Inadequate perioperative pain control has deleterious effects on children’s development and can lead to heightened pain experiences and the avoidance of future medical procedures. Reports of perioperative use of methadone in children are increasing, as it has a favorable pharmacodynamic profile; however, the effectiveness of methadone in reducing postoperative pain has not been established. We, therefore, aimed to provide a scoping review of the literature comparing the effect of intraoperative methadone versus other opioids on postoperative opioid consumption, pain scores, and adverse events in pediatric patients. We identified studies in PubMed, Scopus, Embase, and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases from inception to January 2023. Postoperative opioid consumption, pain scores, and adverse events were extracted for analysis. We screened 1864 studies, of which 83 studies were selected for full-text review. Five studies were included in the final analysis. Postoperative opioid consumption was decreased overall in children who received methadone compared to those who did not. The majority of studies indicated that methadone was superior to other opioids in reported pain scores, while the frequency of adverse events was similar between the groups. Although the data reviewed highlight a potential benefit of intraoperative methadone in pediatric patients, 4 of the 5 studies had serious methodological concerns. Thus, we cannot make strong recommendations for the regular use of methadone in the perioperative setting at this time. Our results highlight the need for large, well-designed randomized trials to fully evaluate the safety and efficacy of intraoperative methadone in diverse pediatric surgical populations.
Adequate management of postoperative pain is a fundamental component of perioperative care. Yet, postoperative pain is inadequately managed in up to 80% of patients. The effects of undertreated postoperative pain extend beyond temporary patient discomfort and dissatisfaction and include a wide range of negative outcomes, including increased morbidity, functional and quality-of-life impairments, delayed recovery, and chronic postsurgical pain. Children are at particular risk of inadequate analgesia, due to heterogeneity in ages and development and challenges in pain assessment. As such, behavioral studies demonstrate the long-term effects of insufficient pain control, including heightened pain experiences and avoidance of future medical procedures.
Short- and intermediate-acting opioids, such as fentanyl, sufentanil, morphine, and hydromorphone, are the primary opioids utilized for perioperative analgesia in children and adults. However, administration of short-acting opioids as intravenous (IV) boluses leads to rapid fluctuations in serum levels and may lead to periods of inadequate analgesia alternating with periods of oversedation. Continuous infusions can lead to increased tolerance and central sensitization, higher-than-required doses of opioids, and inability to respond quickly to changes in pain level. The introduction of patient-controlled analgesia (PCA) has improved perioperative pain control, but this strategy has limitations. PCA is ideally used for the maintenance of analgesia, rather than establishing analgesia de novo, and is challenging in younger populations where a proxy is required.
Methadone is a synthetic opioid that induces analgesic effects primarily through agonism of μ-opioid receptors and secondarily through antagonism of N-methyl-d-aspartate (NMDA) receptors and serotonin transporters. When administered intravenously, methadone has a rapid onset of action of 8 minutes and an elimination half-life of 24 to 36 hours in adult patients. In children and adolescents, methadone has been shown to have similar pharmacokinetics with a rapid onset of action (2 minutes) and a long elimination half-life (19.2–35.5 hours). The extended duration of effect has solidified methadone as a cornerstone therapy in the management of opiate dependence and neuropathic and cancer pain; however, combined with the rapid onset of action, it may be a viable option for postoperative, acute pain as well reflected by successful use in spinal fusions and cardiac anesthesia. Despite these advantages, reports of perioperative use remain limited with no attempts to systematically synthesize the effects of intraoperative methadone on postoperative analgesia in pediatric populations. The objective of this study is to review postoperative analgesia outcomes in pediatric patients receiving intraoperative methadone compared to patients receiving other intraoperative opioids or placebo.
METHODS
Literature Search and Study Selection
A comprehensive search of PubMed, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Embase was conducted. With the expertise of a medical librarian (K.L.), the databases were searched from the date of database inception to January 2023. An additional search was performed on ClinicalTrials.gov in January 2023; principal investigators of completed, but unpublished trials were contacted to obtain study and protocol data. As part of a series of literature reviews, the search strategy for each database included the following terms and their synonyms: methadone, pediatric, surgical, operative, anesthesia, ventilation, critical care (Supplemental Content 1, Appendix 1, https://links.lww.com/AA/E391). References from included articles and review articles were manually searched to identify additional studies for inclusion. The review was not registered, and a protocol was prepared. The study does not qualify as human subject research. Thus, institutional review board approval was not required for the analysis of published data.
Inclusion and Exclusion Criteria
English-language prospective, peer-reviewed studies (randomized or nonrandomized) involving pediatric patients (≤18 years) were included in this study. We included all studies with a prospective component that compared the usage of intraoperative methadone in pediatric patients undergoing surgery to placebo groups, groups receiving other intraoperative opioids, or groups receiving “standard of care.” We also included studies where intraoperative methadone was part of a bundle of interventions that were compared to usual care. Duplicated studies, studies for which an English-language full text was not available, and studies in adult populations were excluded from the review. Given this review’s focus on mapping existing prospective evidence, retrospective studies were excluded.
Data Extraction and Quality Assessment
Search results were imported into the Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia) and deduplicated. Study titles and abstracts were screened by 2 independent investigators (R.A. and D.P.). For studies that passed title and abstract review, the full text was independently analyzed by both reviewers to ensure inclusion criteria were met. The data for predetermined outcomes in the review protocol, postoperative pain scores, postoperative opioid consumption, and adverse events were extracted from studies that met inclusion criteria after a full-text review. Any disagreements were resolved by consensus. For each outcome, studies reporting the outcome were summarized. A summary of the studies reporting each outcome was created. Adverse event data identified by the original authors were extracted.
Table. – Studies Included in the Scoping Review
| Study | Design | Overall risk of bias (tool) | N | Patient sample | Intervention | Intervention timing | Outcome measures and timing | Main findings |
|---|---|---|---|---|---|---|---|---|
| Berde et al 199122 | Randomized, double-blind, controlled trial | High (RoB 2) | 35 | Pediatric patients (3‐7 y) undergoing surgery | Methadone IV 0.2 mg/kg versus morphine IV 0.2 mg/kg | Single, preincisional dose | Total opioid consumption on the operative day and first postoperative day | Decreased supplemental opioid dosages on the first perioperative day |
| Mean pain scores (Oucher, ACCS, and CHEOPS) for the first postoperative 36 h | Lower pain scores in the methadone group | |||||||
| Adverse events | No major adverse events | |||||||
| Berde et al 198823 | Randomized, double-blind, controlled trial | High (RoB 2) | 41 | Pediatric patients (≤18 y) undergoing | Protocol A: methadone IV 0.2 mg/kg versus morphine IV 0.2 mg/kg | Protocol A: single dose immediately after induction | Total opioid consumption in the first postoperative 12 h and 24 h | No significant difference in total opioid consumption for protocol A |
| Protocol A: orthopedic, urologic, and general surgery | Protocol B: methadone IV 0.1 mg/kg versus morphine IV 0.1 mg/kg | Protocol B: single dose after intraoperative wake-up test | Decreased 12-h total opioid consumption in the methadone group in protocol B | |||||
| Protocol B: posterior spinal fusion surgery | ||||||||
| Martin et al 201824 | Randomized, controlled trial | Some concerns (RoB 2) | 60 | Pediatric patients (≤18 y) undergoing posterior spinal fusion surgery | Methadone IV 0.1 mg/kg + remifentanil IV versus magnesium IVB 50 mg/kg + IV 10 mg/kg/h + remifentanil versus remifentanil | Single dose immediately after induction | Total opioid consumption in the OR, PACU, and first postoperative 24 h | Decreased total opioid consumption in the methadone group |
| Mean pain scores (VAS) in PACU, inpatient ward and overall | No difference between remifentanil and magnesium groups | |||||||
| Tams et al 202025 | Nonrandomized interventional study with historical controls | Critical (ROBINS-I) | 40 | Pediatric patients (≤18 y) undergoing posterior spinal fusion | Multicomponent clinical pathway containing intraoperative methadone IVB (0.25‐0.4 mg/kg) | Single intraoperative dose, no specified timing | Total opioid consumption during the first postoperative 24 h | No difference in pain scores |
| Mean pain scores (NRS) for 24 h postoperatively | No difference in the number of adverse effects | |||||||
| Decreased 24 h postoperative opioid requirement | ||||||||
| Decreased postoperative pain scores | ||||||||
| Decreased LOS | ||||||||
| Ye et al 202026 | Nonrandomized interventional study with historical controls | Critical (ROBINS-I) | 122 | Pediatric patients (≤18 y) undergoing posterior spinal fusion | Multicomponent clinical pathway containing intraoperative methadone IVB (0.1 mg/kg) with postoperative Q12H IV methadone boluses (0.1 mg/kg) versus previous practice | Single intraoperative dose, no specified timing | Total opioid consumption on each postoperative day | Increased POD 0 opioid usage |
| Mean pain scores (NRS) for each postoperative day | Higher POD 0 pain scores | |||||||
| Length of stay | Decreased POD 2 and POD 3 pain scores | |||||||
| Decreased overall opioid usage | ||||||||
| Decreased LOS |
Critical appraisal of the evidence was performed with the ROBINS-I tool for nonrandomized studies and RoB 2 tool for randomized studies. Plots were generated using the robvis tool. This article adheres to the applicable PRISMA guidelines.
RESULTS
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram of included studies is depicted in Figure 1. Of the 7548 studies identified by electronic searches for title and abstract review, 5684 duplicates were removed leaving 1864 studies for title and abstract screening. Of those, 83 studies were assessed for eligibility by full-text review. We identified 5 studies for inclusion in the scoping review, comprising a total of 298 patients (Table). Additionally, we identified 3 registered but unpublished randomized, controlled trials. As the quality of the unpublished trials cannot be evaluated, the results are not included in the synthesis. Given the heterogeneity in interventions, outcome measures, patient populations, and surgery types, a meta-analysis of the published findings was not possible.
Quality Assessment
We assessed the evidence quality of the included studies using the ROBINS-I tool for the nonrandomized studies and the RoB 2 tool for the randomized studies (Figure 2). Despite the magnitude of the effect, Tams et al was assessed as having a critical risk of bias due to confounding and heterogeneity of the intervention. Ye et al was assessed as having a critical risk of bias, due to the heterogeneity of the intervention. No nonrandomized study reported information regarding missing data.
Berde et al and Berde et al demonstrated a high risk of bias as the study dosages were not equipotent between the arms of the study. Additionally, the authors measured pain using multiple scales, which raises some concerns regarding the selective reporting of the result domain. The study by Martin et al raises some concerns regarding the risk of bias as there was not sufficient information to assess whether any deviations from the trial protocol occurred.
Postoperative Pain Scores
Postoperative pain scores were reported by 4 studies. Berde et al performed a randomized, double-blind trial comparing intraoperative methadone (0.2 mg/kg) to intraoperative morphine (0.2 mg/kg) in 35 children undergoing major surgery. Mean Oucher and Analogue Chromatic Continuous Scale (ACCS) scores were lower in the methadone group for each period with complete data (P < .05). When ACCS scores were categorized as mild-moderate versus severe, patients in the methadone group had significantly fewer severe pain scores compared to the morphine group (P < .001).
Martin et al compared methadone IV 0.1 mg/kg + remifentanil IV to magnesium IV bolus 50 mg/kg + IV 10 mg/kg/h + remifentanil IV, as well as to remifentanil in a randomized controlled trial in 60 patients undergoing posterior spinal fusion surgery. Visual analogue scale (VAS) scores were not significantly different in either the postanesthesia care unit (PACU) (methadone and remifentanil versus remifentanil: 6.0 vs 5.2, Δ = 0.8, 95% CI [−1.1 to 2.5]) or in the first 24 hours on the inpatient ward (4.8 vs 4.8, Δ = 0, 95% CI [−1.6 to 1.7]).
Tams et al compared the effects of a multicomponent clinical pathway containing gabapentin, acetaminophen, intraoperative methadone (0.25–0.4 mg/kg), hydromorphone PCA as well as additional nutrition, bowel care, and mobilization interventions to previous clinical practice in patients undergoing posterior spinal fusion for adolescent idiopathic scoliosis. They observed decreased postoperative numeric rating scale (NRS) pain scores in the methadone group compared to the control group (3.4 vs 4.8, Δ = −1.4, 95% CI [−2.6, −0.2]). In particular, NRS scores were significantly lower on the operative day. However, no difference in postoperative pain scores was observed when high and low-dose methadone groups were compared separately to the control group.
Finally, Ye et al compared a methadone-based multimodal analgesia protocol containing intraoperative methadone (0.1 mg/kg), as well as postoperative scheduled methadone, oxycodone, methocarbamol, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and pro re nata (PRN) IV opioids, to a previous protocol containing intraoperative intrathecal morphine and postoperative gabapentin, morphine PCA (postoperative day 0 [POD 0]), scheduled oxycodone/hydrocodone (POD 1), and PRN IV morphine, ketorolac, and acetaminophen in patients undergoing posterior spinal fusion for adolescent idiopathic scoliosis. Postoperative NRS pain scores were significantly increased on the operative day, but significantly decreased on POD 2 and POD 3 for the methadone group compared to the control group.
Postoperative Opioid Consumption
Postoperative opioid consumption was reported in 4 studies. Berde et al report the results of a randomized double-blind trial comparing intraoperative methadone to intraoperative morphine in 41 pediatric patients, using 2 different protocols. In the first protocol, used for orthopedic, urologic, and general surgeries, patients received either methadone (0.2 mg/kg) or morphine (0.2 mg/kg) following standard induction. For patients treated with the first protocol, there were no observable differences between the groups in both 12- and 24-hour opioid consumption. In the second protocol, used for posterior spinal fusion cases, patients were initially maintained on fentanyl and isoflurane anesthesia; following the intraoperative wake-up test, patients received either methadone (0.1 mg/kg) or morphine (0.1 mg/kg). Patients receiving methadone had significantly decreased opioid requirements at both 12 and 24 hours postoperatively. Berde et al (1991) found decreased opioid consumption on the operative day (P = .049), but no significant difference on the first postoperative day.
Tams et al observed significantly decreased opioid requirements in the first 24 postoperative hours in the methadone group compared to the control group (10 vs 41 IV morphine milligram equivalents [MMEs]; Δ = −29 IV MME; 95% CI [−45 to −15]). This finding was observed in both the high- and low-dose methadone groups. Ye et al found significantly increased opioid usage during the operative day (29.3 vs 9.9 IV MME; P < .001) in the methadone group compared to the control group. POD 2 and POD 3 opioid usage was significantly decreased in the methadone group, as was total opioid usage during the hospital stay (98.1 vs 127.5 IV MME). Martin et al did not report cumulative postoperative opioid consumption. However, total opioid consumption, including intraoperative opioids, was decreased in patients receiving methadone and remifentanil compared to patients receiving remifentanil alone (0.26 vs 0.34 hydromorphone mg/kg; Δ = −0.08; 95% CI [−0.14 to −0.01]). Opioid consumption in the PACU (0.01 vs 0.01 hydromorphone mg/kg; Δ = 0; 95% CI [−0.01 to 0.00]) or the inpatient ward (0.24 vs 0.29 hydromorphone mg/kg; Δ = −0.05; 95% CI [−0.11 to 0.01]) did not show a statistically significant difference between the groups.
Adverse Events
All 5 studies reported on the presence of adverse events. Berde et al (1991) was not able to identify differences in postoperative recovery measures between the methadone and morphine groups. There were no reported adverse events, including naloxone usage, delayed emergence from anesthesia, or need for postoperative ventilatory assistance. Berde et al (1988) found no clinically significant hypoventilation in either the methadone or morphine group. Martin et al showed no significant differences in times to eye opening, following commands, tracheal extubation, or length of stay between the methadone and remifentanil groups. The authors reported 1 episode of excessive bleeding in the methadone group and no other intraoperative events in the remaining groups. Tams et al did not explicitly discuss perioperative adverse events. They reported decreased emergence time in the low-dose methadone group compared to the control group; they additionally observed increased emergence time in the high-dose methadone group, which led to a protocol change; however, this was not statistically significant. Ye et al did not observe any opioid-related adverse effects in their study.
DISCUSSION
In our scoping review of intraoperative methadone use in pediatric surgical patients, methadone appears to be associated with decreased consumption of opioids in the first 24 hours postoperatively compared to patients receiving other shorter-acting opioids or pain management strategies. This is the first review formally examining the quality of the evidence surrounding methadone usage in pediatric patients. Our formal assessment of existing evidence expands on recent works discussing the heterogeneity in pediatric methadone usage. The low quality of evidence identified by our paper cautions against an overly broad interpretation of the results. However, our results are consistent with several meta-analyses completed in adult populations, showing similarly decreased opioid consumption in the methadone group. Our review identified 3 studies suggesting that compared to patients receiving shorter-acting opioids, pain scores in patients receiving methadone were reduced. One study did not demonstrate a difference in pain scores. The potential benefit of methadone is likely the result of its quick onset, long duration of action, and more consistent plasma concentrations. The multimodal pharmacodynamic effects provide enhanced analgesia with a concomitant lower requirement for overall opioid utilization to achieve an equivalent or enhanced degree of analgesia compared to standard opioids. Additionally, methadone decreases the reuptake of norepinephrine and serotonin potentially modulating the subjective perception of pain. The observed decreased opioid requirements could be the result of the improved pain control resulting from the combined effect of those pathways.
Our review suggests that methadone may be noninferior to other short-acting opioids in subjective measures of pain compared. The heterogeneity in the instruments used to report pain scores prevented a meta-analysis. In individual studies, regardless of the instrument used, methadone was superior to other opioids in the subjective report of pain or did not demonstrate significant differences in pain scores. In one study, subjective measures of pain were increased on POD 0 in patients receiving methadone-based pain control; however, these patients engaged in physical therapy earlier, had shorter lengths of stay, lower pain scores on POD 2 and POD 3, and fewer reports of significant postoperative pain after discharge; additionally, their total opioid consumption was decreased. Several studies in adult populations also highlight the superiority or noninferiority of methadone in managing subjective measures of pain.
The studies identified by this review did not report differences in the frequency of adverse events between the groups. However, due to the small sample size, it is possible that adverse events may not be adequately detected. Several studies examined extubation rates and the need for naloxone, but the results were too heterogeneous for a quantitative analysis. Still, the results suggest that the usage of methadone is likely as safe as the current standard of care.
The existing data suggest potential benefits of methadone in reducing postoperative opioid requirements without affecting pain scores or causing increases in adverse events. However, due to the limited number of high-quality studies, and only 1 recent randomized controlled trial among them, we cannot recommend routine usage of methadone. Large, randomized controlled trials are needed to further evaluate its effectiveness. The role of methadone in enhanced recovery after surgery (ERAS) protocols should also be evaluated but not replace evaluation of individual components of the protocols.
It is important to note that our study focuses exclusively on intraoperative methadone in pediatric populations. The use of preoperative methadone has been reported in some pediatric studies as part of a multimodal analgesia, but the limited data available and the nature of the studies precluded a detailed examination of this topic. The adult literature suggests that preoperative methadone may have the potential to decrease postoperative opioid consumption. However, the benefit of preoperative methadone in pediatric populations remains uncertain due to the limited data available.
The reported doses varied between 0.1 and 0.4 mg/kg, but the variations in protocols and methods make it difficult to draw conclusions regarding the optimal dosage. Tams et al reduced the methadone dose from 0.4 to 0.25 mg/kg due to oversedation concerns; in contrast, Barnett et al utilized a total dose of up to 0.4 mg/kg but administered in multiple doses based on clinical response. Komen et al suggest that a minimum of 0.15 mg/kg methadone is needed to improve postoperative pain variables compared to other opioids. However, the appropriate dosage will likely depend on the surgical procedure as well as the timing of administration. Of note, methadone exhibits significant difference in metabolism depending on the carriage of CYP450 isoforms. To this date, while there are studies examining in vitro and in vivo measures of pediatric methadone metabolism based on CYP2B6 and CYP2C19 status, none of the studies examine outcome measures related to pain control; additionally, existing studies do not examine CYP3A4 or CYP2D6 status, which are additional contributors to methadone metabolism. The influence of genetic mediators of methadone clearance can affect the adequacy of pain control and should be considered when determining adequate methadone dosing strategy for future studies.
Our study has several limitations. First, the sample sizes of the included studies were small, totaling only 298 patients. Second, all the randomized controlled trials exhibited some form of bias, either due to lack of blinding or due to lack of equipotency between the study arms. Nonrandomized studies exhibited significant heterogeneity in interventions and dosing strategies, with all included studies implementing several interventions in addition to the introduction of intraoperative methadone and exhibiting a critical risk of bias in at least one domain. Third, some variability in the opioid used in the control group, as well as the opioids used for postoperative analgesia, exists. Fourth, outcome measures for both opioid usage and pain scores were heterogeneously reported and not standardized; additionally, studies reported adverse reports inconsistently. Fifth, the overall quality of evidence was low, with all studies exhibiting some form of potential bias or methodological flaw. Sixth, given our inability to obtain complete data for the unpublished trials, our synthesis may exclude relevant results. Finally, due to the nature of the study and the available evidence, we are unable to make any recommendations regarding pediatric methadone usage.
CONCLUSIONS
In our scoping review, pediatric patients who received intraoperative methadone had decreased opioid consumption compared to patients who received shorter-acting opioids; pain scores and the rate of adverse events were similar between the groups. However, we cannot make strong recommendations for the regular usage of methadone based on these studies, as only a small number of interventional studies were available for analysis. The results underscore the need for large, well-designed randomized trials to fully evaluate the safety and efficacy of intraoperative methadone in diverse surgical populations.