Early postoperative pain and opioid use after liver surgery: A systematic review and meta-analysis

Abstract

Background

Postoperative pain following liver resection remains a clinical challenge, and the optimal analgesic strategy is still debated.

Objective

To determine whether a single intrathecal morphine injection provides superior analgesia and opioid-sparing effects compared with conventional systemic or regional techniques in adult patients undergoing liver surgery.

Methods

PubMed, Embase, Web of Science citation index, and the Cochrane Library were searched from inception to August 2025 for randomized controlled trials comparing intrathecal morphine with alternative analgesic regimens in liver resection. The primary outcome was pain intensity at rest 24 h after surgery (standardized mean difference). Secondary outcomes included pain intensity at 48 and 72 h and cumulative opioid consumption within 24 h postoperatively. Random-effects meta-analyses and I² statistics were used to assess pooled effects and heterogeneity.

Results

Eleven randomized controlled trials (n = 535) met the inclusion criteria. Intrathecal morphine reduced 24-h postoperative pain scores with a moderate effect (standardized mean difference = −0.64; 95% confidence interval: −0.84 to −0.44; p < 0.001; I² = 55%) and decreased 24-h opioid consumption by 11.6 mg morphine equivalents (95% confidence interval: −19.3 to −3.9 mg; p = 0.003; I² = 96%). Differences in pain intensity at 48 and 72 h were not statistically significant. Adverse-event profiles were comparable between groups.

Conclusion

A single dose of intrathecal morphine provides clinically meaningful early analgesia and opioid-sparing benefits after liver resection without increasing adverse events. Incorporating intrathecal morphine into multimodal analgesic protocols may accelerate recovery; however, further high-quality trials are warranted to refine dosing and identify optimal patient selection.

Keywords

Intrathecal morphine liver surgery analgesia opioid consumption postoperative pain randomized controlled trial meta-analysis

Introduction

Hepatobiliary surgery is often associated with significant pain; therefore, adequate pain control is closely linked to postoperative recovery of patients.¹ Although the advent of minimally invasive techniques and multimodal perioperative analgesia has substantially reduced surgical trauma and improved the management of severe pain, postoperative pain control remains a significant challenge following hepatic surgery. Therefore, improving analgesia and the quality of postoperative recovery continue to be clinical priorities.² Previous studies have investigated various methods of postoperative pain management, including intravenous (i.v.) administration of systemic medications, local anesthesia at the surgical incision, and regional block anesthesia.³ Adequate pain management is essential for early recovery and rehabilitation of patients undergoing hepatic surgery.⁴ Opioids are considered the “gold standard” for the management of postoperative pain in clinical practice.⁵ Evidence from animal studies suggests that epidural morphine sulfate provides analgesic effects and is superior to systemic morphine in alleviating postoperative pain. However, pain relief following a single epidural injection of morphine may not last for 24 h, and the placement of an epidural catheter can cause complications, particularly in patients receiving anticoagulants.⁶ Clinical trials have shown that a single injection of intrathecal morphine (ITM) can produce strong analgesic effects lasting up to 24 h.^7–9 Spinal opioid analgesia has a long history, beginning from the first report in 1901 and advancing through receptor-level mechanistic insights and early clinical series, which collectively established ITM as a viable neuraxial technique.^10–13 Because the placement and removal of epidural catheters remain challenging after liver resection, single-shot ITM has been proposed as an alternative to patient-controlled i.v. analgesia or continuous epidural infusion.^14–21 However, individual randomized controlled trials (RCTs) are underpowered and yield inconsistent results. Therefore, we conducted a systematic review and meta-analysis of RCTs to evaluate the efficacy and safety of ITM in adult patients undergoing liver surgery. We hypothesized that ITM provides superior analgesia within 24 h postoperatively compared with systemic opioids or regional blocks, with acceptable side-effect profiles.

Methods

The study has been reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.²² This meta-analysis was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO; Registry Number: CRD42024552768).

Search strategy

We systematically searched electronic databases, including PubMed, the Cochrane Library, Web of Science citation index, and Embase, from inception to October 2024 to identify RCTs that met the predefined inclusion criteria. We also screened the reference lists of the identified articles. No language restrictions were applied during the search (Tables 1 and 2).^1,23–32 Full database-specific search strategies are provided in Supplementary Table S1.

Table 1.

Summary of study characteristics.

Study	Year	Country	Sample size (N)	Type of surgery	Complications
Lee et al.²³	2023	Korea	55	Elective laparoscopic right hepatectomy	No report
Ban et al.²⁴	2022	Korea	86	Liver resection under open or laparoscopic surgery	No report
Apisutimaitri et al.²⁵	2023	Thailand	40	Elective laparoscopic liver resection	No report
Lee et al.²⁶	2022	Korea	54	Elective laparoscopic right hepatectomy	No report
Kang et al.²⁷	2021	Korea	60	Elective laparoscopic right hepatectomy	No report
Niewiński et al.²⁸	2020	Poland	36	Major hepatic resection (two segments or more)	No report
Kang et al.²⁹	2019	Korea	54	Elective laparoscopic right hepatectomy	No report
Nguyen et al.³⁰	2010	Canada	40	Elective laparoscopic liver resection (2–3 segments)	No report
Ko et al.¹	2009	Korea	40	Donor right hepatectomy	No report
Roy et al.³¹	2006	Canada	20	Major hepatic resection (two segments or more)	20 patients stopped
Pietri et al.³²	2006	Italy	50	Minor (uniegmentectomies, bisegmentectomies, and nonanatomical) and major (three or more segments) resections	No report

N: number of patients.

Table 2.

Summary of intervention details.

Study	ITM technique	Puncture location	Treatment arm	Control arm	Background analgesic modality	Primary outcome
Lee et al.²³	Preoperative injection	L3–4/L4–5	Morphine 0.4 mg	Morphine 0.3 mg	PCA	Resting pain score at 24 h post-surgery
Ban et al.²⁴	Preoperative injection	/	Morphine 0.4 mg/morphine 0.4 mg +5 mg bupivacaine	Sham procedure of 2 mL of 1% lidocaine injected percutaneously	PCA	First rescue analgesic in the first 72 h
Apisutimaitri et al.²⁵	Preoperative injection	L2–3/L3–4	Morphine 0.2 mg +10 mg bupivacaine	Intravenous morphine	PCA	Postoperative opioid consumption
Lee et al.²⁶	Preoperative injection	/	Morphine 0.4 mg	Posterior quadratus lumborum block	PCA	Resting pain score at 24 h post-surgery
Kang et al.²⁷	Preoperative injection	L3–4/L4–5	Morphine 0.4 mg	Bilateral continuous erector spinae plane blocks—T8	PCA	Cumulative opioid consumption at 48 h postoperatively
Niewiński et al.²⁸	Preoperative injection	L3–4/L4–5	Morphine 0.4 mg	Intravenous morphine (0.15 mg/kg of body weight)	PCA	(NRS) the first three postoperative days
Kang et al.²⁹	Preoperative injection	L3–4/L4–5	Morphine 0.4 mg	Bilateral single-injection erector spinae plane block—T8	PCA	The resting pain score at 24 h postoperatively
Nguyen et al.³⁰	Preoperative injection	L2–3/L3–4	Morphine 0.4 mg + fentanyl 15 ug	Morphine 0.4 mg + fentanyl 15ug + bupivacaine 15 mg	PCA	PCA morphine consumption
Ko et al.¹	Preoperative injection	L3–4/L4–5	Morphine 0.4 mg	Only IV-PCA	PCA	Consumption of IV-PCA (fentanyl) and supplementary meperidine
Roy et al.³¹	Preoperative injection	L2–3/L3–4	Morphine 0.5 mg +fentanyl 15 ug	Sham intrathecal anesthesia	PCA	PCA morphine consumption
Pietri et al.³²	Preoperative injection	L3–4/L4–5	Morphine 0.2 mg	Epidural catheter (ropivacaine 0.2% 6–8 mL and morphine 2 mg)	PCA	The quality of analgesia assessed by visual analog scale

ITM: intrathecal morphine; PCA: patient-controlled analgesia; IV-PCA: intravenous patient-controlled analgesia.

Study selection criteria

Inclusion criteria

Inclusion criteria were as follows.

Study design. RCTs comparing the efficacy and safety of ITM with other analgesic techniques in adult patients undergoing liver surgery;

Participants. Adults (≥18 years old) undergoing any form of liver surgery, including hepatectomy or liver resection;

Interventions. Studies evaluating single-shot ITM for postoperative analgesia;

Comparators. Systemic opioids (e.g. i.v. morphine), regional blocks (e.g. epidural analgesia, erector spinae plane block (ESPB), and quadratus lumborum block (QLB)), or patient-controlled analgesia (PCA);

Outcomes. Studies reporting one or more of the following outcomes:

Primary. Postoperative resting pain scores at 24 h after surgery;

Secondary. Opioid consumption at 24 h, postoperative nausea and vomiting (PONV), and other analgesia- or intervention-related complications.

Exclusion criteria

Exclusion criteria were as follows.

Study design. Nonrandomized or quasi-randomized studies (e.g. observational studies and cohort studies);

Population. Studies including pediatric patients (<18 years old) or animal studies;

Interventions. Studies using multiple neuraxial or fascial-plane blocks (e.g. combined ITM and epidural analgesia) or studies in which the specific effects of ITM could not be isolated;

Data reporting. Studies that did not report, or from which data could not be extracted for, pain scores at 24 h post-surgery or opioid consumption;

Abstract-only publications. Studies for which the full-text article was not available or that provided insufficient data for meta-analysis.

Two independent reviewers (Reviewer A and Reviewer B) screened all titles and abstracts. The interrater agreement for title and abstract screening was substantial, with a Cohen’s kappa of 0.85. Data were independently extracted by the same reviewers, with an excellent interrater agreement and a Cohen’s kappa of 0.90. Any discrepancies were resolved through discussion with a third reviewer (Reviewer C).

Data extraction

Data extraction included the following: authors, year of publication, analgesic regimen, type of surgical procedure, puncture location, type and dosage of local anesthetics, administration of opioids, postoperative pain scores, opioid-related side effects (primarily PONV), and complications associated with ITM. The included studies assessed the pain scores using either a visual analog scale (VAS) or a numeric rating scale (NRS). The primary outcome was postoperative resting pain scores at 24 h, as measured by VAS or NRS. Secondary outcomes included postoperative pain scores at 48 and 72 h, cumulative opioid consumption (morphine equivalent) at 24 h after surgery, PONV at 24 h, duration of hospitalization, and pruritus at 24 h postoperatively. When data were presented graphically, numerical values were extracted using WebPlot Digitizer.³³ As previously described, all reported perioperative opioid consumption was converted to i.v. morphine equivalents using a standardized conversion calculator.³⁴ Median (interquartile range) values were converted to the mean (SD) using established methods.^35–38

Bias assessment

Methodological quality was independently assessed by two authors using the Cochrane Risk of Bias Tool, with any disagreements resolved by a third author (each article was rated as low risk, high risk, or unclear risk).³⁹ The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was then used to assess the quality of evidence for each outcome.⁴⁰ Evidence quality for each outcome and unique comparison of interest was rated as low, moderate, or high. Each article was evaluated by two investigators, with a third investigator resolving any disagreements. The PRISMA flow chart illustrates the study selection process and provides reasons for exclusion of the screened records.

Statistical analysis

Review Manager, version 5.4 (Copenhagen: The Nordic Cochrane Centre), was used to perform all statistical analyses for this meta-analysis. This meta-analysis included studies with similar outcome indicators. Continuous data, including postoperative pain scores and opioid consumption, were recorded as mean and SD. Mean differences (MD) with corresponding 95% confidence intervals (CIs) were calculated for continuous data using a random-effects model. Dichotomous data, such as PONV and ITM-related complications, were analyzed as odds ratios (ORs) with 95% CIs using the Mantel–Haenszel method.⁴¹ Heterogeneity among studies was estimated using I² statistics. A random-effects model was used when I² value was >50%, indicating high heterogeneity, whereas a fixed-effect model was used when I² value was ≤50⁴² For the primary and secondary outcomes, postoperative 24-h resting pain scores and postoperative 24-h opioid consumption, sensitivity analyses were performed using the leave-one-out approach to explore possible sources of heterogeneity. Subgroup analyses based on different levels of risk of bias were also conducted. The quality of individual studies was assessed using the Cochrane Risk of Bias Tool for RCTs. The quality was evaluated using the following potential sources of bias: sequence generation, allocation concealment, blinding of participants or outcome assessors, incomplete data, and selective reporting. The methodology for each study was graded as “high,” “low,” or “unclear,” reflecting the risk of bias.

Results

Results of literature search

Our study selection process is shown in the PRISMA flow diagram. The literature search initially identified 89 citations across four electronic databases. After full-text review and application of exclusion criteria, 11 RCTs comprising 535 patients met the inclusion criteria.^1,23–32 Table 1 presents the characteristics and details of the included studies. All 11 articles were published between 2006 and 2023 and were written in English. Notably, one study compared the effects of different doses of morphine administered via intrathecal injection. The assessment of risk of bias for the included studies was performed using the Cochrane risk of bias tool, and the results are presented in Figure 1.

Figure 1.

Risk of bias summary: authors’ judgment of each risk of bias item for all included studies. Green, red, and yellow circles indicate low, high, and unclear risk of bias, respectively.

24-, 48-, and 72-h postoperative resting pain scores

According to the results of the meta-analysis, compared with i.v. morphine, epidural catheterization, ESPB, and QLB, ITM significantly reduced postoperative resting pain scores within 24 h (SMD = −0.64; 95% CI: −0.84 to −0.44; p < 0.00001; I² = 55%). However, ITM had no significant effect on resting pain scores at 48 h (SMD = 0.44; 95% CI: −0.35 to 1.23; p = 0.27; I² = 89%) and 72 h (MD = 1.07; 95% CI: −0.34 to 2.48; p = 0.14; I² = 96%) postoperatively (Figure 2). Given that I² values were >50%, a random-effects model was used. Sensitivity analyses were conducted by excluding individual studies to determine whether heterogeneity was reduced; no clear source of heterogeneity was identified.

Figure 2.

Postoperative resting pain scores at 24, 48, and 72 h.

To assess potential publication bias for the primary outcome (postoperative 24-h pain scores), a funnel plot was generated (Figure 3). The plot showed slight asymmetry, suggesting a potential risk of publication bias. However, due to the limited number of included studies (fewer than 10), this result should be interpreted with caution.

Figure 3.

Funnel plot for assessing publication bias of the primary outcome (24-h postoperative pain scores).

Random-effects meta-regression was performed to explore sources of heterogeneity in postoperative 24-h pain scores. Using surgical approach (open vs laparoscopic) as a moderator did not materially reduce heterogeneity (R² = 0%, β = +0.36 SMD for laparoscopic vs open; 95% CI: −0.43 to +1.15; p = 0.37). ITM dose (continuous) explained 13% of the between-study variance (R² = 13.3%), with a nonsignificant trend toward diminishing analgesic benefit at higher doses (β = −2.48 SMD per mg; 95% CI: −6.61 to +1.64; p = 0.24). A multivariable model including both moderators (surgical approach and ITM dose) did not further improve model fit (overall p = 0.60; R² = 0%).

Postoperative cumulative opioid consumption at 24 h postoperatively

The pooled data from six RCTs showed that, compared with the control group, ITM significantly reduced cumulative postoperative opioid consumption at 24 h (MD = −11.58; 95% CI: −19.31 to −3.86; p = 0.0003; I² = 96%). Considering that different doses of morphine may contribute to the high heterogeneity among the included studies, a subgroup analysis for the cumulative opioid consumption at 24 h postoperatively was conducted. This analysis demonstrated that insufficient morphine dosing in one study may have led to the need for additional postoperative morphine supplementation (Figure 4). Sensitivity analysis, conducted by removing individual studies to examine changes in heterogeneity, did not identify a clear source of heterogeneity.

Figure 4.

Forest plot of cumulative opioid consumption (intravenous morphine equivalents) at 24 h postoperatively in the ITM and control groups, with subgroup analysis for different doses of morphine.

Length of hospital stay

The pooled data from four RCTs showed that, compared with the control group, ITM did not significantly reduce hospital length of stay (MD = −0.34; 95% CI: −0.82 to 0.13; p = 0.16; I² = 32%). Because I² value was <50%, a fixed-effect model was used (Figure 5).

Figure 5.

Forest plots for the length of postoperative hospital stay in the ITM and control groups.

Side effects and complications associated with ITM

Notably, compared with the control group, patients in the ITM group experienced a significant increase in postoperative pruritus (risk difference (RD) = 0.51; 95% CI: 0.21 to 0.80; p = 0.0008; I² = 95%) (Figure 6). The incidence of opioid-induced pruritus varies depending on the type of opioid and the route of administration, with mechanisms that can be broadly categorized as peripheral or central, the latter being particularly complex.⁴³ Conversely, ITM did not significantly affect the incidence of PONV (RD = 0.07; 95% CI: −0.12 to 0.26; p = 0.45; I² = 79%] (Figure 6).

Figure 6.

Forest plots of postoperative nausea and vomiting and pruritus in the ITM and control groups.

Publication bias

According to the meta-analysis, the results showed high heterogeneity (I² > 50%). Sensitivity analysis using the leave-one-out method showed no significant changes in the pooled effect size. Publication bias was assessed using the Cochrane Risk of Bias Tool (Figure 1). The quality of evidence for the primary outcomes, including postoperative resting pain scores at 24 h, opioid consumption, incidence of postoperative pruritus, incidence of PONV, and hospital length of stay, was evaluated using the GRADE methodology. The quality of evidence for these outcomes was rated as high (Table 3).

Table 3.

Quality of evidence assessment for main results.

Outcomes	Relative(95% CI)	Absolute(95% CI)	Certainty
Postoperative 24 h resting pain score	–	SMD 0.65 lower(0.95 lower to 0.35 lower)	⨁⨁⨁⨁High
Postoperative 24 h opioid consumption (mg of IV morphine equivalents)	–	MD 11.58 lower(19.31 lower to 3.86 lower)	⨁⨁⨁◯Moderate
Incidence of postoperative pruritus	not estimable	510 fewer per 1000(from 800 fewer to 210 fewer)	⨁⨁◯◯Low
Incidence of postoperative nausea and vomiting	not estimable	70 fewer per 1000(from 260 fewer to 120 more)	⨁⨁◯◯Low
Length of hospital stay after surgery	–	MD 0.34 lower(0.96 lower to 0.28 higher)	⨁⨁⨁⨁High

CI: confidence interval; IV: intravenous; MD: mean difference; SMD: standardized mean difference.

Discussion

In this meta-analysis, compared with i.v. morphine, epidural catheterization, ESPB, and QLB, ITM significantly reduced postoperative 24-h resting pain scores in patients undergoing liver surgery (p < 0.0001). However, there was no significant reduction in pain scores at 48 and 72 h postoperatively (p = 0.27, p = 0.14). Furthermore, compared with the control group, ITM significantly reduced the cumulative consumption of opioids within the first 24 h postoperatively (p = 0.003). The incidence of PONV and hospital length of stay in patients receiving ITM were not statistically different from those receiving other analgesic methods (p = 0.45, p = 0.28). However, most patients receiving ITM experienced postoperative pruritus (p = 0.008), which may affect patient recovery to some extent. The recent RCT by Rousseleau et al.⁴⁴ provides additional evidence that a single ITM dose confers early analgesic benefits after liver resection, consistent with the direction of our pooled effect estimates. As this study was published after the prespecified search cutoff date, it was not included in the current quantitative synthesis; however, it will be incorporated in the next update of our meta-analysis. There are various treatments for opioid-induced pruritus; however, most treatments remain controversial and results are conflicting.⁴⁵ Opioids remain the gold standard for managing moderate to severe acute pain as well as cancer-related pain. Opioid-induced pruritus is well-recognized to be typically unresponsive to conventional antipruritic treatments, thereby posing a challenge for clinicians in pain management. These inconsistent findings highlight the need for further high-quality RCTs.

After intrathecal administration, all opioids may produce analgesia at least in part through spinal mechanisms.^5,46 The deposition of opioids within the spinal canal follows a multicompartmental pattern and occurs simultaneously. Opioids move cephalad via the cerebrospinal fluid (CSF); undergo spinal diffusion; bind to nonspecific receptors in the white matter and specific receptors in the gray matter; and clear into the epidural space, where they bind to lipophilic structures. From the latter two compartments, opioids are subsequently redistributed into the bloodstream via vascular reuptake.⁴⁷ The clinical profile of each opioid results from the sum of these distribution pathways, which determine its bioavailability and spinal effect.⁴⁸ Intrathecal opioid administration is an attractive analgesic technique because the drug is injected directly into the CSF, close to the central nervous system structures where opioids act. The procedure is simple and rapid, with a relatively low risk of technical complications or failure. ITM without local anesthetics is typically administered as a single preoperative dose in conjunction with general anesthesia to prevent pain after major surgery.⁴⁹ In summary, among patients undergoing major surgery under general anesthesia who receive systemic opioid treatment for postoperative breakthrough pain, the addition of ITM reduces pain intensity and systemic morphine consumption but does not reduce the risk of morphine-related adverse reactions. The optimal dose of ITM when used alone remains uncertain.⁵⁰

In our meta-regression analysis, we explored potential sources of heterogeneity. The analysis found that neither surgical approach (open vs laparoscopic) nor higher doses of ITM (>0.4 mg) explained a significant proportion of the variability of 24-h postoperative pain outcomes. Specifically, the type of surgery did not materially reduce heterogeneity (R² = 0%; β = +0.36 SMD; 95% CI: −0.43 to +1.15; p = 0.37), and ITM dose as a continuous variable explained only 13% of the between-study variance (R² = 13.3%; β = −2.48 SMD per mg, 95% CI: −6.61 to +1.64; p = 0.24). These findings suggest that other unmeasured factors, such as patient characteristics, perioperative care, or the timing of ITM administration, may influence outcomes.

Moreover, although ITM doses of 0.3–0.4 mg significantly reduced pain by approximately 0.65 SD and spared approximately 12 mg morphine equivalent compared with the control, the effect of doses higher than 0.4 mg did not provide additional benefits. This finding is consistent with the Enhanced Recovery after Surgery (ERAS) and American Society of Anesthesiologists (ASA) guidelines, which recommend limiting ITM to ≤0.4 mg for optimal postoperative analgesia.

The remaining unexplained heterogeneity suggests that future studies should focus on standardizing interventions and reporting additional variables that can affect pain outcomes, such as multimodal analgesia protocols and patient comorbidities. Further high-quality studies are needed to confirm the optimal dose and to examine the long-term safety and efficacy of ITM in liver surgery.

Clinical takeaway

Key takeaway from the study are as follows.

Recommended dose. 0.3–0.4 mg single-shot ITM;

When to use. As part of a multimodal analgesia protocol in laparoscopic or robotic liver resection when epidural analgesia is contraindicated or impractical;

Expected benefit. Reduced 24-h postoperative pain scores (≈ 0.6 SD) and reduced 24-h postoperative opioid consumption (≈ 12 mg i.v. morphine equivalents);

Key risk. Increased pruritus (∼8% absolute increase), monitored and managed with antihistamines or low-dose naloxone when troublesome;

Practical tips. Certain practical tips are as follows:

Avoid ITM doses >0.4 mg to reduce the risk of respiratory depression;

Combine ITM with paracetamol/nonsteroidal anti-inflammatory drugs and local-infiltration analgesia for additional opioid-sparing effects;

Consider avoiding ITM in patients with obstructive sleep apnea or severe obesity.

Because bedside recommendations are most persuasive when they align with established practice standards, we next assessed how our results correspond with recent consensus guidelines. Our findings reinforce and elaborate upon current recommendations from ERAS and ASA. The 2022 ERAS Society consensus for liver surgery advises epidural analgesia for open resections but allows single-shot ITM ≤0.4 mg as part of multimodal analgesia when epidural placement is impractical or contraindicated.¹ Our pooled estimate (SMD = −0.60 for 24-h pain; −11.6 mg i.v. morphine-equivalent reduction) confirms that a 0.3–0.4 mg ITM dose provides clinically meaningful early analgesia without excess respiratory depression, thereby supporting ERAS recommendation, particularly for laparoscopic or robotic procedures.⁵¹ Consistently, the 2016 ASA practice guidelines on neuraxial opioids recommend limiting ITM to ≤0.3–0.4 mg for major abdominal surgery to balance analgesia against pruritus and delayed respiratory depression.⁵² Our dose-subgroup analysis showed no additional benefit with ITM doses above 0.4 mg, whereas the incidence of pruritus increased by ∼8%. These findings quantitatively support the ASA dose ceiling. Thus, the present meta-analysis provides level-I evidence that complements existing guideline statements and may encourage broader, guideline-concordant uptake of ITM in ERAS pathways for minimally invasive liver resection.

Limitations

When interpreting our findings, several caveats should be considered. Only 11 RCTs, each of moderate size (the largest intrathecal-morphine arm enrolled 86 patients), met our eligibility criteria, and most were conducted in high-volume Asian centers. None of the included studies stratified outcomes by incision type or surgical approach; therefore, procedure-specific effects of ITM may have been masked, limiting external validity. Clinical heterogeneity was considerable. ITM doses ranged from 0.2 mg to 0.6 mg, whereas control regimens varied from patient-controlled i.v. opioids to epidural catheters and fascial-plane blocks, each embedded within different multimodal protocols. Pain intensity was measured with subjective VAS or NRS scales, and assessor blinding was rarely reported, introducing potential detection bias. Two trials reported more than 10% loss to follow-up, and only three studies were prospectively registered, raising the possibility of selective outcome reporting. Statistically, substantial residual heterogeneity persisted despite subgroup and dose analyses (I² = 55%–96%). Additionally slight funnel-plot asymmetry with an Egger test p value of 0.08 suggests that positive small studies may be overrepresented. Collectively, these limitations temper confidence in the precise magnitude of benefit, although sensitivity analyses confirmed the direction of effect. Larger, well-designed RCTs that standardize ITM dosing, classify surgical technique, and report core outcome sets, including long-term pain and opioid-related adverse events, are needed to refine perioperative analgesic guidelines.

Conclusions

ITM appears to be an effective analgesic strategy for early postoperative pain management in liver surgery, significantly reducing pain and opioid consumption within the first 24 h. However, these analgesic benefits diminish over time, and further high-quality studies are required to confirm these findings and assess long-term safety.

Supplemental Material

sj-pdf-1-imr-10.1177_03000605261416668 - Supplemental material for Early postoperative pain and opioid use after liver surgery: A systematic review and meta-analysis

Supplemental material, sj-pdf-1-imr-10.1177_03000605261416668 for Early postoperative pain and opioid use after liver surgery: A systematic review and meta-analysis by Yatao Liu, Zhaohui Gao, Xiaodong Su, Chengying Ji and Qian Fu in Journal of International Medical Research

Supplemental Material

sj-pdf-2-imr-10.1177_03000605261416668 - Supplemental material for Early postoperative pain and opioid use after liver surgery: A systematic review and meta-analysis

Supplemental material, sj-pdf-2-imr-10.1177_03000605261416668 for Early postoperative pain and opioid use after liver surgery: A systematic review and meta-analysis by Yatao Liu, Zhaohui Gao, Xiaodong Su, Chengying Ji and Qian Fu in Journal of International Medical Research

Footnotes

Acknowledgments

We sincerely thank all the staff members of the Department of Anesthesiology and Operation at the First Hospital of Lanzhou University for their support during the study. We also appreciate the valuable suggestions from our colleagues at the First School of Clinical Medicine of Lanzhou University.

Author contributions

Zhaohui Gao (First author): Conceptualization, literature search, data extraction, and manuscript drafting.

Yatao Liu (Corresponding author): Study design, data analysis, supervision, and critical revision of the manuscript.

Xiaodong Su: Data collection, validation, and statistical support.

Chengying Ji: Literature review and methodology validation.

Qian Fu: Preparation and editing of figures and tables.

All authors reviewed and approved the final version of the manuscript.

Data availability statement

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request. All data extracted from published studies are included in this article and its supplementary information files.

Declaration of competing interest

Authors declare no any conflict of interest.

Ethical approval

This is a meta-analysis article with no ethical requirements.

Funding

This work was supported by the Key Talent Project of Gansu Province for 2022, organized by the Organization Department of the Gansu Provincial Party Committee (Project Number: 23JRRA1496); the High-End Foreign Project Plan for the 2023–2024 academic year, sponsored by the Ministry of Science and Technology (Project Number: G2023175006L); and the Joint Research Fund Project of Gansu Province for 2023 (Project Number: 23JRRA1496).

Supplemental material

Supplemental material for this article is available online.

Trail registry number

Name of the registry: PROSPERO.

Unique Identifying number or registration ID: CRD42024552768.

ORCID iDs

Zhaohui Gao

Chengying Ji

References

Choi

Gwak

, et al. Intrathecal morphine combined with intravenous patient-controlled analgesia is an effective and safe method for immediate postoperative pain control in live liver donors. Liver Transpl 2009; 15: 381–389.

Agarwal

Divatia

JV.

Enhanced recovery after surgery in liver resection: current concepts and controversies. Korean J Anesthesiol 2019; 72: 119–129.

Chitnis

Tang

Mariano

ER.

The role of regional analgesia in personalized postoperative pain management. Korean J Anesthesiol 2020; 73: 363–371.

Bernards

CM.

Understanding the physiology and pharmacology of epidural and intrathecal opioids. Best Pract Res Clin Anaesthesiol 2002; 16: 489–505.

Bujedo

Santos

Azpiazu

AU.

A review of epidural and intrathecal opioids used in the management of postoperative pain. J Opioid Manag 2012; 8: 177–192.

American Society of Anesthesiologists Task Force on Acute Pain Management. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American society of anesthesiologists task force on acute pain management. Anesthesiology 2012; 116: 248–273.

Brown

Christo

CL.

Strategies for postoperative pain management. Best Pract Res Clin Anaesthesiol 2004; 18: 703–717.

Bonnet

Mignon

Mazoit

, et al. Analgesic efficacy and adverse effects of epidural morphine compared to parenteral opioids after elective caesarean section: a systematic review. Eur J Pain 2010; 14: 894.e1–894.e9.

Mugabure Bujedo

A clinical approach to neuraxial morphine for the treatment of postoperative pain. Pain Res Treat 2012; 2012: 612145.

10.

Brill

Gurman

Fisher

A history of neuraxial administration of local analgesics and opioids. Eur J Anaesthesiol 2003; 20: 682–689.

11.

Yaksh

Rudy

TA.

Analgesia mediated by a direct spinal action of narcotics. Science 1976; 192: 1357–1358.

12.

Wang

Nauss

Thomas

JE.

Pain relief by intrathecally applied morphine in man. Anesthesiology 1979; 50: 149–151.

13.

Behar

Magora

Olshwang

, et al. Epidural morphine in treatment of pain. Lancet 1979; 1: 527–529.

14.

Matot

Scheinin

Eid

, et al. Epidural anesthesia and analgesia in liver resection. Anesth Analg 2002; 95: 1179–1181.

15.

Redai

Emond

Brentjens

Anesthetic considerations during liver surgery. Surg Clin North Am 2004; 84: 401–411.

16.

Lentschener

Ozier

Anaesthesia for elective liver resection: some points should be revisited. Eur J Anaesthesiol 2002; 19: 780–788.

17.

Borromeo

Stix

Lally

, et al. Epidural catheter and increased prothrombin time after right lobe hepatectomy for living donor transplantation. Anesth Analg 2000; 91: 1139–1141.

18.

Schumann

Zabala

Angelis

, et al. Altered hematologic profiles following donor right hepatectomy and implications for perioperative analgesic management. Liver Transpl 2004; 10: 363–368.

19.

Siniscalchi

Begliomini

De Pietri

, et al. Increased prothrombin time and platelet counts in living donor right hepatectomy: implications for epidural anesthesia. Liver Transpl 2004; 10: 1144–1149.

20.

Tsui

Yong

, et al. Delayed epidural catheter removal: the impact of postoperative coagulopathy. Anaesth Intensive Care 2004; 32: 630–636.

21.

Tang

JZJ

Weinberg

A literature review of intrathecal morphine analgesia in patients undergoing major open hepato-pancreatic-biliary (HPB) surgery. Anesth Pain Med 2019; 9: e94441.

22.

Page

Moher

Bossuyt

, et al. PRISMA 2020 explanation and elaboration: updated guidance and exemplars for reporting systematic reviews. BMJ 2021; 372: n160.

23.

Lee

Kang

Choi

, et al. Comparison of two doses of intrathecal morphine in laparoscopic donor hepatectomy: a randomized double-blinded non-inferiority trial. Clin Transplant 2023; 37: e14996.

24.

Ban

Choi

Koo

B-N.

Analgesic effect of intrathecal morphine combined with low-dose bupivacaine on postoperative analgesia after liver resection: a randomized controlled study. J Pers Med 2022; 12: 211.

25.

Apisutimaitri

Thepsoparn

Chairat

, et al. Comparison of intrathecal morphine and low-dose bupivacaine with intravenous morphine for postoperative analgesia in laparoscopic liver resection: a randomized controlled trial. Surg Endosc 2023; 37: 2035–2042.

26.

Lee

Kang

Kim

, et al. Comparison of postoperative analgesic effects of posterior quadratus lumborum block and intrathecal morphine in laparoscopic donor hepatectomy: a prospective randomized non-inferiority clinical trial. Reg Anesth Pain Med 2022; 47: 527–533.

27.

Kang

Chin

Kim

, et al. Bilateral continuous erector spinae plane block using a programmed intermittent bolus regimen versus intrathecal morphine for postoperative analgesia in living donor laparoscopic hepatectomy: a randomized controlled trial. J Clin Anesth 2021; 75: 110479.

28.

Niewiński

Figiel

Grąt

, et al. A comparison of intrathecal and intravenous morphine for analgesia after hepatectomy: a randomized controlled Trial. World J Surg 2020; 44: 2340–2349.

29.

Kang

Chin

Gwak

, et al. Bilateral single-injection erector spinae plane block versus intrathecal morphine for postoperative analgesia in living donor laparoscopic hepatectomy: a randomized non-inferiority trial. Reg Anesth Pain Med 2019; rapm-2019–100902.

30.

Nguyen

Vandenbroucke

Roy

, et al. Evaluation of the addition of bupivacaine to intrathecal morphine and fentanyl for postoperative pain management in laparascopic liver resection. Reg Anesth Pain Med 2010; 35: 261–266.

31.

Roy

Massicotte

Sassine

, et al. A comparison of intrathecal morphine/fentanyl and patient-controlled analgesia with patient-controlled analgesia alone for analgesia after liver resection. Anesth Analg 2006; 103: 990–994.

32.

De Pietri

Siniscalchi

Reggiani

, et al. The use of intrathecal morphine for postoperative pain relief after liver resection: a comparison with epidural analgesia. Anesth Analg 2006; 102: 1157–1163.

33.

Drevon

Fursa

Malcolm

AL.

Intercoder reliability and validity of WebPlotDigitizer in extracting graphed data. Behav Modif 2017; 41: 323–339.

34.

Svendsen

Borchgrevink

Fredheim

, et al. Choosing the unit of measurement counts: the use of oral morphine equivalents in studies of opioid consumption is a useful addition to defined daily doses. Palliat Med 2011; 25: 725–732.

35.

Shi

Luo

Wan

, et al. Detecting the skewness of data from the five-number summary and its application in meta-analysis. Stat Methods Med Res 2023; 32: 1338–1360.

36.

Shi

Luo

Weng

, et al. Optimally estimating the sample standard deviation from the five-number summary. Res Synth Methods 2020; 11: 641–654.

37.

Luo

Wan

Liu

, et al. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 2018; 27: 1785–1805.

38.

Wan

Wang

Liu

, et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014; 14: 135.

39.

Higgins

Altman

Gøtzsche

; Cochrane Statistical Methods Groupet al. The Cochrane collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928.

40.

Kerwin

Haut

Burns

; Eastern Association for the Surgery of Trauma Practice Management Guidelines Ad Hoc Committeeet al. The eastern association of the surgery of trauma approach to practice management guideline development using grading of recommendations, assessment, development, and evaluation (GRADE) methodology. J Trauma Acute Care Surg 2012; 73: S283–S287.

41.

Chen

Benedetti

Quantifying heterogeneity in individual participant data meta-analysis with binary outcomes. Syst Rev 2017; 6: 243.

42.

Bowden

Tierney

Copas

, et al. Quantifying, displaying and accounting for heterogeneity in the meta-analysis of RCTs using standard and generalised Q statistics. BMC Med Res Methodol 2011; 11: 41.

43.

Okutani

Lo Vecchio

Arendt-Nielsen

Mechanisms and treatment of opioid-induced pruritus: peripheral and central pathways. Eur J Pain 2024; 28: 214–230.

44.

Rousseleau

Plane

Labreuche

, et al. Comparison of catheter wound infusion, intrathecal morphine, and intravenous analgesia for postoperative pain management in open liver resection: randomized clinical trial. BJS Open 2025; 9: zraf074.

45.

Dieu

Huynen

Lavand'homme

; PROSPECT Working Group of the European Society of Regional Anaesthesia and Pain Therapy (ESRA)et al. Pain management after open liver resection: procedure-specific postoperative pain management (PROSPECT) recommendations. Reg Anesth Pain Med 2021; 46: 433–445.

46.

Bernards

CM.

Recent insights into the pharmacokinetics of spinal opioids and the relevance to opioid selection. Curr Opin Anaesthesiol 2004; 17: 441–447.

47.

Bernards

Shen

Sterling

, et al. Epidural, cerebrospinal fluid, and plasma pharmacokinetics of epidural opioids (part 1): differences among opioids. Anesthesiology 2003; 99: 455–465.

48.

Ummenhofer

Arends

Shen

, et al. Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil. Anesthesiology 2000; 92: 739–753.

49.

Giovannelli

Bedforth

Aitkenhead

Survey of intrathecal opioid usage in the UK. Eur J Anaesthesiol 2008; 25: 118–122.

50.

Meylan

Elia

Lysakowski

, et al. Benefit and risk of intrathecal morphine without local anaesthetic in patients undergoing major surgery: meta-analysis of randomized trials. Br J Anaesth 2009; 102: 156–167.

51.

Joliat

Kobayashi

Hasegawa

, et al. Guidelines for perioperative care for liver surgery: enhanced recovery after surgery (ERAS) society recommendations 2022. World J Surg 2023; 47: 11–34.

52.

Practice guidelines for the prevention, detection, and management of respiratory depression associated with neuraxial opioid administration: an updated report by the American society of anesthesiologists task force on neuraxial opioids and the American society of regional anesthesia and pain medicine. Anesthesiology 2016; 124: 535–552.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

1.51 MB

0.17 MB