Low-dose methadone added to another opioid for cancer pain: a multicentre prospective study

Abstract

Context: The use of methadone for cancer pain management is gaining wider acceptance. However, switching to methadone treatment can still pose challenges. Consequently, there is ongoing development of its use in low doses in combination with other opioids, despite a lack of clinical evidence regarding its efficacy and safety.

Objectives: This study aimed to evaluate the efficacy and tolerability of low-dose methadone in combination with another opioid in patients with moderate-to-severe cancer-related pain in a clinical setting.

Patients and methods: This was a prospective, open-label study conducted in 19 pain and/or palliative care centres treating patients with cancer-related pain. Pain intensity, patients' global impression of change, and adverse effects were assessed on day 7 and day 14. The main outcome measure was the proportion of responders.

Results: The study included 92 patients. The daily dose of methadone was 3 [3-6] mg at baseline, 9 [4-10] mg on day 7 and 10 [6-15] mg on day 14. The NRS pain ratings significantly decreased from 7 [6-8] at baseline to 5 [3-6] on visit 2 (p < .0001) and 4 [3-6] on visit 3 (p < .0001). Similarly, the VRS pain ratings decreased from 3 [3-3] at baseline to 2 [2-3] on visit 2 (p = 0.026) and 2 [1-3] (p < 0.001) on visit 3. At Visits 1 and 2, half of the patients were considered Responders. Of those responders, 73.5% were High-Responders at Visit 1 and 58.7% were High-Responders at Visit 2. No adverse events related to the risk of QT prolongation, overdose, or drug interactions were reported.

Conclusion: For patients experiencing moderate to severe cancer-related pain despite initial opioid treatment, our study found that low-dose methadone, when used in combination with another opioid, was both safe and effective. This supports the use of methadone as an adjunct to opioid-based treatment for cancer pain.

Keywords: Cancer pain; Efficacy; Methadone co-analgesia; Titration; Tolerance.

Fig. 1

Flow chart

Fig. 2

Pain response. Changes in pain intensity were assessed using the Numeric Rating Scale (NRS) and the Verbal Rating Scale (VRS) over the study period. The box plot shows the interquartile range and median, with whiskers representing the full data range. NRS pain ratings significantly decreased from 7 [6–8] at Visit 1 to 5 [3–6] at Visit 2 (p < 0.0001) and 4 [3–6] at Visit 3 (p < 0.0001). VRS pain ratings also decreased from 3 [3] at baseline to 2 [2, 3] at Visit 2 (p = 0.0026) and 2 [1–3] at Visit 3 (p < 0.001)

Fig. 3

Patients’ Global Impression of Change during the study period. The box plot displays the interquartile range with the median value. The whiskers represent the maximum and minimum data values. ****p < 0.0001

Fig. 4

Response profile: High Responder (≥ 50% reduction in pain intensity or 'very much improved' on the PGIC compared to baseline), Responder ((≥ 30% reduction in pain intensity or 'much improved' on the PGIC compared to baseline), Non-Responder (< 30% reduction in pain intensity or 'minimally improved' or less on the PGIC compared to baseline)

Fig. 5

Opioid-sparing effect among responders. The figure illustrates the opioid-sparing effect in responders, as indicated by the Oral Morphine Equivalent Daily Dose (OMEDD) over time. The box plot represents the interquartile range and median, with whiskers showing the full data range. Significant reductions in OMEDD were observed from baseline to Visit 2 (p = 0.038) and from baseline to Visit 3 (p = 0.0023)