Single dose intraoperative methadone and QTc interval: A prospective observational cohort investigation

Abstract

Background:

Methadone is increasingly used for perioperative care. High-dose methadone, for opioid use disorder or chronic pain, can prolong the cardiac QTc interval, which increases the risk of dangerous cardiac arrhythmias. This investigation evaluated single-dose perioperative methadone effects on QTc.

Methods:

This prospective observational cohort study evaluated adults undergoing elective surgery under general anaesthesia. Patients received intravenous methadone or no methadone (typically fentanyl) at induction (provider discretion). QTc was determined before and for 1 hr after opioid administration and rate-corrected using Fridericia’s formula (QTcF). The primary outcome was new-onset QTcF>500 ms. Secondary outcomes were any QTcF>500 ms; QTcF increase (ΔQTcF)>60 ms; QTcF>500 ms for >15 min; QTcF>450 ms (males) or >470 ms (females); maximum QTcF and ΔQTcF; and methadone dose vs QTcF or ΔQTcF.

Results:

Patients were (median) 59 yr (range 18–86) and received methadone (n=282, median 20 mg, IQR [15–20], range 10–60 mg) or no methadone (n=265, typically fentanyl, 250 μg [100, 350], 0–750 μg). New QTcF>500 ms occurred in 2.5% of patients receiving methadone and 8.3% receiving no methadone (relative risk (RR) 0.34, 95% CI [0.16–0.75] P=0.009). Secondary outcomes with methadone vs no methadone found that any QTcF>500 ms occurred less (3.5 vs 8.3%, RR 0.43); ΔQTcF>60 ms occurred less (4.6% vs 12.1%, RR 0.39); maximum ΔQTcF was less (28 vs 37 ms); and sex-specific thresholds were exceeded less (22.3 vs 33.6%) (all P<0.03). There was no correlation between methadone dose and QTcF or ΔQTcF.

Conclusions:

A single-dose of methadone i.v. at induction did not prolong QTcF. Methadone had no clinically meaningful QTcF effects, specifically or in comparison with no use of methadone.

Methadone is commonly used to treat opioid use disorder and acute and chronic pain. The use of methadone for perioperative anaesthesia has undergone rediscovery, reappraisal, reinvigoration, and increasing use in adults and children.^1–5 Methadone has several therapeutic advantages compared with other perioperative opioids, including faster onset and analgesia which better matches the duration of pain.^{1, 6} A single intraoperative dose (0.2–0.3 mg kg⁻¹) provides superior postoperative analgesia (30–40% lower pain scores, 30–40% less postoperative opioid use, greater patient satisfaction) compared with more commonly used short-duration opioids (e.g. fentanyl, hydromorphone), in both inpatient and outpatient surgery,^{3, 7–9} and may have analgesic and opioid-sparing effects for days-weeks after surgery.^{8, 10} Methadone is an opioid-sparing opioid. These clinical advantages do not come at a cost of greater opioid-related side effects (e.g. respiratory depression).^11–14

Methadone can, however, prolong the cardiac QTc interval. The US Food and Drug Administration (FDA)-approved drug label warns that QT interval prolongation and serious arrhythmia (torsades de pointes) have occurred during treatment with methadone. Drug-related QTc prolongation increases torsades risk,¹⁵ and QTc prolongation is an accepted surrogate marker for arrhythmia risk.^16–18 Some, but not all guidelines, suggest ECG monitoring before and during methadone treatment.^{19, 20}

The clinical relevance of methadone QTc effects, particularly for perioperative use, is uncertain and controversial, and has been debated for decades.^21–24 Data on which the FDA warning and practitioner concerns were based were from oral methadone for chronic pain and/or opioid use disorder and in patients receiving high doses and for long duration.^25–27 Any relevance of this to perioperative use is not apparent, particularly since methadone QT prolongation is dose- and time-dependent, increasing over the course of months.^{28, 29} In reports on methadone-related arrhythmias, the average methadone dose exceeded 400 mg and other risk factors for torsades de pointes were found in 75% of cases.²⁷ In contrast to opioid use disorder (80 to >120 mg), typical perioperative doses are much lower (10–40 mg), and dosing is typically singular rather than daily.

Nevertheless, warnings of QT prolongation may cause concern or caution regarding perioperative methadone use. A recent survey of anesthesiologists found that concern for QT prolongation was a barrier to intraoperative methadone administration.³⁰ Despite the above considerations, concerns, uncertainties, and debates, QTc effects of intravenous methadone in anesthetic doses in the immediate perioperative period remain unknown. This prospective observational investigation evaluated single-dose intravenous methadone effects on the QT interval when given at induction of anaesthesia. Objectives were to evaluate QT effects of methadone using standard QT clinical criteria, and secondarily to compare QT effects of anaesthesia with or without methadone. We tested the null hypothesis that the incidence of cardiac QTc interval prolongation would not differ between patients receiving or not receiving single-dose intraoperative methadone. The expected result was that the null hypothesis would be rejected, with significantly more frequent and greater prolongation of the QTc interval in patients receiving intraoperative methadone vs no methadone.

Methods

Study design and population

This was a prospective observational cohort study of adults (≥18 yr) undergoing elective surgery under general anaesthesia at Duke University Hospital. The study underwent Duke University IRB review and was deemed exempt from further review and informed consent.

Inclusion criteria

Inclusion criterion was surgery under general anaesthesia and receiving an intravenous opioid during induction.

Exclusion criteria.

Exclusion criteria included patients on chronic preoperative methadone, active cardiac arrhythmia, and known pacemaker dependency.

Clinical care

The choice and dose of opioid were at the discretion of the anaesthesia provider Anaesthesia and surgical care and monitoring, including all anesthetic drugs, were independent of any decision to collect ECGs, and were not altered for study purposes. Intraoperatively, all patients had standard 5-lead ECG monitoring (GE CARESCAPE B850, GE Healthcare). Patients received an intraoperative opioid bolus (methadone, fentanyl or other, and dose) at the discretion of the anaesthesia care team. Opioid bolus was at the beginning of anaesthesia, typically before propofol administration, and redosing is rare, if ever, in the hour after induction. Intraoperative ECG leads II and V5 were recorded by paper chart recorder before opioid administration and induction of anaesthesia, and 1, 5, 10, 15, 30, 45, and 60 min after opioid administration. QT was measured when drug concentrations were greatest, in accordance with US Food and Drug Administration guidance.³¹ Anaesthesia was typically induced with propofol and lidocaine, endotracheal intubation facilitated by rocuronium, and maintained by propofol, sevoflurane or isoflurane, at the discretion of the anesthesia care team. Data collection was complete after 1 hr. The study was a convenience sample, based on investigator availability to collect ECG printouts. Patient demographics and drug dosing were obtained from the electronic medical record.

Primary endpoint

Manual QT interval measurements used the tangent technique,³² and were corrected for heart rate using both Bazett (QTcB) and Fridericia methods (QTcF). QTcF is reported, per standard.³¹ While QTcB is frequently used in clinical practice, it under-corrects at low heart rates (<60 min⁻¹) and overcorrects at elevated heart rates and hence is not recommended.³³ Various definitions of QTc prolongation exist, but QTc is often considered prolonged when >450 ms (males) and >470 ms (females),³⁴ or when QTc is increased >60 ms compared with baseline.³⁵ Severe prolongation is defined as QTc >500 ms.³⁵ These definitions are used by the US Food and Drug Administration,^{31, 36} and the NIH Common Terminology Criteria for Adverse Events.¹⁷ We also measured QTcF change from intraoperative (preopioid) baseline (ΔQTcF).

Primary outcome

The primary outcome was new onset QTcF >500 ms after opioid administration in patients with baseline QTcF not >500 ms.

Secondary outcomes

Secondary outcomes included any incidence of QTcF>500 ms, change in QTcF (ΔQTcF) >60 ms, and both QTcF >500 ms and ΔQTcF >60 ms.

Exploratory outcomes

Exploratory outcomes were:

• QTcF >500 ms for >15 min continuous duration (to diminish the possibility of a single time point influencing the primary outcome (QTcF >500 ms) and because a duration ≥15 min is defined as clinically significant for QTc >500 ms³⁷).

• QTcF >450 ms (males) or >470 ms (females)

• QTcF and ΔQTcF at each 1–60 min time point

• Maximum QTcF and maximum ΔQTcF

• Influence of maintenance anesthetic (propofol vs volatile) on QTcF >500 ms and ΔQTcF

• Relationship between methadone dose and maximum QTcF and maximum ΔQTcF

• Any new onset cardiac arrhythmia

Outcomes were evaluated specifically for methadone effects on QTcF using these standard QT criteria, and also comparing QTcF effects of anesthesia with methadone vs no methadone.

Sample Size estimation

Sample size was based on the primary outcome measure, new onset QTcF >500 ms. To detect a relative risk (effect size) of 2 required 214 subjects per group based on Fisher's exact test, assuming a 10% incidence in the non-methadone group and 20% in the methadone group, with a target power of 0.80 (80%) and alpha =0.05. For a secondary outcome measure of both QTcF >500 ms and ΔQTcF >60 ms, to detect a risk ratio (effect size) of 2 required 256 subjects per group based on Fisher's exact test, assuming a 10% incidence in the non-methadone group and 20% in the methadone group, with a target power of 0.80 (80%) and alpha =0.025. The study was powered for both primary and secondary outcomes.

Statistical Analysis

Data are reported as mean and standard deviation or median and interquartile range for continuous characteristics, and as count and percentage for categorical characteristics, as appropriate. Missing data were compared to evaluate possible bias. Subjects with more than 2 missing 1–60 min ECGs were to be omitted from analysis, but none were ever included. Analysis was performed in SigmaPlot (Grafiti LLC, Palo Alto, CA). Statistical significance was two-sided alpha 0.05. For outcomes measured at multiple time points, analysis was based on repeated measures ANOVA with post-hoc time-specific pairwise comparisons between groups using Holm correction. Frequency events (primary and secondary outcomes) were compared between groups by Chi-square or t-tests as appropriate. In case of violation of distributional assumptions, a Wilcoxon rank sum test was used. Relationships between methadone dose and QTcF were analyzed by linear regression.

Results

Study characteristics

Between August 16, 2023 and October 16, 2025, intraoperative ECGs were obtained from 547 patients. Median age was 59 yr (IQR 47–69, range 18–86) and 277 (50.6%) were female. Baseline characteristics were comparable between methadone and non-methadone groups (age, sex, weight, BMI, race, ASA physical status, baseline preinduction QTcF), with small standardized mean differences between groups (0.03–0.16) (Table 1). The exception was certain case types (spine and head and neck surgery), and duration of anaesthesia and surgery which were moderately longer in patients who received methadone.

Table 1.

Baseline Patient and Clinical Characteristics

	Methadone (N=282)	No methadone (N=265)	All (N=547)
Age, median [Q1, Q3], yr	58 [45, 68]	61 [47, 71]	59 [47, 69]
Weight, median [Q1, Q3], kg	85 [72, 98]	81 [68, 98]	83 [70, 98]
BMI, median [Q1, Q3], kg m−2	29 [25, 33]	28 [25, 34]	29 [25, 33]
Sex, No. (%)
Male	150 (53.2)	120 (45.3)	270 (49.4)
Female	132 (46.8)	145 (54.7)	277 (50.6)
Race, No. (%)
White	189 (67.0)	182 (68.7)	371 (67.8)
Black	69 (24.5)	55 (20.8)	124 (22.7)
Asian	7 (2.5)	5 (1.9)	12 (2.2)
American Indian or Alaskan Native	3 (1.1)	5 (1.9)	8 (1.5)
Other/not reported/declined	10 (3.5)	10 (3.8)	20 (3.7)
Hispanic	4 (1.4)	8 (3.0)	12 (2.2)
ASA physical status, No (%)
I (Healthy)	13 (4.6)	11 (4.2)	24 (4.4)
2 (Mild systemic disease)	127 (45.0)	123 (46.4)	250 (45.7)
3 (Severe systemic disease)	139 (49.3)	125 (47.2)	264 (48.3)
4 (Life-threatening severe systemic disease)	3 (1.1)	6 (2.3)	9 (1.6)
Preoperative opioid use, No. (%)	76 (27.0)	39 (14.7)	115 (21.0)
Baseline QTcF, median [Q1, Q3] ms	413 [395, 426]	414 [402, 432]
Anaesthesia duration, median [Q1, Q3] min	324 [222, 453]	214 [154, 332]
Surgery duration, median [Q1, Q3] min	218 [135, 326]	125 [79, 224]
Surgery Type, n (%)
Abdominal	32 (11)	23 (9)
Genitourinary	29 (10)	36 (14)
Gynecology	17 (6)	7 (3)
Head and Neck	43 (15)	105 (40)
Intracranial	41 (15)	38 (14)
Spine	107 (38)	54 (20)
Plastics	13 (5)	2 (1)
Anaesthesia Induction opioid
Methadone, median [Q1, Q3] (range), mg	20 [15, 20] (10–60)
Methadone, median [Q1, Q3] (range), IV morphine mg equivalents	20 [15, 20] (10–60)
Fentanyl, median [Q1, Q3] (range), μg		250 [100, 350] (0–750)
Fentanyl, median [Q1, Q3] (range), IV morphine mg equivalents		25 [10, 35] (0–75)
Intraoperative anesthetic maintenance No. (%)
Propofol	157 (56)	159 (60)
Volatile anesthetic (sevoflurane, isoflurane)	125 (44)	106 (40)

At induction of anaesthesia 282 patients received methadone (20 mg, IQR 15–20, range 10–60; 0.22 mg kg⁻¹ actual body weight, IQR 0.18–0.28, range 0.06–0.65), and 265 received no methadone (typically fentanyl, median 250 μg, IQR 100–350, range 0–750; 3.2 μg kg⁻¹ actual body weight, IQR 1.6–4.3, range 0.6–13.6). Remifentanil infusions were used in 147 (52%) patients who received methadone (52%) and 149 (56%) who did not receive methadone (typically during spine, head and neck, and craniotomy surgery, where dense opioid anesthesia was needed and neuromuscular blockade was not allowed). A single time point ECG was not obtained in 11 (3.9%) methadone and 13 (4.9%) non-methadone patients, and two time points were not collected in one methadone patient. These patients were not excluded from the data analysis.

Primary Outcome

New onset QTcF >500 ms occurred in 8/282 (2.5%) of patients receiving methadone compared with 22/265 (8.3%) patients who did not receive methadone (relative risk 0.34 [95%CI,0.16–0.75], P=0.009) (Table 2). The incidence of new onset QTcF >500 was less in patients who received methadone than those who did not. Time-specific increases in intraoperative QTcF from preinduction were observed, from 413 ms [396–426] to 435 ms [414–456] in methadone and from 414 ms [402–432] to 449 ms [427–466] in non-methadone groups after 60 min (Figure 1A). However, peak QTcF was lower in patients who received methadone, compared with patients who did not receive methadone (Figure 1B; Table 3) despite variability over time in individual patient QTcF intervals (Supplemental Figure S1), which is well-known.³⁸ The greatest maximum QTcF in any patient was 621 and 604 ms in methadone and non-methadone patients, respectively. Opioid effects on QTcF were not associated with the type of surgery (Supplemental Table S1).

Table 2.

Primary and Secondary Outcomes

	Methadone (N=282)	No methadone (N=265)	Relative Risk [95% CI]	P-value Relative Risk
Primary outcome
New QTcF>500 ms, No. (%)	8 (2.5)	22 (8.3)	0.34 [0.16, 0.75]	0.009
Secondary outcomes
Any QTcF>500 ms, No. (%)	10 (3.5)	22 (8.3)	0.43 [0.21, 0.88]	0.029
QTcF increase >60 ms from baseline, No. (%)	13 (4.6)	32 (12.1)	0.39 [0.21, 0.74]	0.004
QTcF>500 ms and >60 ms increase, No. (%)	3 (1.1)	13 (4.9	0.22 [0.06, 0.75]	0.016

Figure 1.

Fridericia-corrected QT intervals (QTcF) in the hour after intravenous opioid administration in patients receiving methadone or no methadone during induction of anaesthesia. A. Time course of QTcF intervals. Results are shown as box plots. Boxes represent the 25th and 75th percentiles; whiskers (error bars) above and below the box indicate the 10th and 90th percentiles, solid and dotted lines within the box are the median and mean, respectively, and individual data points are outliers (outside the 10th and 90th percentiles). QTcF was significantly different between methadone and no methadone groups at all times after baseline (P=0.002 at 1 min, P<0.001 at 5–60 min). B. Maximum QTcF interval. Results are violin and box plots. The width of each violin plot corresponds with the approximate frequency of data points in each region. Boxes represent the 25th and 75th percentiles; whiskers (error bars) above and below the box indicate the 10th and 90th percentiles, solid and dotted lines within the box are the median and mean, respectively, and individual data points are outliers (outside the 10th and 90th percentiles).

Table 3.

Exploratory Outcomes

	Methadone (N=282)	No methadone (N=265)	P-value
Maximum QTcF, median [Q1, Q3], ms	442 [423, 462]	455 [434, 473]	<0.001
Maximum ΔQTcF from OR baseline, median [Q1, Q3], ms	28 [20, 38]	37 [26, 49]	<0.001
QTcF >500 ms, >15 min continuous duration, No. (%)	2 (0.7)	9 (3.4)	0.025
QTcF >450 ms (males), >470 ms (females), No. (%)	63 (22.3)	97 (36.6)	<0.001

Secondary Outcomes

Whereas the primary outcome was specific to new-onset QTcF >500 ms, a secondary outcome was any QTcF >500 ms. This occurred less in patients who received methadone compared with patients who did not receive methadone (relative risk 0.43, 95% CI [0.21–0.88], P=0.029) (Table 2). For patients with baseline QTcF >500 ms, methadone QTcF effects were not greater in these patients. The incidence of ΔQTcF >60 ms was less in patients who received methadone compared with patients who did not receive methadone (relative risk 0.39, 95% CI [0.21–0.74], P=0.004) (Figure 2). Further exploration evaluated the time course of ΔQTcF (Figure 2A) and the maximum ΔQTcF (Figure 2B). Median maximum ΔQTcF was significantly less in methadone compared with non-methadone patients (28 vs 37 ms, P<0.001, Table 3). The maximum ΔQTcF in any patient was 96 and 127 ms in methadone and non-methadone patients, respectively. Effects on ΔQTcF were not associated with the type of surgery (Supplemental Table S1). The last secondary outcome, incidence of both QTcF >500 ms and ΔQTcF >60 ms. occurred less after methadone compared with not receiving methadone (relative risk 0.22, 95% CI [0.06–0.75], P=0.016) (Table 2).

Figure 2.

Change in Fridericia-corrected QT from intraoperative preinduction baseline QT (ΔQTcF) in the hour after intravenous opioid administration in patients receiving methadone or no methadone during induction of anaesthesia. A. Time course of ΔQTcF. Results are shown as box plots. Boxes represent the 25th and 75th percentiles; whiskers (error bars) above and below the box indicate the 10th and 90th percentiles, solid and dotted lines within the box are the median and mean, respectively, and individual data points are outliers (outside the 10th and 90th percentiles). ΔQTcF was significantly different between methadone and no methadone groups at all times (P=0.004 at 1 min, P<0.001 at 5–60 min). B. Maximum ΔQTcF. Results are violin and box plots. The width of each violin plot corresponds with the approximate frequency of data points in each region. Boxes represent the 25th and 75th percentiles; whiskers (error bars) above and below the box indicate the 10th and 90th percentiles, solid and dotted lines within the box are the median and mean, respectively, and individual data points are outliers (outside the 10th and 90th percentiles).

Exploratory Outcomes

The incidence of QTcF >500 ms for ≥15 min was less in patients receiving methadone than those not receiving methadone (P=0.025) (Table 3). Using standard sex-specific criteria, the incidence of QTcF >450 ms (males) or >470 ms (females) was significantly less in patients receiving methadone compared to those who did not receive methadone. The incidence of QTcF>500 ms was not different between propofol or volatile anaesthesia, although maximum QTcF, and the ΔQTcF >60 ms were significantly but not clinically meaningfully greater with volatile vs propofol anaesthesia (Supplemental Table S2). There was no significant relationship between methadone dose (Figure 3A) or log methadone dose (Figure 3B).and maximum QTcF or maximum ΔQTcF. Linear regression analysis showed that the slope of the dose-response was not significantly different from zero. There was also no significant relationship between weight-normalized methadone dose and maximum QTcF or ΔQTcF (Supplemental Figure S2). There was a single occurrence of torsades de pointe, intraoperatively, in a patient who did not receive methadone, and no occurrence in any patient receiving methadone.

Figure 3.

Relationship between methadone dose and the QT interval. A. Relationship between methadone dose and maximum QTcF interval and the maximum change from baseline in QTcF, using a linear dose model. B. Relationship between log methadone dose and maximum QTcF interval and the maximum change from baseline in QTcF. There was no significant relationship between methadone dose and maximum QTcF interval or change from baseline, and between log methadone dose and maximum QTcF interval or change from baseline. Linear regression analysis was performed, and the slope of the dose-response was not significantly different from zero.

Potential confounders were explored. For example, there was no difference between groups in heart rates, which might have affected the Fridericia correction of measured QT intervals.

Discussion

The purpose of this investigation was to identify the effects of intraoperative intravenous methadone on the cardiac QTc interval, and to compare QTc intervals in patients receiving and not receiving intravenous methadone for induction of anaesthesia. We tested the null hypothesis that QTc interval prolongation after opioid administration did not differ between patients receiving or not receiving methadone. We evaluated both statistical significance and clinical significance, using standard QTc metrics. The expected result was that the null hypothesis would be rejected, with significantly more frequent QTcF prolongation and significantly longer QTcF in patients receiving methadone vs no methadone.

The overall finding was that the null hypothesis of no difference was rejected. However, the direction of the difference was unexpected and completely opposite to the anticipated result. Every QTcF metric showed a lesser incidence of QTcF prolongation and a smaller ΔQTcF in patients who received methadone vs no methadone. Furthermore, there was no relationship between methadone dose and QTcF or ΔQTcF.

The primary and secondary and exploratory outcomes were all consistent. The primary outcome (new onset QTcF >500 ms) occurred less in methadone vs non-methadone patients, and maximum QTcF was less in methadone patients. A small and gradual time-dependent increase in QTcF occurred after opioid administration, but this was smaller in methadone vs non-methadone patients. The incidence of both QTcF >500 ms and ΔQTcF >60 ms, QTcF >500 ms for ≥15 min, ΔQTcF >60 ms, maximum ΔQTcF, QTcF >450 ms (males) or >470 ms (females) was all less in patients receiving methadone vs no methadone. There was no methadone dose-effect relationship for either QTcF or ΔQTcF. These novel findings support the unexpected and remarkable conclusion that a single 10–60 mg dose of intravenous methadone, administered at induction of general anaesthesia, did not prolong QTcF more than other opioids. In fact, the effect was less.

Myriad studies have evaluated QTc effects of chronic, long-duration, high-dose, oral methadone, used for treating opioid use disorder and chronic pain. In contrast, scant few (only two) evaluated perioperative methadone, and both were retrospective and in cardiac surgery. Intraoperative methadone (0.1 mg kg⁻¹), compared with no methadone, did not differentially affect QTc change (preoperative vs postoperative at intensive care unit admission).³⁹ Methadone, compared with other opioids, did not differentially affect postoperative QTc measured once within 2 days after surgery.⁴⁰ In comparison, the present investigation was prospective, evaluated higher methadone doses, and measured QTc immediately and repeatedly after administration when plasma concentrations are highest, and is the most comprehensive evaluation yet reported. Thus, the present and previous studies demonstrate no clinically meaningful QTc prolongation by intravenous intraoperative methadone in the minutes to days after administration.

A likely explanation for the lack of methadone QTcF effects is the dose, dosing, and duration of methadone administration, and potentially also an absence of additional risk factors. Positive correlations between methadone dose and QTc prolongation (and torsades de pointes) is well-established, yet the associations have been at much higher doses, and with daily and long-duration (weeks-months) dosing.¹⁸ Initial reports of QTc prolongation and torsades de pointes were with high methadone doses (410 ± 349 mg d⁻¹, median 345).^25–27 Additionally, other risk factors were found in 75% of cases,²⁷ and subsequent review found that 100% of patients with prolonged QTc receiving methadone had at least one additional risk factor and 85% had at least two.⁴¹ Methadone dose clearly influences QTc and QTc prolongation, with higher doses for opioid use disorder (typically 80–120 mg) having a greater effect than lower doses used for chronic pain (5–30 mg d⁻¹).²⁴ For example, QTc prolongation and positive correlations between QTc and methadone dose were found for median or mean doses of 70–145 mg d⁻¹ (Supplemental Table S3). In contrast, no significant QTc effects were found for median or mean methadone doses of 5–30 mg d⁻¹ (Supplemental Table S3). Modeling and simulation predicted that doses >120 mg d⁻¹ would increase QTcF by >20 ms, that 1–3% of patients would have ΔQTcF >60 ms, and 0.3–2.0% would have QTcF >500 ms at 160–200 mg d⁻¹.⁴² QTc prolongation also depends on duration of chronic daily dosing, increasing over several months.²⁹ We conclude that the present and previous lack of significant QTc effects of intravenous perioperative methadone derive from the comparatively low and single dose used.

A second potential explanation is that perioperative factors themselves prolong QTc, and any additional marginal effects of methadone, even if present, are negligible. After noncardiac surgery, 80% of patients had significant QTcF prolongation; 4% had QTc >500 ms, and 8% had ΔQTcF >60 ms.⁴³ This was attributable to effects of general anaesthesia, not surgery, because QT changes occurred minutes after induction and airway management, and did not occur with local anaesthesia.⁴⁴ More than 200 FDA-approved drugs prolong QTc,^{15, 45} or are known to cause torsades de pointes,¹⁶ including volatile anesthetics, neuromuscular blocking drugs, 5-HT₃ and D₂ dopamine receptor antagonist antiemetics, opioids (including fentanyl), and antibiotics, all frequently administered in the first hour of general anaesthesia.^{43, 46, 47} Thus, while single-dose perioperative methadone can affect QTcF, the magnitude of the effect is unremarkable, not greater than other opioids and anesthetics, and potentially “lost in the noise” of anesthesia and other potential effects. It is not apparent why QTcF effects were less, not just not greater, after methadone vs no methadone. It may be that fentanyl QTcF effects are greater than appreciated. Fentanyl, in doses (1 μg kg⁻¹) smaller than used here, was recently reported to cause QTcB >500 ms or ΔQTcB >60 ms in one-third of patients.⁴⁸

The methadone label carries a black box warning of life-threating QTc prolongation and serious cardiac arrhythmias (torsades). This warning appeared after several reports of adverse events in patients taking chronic daily oral methadone for chronic pain or opioid use disorder, in relatively high doses.^{25–27, 49} The label advises that reported adverse cardiac events were more commonly associated with, but not limited to, higher doses (> 200 mg d⁻¹). The past decades of experience with chronic daily lower-dose oral methadone, and recent data on perioperative single lower-dose intravenous methadone, suggest that the methadone label may well merit revision to more explicitly define and refine the risks of QTc prolongation and serious cardiac arrhythmias, particularly with regard to dose, duration, and indication for use.

The present investigation has immediate clinical significance, and should provide reassurance to anesthesiologists and surgeons concerned about potential methadone QT prolongation, as such concern has been a barrier to intraoperative methadone use.³⁰. This is particularly important given the utility and potential superiority of perioperative methadone in decreasing postoperative pain and opioid use,^{1–3, 5} and increasingly recognized risks of postoperative opioids.⁵⁰ Another aspect of clinical relevance attends to preoperative ECG screening and postoperative ECG monitoring. Recommendations and guidance for ECG and QTc screening before methadone administration vary widely and are still unsettled,^{19, 22, 51–53} including dose cut-offs for screening.⁴² The present results do not suggest a need for preoperative QTc screening before intraoperative methadone administration, or a QTc cut-off avoiding methadone use. This is similar to antiemetics (onansetron, droperidol) even though they are known to prolong the QTc interval.

There are limitations to the present investigation. Most obvious is that it was observational rather than randomized. This practical consideration allowed waiver of informed consent, pragmatic data gathering, and cost-effectiveness. Duration of anaesthesia and surgery were moderately longer in patients who had received methadone, but this is of no consequence because the study period was only one hr after induction. One hour observation was chosen in order to measure QT intervals at maximum drug exposure, in accordance with US Food and Drug Administration guidance.³¹ The choice of intraoperative opioid and dose were not randomized but were at the discretion of the anaesthesia care team, independent of any ECG recording exercise, and reflect real world clinical practice. Methadone and fentanyl concentrations after a bolus are greatest during the distribution phase, which is complete by one hr. QT effects beyond one hr were not measured, however it was recently reported that a single intraoperative IV methadone dose did not significantly prolong the QTc interval, measured upon ICU admission after surgery or after 1–2d.^39,40 Concomitant perioperative drugs or other potential QTc confounders were not controlled or analyzed. There are numerous factors which can affect QTc, including genetic syndromes, demographics, comorbidities, electrolytes, and more than 300 QT-prolonging drugs.⁵⁴ Nevertheless, these would likely be comparable in the two study groups, and few drugs are typically administered in the first hour after anesthesia induction (save for antibiotics, which are not known to affect QTc) and particularly those which affect QTc.⁵⁵ QT effects were greater with volatile vs propofol anaesthesia, but this was comparable in methadone and non-methadone patients, and consistent with known effects on QTc.⁵⁶ Home medication use was not characterized in the two groups, and it cannot be excluded that there was a systematic bias of greater QT prolonging drugs taken the morning before surgery in patients who would later receive fentanyl. We identified no apparent performance or analysis bias or confounders. Results appear generalizable. The present study was powered for both primary and secondary outcomes.

In summary, a single intraoperative 10–60 mg dose of intravenous methadone at induction of general anaesthesia had no clinically meaningful effects on cardiac QTcF, particularly when measured at highest plasma concentrations, with no adverse cardiac effects observed. QTcF effects in patients receiving methadone were not greater than in patients who did not receive methadone. Routine preoperative QTc interval assessment and postoperative ECG telemetry do not appear warranted in patients receiving 10–60 mg intraoperative IV methadone.

Supplementary Material

Online Supplementary File S1: Additional figures and tables

Editor’s key points.

• The impact of single-dose perioperative methadone on the cardiac QT interval remains unclear.

• In this prospective observational cohort study, corrected QT interval (QTc) was measured before and for 1 hr after intravenous methadone administration in adults undergoing elective surgery under general anaesthesia, compared with no methadone (fentanyl).

• New QTc >500 ms occurred in 2.5% of patients receiving methadone, compared with 8.3% receiving no methadone (relative risk (RR) 0.34, 95% CI [0.16–0.75]).

• There was no correlation between methadone dose and any measure of corrected QT interval.

• Intraoperative methadone appears to have no clinically meaningful effects on the QTc interval