E EDITORIAL

Methadone: New Indications for an Old Drug?

Glenn S. Murphy, MD,* Christopher L. Wu, MD,†‡ and Edward J. Mascha, PhD§

See Article, p 1723

GLOSSARY
TSA = trial sequential analysis

O
ver the past 4 decades, there has been a transition analgesia throughout the most painful period of the early
in clinical practices from the use of long-acting to recovery process. In addition, methadone is a mixture of 2
shorter-acting anesthetic agents, which have the enantiomers (a µ-opioid receptor agonist and a N-methyl-d-
advantages of ease of titration and more rapid recovery aspartate receptor antagonist)7; N-methyl-d-aspartate recep-
profiles. Older drugs such as isoflurane, pancuronium, and tor antagonism may reduce the risk of the development of
morphine have been replaced at most medical centers by hyperalgesia, opioid tolerance, and chronic postsurgical pain.
sevoflurane, rocuronium, fentanyl, and remifentanil. The Furthermore, an inhibition of serotonin and norepinephrine
use of these agents has been demonstrated to result in more uptake in the central nervous system by this agent may fur-
rapid emergence times, a lower risk of residual neuromus- ther attenuate pain and enhance recovery.8 Despite these
cular blockade, and potentially a lower risk of postoperative potential advantages, methadone is infrequently utilized by
respiratory depression.1–3 In this era of Enhanced Recovery clinicians in the perioperative setting. The reasons why anes-
After Surgery protocols, the administration of medications thesiologists may be reluctant to introduce methadone into
that facilitate shorter recovery times, earlier mobilization, their clinical practices are uncertain, but may be related to
reduced drug-related complications, and decrease opioid use concerns about prolonged respiratory depression, the limited
and opioid-related side effects, has assumed increased impor- number of published clinical studies (20), as well as current
tance. In light of these developments, it appears somewhat trends to reduce the use of intraoperative opioids. We hope
counterintuitive to consider the administration of a much that the findings from the meta-analysis by Machado et al4
older and much longer-acting opioid, methadone (devel- may encourage clinicians to consider methadone as an alter-
oped in Germany in 1939), to patients undergoing surgical nate opioid in the perioperative setting.
procedures. The meta-analysis by Machado et al4 in this issue Machado et al4 provide important new data about the effi-
of Anesthesia & Analgesia provides important information to cacy and safety of methadone in surgical patients. The authors
clinicians as to whether the potential benefits of methadone reported that subjects administered methadone had lower
outweigh the risks in contemporary anesthesia practices. pain scores at rest and with movement 24, 48, and 72 hours
As noted by the authors, methadone has several unique postoperatively, when compared to patients given traditional
pharmacokinetic and pharmacodynamic properties that may shorter-acting opioids. Furthermore, subjects in the metha-
be advantageous in the patients undergoing a surgery. When done groups had significant reductions in the need for postop-
larger doses of methadone are administered at anesthetic erative opioids in the first 72 hours after surgery. Surprisingly,
induction (20 mg), a prolonged plasma half-life of approxi- the greatest analgesic benefit appeared to be present during
mately 35 hours has been reported,5,6 which may provide the 24- to 48-hour postoperative period, with significant reduc-
tions in pain scores and opioid requirements persisting up to
From the *Department of Anesthesiology, NorthShore University 72 hours. Following the administration of a single 20-mg dose
HealthSystem, University of Chicago Pritzker School of Medicine, Evanston,
Illinois; †Department of Anesthesiology, Critical Care and Pain Management, of methadone (doses of ≤20 mg were used in most trials), sim-
Hospital for Special Surgery, New York, New York; ‡Department of ulated blood methadone concentrations drop below the mini-
Anesthesiology, Hospital for Special Surgery, Weill Cornell Medicine, New mal effective analgesic concentrations (31.6 ± 11.1 ng/mL)6
York, New York; and §Departments of Quantitative Health Sciences and
Outcomes Research, Cleveland Clinic Lerner College of Medicine at Case within 24 hours.5 These findings suggest that mechanisms
Western Reserve University, Cleveland, Ohio. other than µ-receptor activation may play an important role
Accepted for publication September 4, 2019. in the prolonged analgesic efficacy of this agent. Only 1 inves-
Funding: None. tigation examined postoperative recovery from methadone
Conflicts of Interest: See Disclosures at the end of the article. beyond 72 hours. In this study, ambulatory surgical patients
Reprints will not be available from the authors. administered 0.15 mg/kg methadone (median dose of 9 mg)
Address correspondence to Glenn S. Murphy, MD, Department of Anesthe- had significantly less pain at rest and required 50% fewer opi-
siology, NorthShore University HealthSystem, 2650 Ridge Ave, Evanston, IL
60201. Address e-mail to [email protected].
oid pills during the first 30 postoperative days.9 Further inves-
Copyright © 2019 International Anesthesia Research Society
tigations are needed to determine if intraoperative methadone
DOI: 10.1213/ANE.0000000000004472 enhances patient recovery after hospital discharge.

1456 www.anesthesia-analgesia.org December 2019 • Volume 129 • Number 6

Copyright © 2019 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
 Methadone in Surgery

Machado et al4 also reported that postoperative compli- imposed no restrictions with respect to language; a ran-
cations did not differ between the methadone and control dom-effects method was used for studies with high het-
groups. No differences were observed between groups in erogeneity, and the small-study effect was examined with
the incidences of nausea and vomiting, cardiovascular funnel plot. The risk of bias assessment was performed for
complications, or adverse respiratory events. Of particular each study included in the meta-analysis including selec-
concern for clinicians is the potential for prolonged respira- tion bias, performance bias, detection bias, attrition bias,
tory depression following the use of a long-acting opioid. and reporting bias.
However, due to rapid redistribution after a bolus dose A salient statistical feature of the study by Machado et
at induction of anesthesia, anticipated blood methadone al4 is the incorporation of a joint hypothesis testing frame-
decreases below the threshold of respiratory depression work in which they defined the primary outcome as “pain
(approximately 100 ng/mL) within 45 minutes (at a time management,” comprising of postoperative pain scores
when the airway is controlled).5 Furthermore, the adminis- and opioid consumption. The authors designed the study
tration of intraoperative methadone may potentially attenu- to only conclude methadone is better than other opioids on
ate the risk of respiratory depression by decreasing the need pain management if it was shown to be superior on both
for postoperative opioid medications. However, caregivers of these 2 components in the meta-analysis.13 Because pain
at all levels should be educated to administer smaller doses scores and opioid consumption are obviously related, and
of traditional postoperative opioids to avoid the potential may depend on each other, a joint hypothesis test was
for an additive or synergistic respiratory depressant effect appropriate. It would not have been appropriate in this
with the intraoperative dose of methadone. Although no setting to make opioid consumption the lone primary end
studies (randomized, observational, or retrospective) have point and leave pain scores as secondary measures—or vice
documented an increased risk of respiratory depression or versa. Reducing opioid consumption while allowing pain
hypoxemic events in patients administered methadone dur- to be higher is not the desired pain management strategy.
ing the hospitalization, it is important to note that continu- Neither would it be desirable to show superiority on opioid
ous respiratory rate monitoring and pulse oximetry were consumption as the primary end point and report that “no
not used in any of the studies, and no investigation was difference was found” on mean pain scores (or vice versa).
adequately powered to assess these important outcomes. In A joint hypothesis testing framework allows investigators
addition, Machado et al4 do not report on the effect of meth- to state a priori what the decision rule across a set of related
adone on bowel function. Opioid-induced postoperative outcomes will be for claiming one intervention is better than
ileus is a primary cause of increased hospital length of stay another. Requiring superiority on all outcomes, as specified
after abdominal surgery, and only 1 randomized trial has by Machado et al,4 is only 1 option. When a prespecified
assessed the effect methadone on return of bowel function result (eg, superiority) is required on all outcomes in the
(no difference between the methadone and control group).10 joint hypothesis, it is called an “intersection-union test” and
The meta-analytic technique used by Machado et al4 no adjustment for type I error is required. Another option
is a widely accepted method for this type of investigation would have been to require at least noninferiority on both
but it is not without its detractors. Although many health outcomes, and superiority on at least one of them. In that
care professionals are drawn to the simplicity of the single case, an adjustment for multiple testing would be needed
pooled estimate that a meta-analysis provides with the for the second stage, superiority testing, because signifi-
summation of all available trials, one must realize that the cance on either outcome would suffice. We recommend that
meta-analytic technique is in essence the result of com- joint hypothesis testing be considered for pain management
bining many design differences (eg, study quality, study studies, as well as other designs in which a single outcome
populations, surgical procedures, drug regimens, outcomes variable does not sufficiently address the primary objective.
assessed)11 into a single pooled estimate. Often, there may Trial Sequential Analysis (TSA) is a modern statistical tool
be significant bias or confounding in the pooling of highly whose goals are 2-fold: (1) control the type I error (or chance
varied studies.12 In addition, a number of meta-analyses of false-positive findings) over the repeated meta-analysis
will limit their systematic literature searches to include only “looks” across time in the history of a research question, and
English language papers and may not include data from (2) give guidance to the research community on whether or
nontraditional sources or abstracts. As such, it may be dif- not the current meta-analyses provides sufficient evidence
ficult to extrapolate the results of a meta-analysis back to an to make a definitive statistical (not clinical or qualitative)
individual patient or condition. determination on whether the intervention of interest is
The authors have acknowledged the limitations of effective or not, or whether more studies are needed.14 TSA
using the meta-analytic technique for their work including controls the type I error across a series of meta-analyses
the low quality of evidence used, different types of sur- over time analogous to how a “group sequential” design is
gical procedures examined, multiple analgesic and anes- used to control type I error across multiple interim analyses
thetic approaches among studies, wide variation in the in a clinical trial.15 As displayed in Figure 4 of Machado et
doses of opioids, and the presence of small sample sizes al,4 crossing the green lines would determine significance
in available trials (only 3 of the 13 investigations included if no adjustment for multiple analyses over time was made
in this meta-analysis enrolled ≥100 subjects). Nevertheless, on the research topic, while the Z-statistic line (blue line,
the current study does undertake a number of steps to signal-to-noise ratio) landing outside the red lines indicates
mitigate the potential limitations of the meta-analytic significance (efficacy or harm) after accounting for the mul-
technique. The authors undertook a detailed search pro- tiple analyses over time. In this study, the statistical signal
cess that included published and unpublished papers and for pain score was strong, evidenced by the Z-statistic line

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 EE EDITORIAL

showing efficacy, as well as surpassing the required sample Conflicts of Interest: None.
size determined by the TSA algorithm to definitively answer This manuscript was handled by: Honorio T. Benzon, MD.
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