Analgesic efficacy of peri-operative methadone in orthopaedic surgery: protocol for a systematic review of randomised controlled trials

Abstract

Introduction

Optimising post-operative pain management is crucial for recovery in orthopaedic surgery. Methadone has attracted interest due to its long half-life, N-methyl-D-aspartate -receptor antagonism and potential to reduce post-operative opioid consumption. Existing reviews combine multiple surgical populations, limiting applicability to orthopaedic settings. This protocol outlines a systematic review assessing the analgesic efficacy and safety of peri-operative methadone in adult and adolescent orthopaedic patients.

Methods and analysis

This review will include randomised controlled trials evaluating intravenous peri-operative methadone vs placebo or standard analgesic regimens in orthopaedic surgery. Primary outcomes are post-operative rescue opioid consumption and pain intensity within 72 hours. Secondary outcomes include adverse events, mobility scores and the length of hospital stay. If available data permit, a methadone dose–response pattern may be investigated. Searches will be conducted in MEDLINE (Ovid), Embase (Ovid), CINAHL, CENTRAL, Web of Science and ClinicalTrials.gov without date restrictions. Two reviewers will independently screen studies, extract data and assess risk of bias using the Cochrane risk-of-bias tool for randomised trials. When appropriate, random-effects meta-analysis methods will be performed. Certainty of evidence will be assessed using Grading of recommendations assesment, development and Evaluation (GRADE).

Ethics and dissemination

As this study uses previously published data, ethical approval is not required. Findings will be disseminated through a peer-reviewed publication and conference presentations.

PROSPERO registration number

CRD42025616291.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This review focuses exclusively on orthopaedic procedures, minimising heterogeneity across surgical pain mechanisms.

• Comprehensive searches across major databases and trial registries.

• Use of state-of-the-art risk-of-bias assessment, robust random-effects models and Grading of recommendations assesment, development and Evaluation (GRADE) certainty appraisal.

• Potential heterogeneity in methadone dosing regimens and variability in reporting of pain and opioid outcomes may limit pooling.

• A limited number of eligible randomised controlled trials may restrict meta-analyses or sub-group analyses (eg, by surgery type or age group).

Introduction

Effective post-operative pain management is essential for patients undergoing orthopaedic surgery.¹ Procedures such as joint arthroplasty, fracture repair, ligament reconstruction and spine surgery are often associated with substantial post-operative pain and a high need for analgesia.² Despite advances in multimodal pain management, many orthopaedic patients still experience inadequate relief, which can impair early mobilisation, delay rehabilitation and reduce overall recovery quality.²,⁴ Surveys also show that a considerable proportion of surgical patients worry about post-operative pain and report dissatisfaction with pain control after orthopaedic procedures.^{3 5}

Methadone has received renewed interest as a peri-operative analgesic because of its long elimination half-life, N-methyl-D-aspartate receptor antagonism and inhibition of serotonin and norepinephrine reuptake.⁶ These pharmacological properties may offer more sustained analgesia than short-acting opioids and may reduce post-operative opioid requirements.⁷,⁹ Evidence from mixed surgical populations—including abdominal, spine and gynaecologic procedures—suggests that intraoperative methadone can reduce post-operative morphine use and improve early pain scores.^{8 10 11} However, clinical implementation remains inconsistent, partly due to concerns about safety, dose selection and inter-individual variability in opioid response.^{9 12}

Importantly, existing systematic reviews have combined heterogeneous surgical groups. Findings derived from these pooled populations may not apply directly to orthopaedic surgery, which has distinct pain profiles, analgesic needs and rehabilitation trajectories.² Some studies suggest that methadone’s analgesic effect may vary meaningfully across surgical types.^{7 8 10} Moreover, orthopaedic patients, particularly those undergoing high-pain procedures such as fracture surgery or complex spine operations, may benefit from longer-acting opioid strategies that support early mobilisation and reduce reliance on repeated patient-driven dosing.²

These considerations highlight a critical knowledge gap: no systematic review has synthesised randomised evidence on peri-operative methadone specifically within orthopaedic surgery. A focused evaluation is needed because orthopaedic patients often face unique pain burdens and may differ in their risk–benefit profile compared with other surgical populations. Understanding methadone’s efficacy and safety in this context is increasingly important as healthcare systems work toward opioid-sparing strategies that maintain high-quality analgesia.

This systematic review aims to evaluate the analgesic effects and safety of peri-operative methadone compared with standard analgesic regimens or placebo in orthopaedic surgery. By focusing exclusively on randomised controlled trials in orthopaedic populations, the review seeks to provide clinically relevant evidence to guide practice, inform dosing considerations and identify whether orthopaedic patients experience benefits comparable to those reported in mixed surgical cohorts.

Objectives

Primary question

This review will address the following primary question: What is the analgesic effect of peri-operative methadone compared with placebo or standard analgesic treatment in orthopaedic patients?

Sub-questions

1. How does peri-operative methadone affect post-operative opioid consumption within the first 72 hours after surgery in orthopaedic patients compared with placebo or standard analgesic treatment?

2. What is the effect of peri-operative methadone on post-operative pain scores within the first 72 hours after surgery in orthopaedic patients compared with placebo or standard analgesic treatment?

3. Is there an association between the peri-operative methadone dose and the magnitude of its analgesic effect (on post-operative opioid consumption and pain scores) across different types of orthopaedic surgery?

Methods and analysis

The methodology for this systematic review will be based on the Cochrane Handbook for Systematic Reviews of Interventions, with the PRISMA extension for review protocols (PRISMA-P) as a reporting guideline.^{13 14}

Eligibility criteria

Study design

Randomised controlled trials (RCTs) are included. Non-randomised trials, observational studies, case reports or reviews are excluded.

Intervention

Intravenous methadone administered peri-operatively as part of an analgesic regimen is included. Other administration routes (oral, epidural, intra-articular) or use for chronic pain management outside the peri-operative setting are excluded.

Participants

Adult (≥18 years) and adolescent (12–18 years) patients undergoing acute or elective orthopaedic surgery, including spine surgery involving bony structures, fracture surgery, joint replacement (eg, hip, knee) and ligament repair (eg, Anterior cruiciate ligament (ACL) reconstruction) are included. Non-orthopaedic surgeries, mixed surgical populations without isolated orthopaedic data and spine surgeries primarily addressing disc herniation, nerve involvement, radiculopathy or chronic back pain are excluded.

Outcomes

Studies must report at least one of the following:

• Post-operative opioid consumption within 72 hours post-surgery

• Post-operative pain scores (on or converted to a 0–10 scale) within 72 hours post-surgery

Studies without these outcomes are excluded.

Language and publication: Only studies published in English are included.

Information sources

A search in Pubmed and PROSPERO yielded no recent or ongoing review activity about the research question. Therefore, a systematic block search will be conducted in Medline (via Ovid), Embase (via Ovid), CINAHL (via EBSCO) and CENTRAL (Cochrane Library) with no date or language limitations. Articles in languages other than English will be considered according to translation resources within the hospital. The Web of Science database will be used for citation searches of the included articles. We will also search Clinicaltrials.gov for trials that are on-going.

Search strategy

The search strategy will be developed through an iterative process that analyses keywords and subject headings from health databases for seed articles. The search string will be based on the PICO typology, which stands for population, intervention, comparrison and outcome: comparison, but the outcome will not be included in the search.¹⁵ The search string will be developed in Embase with the input of an experienced medical information specialist and consist of three blocks: Orthopaedic patients, methadone and the Cochrane RCT filter.¹⁶ The terms within a specific block will be combined with the Boolean operator OR, and the three blocks will be combined with the Boolean operator AND. Proximity operators or truncation will be used within the blocks to capture all anticipated instances of the search terms. The search strategy will be peer-reviewed by a second librarian from the University of Southern Denmark.

The complete Embase search string, including line numbers and hit counts, is presented in table 1. This represents the complete, database-specific implementation of the three-block structure described above. Searches in MEDLINE (Ovid), CINAHL, CENTRAL, Web of Science and ClinicalTrials.gov will also be conducted using conceptually equivalent strategies based on the same three blocks (orthopaedic surgery, methadone and randomised trials) but adapted to each database’s controlled vocabulary and syntax. These adaptations follow the structure of the Embase strategy but are not reproduced in full in this protocol. All searches will be rerun immediately before the final analysis to ensure that newly published studies are included.

Table 1. The Embase search string.

#	Searches	Results
1	(arthroplasty or surgery or surgeries or postoperative or post-operative or post operative).mp.	5430 946
2	exp orthopedic surgery/	723 873
3	1 or 2	5 570 019
4	exp Methadone/	42 262
5	(methadon* or d$methadone or l$methadone or r$methadone or s$methadone or dolophine or phenadone or physeptone or phymet or symoron or metadol or metasedin or methadose or methex or pinadone or amidone or biodone).tw.	23 969
6	4 or 5	45 186
7	exp randomized controlled trial/	879 794
8	controlled clinical trial/	445 632
9	random$.ti,ab.	2 202 399
10	randomization/	100 804
11	intermethod comparison/	313 588
12	placebo.ti,ab.	396 160
13	(compare or compared or comparison).ti,ab.	8 540 083
14	((evaluated or evaluate or evaluating or assessed or assess) and (compare or compared or comparing or comparison)).ab.	3 119 421
15	(open adj label).ti,ab.	123 001
16	((double or single or doubly or singly) adj (blind or blinded or blindly)).ti,ab.	298 819
17	double blind procedure/	233 088
18	parallel group$1.ti,ab.	35 286
19	(crossover or cross over).ti,ab.	134 677
20	((assign$ or match or matched or allocation) adj5 (alternate or group$1 or intervention$1 or patient$1 or subject$1 or participant$1)).ti,ab.	458 253
21	(assigned or allocated).ti,ab.	542 214
22	(controlled adj7 (study or design or trial)).ti,ab.	504 118
23	(volunteer or volunteers).ti,ab.	303 634
24	human experiment/	688 611
25	trial.ti.	463 791
26	7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25	11 175 113
27	(random$ adj sampl$ adj7 (“cross section$” or questionnaire$1 or survey$ or database$1)).ti,ab. not (comparative study/ or controlled study/ or randomi?ed controlled.ti,ab. or randomly assigned.ti,ab.)	10 487
28	cross sectional study/ not (exp randomized controlled trial/ or controlled clinical trial/ or controlled study/ or randomi?ed controlled.ti,ab. or control group$1.ti,ab.)	435 698
29	(((case adj control$) and random$) not randomi?ed controlled).ti,ab.	23 427
30	systematic review.ti,ab. not (trial or study).ti.	395 962
31	(nonrandom$ not random$).ti,ab.	20 235
32	“random field$".ti,ab.	3144
33	(random cluster adj3 sampl$).ti,ab.	1740
34	(review.ab. and review.pt.) not trial.ti.	1 273 330
35	“we searched”.ab. and (review.ti. or review.pt.)	57 411
36	“update review”.ab.	153
37	(databases adj4 searched).ab.	75 273
38	(rat or rats or mouse or mice or swine or porcine or murine or sheep or lambs or pigs or piglets or rabbit or rabbits or cat or cats or dog or dogs or cattle or bovine or monkey or monkeys or trout or marmoset$1).ti. and animal experiment/	1 295 372
39	animal experiment/ not (human experiment/ or human/)	2 733 730
40	27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39	4 831 574
41	26 not 40	9 759 197
42	3 and 6 and 41	755
43	exp Methadone/	42 262
44	(methadon* or d$methadone or l$methadone or r$methadone or s$methadone or dolophine or phenadone or physeptone or phymet or symoron or metadol or metasedin or methadose or methex or pinadone or amidone or biodone).tw.	23 969
45	43 or 44	45 186
46	(surgery or surgeries or postoperative or post-operative or post operative).tw.	2 777 681
47	41 and 45 and 46	597
48	42 not 47	158

Embase Classic+Embase <1947 to 2025 April 07>

Study records

Search results will be managed in Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia, www.covidence.org), facilitating duplicate removal, study screening and data extraction.

The study selection will consist of a three-stage process: title and abstract screening for potentially eligible studies, full-text screening evaluation of the publications concerning the inclusion and exclusion criteria and a manual search using backward and forward citation searching of the included publications. The deduplication and blinded screening process will be performed using Covidence. These three stages will be conducted by two reviewers independently, and any disagreements will be resolved through discussion or a third reviewer. Authors of clinical trials or eligible conference abstracts will be contacted for further details if no corresponding full text is identified.

Data will be extracted using a customised Covidence template designed to systematically capture study characteristics and outcomes. Using this template, two independent reviewers will extract data on key variables from eligible studies. Discrepancies will be resolved by consensus or adjudicated by a third reviewer. Study authors will be contacted for clarification or additional data when required information is missing. The data extraction process will include piloting the form on a subset of studies to ensure consistency and reliability.

Study characteristics to be extracted will include the items listed in table 2, such as study design, sample size, methadone regimen and comparator. Outcome measures will follow the structure outlined in table 3, detailing primary outcomes (eg, post-operative opioid consumption), secondary outcomes (eg, mobility scores, adverse events), and corresponding assessment tools and time points.

Table 2. Study Characteristics.

Category	Details
Study ID	Unique identifier (eg, first author, year).
Title	Title of the study.
Country	Location where the study was conducted
Study design	Randomised controlled trials: parallel groups, cross-over, number of arms, etc.
Setting	Hospital, outpatient clinic or other
Sample size	Number of participants included in the study.
Eligibility criteria	Inclusion and exclusion criteria for participants.
Surgery type	Type of orthopaedic surgery (eg, hip fracture repair, knee arthroplasty).
Methadone regimen	Dose, route, timing (peri-operative phase) and frequency of administration.
Comparator	Standard analgesic treatment used as control or placebo.
Follow-up duration	Length of time participants were monitored.
Funding source	Source of funding for the study.
Conflict of interest	Disclosure of potential conflicts of interest.

Table 3. Outcome Measures and Key Results.

Outcome	Details
Primary outcome	Total opioid consumption (mg of morphine equivalents) and pain intensity scores (eg, NRS, VAS) within 72 hours post-operatively.
Secondary outcomes	Adverse events (eg, respiratory depression, nausea, vomiting, sedation or constipation), mobility scores (eg, CAS, NMS) and length of hospital stay (measured in days from surgery to discharge).
Pain assessment tool	Method used to measure pain intensity (eg, NRS) and range.
Adverse events	Frequency and type of adverse events (eg, sedation, respiratory depression)
Length of hospital stay	Duration of hospital stay (days).
Patient-reported outcomes	Reported satisfaction or mobility outcomes (eg, CAS, NMS)
Data collection time points	Timing of outcome assessment (eg, 24 hours, 48 hours, 72 hours post-operatively)
Analysis method	Statistical tests or models used to analyse the outcomes.
Key findings	Summary of the study’s main findings.

CAS, Cumulated Ambulation Score; NMS, New Mobility Score; NRS, numeric rating scale; VAS, visual analogue scale.

Data items

Data extraction will follow the predefined structure outlined in table 2 (study characteristics) and table 3 (outcomes). Extracted variables include study design, population details, methadone regimen (dose in mg and/or mg/kg, timing and number of administrations), and comparator interventions (table 2). Outcomes will be categorised into primary (opioid consumption and pain scores) and secondary measures (adverse events, mobility and hospital stay), as detailed in table 3.

Data assumptions and simplifications will follow pre-established guidelines: for example, missing data on outcomes will be addressed through direct correspondence with authors, and surrogate measures will be avoided unless explicitly justified.

Outcomes and prioritisation

Primary outcomes

The primary outcomes of this review are selected for their clinical relevance in evaluating the effectiveness of peri-operative methadone. These include:

• Post-operative opioid consumption: Defined as the total morphine-equivalent dose required within the first 72 hours post-surgery.

• Pain intensity scores: Assessed at rest and during movement over the first 72 hours post-surgery, using validated tools such as the visual analogue scale or numeric rating scale.

Secondary outcomes

Secondary outcomes aim to provide additional insights into the safety and broader clinical impact of peri-operative methadone. These include:

• Adverse events: Frequency of events such as respiratory depression, nausea, vomiting, sedation or constipation.

• Mobility scores: Assessed using validated tools such as the Cumulated Ambulation Score or the New Mobility Score.

• Length of hospital stay: Measured in days from surgery to discharge.

• Methadone dosing characteristics and dose–response patterns: The range and distribution of peri-operative methadone doses (for example, mg or mg/kg), timing of administration and exploratory associations between dose and the primary outcomes (post-operative opioid consumption and pain intensity scores).

Outcomes will be defined according to published standards or as specified in the included studies. Any variations in definitions or measurement tools across studies will be documented and considered during synthesis. For mobility and pain scores, thresholds and scoring systems will be specified to standardise comparisons across studies.

Primary outcomes will be prioritised for their ability to directly measure the efficacy of peri-operative methadone in reducing opioid use and managing post-operative pain. Secondary outcomes will provide additional insights into the intervention’s safety, mobility outcomes and broader clinical effects. The emphasis on adverse events, mobility scores and hospital stay reflects the clinical importance of balancing effective pain management with functional recovery and overall patient safety.

Amendments

Any protocol amendments will be documented and reported transparently. Substantive changes to the objectives, eligibility criteria, search strategy, data extraction process or data analysis methods will be described in detail, along with the rationale for each amendment. Amendments will be registered in PROSPERO with an updated protocol version, ensuring the traceability of all modifications.

Risk of bias in individual studies

Two researchers will independently perform a Risk-of-bias assessment using the revised Cochrane risk-of-bias tool for randomised trials.¹⁷ This tool evaluates potential bias in the following domains:

• Selection bias (adequacy of sequence generation and allocation concealment).

• Detection bias (blinding of outcome assessment).

• Attrition bias (handling of incomplete outcome data).

• Reporting bias (selective outcome reporting).

Findings from the risk-of-bias assessment will guide sensitivity analyses, ensuring robustness in the conclusions drawn.

At the meta-analysis level, potential biases affecting the overall findings will be examined. Publication bias will be evaluated using funnel plots if a sufficient number of studies are included. Selective reporting bias will be assessed by comparing reported outcomes with study protocols or trial registries. Bias due to small study effects will be explored through sensitivity analyses, excluding small studies to observe their impact on pooled effect estimates. Additionally, funding bias and conflicts of interest will be documented and considered when interpreting findings.

By integrating both individual study risk of bias and broader meta-bias considerations, this systematic review aims to provide a transparent and rigorous assessment of the quality and reliability of the included evidence.

Data synthesis

Quantitative synthesis will be conducted if the included studies are sufficiently homogeneous regarding study design, population, interventions, comparators and outcomes. Specifically, studies reporting similar outcomes (eg, post-operative opioid consumption or pain scores) measured in a comparable manner and at identical time points (eg, within 72 hours post-surgery) will be considered suitable for meta-analysis. If time points are not identical but allow for meaningful synthesis, meta-regression may be considered to account for variability in timing, mainly if this approach enables the inclusion of substantially more studies. Studies with substantial clinical or methodological heterogeneity that cannot be addressed through meta-regression may be excluded from quantitative synthesis and summarised narratively.

When sufficient comparable data are available, a random-effects meta-analysis will be employed for primary outcomes, using the Hartung–Knapp–Sidik–Jonkman method to estimate random effects.

For continuous outcomes

• Post-operative opioid consumption: Results will be synthesised as mean differences (MD) in milligrams. Standardised mean differences (SMD) will be calculated if studies report consumption on different scales. Parametric estimates from primary studies will be used where available.

• Post-operative pain scores: MD will be used for studies reporting scores on a common 0–10 scale. For different pain scales, SMD will be applied. Parametric estimates from primary studies will be used where available.

For binary or categorical outcomes

The adverse event rates, risk ratios or OR with 95% CIs will be calculated. A random-effects model will account for variability across studies unless heterogeneity is negligible according to measures for ${\tau }^2$ and I², in which case a fixed-effect model may be applied.

The normality assumption will be carefully evaluated for studies reporting medians and interquartile ranges (IQRs) or ranges. If evidence suggests data are approximately normal (eg, explicit testing in primary studies), conversion methods such as Wan’s formula may be applied to estimate means and SD. However, this approach will be documented as a limitation, acknowledging the potential bias introduced by approximation. If normality cannot be verified or is deemed unlikely, the feasibility of conducting a meta-analysis will be revisited, and alternative methods will be considered.

Heterogeneity will be assessed using τ² estimates, their 95% prediction intervals and the I² statistic.¹⁸ Forest plots will visually present pooled estimates and heterogeneity measures. Publication bias will be assessed using funnel plots and skewness tests. The packages metafor and altmeta will be used in the analyses.

If sufficient data are available, sub-group analyses can be conducted based on predefined characteristics, such as type of surgery (eg, hip replacement vs spine surgery), patient age and methadone dosing regimen. Sensitivity analyses will be performed by excluding studies at high risk of bias or those using different statistical approaches to assess the robustness of findings. Meta-regression may also explore potential factors influencing treatment effectiveness, including methadone dose as a continuous study-level variable, baseline pain scores and sociodemographic characteristics (eg, age, comorbidities and lifestyle factors). The outlined methods provide a framework for data synthesis but are not exhaustive. Final analytical decisions may adapt to the data characteristics encountered during the review process. The final review report will justify and transparently document deviations from planned methods.

A narrative synthesis will be conducted if a meta-analysis is unsuitable because of significant incongruence of measures or inadequate data. This will feature a detailed table and text summary outlining the studies’ characteristics, the interventions’ effects, and relevant contextual factors. Additionally, it will highlight patterns in the results and potential reasons for any inconsistencies, providing a thorough overview of the available evidence.

Confidence in cumulative evidence

To assess the certainty of the evidence, the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach will be applied to primary outcomes and any secondary outcomes for which a meta-analysis is feasible.¹⁹ The GRADE approach assesses the extent to which there can be confidence in the effect estimate. This involves evaluating the within-trial risk of bias, the evidence’s directness, heterogeneity, the effect estimates’ precision and the risk of publication bias. If a meta-analysis is not possible for a given outcome, the certainty of the evidence will be described narratively, considering these same domains qualitatively.

Discussion

The selection of surgical procedures for this systematic review was guided by a focus on orthopaedic surgeries that involve pain arising from ligaments, bone, periosteum, muscle and tendons. These tissues are predominantly associated with nociceptive pain pathways, specifically Aδ- and C-fibres, which are key contributors to orthopaedic settings’ acute and localised pain profiles.^{2 4 20} This focus aligns with the review’s aim to explore methadone’s role in addressing pain types from orthopaedic procedures, as highlighted in the introduction.

Inclusion of spine surgery

The inclusion of spine surgeries in this review warrants particular consideration, given the potential controversy surrounding their classification. While spine surgeries inherently involve bone structures, they may also affect intervertebral discs and nerve roots, raising the possibility of radicular pain or other neurogenic components. To address this, it was chosen to include spine surgeries that focus on bony structures while explicitly excluding those involving disc herniation, nerve involvement, radiculopathy or chronic back pain. Chronic back pain, often characterised by multifactorial and mixed nociceptive and neuropathic components, complicates the pain manifestation and behaviour from the typical acute nociceptive pain caused by surgical interventions. By maintaining these exclusions, this review aims to ensure the applicability of the findings to surgeries characterised by nociceptive pain, minimising heterogeneity in pain mechanisms while preserving the relevance of bone-related surgical pain.

Consideration of paediatric and adolescent populations

Another significant consideration is whether to include children and adolescents undergoing orthopaedic procedures such as scoliosis surgery. While scoliosis surgery aligns with the focus on bone-related pain, the physiological response to methadone and analgesic treatments may differ between children and adults. Methadone’s pharmacokinetics, potential side effects and efficacy in younger populations are not as well-documented, introducing uncertainty regarding the generalisability of findings from adult studies. Despite these concerns, adolescents undergoing major spinal procedures may experience pain profiles comparable to those in adults. Thus, age-related physiological differences will be carefully considered in sub-group analyses to ensure that conclusions drawn about methadone’s efficacy remain appropriately contextualised.

Clinical relevance

By targeting surgeries that emphasise nociceptive pain from musculoskeletal structures, this review seeks to provide clinically meaningful insights into methadone’s peri-operative role. The deliberate exclusion of procedures with mixed pain mechanisms, such as those involving visceral, neuropathic or chronic pain, supports a focused investigation into methadone’s utility in orthopaedic contexts. Furthermore, by addressing potential heterogeneity arising from patient age and procedural variation, this review aims to offer a nuanced understanding of methadone’s benefits and limitations across different orthopaedic populations.

Limitations of the planned review

Several factors may limit this systematic review. First, the number of randomised trials evaluating peri-operative methadone in orthopaedic surgery is expected to be small, which may restrict the feasibility of meta-analysis and sub-group exploration. Second, heterogeneity in methadone dosing regimens, surgical procedures and outcome measurement methods may introduce variability that statistical techniques cannot fully resolve. Third, some studies may report insufficiently detailed opioid consumption or pain outcomes, limiting data extraction and comparability across trials. Finally, publication bias and selective reporting cannot be excluded, particularly in a field with few existing trials. A further limitation relates to the expected distribution of post-operative opioid consumption data. Morphine consumption is frequently right-skewed, and consequently, several eligible trials may report medians and IQRs rather than means and SD. This may restrict the ability to perform meta-analyses based on parametric effect measures or require statistical approximations whose validity depends on assumptions about underlying distributional properties. If normality cannot be verified, pooling across studies may not be feasible for some outcomes.