Methadone Dose Selection for Treatment of Pain Compared with Consensus Recommendations

Introduction

Methadone is a long-acting opioid agonist and N-methyl-D-aspartate receptor antagonist; these features are thought to allow it to efficiently target both nociceptive and neuropathic pain. ¹ Methadone's status as chemically unrelated to morphine makes it an appealing option for patients unresponsive to that opioid and other chemically related opioids (e.g., oxycodone, hydrocodone, and hydromorphone); patients with end-stage renal failure; and those with a true morphine allergy or morphine intolerance. ² Methadone has a long and variable half-life of ∼15–60 hours, which (in some reports) is as high as 150 hours. ³ About one in every three opioid-related deaths is associated with methadone, a value significantly higher than any other opioid. ⁴ This increase in the number of methadone poisoning deaths in recent years has called into question the safe use of methadone for the indication of pain, ⁵ although the evidence for disproportionate risk of methadone in those with cancer-related pain is limited. ⁶

The variable half-life of methadone leads to prolonged exposure to a given dose in some patients, placing them at higher risk of toxicity. ⁷ Without knowledge of the drug's half-life in each patient, risk of overdose can be minimized by starting methadone at conservative doses and uptitrating slowly. As a result, dose individualization and close monitoring following the start of methadone are necessary. Various dose conversation strategies exist to facilitate safe and effective rotation to methadone from other opioids, but evidence to guide optimal strategies for initiation and titration is limited and conversion ratios are highly variable. The Freidman ⁸ and End of Life/Palliative Education Resource Center (EPERC) ¹ methods are two widely used approaches that account for previous opioid exposure to allow for the best estimate of target dosing. Each of these methods recommends—based on evidence of increased overdose risk for patients starting at higher morphine equivalent daily dose (MEDD) ⁹ —that only after the patient shows both safety and efficacy at a conservative initial dose should larger doses be considered. ⁷

The American Pain Society and the College on Problems of Drug Dependence in collaboration with the Heart Rhythm Society developed an additional clinical practice guideline in 2014 addressing methadone initiation, uptitration, and monitoring parameters. ⁷ Subsequent to publication of this guideline, a group of hospice and palliative care (HPC) experts largely agreed with these safety recommendations ¹⁰ specifically as related to dosing and titration when switching from other opioids to methadone with a focus on minimizing the risk of overdose and cardiac arrhythmia. Both guidelines advocate that if a patient is on higher doses of another opioid, initial dose should be 75%–90% less than the calculated equianalgesic dose and no higher than 30–40 mg per day.^7,10,11

The purpose of this retrospective chart review is to compare the current prescribing patterns with consensus recommendations for clinicians rotating opioid-tolerant patients to methadone for pain in a large academic medical center. A previous publication ¹² described the demographic characteristics of this patient population, including the fact that chart documentation identified clinicians' target dose in only 6% of cases and conversion factors were indicated in only 2%.

Methods

The University of California San Diego Human Research Protections Program granted institutional review board approval. This retrospective data analysis evaluated 98 adult hospitalized patients initiated on oral methadone for pain while in inpatient care from January 1, 2013, to January 1, 2015, at a large academic health system. This study utilized a subset of patients from a prior study ¹² with two further exclusions of patients who did not meet criteria for inclusion. One patient was discharged before receiving methadone and the other received methadone for both pain and substance use disorder. All data were collected from a single electronic medical record and captured on an Excel™ spreadsheet. Prior opioid therapy, medical services by specialty, and final daily dose of methadone during hospitalization were collected. Final daily dose of methadone was defined as the dose before discharge. MEDD in the 24 hours before methadone start was utilized to calculate recommended target dosing by both the EPERC ¹ and Friedman ⁸ conversion methods (see Appendix Table A1); all calculations were performed by the senior author (K.P.E.). Continuous data such as final daily dose of methadone are reported as means and standard deviations for overall and for each medical service.

Results

The overall mean MEDD for study patients in the 24 hours before methadone start was 677.5 mg (median 354.8 mg). Individual primary team averages included medicine, 585.8 mg (median 190 mg); burn, 991 mg (median 765 mg); and surgery (including trauma), 529.4 mg (median 466 mg). ¹² Average final daily methadone dose for new starts was 18.1 ± 16.7 mg. The overall, average recommended target dosing range was 35.2–43.6 mg (11.9–99.9 mg by the EPERC method and 2.8–81.3 mg by the Friedman method) compared with the range of the actual, average final methadone doses, which was 4.6–50 mg.

Those followed by the acute pain service had the highest average final daily methadone dose (27.8 ± 15.8 mg), followed by medicine (22.8 ± 19.2 mg), surgery (22.5 ± 13 mg), and palliative care (20.4 ± 20.1 mg) (see Table 1; Fig. 1). Considered together (n = 50), patients seen by the acute pain or palliative care service had a final daily methadone dose of 21.8 ± 19.4 mg. Based on the EPERC and Friedman guidelines, calculated target methadone dose was, respectively, 45.2 and 37.9 mg per day for pain service, 26 and 10.2 mg per day for medicine, 42.6 and 41 mg per day for surgery, and 42.4 and 37.6 mg per day for palliative care services. In 67.4% (n = 66) of patients, the final daily dose of methadone was below the calculated methadone equianalgesic dose target by both methadone conversion methods used. Only 13.3% of the time (n = 13) was the final dose above the recommended target dose; 38.5% (n = 5) of these patients were being followed by the palliative care service.

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FIG. 1.

Final mean methadone dose by specialty.

Methadone use by the burn service was notable, in that final methadone dose was below the target range 91.7% of the time (overall burn target range: 7.5–262.5 mg compared with average burn final dose of 8.2 ± 5.2 mg). As previously demonstrated, ¹² median MEDD in the 24 hours before methadone initiation for patients being started on methadone for pain by the burn service was 765 mg (range 75–3660 mg).

As previously reported, patients' overall hospital length of stay median, 25th, and 75th percentile were 23.5, 9, and 45.5 days, respectively. Length of stay after methadone was initiated was under 3 days for 13 patients, 4–7 days for 21 patients, and over 7 days for 64 patients. ¹² The final daily dose of methadone was frequently below the recommended range in those followed by pain (66.7% of patients' doses were below the recommended range), palliative (66.7%), surgery (57%), and medicine (25%) (see Fig. 2). For patients with a dose below the recommended target range, the average dose was 35 mg (64.1%) below the lowest recommended target dose. No patient received an opioid reversal agent during the course of their index hospitalization. ¹²

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FIG. 2.

Final mean methadone dose compared with recommended dose by conversion method.

Discussion

In this retrospective study of the dosing behavior of prescribers rotating patients to methadone for pain at a large academic health system, we found an average, final methadone dose range of 18.1 ± 16.7 mg. This compares favorably with the conservative HPC-specific recommendation that starting doses be no higher than 30–40 mg per day.^10,11 Given that so few prescribers documented their rationale for selecting methadone doses, it is unclear whether those providers were explicitly utilizing these guidelines or others like them. ¹² Regardless, as demonstrated in a previous publication, this patient population did not have any adverse effects related to methadone while in the hospital. ¹² Additionally, these findings demonstrate that in two-thirds of inpatients, the final methadone dose was below the equianalgesic range (as calculated by the EPERC and Friedman methods) by an average of 35 mg or 64%. This falls somewhat short of recommendations that an initial methadone dose in an opioid-tolerant patient should be 75%–90% less than the calculated equianalgesic dose.^7,10 This is even more notable given that 64% of patients in this study had a length of stay of more than seven days after the start of methadone, ¹² giving reasonably ample time for the methadone to come to steady-state levels.

More than 80% of patients' methadone doses fell below the range recommended by the EPERC and Friedman methods without evidence of adverse effects. If we presume that final methadone doses in this study were deemed clinically effective and without unwanted effects by prescribers, these findings may call into question the utility of selecting doses larger than 30–40 mg per day in the event the EPERC and Friedman calculations recommend higher doses than this range. Meanwhile, methadone use by the burn service for patients with pain due to acute burns falls markedly outside ranges of recommended dosing, suggesting that methadone may be acting more as an adjuvant in this situation, although this deserves further attention.^13,14

These data are limited by our study's small sample size and retrospective nature. We have also not taken into account all of the variety of recommended methods of methadone dosing. This study was designed to analyze only those patients started on methadone for the first time while in the hospital and only for the treatment of pain. Additionally, titration may have continued after hospital discharge, which was not possible to capture. As such, we may have missed descriptive data related to other uses of methadone such as ambulatory prescribing habits, patterns related to methadone uptitration, or practices in the setting of opioid use disorders.

Conclusions

Retrospective chart review of the prescribing patterns for target dose selection during rotation to methadone for pain indicates that prescribers vary from recommended consensus methodologies, but fall within more recent, conservative palliative care-specific guidance. ¹⁰ Further prospective research is necessary to determine the safest and most effective manner for selecting methadone target dosing in the management of pain. Until such time, health system-specific guidelines for methadone dose selection, monitoring parameters, documentation, and follow-up may help mitigate practice variation.