Pain is one of the most common and unbearable symptoms experienced by cancer patients; it seriously impairs their quality of life [1, 2]. Approximately 53% of cancer patients, and 60–70% of advanced cancer patients experience pain, more than one-third of which is moderate-to-severe [3]. Opioids, including morphine, oxycodone, and fentanyl, are cornerstones for the treatment of moderate-to-severe cancer pain [4]. However, 10–20% of patients who are prescribed opioids still experience inadequate pain relief and/or intolerable adverse reactions, which can be defined as refractory pain [5,6,7]. Methadone is commonly considered an alternative opioid treatment for refractory cancer pain [8,9,10,11].
Methadone is a synthetic µ-opioid receptor agonist that has a stronger affinity for δ opioid receptors than morphine [12]. Methadone is also an antagonist of the N-methyl-D-aspartic acid (NMDA) receptor and inhibits the reuptake of serotonin and norepinephrine [13, 14]. Given the advantages of methadone, including long-lasting analgesia, high oral bioavailability, good safety in patients with renal dysfunction, and low cost, its application in cancer pain treatment has attracted great attention [15]. Furthermore, the characteristics of extra-opioid analgesic action and anti-hyperalgesic properties make methadone a promising agent for the treatment of opioid resistance, central sensitization, and opioid-induced hyperalgesia [10, 16].
However, the application of methadone in cancer pain treatment remains challenging due to its complicated and inconsistent conversion ratio from pre-switching opioid dose to methadone [17]. Additionally, adverse methadone-related cardiac events are of concern, especially cardiotoxicity of prolonged corrected QT interval (QTc) and torsade de pointes (TdP) [18, 19]. Clinical data on methadone for cancer pain management are still limited, especially for Asian patients [8, 9, 17, 20]. Therefore, the present study aimed to evaluate the efficacy, tolerance, and economy of opioid switching to methadone in the management of refractory cancer pain.
Methods
A retrospective study was conducted in patients who used methadone for cancer pain in Zhejiang Cancer Hospital from April 2016 to December 2020.
Patients were included if they met the following inclusion criteria: (1) they had methadone prescribed for compromised pain control and/or intolerable opioid-related adverse reactions to opioids, including long-acting morphine and oxycodone, transdermal fentanyl, and patient-controlled analgesia; (2) they had available data on pain control, adverse events, and cost of both methadone and opioid regimens prior to methadone administration. This study conformed with the principles of the Declaration of Helsinki and was approved by the institutional ethics board of the Zhejiang Cancer Hospital (No. IRB-2022-86).
Data on patient demographics, cancer diagnosis, disease stage, bone metastasis, pain type, and Karnofsky score were collected. Details regarding previously prescribed opioids, reason for methadone prescription and discontinuation, methods of methadone switching, initial and maintenance doses of methadone, and pain control and adverse events of both methadone and prior opioids were also recorded. Pre- and post-switching analgesia efficacy was assessed and compared using the pain intensity score and daily frequency of breakthrough pain (BTP). Pain intensity scores were measured using the numeric rating scale (NRS) (ranging from 0 to 10, with 0 = no pain and 10 = worst pain imaginable). Successful switching of methadone was defined as adequate pain relief (pain intensity score ≤ 3 requiring no more than three supplemental doses for breakthrough pain per 24 h) with no occurrence of intolerable adverse events. Adverse events were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0) [21].
The oral morphine equivalent daily dose (OMEDD) of long-acting opioids and opioids for patient-controlled analgesia (PCA) was calculated according to the recommendation of opioid equivalences and relative potency of the National Comprehensive Cancer Network (NCCN) clinical practice guidelines for cancer pain [22]. The conversion ratio from opioids to methadone was calculated by dividing the OMEDD of prior opioids by the dosage of methadone.
Costs of analgesic regimens were calculated based on the costs of disposable infusion devices for electric infusion pumps and drugs for pain control: oxycodone hydrochloride prolonged-release tablets, fentanyl transdermal patches, methadone hydrochloride tablets, sufentanil citrate injection, hydromorphone hydrochloride injection, morphine hydrochloride injection, celecoxib, etoricoxib, and adjuvant analgesics such as gabapentin and pregabalin. Values/costs in Chinese Yuan were converted to US dollars (1 USD = 6.3715 CNY).
The Wilcoxon signed rank test was used to compare efficacy and cost before and after methadone switching, and the chi-squared test was used to analyze differences in the incidence of adverse reactions between methadone and other opioids. Binary logistic regression was conducted to evaluate the relationship between successful switching and factors including types of pain, reasons for switching, methods of switching, NRS before switching, BTP before switching, opioids prior to switching, and OMEDD of prior opioids. Odds ratios (ORs), including 95% confidence intervals, were calculated. Subsequently, multivariate analysis was performed to evaluate independent predictors of successful switching using the backward stepwise elimination method. Furthermore, subgroup analysis of subpopulations with compromised pain control was performed. Statistical analyses were performed using SPSS Statistics 23.0, and statistical significance was set at p < 0.05.
