Addition of Methadone to Another Opioid in the Management of Moderate to Severe Cancer Pain: A Case Series

Introduction

Amongst the strategies for the treatment of moderate to severe cancer pain, there is growing interest in simultaneously combining two opioids that target different opioid receptors. This approach, known as combination opioid therapy, has the potential to improve analgesic control, limit the development of opioid tolerance, and decrease opioid-related adverse effects. ¹ The scientific basis for combination opioid therapy is complex, but preclinical and clinical scientific work in this area is encouraging.^2–5

Due to the action of methadone on unique opioid and nonopioid receptor sites not shared by other opioids, methadone seems to be a particularly good candidate for combination opioid therapy, but literature on combination therapy with methadone is scant.^6–8 To the best of the authors' knowledge there are only two published case series on the use of methadone in addition to another opioid in the context of malignant pain.^7,8 These case series have suggested that low-dose methadone may be used safely as a coanalgesic, but both lacked a quantitative outcome measure.

The aim of this retrospective review was to assess quantitatively the impact of adding methadone to an existing opioid in the management of moderate to severe cancer-related pain.

Methods

Ethical approval was obtained from the University Health Network (UHN) research ethics board. All outpatients attending the Oncology Palliative Care Clinic (OPCC) at Princess Margaret Hospital from September 2010 to September 2011, who had received methadone, were identified from pharmacy records. Inclusion criteria were histological diagnosis of malignancy, over 18 years of age, Edmonton Symptom Assessment System (ESAS) pain score prior to starting methadone of ≥4, and taking methadone in addition to another opioid. Exclusion criteria were patients rotated completely to methadone and those with no available follow-up ESAS pain score.

The data were obtained from the electronic patient database and were reviewed retrospectively for demographic information (age and gender); diagnosis and extent of disease; adverse effects; and ESAS pain, nausea, drowsiness, and constipation scores. The ESAS is a valid and reliable measure and is one of the key assessment tools used in palliative care.^9–11 Patients visiting the OPCC are requested to complete the ESAS at each clinic visit. Follow-up visits are generally scheduled at one-month intervals, depending on the need and convenience of the individual patient. Titration of methadone was based on the analgesic control achieved, and how well methadone was tolerated by patients. Titration was performed during regular patient assessments in the OPCC or by telephone between clinic appointments.

The primary outcome for the study was the difference in ESAS pain score from methadone initiation to one month later. A decrease in ESAS of two points was considered clinically meaningful; this is a conservative definition, with scores of one to two used in previous studies.^12–14 If no pain score was available at one month, the score closest to the one-month interval was used. Dosage of all concomitant analgesics at baseline and follow-up were recorded. All routine opioids were converted to daily morphine equivalents and a daily routine morphine equivalent (DRME) was calculated using standard conversion factors^15–19 (see Table 1); breakthrough doses could not be captured, because these were not consistently recorded in the patient's medical record. All adjuvant medications at methadone initiation and follow-up were also noted. Secondary outcome measures, which included ESAS nausea, constipation, and drowsiness scores, were recorded concomitantly.

Results

Thirty-seven patients were identified from pharmacy records as having been prescribed methadone during the study period. Eleven patients with no documented ESAS at initiation or follow-up were excluded. Also excluded were three patients who were not taking another opioid, two patients who were rotated solely to methadone, and one patient with a baseline ESAS pain score <4. Twenty patients were prescribed methadone in conjunction with another opioid and had ESAS pain scores available for analysis (see Table 2). Nineteen of these were taking long-acting opioids at methadone initiation: seven oxycontin (35%), six hydromorphone (30%), four topical fentanyl (20%), and two morphine (10%). One patient was unable to absorb long-acting opioids due to previous bowel surgery and was unable to tolerate topical opioids. This patient was taking oxycodone immediate-release (IR) at routine intervals.

The mean DRME (excluding methadone) at methadone initiation was 338+/−217.8 mg/day (median 291 mg, range 90–900 mg). Each patient was taking a mean of 1.8+/−1.9 (median 2, range 0–3) adjuvant analgesic agents at methadone initiation, which was unchanged at the time of evaluation. Fourteen patients (70%) were using adjuvant anticonvulsant neuropathic agents: gabapentin (n=12) and pregabalin (n=2).

The mean methadone dose at initiation was 4.4+/−1.4 mg/day (median 5 mg, range 2–7.5 mg). At the time of evaluation, the dose was increased from the initiation dose in 17 (85%) of the 20 patients; 3 patients remained on the same methadone dose. The mean final dose of methadone was 15.5+/−15.9 mg/day (median 10 mg, range 3–60 mg). The mean daily routine morphine dose (excluding methadone) at the time of evaluation was 332+/−191 mg/day (median 228, range 60–675). The mean ESAS pain score at methadone initiation was 7.7+/−1.8 (median 8, range 4–10) and decreased to 5.2+/−2.4 (median 5, range 2–10) at the time of evaluation. In 15 of 20 cases (75%) there was a decrease of two or more points; of these, eight (40%) had a decrease in ESAS of two or greater at one month. Seven patients (35%) had no ESAS documented at one month but had an improved pain score at the time point closest to one month.

Methadone was well tolerated by 17 patients (85%). The mean ESAS for drowsiness was 5.7+/−2.5 (median 6, range 0–10) at methadone initiation and 4.3+/−2.7 (median 4, range 0–10) at evaluation. The mean ESAS for nausea was 2.4+/−2.3 (median 1.5, range 0–6) at methadone initiation and 2.2+/−3.4 (median 1, range 0–10) at evaluation; and the mean ESAS for constipation at methadone initiation was 4.4+/−3.7 (median 3.5, range 0–10) and 3.1+/−3.3 (median 2, range 0–10) at evaluation. Twelve patients also had routine electrocardiograms performed while on methadone. Two of these patients (17%) developed a prolonged corrected QT interval during the titration period and thus the doses were not titrated upwards any further.

Discussion

The addition of methadone as a coanalgesic to another opioid appears to have a beneficial impact on uncontrolled moderate to severe cancer pain, with improved pain control in 40% of patients in our study at one month and a further 35% at a different time point. Adding methadone was safe and well-tolerated. The addition of methadone as a coanalgesic may offer an alternative and practical approach for the treatment of pain in patients already taking another opioid. This study also provides evidence on the incidence of possible adverse effects of this combination, including nausea, drowsiness, and constipation.

Compared with many other pain medications currently in use, methadone is a less expensive option and is associated with greater ease of administration. ²⁰ Typically, patients are admitted to hospital for rotation to methadone under specialist supervision in order to ensure adequate monitoring for delayed toxicity. ²¹ Inpatient admission for commencing methadone as a coanalgesic may not be necessary, as patients in our study were safely titrated on an outpatient basis. Methadone as a coanalgesic may therefore represent a practical option for patients with advanced cancer and complex pain in the outpatient setting, providing that close monitoring is performed.

The starting dose and frequency of methadone administration in our study varied according to the prescribing physician, but doses at initiation were quite small, with the most commonly used starting dose of 2.5 mg bid (65% of cases). This compares to a starting dose of 2.5–5 mg/day for the Haughey and colleagues case series and 10 mg/day in the McKenna and Nicholson case series.^7,8 Increments of 2.5 mg bid were most commonly used for titration, depending on the analgesic response and how well the medication was tolerated by the patient. The final methadone dose at the time of evaluation was 15.2 mg, which compares to 20 mg in the other two case series.^7,8

When considering using methadone as a coanalgesic, we suggest that a low dose (at most, 2.5 mg bid) should be initiated and the dose gradually increased in increments of 2.5 mg bid every three to four days, as tolerated. Methadone titrated according to this regime in our study was safe and well tolerated. Adverse effects of opioids, such as sedation, constipation, nausea, and respiratory depression, which also apply to methadone, were monitored during this study and did not change substantially during the evaluated time period. No patients in our study discontinued methadone. Methadone was temporarily discontinued in one patient, but was later successfully recommenced and the dose titrated with good effect.

Limitations of this study include the retrospective uncontrolled study design and the small sample size. Due to patients not necessarily having appointments with ESAS pain scores at one-month intervals and nonrecording of pain scores during some methadone titrations via telephone, it was not always possible to determine ESAS values at the desired point of evaluation (i.e., one month). Changes to concurrent opioids or other adjuvant medications might also have contributed to the beneficial effect of methadone. It was not possible to establish the amount of breakthrough doses that patients were taking, as this was a retrospective study and patients and did not keep records of their breakthrough dose. However, the overall daily routine opioid dose (excluding methadone) either remained the same or was decreased in the majority of patients and there were no substantial changes in adjuvant pain medications.

This study on adding methadone to another opioid for moderate to severe pain provides promising retrospective, quantitative data regarding the addition of methadone to another opioid in the management of cancer-related pain. Appropriately designed prospective studies, including randomized controlled trials, are needed to confirm the efficacy of this novel approach.