under adequate monitoring.
A recent focus has been on induction with low-dose methadone in combination with conventional opioids. 1–3 It is presumed that less exacerbation of pain will occur after introducing methadone with the continued use of ongoing opioids by not completely switching from other opioids to methadone. However, no prospective studies have been conducted, and the findings are insufficient. Therefore, we designed a single-arm study to investigate the analgesic efficacy and safety of low-dose methadone combination therapy in patients with cancer pain and inadequate analgesic effects, regardless of opioid therapy.
Methods
Study design
This was a prospective, single-arm observational study of patients with advanced cancer, including those with solid tumors and hematological malignancies, at Nagoya City University Hospital. Consecutive patients who had follow-up appointments with a palliative care center (including an outpatient palliative care clinic and an inpatient consultation team) at Nagoya City University Hospital were enrolled from February 2020 to August 2022. Both outpatients and inpatients were included in the study. This study was approved by the Institutional Review Board and Ethics Committee of Nagoya City University Graduate School of Medical Science and was conducted in accordance with the principles of the Declaration of Helsinki. All participants were provided with a detailed description of the purpose and methods of the study before completing the questionnaire. Written informed consent was obtained from all the participants. The study was registered with the University Hospital Medical Information Network (UMIN000038924).
Patients
Inclusion criteria were as follows: (a) diagnosis of any cancer type including hematological malignancy, (b) age 20-75 years, (c) pain related to cancer, (d) average pain intensity ≥4 on a 0-10 Numerical Rating Scale in the last 24 hours, (e) adequate dose titration and current treatment with oral morphine equivalent of 60 mg/day or more, and (f) ability to take oral medication. The exclusion criteria were as follows: (a) disturbed consciousness, (b) cognitive impairment, (c) undergoing or preplanned concurrent radiotherapy, (d) first-line chemotherapy started 7 days before enrollment, (e) QTc prolongation (male >470 ms, female >480 ms), and (f) contraindications for methadone.
Study treatments
In patients receiving ongoing opioids with oral morphine equivalents less than 120 mg/day, oral methadone was started at a dose of 5 mg/day. In patients with ongoing opioids receiving oral morphine equivalents ≥ 120 mg/day, oral methadone was started at a dose of 10 mg/day. Oral methadone has been introduced as an add-on medication to ongoing opioid therapy. In patients who experienced uncomfortable somnolence before combination therapy, the ongoing opioid therapy dose was reduced by 20 mg of oral morphine equivalents per 5 mg of methadone (methadone was started as a partial opioid switch). The use of low-dose methadone and ongoing opioid therapy is shown in Figure 1 .
On day 8, the patients who reported satisfactory analgesia continued to receive the same dose of methadone. After day 7, the physicians increased the methadone dose. Ongoing opioid or methadone use was reduced in patients with uncomfortable somnolence during the study period. Adjuvant drugs could also be added by the physicians. The study period was 15 days.
Measurement
All patients reported pain intensity (both average pain and worst pain) over the last 24 hours, number of breakthrough opioids used, and the Patient-Reported Outcome (PRO)—Common Terminology Criteria for Adverse Events v.1.0, Japan Clinical Oncology Group version (CTCAE) at baseline and on days 8 and 15. 20
The primary endpoint was the percentage of patients with ≥33% average pain reduction from baseline. 5 , 21 The proportion of pain reduction was calculated using the following formula: (pain intensity at baseline − pain intensity on day 15)/(pain intensity at baseline) × 100. The secondary endpoints included the percentage of pain reduction (≥33% reduction in the worst pain from baseline, ≥50% reduction in average from baseline, and ≥50 reduction in the worst pain from baseline), pain intensity over the last 24 hours on days 8 and 15 (both average pain and worst pain), frequency of daily breakthrough opioid use, and adverse events. Adverse events, including nausea, vomiting, constipation, and somnolence, were assessed using PRO-CTCAE. Delirium was assessed using the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, when the patient developed disturbance of consciousness during the study period.
Data collection
At the baseline assessment, patient characteristics, including age, sex, primary cancer site, clinical stage, comorbidity, Eastern Cooperative Oncology Group performance status, and laboratory tests (serum bilirubin, aspartate aminotransferase, alanine aminotransferase, creatinine, calcium, potassium, magnesium, and QTc interval 22 ) were assessed from the medical records. Pain intensity, frequency of daily rescue use, and adverse events, including QTc prolongation, were assessed at baseline, on days 8 and 15. The mechanism of cancer pain was assessed by a palliative care physician (Diplomate, Specialty Board of Palliative Medicine, Japanese Society for Palliative Medicine), and neuropathic pain was diagnosed based on the International Association for the Study of Pain algorithm. Opioids, nonsteroidal anti-inflammatory drugs, acetaminophen, and other co-analgesics (such as anticonvulsants, antidepressants, and steroids) were also recorded at baseline, on days 8 and 15. Continued methadone use was assessed on days 8, 15, and 29.
Sample size calculation
Opioid switching is a standard strategy for refractory pain despite adequate opioid dose titration. 7–9 Based on previous studies, 5 we assumed that the response rate (≥33% reduction in average pain) to opioid switching for refractory pain would be approximately 40%. In this study, we set the threshold for the primary endpoint as the percentage of patients with ≥33% reduction in average pain from baseline at 40%. Assuming a set expected value of 70%, 16 patients were required in this study according to the exact binomial test (2-sided α = 0.1, 1 − β = 0.8). Considering patient ineligibility, a sample size of 19 patients was used.
Statistical analysis
Efficacy and adverse event analyses were performed on the intent-to-treat dataset, which included patients who received at least one methadone dose. The last observation-carried-forward method was used to impute missing and dropout data, including pain scores and adverse events, and the last observed non-missing value was used to fill in missing values at a later point in the study. We also adopted a complete case analysis for the sensitivity analysis to investigate the stability of the results.
To investigate pain reduction after the intervention, we conducted repeated-measures analyses of variance for all measures. Statistical significance was set at P < .05. Statistical analyses were performed using SPSS v.28.0 (IBM Corp., Armonk, NY, US).
Results
Characteristics
From February 2020 through August 2022, 27 patients received a combination of low-dose methadone and an ongoing opioid treatment. Of these 27 patients, 8 patients were excluded for the following reasons: undergoing radiotherapy ( n = 4), pre-planned radiotherapy ( n = 2), NRS (average pain intensity) < 4 ( n = 1), and delirium ( n = 1). Of the remaining 19 patients, all of whom were eligible and agreed to participate. All participated in the follow-up survey on day 8, and 14 participated on day 15 ( Figure 2 ). The median overall survival was 66 days (interquartile range, 52-206 days). During the 15-day study period, one participant died on day 14 because of cancer progression. The causes of pain were variable and included neuropathic pain, multiple bone metastases, cancerous skin ulcers, spinal cord infiltration, and visceral pain.
Before combination therapy, the following strong opioids were used: oxycodone in 9 patients (47.4%), morphine in 5 patients (26.3%), and fentanyl in 5 patients (26.3%). The mean oral morphine equivalent before combination therapy was 112.6 mg (standard deviation [SD], 44.8 mg), ranging from 60 to 216 mg (median, 90 mg; interquartile range [IQR], 80-120 mg).
The initial methadone dose was 5 mg in 12 patients (63.2%) and 10 mg in 7 (36.8%). Fourteen (73.7%) patients continued methadone treatment at the end of study period. On day 15, the methadone dose was 5 mg in 4 patients (21.1%), 10 mg in 6 (31.6%), 15 mg in 1 (5.3%), and 20 mg in 3 (15.8%).
At baseline, co-analgesics included nonsteroidal anti-inflammatory drugs in 13 patients (68.4%), acetaminophen in 8 (42.1%), anticonvulsants in 8 (42.1%), and corticosteroids in 2 (10.5%).
The average number of breakthrough opioids use at baseline was 2.7 times per day, ranging from 0 to 10 (IQR, 1-4).
Response rate and pain intensity
On day 15, ≥33% reduction in average pain from baseline was achieved in 13 (68.4%; 95% CI, 43.4 - 87.4)—the lower limit of the 95% CI exceeded the 40% threshold. In sensitivity analysis using complete cases, pain reduction of 33% or more from baseline (average pain) was achieved in 10 (71.4%; 95% CI, 41.9-91.6) ( Table 1 ).
Table 1.
Percentage of patients with a ≥ 33% or ≥50% reduction in average and worst pain from baseline on days 8 and 15.
Abbreviation: CI, confidence interval.
| Definition of response | ≥33% pain reduction | ≥50% pain reduction |
| Percentage (95% CI) | Percentage (95% CI) | |
| Average pain | ||
| Day 8 | 42.1 (20.3-66.5) | 26.3 (9.1-51.2) |
| Day 15 | 68.4 (43.4-87.4) | 52.6 (28.9-75.6) |
| Worst pain | ||
| Day 8 | 26.3 (9.1-51.2) | 15.8 (3.4-39.6) |
| Day 15 | 36.8 (16.3-61.6) | 21.1 (6.1-45.6) |
Regarding pain intensity ( Figure 3 ), the mean average pain intensity significantly decreased from 5.9 (SD 1.8) at baseline to 4.2 (2.2) on day 8 and 3.3 (1.4) on day 15 ( P < .001), and the mean worst pain intensity significantly decreased from 8.7 (1.0) at baseline to 6.8 (2.3) on day 8 and 6.2 (2.3) on day 15 ( P < .001). The mean change in average pain intensity on day 15 was 2.6 (1.4); the mean change in worst pain intensity on day 15 was 2.5 (2.1). During the 15-day study, no patient experienced worse average pain, and only one patient experienced an exacerbation of the worst pain.
Adverse events
The most common opioid-related side adverse effect before combination therapy was somnolence (100%). Nausea, vomiting, constipation, and somnolence that was new or had worsened from baseline were reported in 26.3%, 26.3%, 5.3%, and 26.3% of patients, respectively. One patient reported Grade 4 somnolence, but there were no limitations in activities of daily living.
QTc prolongation was observed in 2 patients. In 1 male patient, the QTc was 507 msec on day 14. In addition to methadone 20 mg/day, levofloxacin 500 mg/day and trazodone 75 mg/day were administered. Methadone was continued at 20 mg/day, levofloxacin was discontinued, and the trazodone dose was reduced, resulting in a QTc of 420 ms. In 1 female patient, the QTc was 532 msec on day 13. In addition to methadone 20 mg/day, levofloxacin 250 mg/day and fluconazole 50 mg/day were administered. Discontinuation of levofloxacin and fluconazole was not possible, and the methadone dose was reduced to 15 mg/day, resulting in a QTc of 425 ms. No QTc prolongation was observed in other patients. Delirium was observed in one patient. Besides methadone, a direct risk factor for delirium is tumor brain invasion.
Co-intervention
The average number of breakthrough opioids use was 2.3 times (0-7 times) per day on day 8 and 2.4 times (0-6 times) per day on day 15.
The mean oral morphine equivalents of other combination therapy were 87.7 mg (SD, 25.6 mg), ranging from 60 to 120 mg (median, 90 mg; IQR, 60-120 mg) on day 8, 66.3 mg (SD, 28.8 mg), ranging from 30 to 120 mg (median, 60 mg; IQR, 46-90 mg) on day 15.
No patient received new co-analgesics other than an opioid during the study period. Furthermore, no patients received radiotherapy during the study period. Of the 19 patients, 11 received ongoing anticancer treatment during the study period. Only one patient with multiple myeloma had an anti-tumor effect but failed to achieve pain reduction of ≥33% from baseline. The remaining 10 patients, who received ongoing anticancer treatment, showed no antitumor effects.
Conclusion
In this open-label prospective study, the combined use of low-dose methadone and ongoing opioid treatment appeared to be safe, and reduced cancer pain that did not respond to conventional opioid therapy. Further research is needed to investigate the efficacy of the combined use of low-dose methadone and ongoing opioids, using appropriately designed randomized controlled trials.
Acknowledgments
We convey our sincere appreciation to all participants.
Funding
This work was supported in part by a Grant-in-Aid for Scientific Research from the Japanese Society for the Promotion of Science, Japan (Grant Number 23K16438 to T.H.).
Conflict of interest
The authors have no conflicts of interest to disclose.
Data availability
The data underlying this article will be shared on reasonable request to the corresponding author.
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