FormalPara Key Summary Points

Why carry out this study?

Published literature showed that various preemptive analgesia protocols had been used before laparoscopic cholecystectomy (LC) to control postoperative pain. Unfortunately, clinical guidelines do not clearly provide the best methods, types of drugs, or recommended dosages for preemptive analgesia in LC surgery. Furthermore, no studies had systematically compared the effectiveness and safety of these protocols for controlling pain after LC.

Forty-nine randomized controlled trials (RCTs) with 5987 patients were included in our network meta-analysis for evaluating the efficacy and safety of 26 preemptive analgesia measures in LC.

What was learned from the study?

Our findings indicated that preemptive analgesia significantly reduced postoperative pain intensity, opioid consumption, extended the time to first rescue analgesia, and decreased the incidence of postoperative nausea and vomiting (PONV) and postoperative headache and dizziness.

Our findings indicated that multimodal analgesia, nerve blocks, pregabalin, and gabapentin all showed good efficacy. Subgroups analysis showed that gabapentin 300 mg given preoperatively significantly reduced postoperative pain and adverse drug reaction incidence, recommended for preemptive analgesia in LC.

This study provided robust evidence to support the routine use of preemptive analgesia and to provide the optimal preemptive analgesia interventions for LC.

Introduction

Laparoscopic cholecystectomy (LC) is the preferred surgical treatment for benign gallbladder diseases, such as gallstones, gallbladder polyps, and cholecystitis [1]. Annually, over 750,000 patients in the United States undergo LC [2]. Although LC significantly reduces postoperative pain compared to traditional open surgery [3, 4], studies report that 17–41% of patients still experience significant pain after LC, and 3.4–7.0% suffer from persistent pain [5]. This not only affects patients’ postoperative recovery and prolongs hospital stays but also increases medical costs. Furthermore, the pain after LC is often moderate to severe [3, 6], necessitating high doses of opioids for relief. This can lead to more complications, especially among elderly patients or patients with obesity, and contributes to the opioid crisis, particularly in the United States and many European countries, contradicting current policies advocating for limited opioid use [7]. Therefore, pain management after LC is crucial.

In recent years, the concept of preemptive analgesia, which involves administering analgesic interventions before the onset of noxious stimuli to prevent peripheral and central sensitization, reduce surgical stress, and inflammatory responses, has gained attention with the development of Enhanced Recovery After Surgery (ERAS) protocols [8, 9]. Studies have shown that preemptive analgesia significantly alleviates postoperative pain and is more effective than the same analgesic interventions administered postoperatively. Additionally, preemptive analgesia reduces postoperative opioid consumption, decreases the incidence of nausea and vomiting, and delays the time to rescue analgesia [10]. It has become an essential component of perioperative pain management recommended by guidelines [11, 12].

Clinically, various preemptive analgesia protocols, such as nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, anticonvulsants, N-methyl-d-aspartic acid (NMDA) receptor antagonists, α-receptor agonists, corticosteroids, local wound infiltration, nerve blocks, or multimodal analgesia, have been used before LC to control postoperative pain [3, 10, 12,13,14,15,16,17,18,19,20,21,22,23]. Unfortunately, clinical guidelines do not clearly provide the best methods, types of drugs, or recommended dosages for preemptive analgesia in LC surgery. Furthermore, no studies have systematically compared the effectiveness and safety of these protocols for controlling pain after LC. This creates significant confusion and challenges in the clinical practice of preemptive analgesia for LC.

This study employed a network meta-analysis to evaluate the impact of different preemptive analgesia protocols on postoperative pain, opioid consumption, PONV, and the incidence of headache and dizziness after LC. The aim was to clarify the clinical efficacy and safety of various preemptive analgesia protocols in managing postoperative pain after LC, providing more evidence-based medicine evidence to guide the development of preemptive analgesia protocols for LC surgery.

Methods

This study had been registered on the PROSPERO database with the registration number CRD42024522185 and reported in line with PRISMA (preferred reporting items for systematic reviews and meta-analyses) [24] and AMSTAR (assessing the methodological quality of systematic reviews) guidelines [25].

Inclusion Criteria

  1. 1.

    Population: Adult inpatients aged ≥ 18 years, scheduled for elective LC under general anesthesia.

  2. 2.

    Interventions: Preemptive analgesia in this study was defined as the administration of one of 26 different analgesic protocols before the initial surgical incision in LC. These protocols included acetaminophen; NSAIDs such as ibuprofen, parecoxib, lornoxicam, etoricoxib, indomethacin, diclofenac sodium, and ketorolac; anticonvulsant antidepressant analgesics such as pregabalin, gabapentin, duloxetine, levetiracetam, and acetazolamide; opioids such as morphine, dezocine, nalbuphine, pentazocine, and tramadol; corticosteroids such as dexamethasone and methylprednisolone; α-receptor agonists such as clonidine and dexmedetomidine; NMDA receptor antagonists such as memantine; and modalities such as incision infiltration, nerve blocks, and multimodal analgesia (defined as the administration of two or more types of analgesic treatments preoperatively, including different categories of medications or analgesic techniques). The experimental group received one of the mentioned protocols while the control group received another of the mentioned protocols, a placebo, or saline. The intervention included any dosage form, dosage amount, route of administration, and with no restrictions on postoperative pain management protocols.

  3. 3.

    Outcomes: Postoperative visual analogue scores (VAS) at different time points (2, 6, 12, and 24 h), opioid consumption within the first 24 h postoperatively, time to first rescue analgesia, incidence of postoperative nausea and vomiting (PONV), and incidence of postoperative headache or dizziness.

  4. 4.

    Study types: Published randomized controlled trials (RCTs).

Exclusion Criteria

Exclusion criteria included (1) patients receiving interventions other than the preemptive analgesia protocols studied in this article, or patients allergic to the interventions defined herein; (2) patients with a history of chronic pain (excluding pain caused by gallstones); (3) patients whose LC was converted to an open cholecystectomy; (4) pregnant or lactating women; (5) studies where the clinical outcome data do not match the outcome measures defined in this research; (6) interventions administered intraoperatively or postoperatively; (7) patients undergoing other types of surgery simultaneously; (8) studies deemed to be of low quality (scoring 1–3 on the modified Jadad scale); (9) retrospective studies; (10) duplicated publications; (11) studies that are mere case reports; (12) conference abstracts or study protocols; (13) studies where the full text could not be accessed, even after attempting to contact the authors; (14) non-English publications.

Literature Search Strategy

A computerized search was conducted in databases such as PubMed, Web of Science, Embase, and the Cochrane Library. The search period extended from the inception of the databases until March 2024. Search terms included combinations of keywords and phrases such as (((“preemptive” OR “preoperative” OR “perioperative”) AND (“analgesia*” OR “pain” OR “analgesic*”)) OR (“preemptive analgesia” OR “preoperative analgesia” OR “perioperative analgesia”)) AND (“cholecystectomy”). The search strategy involved both MeSH terms and free text terms, adjusted according to each database’s specific requirements. References of included studies was also searched to capture additional relevant materials.

Data Selection and Extraction

Three researchers (LC, SYY, and TFY) independently screened literature and extract data, cross-checking each other’s work. Discrepancies was resolved through discussion among the three or by a fourth reviewer, if necessary. Data to be extracted includes: (i) basic details of the publications such as first author, publication date, and study design; (ii) clinical characteristics of the subjects including age, number of cases, and types of diseases; (iii) details about the intervention and control measures; (iv) surgical procedures and postoperative analgesia plans; (v) outcome measures; (vi) quality assessment indicators for the literature. If pain scores are assessed using a numerical rating scale (NRS), they will be converted to VAS scores for analysis [10]. To compare total opioid consumption, all doses of opioids were converted into i.v. milligrams of morphine equivalents (IMME) using data from published literature [26].

Assessment of Methodological Quality of Included Studies

Only RCTs was included in this study; hence, the methodological quality was assessed using the modified Jadad scale [27]. This evaluation considered the generation of random sequences, concealment of allocation, blinding, and accounting for dropouts and withdrawals. Studies scoring 1–3 was considered low quality, while those scoring 4–7 was classified as high quality, with less risk of bias and thus suitable for inclusion in this network meta-analysis.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Statistical Analysis

Network meta-analysis under the frequency framework was implemented using the network and mvmeta commands of Stata 15.1 software fitting a multivariate random-effects meta-analysis model using restricted maximum likelihood. Network diagrams were drawn to provide a simplified summary representation showing all available evidence for various interventions. Continuous variables such as VAS scores at different time points were pooled using the weighted mean difference (WMD) and its 95% confidence interval (CI), while total opioid consumption and time to first rescue analgesia, due to large inter-study variance, were pooled using standardized mean difference (SMD). Dichotomous outcomes such as incidence of adverse drug reactions (ADRs) were pooled using relative risk (RR) and its 95% CI. Consistency and inconsistency models were assessed to check the overall network inconsistency, with P < 0.05 indicating the presence of inconsistency. Node-splitting methods were used for local inconsistency testing in each node of the network, and a P value < 0.05 indicates local inconsistency. Inconsistency tests were conducted for closed loops, calculating inconsistency factors (IF), their 95% CI, and P values of Z test; P > 0.05 and a lower limit of 95% CI for IF equal to zero indicates good consistency between direct and indirect comparisons. Otherwise, the closed loop was considered to have obvious inconsistency. League tables showed the results of pairwise comparisons between different interventions. The surface under the cumulative ranking curve (SUCRA) was used to rank interventions based on their effectiveness, with higher SUCRA values indicating a greater likelihood of an intervention being among the top-ranked or most effective options. Publication bias and small study effects were assessed through the generation of comparison-adjusted funnel plots and by qualitatively assessing the symmetry of the plot distributions to detect potential publication biases in the included studies.

Results

Literature Search Results and Methodological Quality Assessment

A total of 2835 articles were initially identified through the database searches using the predefined search terms. After applying the inclusion and exclusion criteria defined in this paper, 49 RCTs [1, 7, 15, 21, 28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72] were ultimately included for the network meta-analysis. The literature selection process was depicted in Fig. 1. The methodological quality of the included studies was assessed using the modified Jadad scale, which resulted in all studies being classified as high quality (scores of 4–7). The overall methodological quality was acceptable, with specific scores detailed in Table 1.

Fig. 1
figure 1

Literature selection flowchart

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Table 1 Characteristics and quality assessments of the included studies
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Characteristics of Included Studies

The 49 studies included a total of 5987 patients, of which 3416 were included in various intervention groups with 2571 in the placebo group. The experimental and control groups were considered comparable in terms of patient demographics and disease types. Basic characteristics of the included studies were shown in Table 1.

Network Diagrams

Visual network graphs were used to illustrate the relationships among the various interventions. Nodes represented the interventions and the number of patients involved, and larger nodes indicated more patients. Solid lines connecting interventions represent the comparisons made, with thicker lines indicating more studies involved. A total of 49 articles including 26 interventions were included in this study. The network graphs for the predefined outcome measures were shown in Figs. 2 and 3 and Figures S1–S6 in the electronic supplementary material for details.

Fig. 2
figure 2

Evidence structure of different intervention measures in opioid consumption within 24 h

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Fig. 3
figure 3

Evidence structure of different intervention measures in the incidence rate of postoperative nausea and vomiting (PONV)

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Network Meta-Analysis Results

VAS at 2 Hours

Eighteen studies reported differences in VAS levels at 2 h post-LC, involving 12 interventions. The pairwise comparison results were shown in Fig. 4. League tables indicated that compared to placebo, preoperative use of multimodal analgesia, nerve blocks, ibuprofen, morphine, gabapentin, and pregabalin significantly reduced pain intensity at 2-h post-LC. Compared to acetaminophen, interventions such as multimodal analgesia, nerve blocks, ibuprofen, gabapentin, and pregabalin significantly lowered the VAS scores at 2 h. No statistically significant differences were observed among the remaining interventions.

Fig. 4
figure 4

Comparing VAS scores at 2 h after surgery between different intervention groups. Blue boxes indicate different interventions and the remaining boxes were the results of pairwise comparisons between different interventions where statistically significant pair-wise comparisons of interventions are highlighted in orange. Reading from left to right, both SMD/WMD and its 95% CI were < 0 or both RR and its 95% CI were < 1 indicating a statistically significant difference. CI confidence interval, RR relative risk, SMD standardized mean difference, VAS visual analogue scores, WMD weighted mean difference

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VAS at 6 Hours

Fourteen studies reported differences in VAS levels at 6 h post-LC, involving 12 interventions. The pairwise comparison results were shown in Fig. 5. League tables indicated that compared to placebo, preemptive analgesia protocols involving pregabalin, multimodal analgesia, gabapentin, nerve blocks, incision infiltration, and clonidine significantly reduced pain intensity at 6 h post-LC. Pregabalin and multimodal analgesia were more effective in reducing the VAS levels at 6 h compared to diclofenac, lornoxicam, and acetaminophen, with gabapentin being more effective than diclofenac and acetaminophen, and nerve blocks being more effective than diclofenac. Differences among these comparisons were statistically significant. No statistically significant differences were observed among the remaining interventions.

Fig. 5
figure 5

Comparing VAS scores at 6 h after surgery between different intervention groups. Blue boxes indicate different interventions and the remaining boxes were the results of pairwise comparisons between different interventions where statistically significant pair-wise comparisons of interventions are highlighted in orange. Reading from left to right, both SMD/WMD and its 95% CI were < 0 or both RR and its 95% CI were < 1 indicating a statistically significant difference. CI confidence interval, RR relative risk, SMD standardized mean difference, VAS visual analogue scores, WMD weighted mean difference

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VAS at 12 Hours

Nineteen studies reported differences in VAS levels at 12 h post-LC, involving 12 interventions. The pairwise comparison results were shown in Fig. 6. League tables indicated that compared to placebo, preoperative use of multimodal analgesia, duloxetine, pregabalin, gabapentin, and nerve blocks significantly reduced VAS levels at 12 h. No statistically significant differences were observed among the remaining interventions.

Fig. 6
figure 6

Comparing VAS scores at 12 h after surgery between different intervention groups. Blue boxes indicate different interventions and the remaining boxes were the results of pairwise comparisons between different interventions where statistically significant pair-wise comparisons of interventions are highlighted in orange. Reading from left to right, both SMD/WMD and its 95% CI were < 0 or both RR and its 95% CI were < 1 indicating a statistically significant difference. CI confidence interval, RR relative risk, SMD standardized mean difference, VAS visual analogue scores, WMD weighted mean difference

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VAS at 24 Hours

Nineteen studies reported on the differences in VAS levels at 24 h post-LC, involving 13 interventions. The pairwise comparison results were shown in Fig. 7. League tables indicated that preemptive analgesia with gabapentin, nerve blocks, multimodal analgesia, and pregabalin significantly reduced pain intensity at 24 h post-LC compared to placebo. No statistically significant differences were observed among the other interventions.

Fig. 7
figure 7

Comparing VAS scores at 24 h after surgery between different intervention groups. Blue boxes indicate different interventions and the remaining boxes were the results of pairwise comparisons between different interventions where statistically significant pair-wise comparisons of interventions are highlighted in orange. Reading from left to right, both SMD/WMD and its 95% CI were < 0 or both RR and its 95% CI were < 1 indicating a statistically significant difference. CI confidence interval, RR relative risk, SMD standardized mean difference, VAS visual analogue scores, WMD weighted mean difference

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Opioid Consumption within 24 Hours Postoperatively

Twenty-three studies reported differences in opioid consumption within 24 h postoperatively among various preemptive analgesia interventions, involving 15 different protocols. The pairwise comparison results were shown in Fig. 8. League tables indicated that multimodal analgesia, gabapentin, ibuprofen, pregabalin, clonidine, and nerve blocks significantly reduced opioid consumption within 24 h postoperatively compared to placebo. No statistically significant differences were observed among the remaining interventions.

Fig. 8
figure 8

Opioid consumption within 24 h postoperatively. Blue boxes indicate different interventions and the remaining boxes were the results of pairwise comparisons between different interventions where statistically significant pair-wise comparisons of interventions are highlighted in orange. Reading from left to right, both SMD/WMD and its 95% CI were < 0 or both RR and its 95% CI were < 1 indicating a statistically significant difference. CI confidence interval, RR relative risk, SMD standardized mean difference, WMD weighted mean difference

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Time to First Rescue Analgesia

Thirteen studies reported differences in the time to first rescue analgesia postoperatively among different preemptive analgesia protocols, involving 11 interventions. The pairwise comparison results were shown in Fig. 9. League tables indicated that tramadol, pregabalin, gabapentin, and clonidine significantly extended the time to first rescue analgesia post-LC compared to placebo. Compared to acetaminophen, acetazolamide, diclofenac, memantine, clonidine, and gabapentin, tramadol and pregabalin extended the time to first rescue analgesia, with statistically significant differences. Tramadol significantly extended the time to first rescue analgesia more than multimodal analgesia and dexmedetomidine. No statistically significant differences were observed among the other interventions.

Fig. 9
figure 9

Time to first rescue analgesia. Blue boxes indicate different interventions and the remaining boxes were the results of pairwise comparisons between different interventions where statistically significant pair-wise comparisons of interventions are highlighted in orange. Reading from left to right, both SMD/WMD and its 95% CI were < 0 or both RR and its 95% CI were < 1 indicating a statistically significant difference. CI confidence interval, RR relative risk, SMD standardized mean difference, WMD weighted mean difference

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Incidence of PONV

Thirty-seven studies reported differences in the incidence of PONV among various preemptive analgesia interventions, involving 26 protocols. The pairwise comparison results were presented in Table S1 in the electronic supplementary material for details. League tables showed that ibuprofen significantly reduced the incidence of PONV compared to placebo, gabapentin, and tramadol. No statistically significant differences were observed among the other interventions.

Incidence of Postoperative Headache or Dizziness

Fifteen studies reported differences in the incidence of postoperative headache and dizziness, involving 11 interventions. The pairwise comparison results were shown in Fig. 10. League tables indicated that pregabalin significantly increased the incidence of postoperative headache and dizziness compared to tramadol and placebo. No statistically significant differences were observed among the other interventions.

Fig. 10
figure 10

Incidence of postoperative headache/dizziness. Blue boxes indicate different interventions and the remaining boxes were the results of pairwise comparisons between different interventions where statistically significant pair-wise comparisons of interventions are highlighted in orange. Reading from left to right, both SMD/WMD and its 95% CI were < 0 or both RR and its 95% CI were < 1 indicating a statistically significant difference. CI confidence interval, RR relative risk, SMD standardized mean difference, WMD weighted mean difference

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Ranking of Intervention Efficacy

To visually represent the intervention outcomes for each outcome measure, SUCRA curves were drawn to rank each intervention, shown in Figures S7–S14 in the electronic supplementary material for details. The top three interventions for each outcome measure were listed. For VAS at 2 h, the ranking from highest to lowest efficacy was: multimodal analgesia (78.8%), nerve block (73.3%), ibuprofen (68.1%). For VAS at 6 h, the ranking was: pregabalin (90.2%), multimodal analgesia (87.5%), gabapentin (72.1%). For VAS at 12 h, the ranking was: multimodal analgesia (81.7%), duloxetine (79.7%), pregabalin (65.8%). For VAS at 24 h, the ranking was: duloxetine (71.4%), gabapentin (68.7%), nerve block (65.4%). For reducing opioid consumption within 24 h postoperatively, the best intervention was multimodal analgesia (86.2%), followed by gabapentin (74.5%) and ibuprofen (66.9%). For extending the time to first rescue analgesia, the best intervention was tramadol (98.3%), followed by pregabalin (89.3%) and dexmedetomidine (61.6%). For PONV incidence, the ranking from lowest to highest was: ibuprofen (89.3%), acetaminophen (71.5%), duloxetine (70.1%). For the incidence of postoperative headache or dizziness, the ranking from lowest to highest was: tramadol (88.2%), duloxetine (68.6%), indomethacin (60.2%).

Publication Bias Assessment

Comparison-adjusted funnel plots for each outcome measure showed relatively symmetric distributions of data points, suggesting no significant publication bias or small-study effects in this network meta-analysis, as depicted in Fig. 11.

Fig. 11
figure 11figure 11

a, b Comparison-adjusted funnel plots of intervention. PONV postoperative nausea and vomiting, VAS visual analogue scores

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Subgroup Analysis

From the results above, pregabalin and gabapentin were the only single-agent medications that demonstrated a positive effect on reducing pain intensity within 24 h post-LC, decreasing opioid consumption within 24 h postoperatively, and extending the time to first rescue analgesia. The included studies (see Table S2 in the electronic supplementary material for details) involved various doses of these two drugs. Further exploration was conducted to determine the impact of different doses of pregabalin (150 and 300 mg) and gabapentin (20 mg/kg, 300 mg, and 600 mg) on postoperative pain intensity and ADRs.

Nineteen studies including 1759 patients were involved, with 1000 in the study groups, including: 343 receiving pregabalin 150 mg, 145 pregabalin 300 mg, 267 gabapentin 600 mg, 200 gabapentin 300 mg, and 45 gabapentin 20 mg/kg, with 759 in the placebo group. Network graphs are shown in Figures S15–S22 in the electronic supplementary material for details. Network meta-analysis results indicated that different doses of pregabalin and gabapentin were significantly superior to placebo in reducing pain scores at 2, 6, 12, and 24 h postoperatively, and in reducing opioid consumption within 24 h postoperatively. However, no statistically significant differences were found between pregabalin 300 mg, pregabalin 150 mg, gabapentin 600 mg, gabapentin 300 mg, and gabapentin 20 mg/kg, suggesting that pregabalin and gabapentin are broadly equivalent in reducing postoperative pain scores and opioid consumption. Increasing the doses of these medications did not enhance their analgesic effects, as shown in Figures S23–S27 in the electronic supplementary material for details. Compared to gabapentin and placebo, pregabalin significantly extended the time to first rescue analgesia; similarly, pregabalin 300 mg and pregabalin 150 mg were essentially equivalent, and increasing the dose did not extend this time, as shown in Figure S28 in the electronic supplementary material for details. Gabapentin 600 mg significantly increased the incidence of PONV, and although there were no statistically significant differences, increasing the doses of pregabalin and gabapentin did indeed raise the incidence of PONV, as shown in Figure S29 in the electronic supplementary material for details. Regarding the incidence of postoperative headache or dizziness, the gabapentin 600 mg group had the highest incidence. Apart from this dose, pregabalin compared to gabapentin and placebo was more likely to cause headache and dizziness, and increasing the dose of pregabalin raised the incidence of these effects. Compared to gabapentin 20 mg/kg and 600 mg, gabapentin 300 mg significantly reduced the incidence of postoperative headache and dizziness, as shown in Figure S30 in the electronic supplementary material for details.

Comparison-adjusted funnel plots for each outcome measure showed relatively symmetric distributions of data points, indicating no significant publication bias or small-study effects in this subgroup analysis, as depicted in Figure S31 in the electronic supplementary material for details.

Discussion

Laparoscopic cholecystectomy is recognized as a safe and minimally invasive procedure compared to traditional open surgery, facilitating early recovery. Although laparoscopic procedures reduce postoperative pain, there is a significant sympathetic-adrenal response during LC, increasing the demand for postoperative analgesia [73]. Acute pain or nausea/vomiting after LC may extend hospital stays [74]. Preemptive analgesia, which involves taking effective measures before surgery to alleviate pain and reduce sensitivity of central and peripheral nerves to pain, has become an important aspect of perioperative pain management. This approach can lessen the trauma of surgery and reduce postoperative pain, thereby promoting early postoperative activity and functional recovery [74, 75]. However, the specific protocols for preemptive analgesia are still controversial. Traditional analgesics, such as opioids, are known for their potential for tolerance and dependence when used long term, as well as side effects like nausea and vomiting when used in large doses [76]. Previously, opioids were only used in cases of severe pain. The European Society of Anesthesiology (ESA) only recommends opioids for rescue analgesia in LC [77], and the American Pain Society (APS) guidelines also advise against preoperative opioid administration, instead suggesting an increase in non-opioid medications such as NSAIDs, anticonvulsant antidepressants, and nerve block agents for pain management to reduce the prevalence of opioid use [12]. The type of surgery is one of the primary determinants of postoperative pain severity. The intensity of postoperative pain varies with the type of surgery [10]. Research has shown that the development of postoperative pain is also related to the choice of preoperative analgesics. Thus, identifying effective and safe preemptive analgesia methods tailored to specific surgical types is crucial for alleviating postoperative pain and reducing opioid consumption. Currently, there is no evaluation of different preemptive analgesia plans in LC surgery. This study employs a network meta-analysis approach, including 49 randomized controlled trials, to assess the efficacy and safety of various preemptive analgesia protocols in LC surgery, clarifying the clinical efficacy and safety of 26 different preoperative analgesia protocols in post-LC pain management, aiming to provide more evidence-based medical evidence for the formulation of preemptive analgesia protocols for LC surgery.

In our study, multimodal analgesia, nerve blocks, pregabalin, and gabapentin significantly outperformed placebo at various time points after LC in terms of Visual Analogue Scale (VAS) scores. Postoperative pain from LC is typically due to visceral trauma (gallbladder removal, peritoneal CO2 exposure, and stretching) as well as somatic pain (skin incisions). Multimodal analgesia and nerve blocks can block both visceral and somatic pain. Gabapentin and pregabalin are structural analogs of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which function by binding to the α-2-δ subunit of voltage-gated calcium channels, reducing the release of several excitatory neurotransmitters, thereby preventing the development of pain hypersensitivity and central sensitization, achieving the goal of reducing postoperative pain [78, 79]. Previous studies in LC surgery have consistently shown results similar to ours [21, 80,81,82]. Beyond LC surgery, these four administration methods also significantly reduce postoperative pain in procedures such as hemorrhoidectomy, inguinal hernia repair, spinal surgery, shoulder arthroscopy, and thoracoscopic surgery [83,84,85,86,87]. Our results suggested that compared to acetaminophen, using multimodal analgesia, nerve blocks, ibuprofen, gabapentin, and pregabalin for preemptive analgesia significantly lowers patients’ VAS scores 2 h postoperatively. Wang et al. also reached a consistent conclusion in total knee arthroplasty, where adding acetaminophen to preemptive multimodal analgesia did not alleviate pain or reduce postoperative morphine use [88]. Kim et al. found no improvement in postoperative pain and opioid consumption with preemptive acetaminophen in pediatric and adolescent posterior spinal fusion [89]. Conversely, Gousheh et al. indicated that acetaminophen significantly reduces postoperative pain in LC surgery but does not reduce morphine consumption, a discrepancy that may relate to different anesthesia protocols, surgical types, and dosages of acetaminophen, which can affect its plasma concentration and metabolism [90]. NSAIDs are involved only in inhibiting pain originating from inflammation, thus they are more effective in relieving somatic pain [91]. The sources of post-LC pain include both visceral and somatic components, which may explain their inferior analgesic effect compared to multimodal analgesia, pregabalin, and gabapentin. Other studies have shown that ibuprofen positively affects the frequency of muscle pain within 24 h postoperatively, but not pain intensity [92]. Hill et al. compared 300 mg of pregabalin and 400 mg of ibuprofen for dental pain, finding a significantly longer duration of analgesia in the pregabalin group [93]. Our findings indicated that aside from a positive significance in pain intensity at VAS 2 h with ibuprofen, NSAIDs showed no significant results at other time points. However, NSAIDs can play an effective postoperative analgesic role as part of multimodal analgesia, as reported by Golladay et al. in total joint replacement surgery, where NSAIDs were used preemptively as part of multimodal analgesia [94]. Currently, guidelines from APS and WSES-GAIS-SIAARTI-AAST recommend including NSAIDs in multimodal analgesia. WSES-GAIS-SIAARTI-AAST guidelines also recommend gabapentinoids as components of multimodal analgesia, with future studies needed to further compare components of multimodal analgesia [95]. Postoperative inflammatory pain, aside from being derived from prostaglandin E2 (PGE2), may also originate from arachidonic acid, involving substances like bradykinin, leukotrienes, and tumor necrosis factor (TNF-α). Dexamethasone is thought to exert analgesic effects by affecting the arachidonic acid pathway, potentially producing a synergistic effect when combined with NSAIDs. Gustavo et al. used dexamethasone combined with various NSAIDs for preemptive analgesia, finding that combinations of dexamethasone with etoricoxib and ketorolac were superior to those with ibuprofen and loxoprofen [96]. In our study, no beneficial effects on postoperative pain were observed after administering dexamethasone alone, which may relate to its solo use.

Multimodal analgesia, gabapentin, ibuprofen, pregabalin, clonidine, and nerve blocks significantly reduced postoperative opioid consumption compared to placebo. Research indicated that multimodal analgesia could decrease the use of postoperative opioids and their associated side effects. This study suggested that the lidocaine group significantly reduced opioid usage compared to the ketamine group [97], indicating that more effective multimodal analgesia protocols need to be researched in the future. In a study assessing the effects of preoperative administration of melatonin, gabapentin, and clonidine on preoperative anxiety and postoperative pain in LC, Hoseini and colleagues concluded that these three drugs had similar efficacy in alleviating postoperative pain and reducing opioid consumption compared to placebo [98]. Similarly, Mishra and others in hip replacement surgery [99] and Rajendra and colleagues in tympanoplasty using pregabalin for preemptive analgesia reached similar conclusions compared to placebo [100]. Additionally, Barba and others observed that nerve blocks decreased pain thresholds at rest and during activity following surgery for uterine prolapse, also reducing opioid consumption [101]. The preoperative use of non-opioid medications effectively reduced postoperative opioid consumption.

Tramadol, pregabalin, gabapentin, and clonidine significantly prolonged the time to first rescue analgesia postoperatively, with no significant differences noted in other outcomes. Chandni compared the efficacy of gabapentin with placebo in pediatric urogenital surgeries and reached a conclusion consistent with ours, finding that gabapentin significantly extended the time for rescue analgesia in pediatric patients [102]. Raden observed similar outcomes in non-obstetric lower abdominal surgeries [103]. In our study, administering dexamethasone did not affect the time to first rescue analgesia; however, in Zhao’s study, the combination of dexamethasone with ropivacaine, compared to ropivacaine alone in pediatric craniotomy for preemptive analgesia, significantly prolonged the rescue analgesia time. This discrepancy suggests that the combination regimen of dexamethasone, due to its anti-inflammatory properties and reduction of postoperative edema, has a stronger effect [104]. Our study found that administering diclofenac had no impact on the time to first rescue analgesia. Similarly, Edson and others in a study using NSAIDs for preemptive analgesia prior to third molar surgery concluded that NSAIDs did not affect the average time to first rescue analgesia [105], indicating that the mechanisms of NSAIDs in preemptive analgesia require further in-depth research.

Our research had identified ibuprofen as the most effective intervention for reducing the incidence of PONV, while the tramadol group exhibited the highest rate of PONV. The mechanisms behind postoperative PONV are not yet fully understood but are generally believed to be related to reduced consumption of opioids. Tramadol, a weak opioid and a μ-opioid receptor agonist, frequently leads to nausea/vomiting which is the most common complication for patients using tramadol for analgesia [106] and the most prevalent reason for discontinuing clinical use of tramadol in the United States. In a study on preemptive analgesia in abdominal hysterectomy, Farnoush administered 100 mg of tramadol, 300 mg of gabapentin and placebo, found a higher incidence of nausea and vomiting in the tramadol group, though these results were not statistically significant [107]. Studies suggest that modifying the infusion rate of intravenous tramadol could reduce the probability of nausea and vomiting. Wanxia and colleagues, in a study administering intravenous tramadol over 1, 2, and 3 min to patients under general anesthesia, observed that extending the infusion time to 3 min significantly reduced nausea and vomiting occurrences [108]. The tramadol interventions analyzed in our article involved preoperative oral administration, suggesting future investigations could explore whether changing the administration method to a slow intravenous infusion might reduce tramadol’s adverse reactions. Ibuprofen, an NSAID that offers analgesic, anti-inflammatory, and antipyretic effects, operates through competitive, reversible inhibition of cyclooxygenase (COX)-1 and COX-2 enzymes. The analgesic, antipyretic, and anti-inflammatory actions of ibuprofen are associated with COX-2 inhibition, while the side effects are linked to COX-1 inhibition [109]. Studies have shown that preoperative intravenous injection of ibuprofen can regulate stress and inflammatory responses by lowering levels of catecholamines, cortisol, and cytokines following LC [110]. Typically, ibuprofen’s side effects are tolerable. In LC, most studies assert that ibuprofen reduces opioid consumption, thereby diminishing the side effects of nausea and vomiting. Conversely, research in pediatric urologic surgery using ibuprofen for preemptive analgesia revealed no improvement in nausea and vomiting in children, potentially due to different metabolic mechanisms [111]. Thus, caution is advised when extrapolating results of adult preemptive analgesia to children.

Regarding the reduction of postoperative headache or dizziness incidence, tramadol proved to be the most effective intervention, whereas the pregabalin group experienced the highest rate of these symptoms. Clinically, opioids are utilized to manage severe headaches, and as a weak opioid, tramadol may reduce headache incidence [112]. Nonetheless, dizziness and other central nervous system effects are also common side effects of opioids. Reports indicate that increasing tramadol dosage may escalate the occurrence of side effects [113]. Unfortunately, due to the limited number of studies, our analysis did not further differentiate tramadol dosages. Dizziness is one of the most common adverse reactions to pregabalin. In a gynecological surgery involving the uterus, administering 100 mg of pregabalin, compared to placebo, reduced pain but increased the incidence of dizziness, visual disturbances, and walking difficulties [114]. Scholars believe that the type of surgery is an essential factor; pregabalin shows optimal efficacy and minimal side effects in minor to moderate surgeries [115]. However, due to the small sample size, variance in sample populations, and the potential interference of postoperative rescue medications, the results of our study should be interpreted with caution.

In summary, pregabalin and gabapentin might play favorable roles in preemptive analgesia for LC, significantly reducing postoperative pain intensity, decreasing postoperative opioid consumption, and prolonging the time to first rescue analgesia, with tolerable ADRs. Further subgroup analysis indicated that compared to placebo, pregabalin at doses of 300 mg and 150 mg, and gabapentin at doses of 300 mg, 600 mg, and 20 mg/kg, significantly reduced patient VAS scores at various postoperative time points, reduced opioid consumption within 24 h postoperatively, and extended the time to first rescue analgesia. However, pregabalin had the highest incidence of headache and dizziness side effects, with the incidence increasing with dosage, suggesting that gabapentin 300 mg may be a better choice. The core of preemptive analgesia is to reduce the sensitization of peripheral and central pain, advancing the patient’s pain threshold, which is closely related to lower levels of inflammatory mediators and the reduction of peripheral and central pain sensitization [116]. Gabapentin and pregabalin, both gabapentinoid medications, demonstrate superior efficacy due to their multiple mechanisms of pain control, including control of neuropathic pain. Similar to our results, Mohamed found in a study on post-LC shoulder pain that preoperative use of 600 mg gabapentin and 150 mg pregabalin compared to placebo significantly reduced shoulder joint pain at 48 h postoperatively (P < 0.05). The gabapentin group had a lower incidence of PONV and better sleep quality on the first postoperative night [56]. However, this study used a direct dose of 600 mg gabapentin and did not explore different doses of gabapentin compared to pregabalin. A meta-analysis on neuropathic pain following spinal cord injury concluded that there was no significant difference in analgesic effects between pregabalin and gabapentin [117]. Our study found no significant difference between low and high doses of analgesia; a study administering 400, 800, and 1200 mg of gabapentin 2 h preoperatively for infraumbilical surgeries identified 400 mg as the optimal dosage. Similarly, increasing the dose from 400 to 1200 mg did not enhance analgesic effects but did increase adverse reactions [118]. Some studies suggested a dose–response relationship for preoperative analgesic effects, with high doses (≥ 150 mg) of pregabalin more effectively reducing pain scores than 75 mg [119], and the differences in this outcome could be due to the range of dosages and types of surgeries included in their study, which did not differentiate between surgical types. Our research included the smallest dose of pregabalin at 150 mg, and compared to 75 mg, scholars generally recommend 150–300 mg of pregabalin for preemptive analgesia [120]. Studies reported that 22–29% of patients taking pregabalin experience tolerable dizziness and somnolence, while gabapentin’s side effects were milder and better tolerated [121, 122]. Our research found that increasing the dosage of pregabalin and gabapentin increased the incidence of PONV and postoperative headaches and dizziness, with the highest rates in the gabapentin 600 mg group. Compared to gabapentin (20 mg/kg and 300 mg), pregabalin more readily led to PONV and postoperative headaches and dizziness. Aside from preemptive analgesia, pain management during and after LC surgery is necessary, and the occurrence of PONV and headaches and dizziness may be related to their interactions. Sarakatsianou’s study suggested that 600 mg pregabalin reduced post-LC pain and opioid consumption but increased the incidence of dizziness, likely related to the high dosage [41]. Similarly, a meta-analysis showed that perioperative administration of pregabalin over 300 mg significantly alleviated pain within 24 h while also significantly increasing the side effects of pregabalin [123]. Previous meta-analyses investigating the safety of preemptive analgesia, focusing on nausea and vomiting as the primary clinical outcomes (44 studies, n = 3489), found gabapentin to be associated with a reduction in PONV [124]. A study in thoracic surgery showed a lower incidence of PONV in patients treated with gabapentin, which may be associated with reduced opioid consumption [125]. Studies had also found that high doses of gabapentin (1200 mg) can increase the incidence of PONV [119], a discrepancy that could relate to different surgical types, sample sizes, and drug dosages. However, the side effects of gabapentin and pregabalin were mostly within tolerable limits. In our research, gabapentin 300 mg, compared to higher doses of gabapentin and 150/300 mg of pregabalin, demonstrated comparable analgesic effects but with fewer side effects, thus we recommended gabapentin 300 mg as the optimal dose for preemptive analgesia in LC surgery.

This study possessed several advantages. Firstly, to our knowledge, this was the first study to evaluate the effectiveness and safety of different preemptive analgesia protocols in postoperative pain management in patients undergoing LC. As the intensity of analgesic effects varies across different types of surgeries, this research addressed gaps in the current published literature. Secondly, our study included an analysis of 26 commonly used preemptive analgesia protocols prior to LC, offering a comprehensive comparison of these measures as currently practiced clinically. Importantly, we conducted subgroup analyses on different dosages of pregabalin and gabapentin for the first time, clarifying their effectiveness and safety. This not only provided robust evidence-based medical evidence to promote rational drug use but also aided clinicians in tailoring the optimal preemptive analgesia protocol to individual patient clinical characteristics. Additionally, our study incorporated eight clinical outcomes for analysis, particularly including adverse reactions such as headaches and dizziness apart from PONV, thus providing a comprehensive, multi-faceted, and multi-dimensional assessment of the advantages and disadvantages between different preemptive analgesia protocols. Moreover, we conducted an extensive literature search, including more and newer studies than other research in this field. Finally, the selection of preemptive analgesia protocols prior to LC was critically important and urgently needed in clinical practice, yet there were currently almost no meta-analyses on this topic, highlighting the unique significance of this study.

This study also had certain limitations: (1) Due to the lack of relevant data, we did not assess ADRs other than PONV and headaches and dizziness, such as ataxia, delirium, and respiratory failure, which might affect the safety outcomes of our research. (2) Due to the limited number of studies, multimodal analgesia and nerve block interventions were not specifically categorized, preventing a clear determination of the efficacy and safety between different combinations. (3) As we only included studies published in English, excluding publications in other languages might introduce potential bias. (4) Some studies had small sample sizes and short durations, which could potentially lead to an inadequate assessment of the impact on clinical outcomes. (5) Most studies included were single-center studies, which could introduce some bias in the results.

Conclusions

Preemptive analgesia could significantly reduce postoperative pain intensity, decrease opioid consumption, prolong the time to first rescue analgesia, and lower the incidence of PONV as well as headaches or dizziness in patients undergoing LC. Multimodal analgesia, nerve block, pregabalin, and gabapentin all demonstrated effective outcomes. Notably, a preemptive analgesia regimen with 300 mg of gabapentin had shown to significantly enhanced analgesic efficacy while also reducing the rate of ADRs, making it a recommended option for preemptive analgesia in LC. However, specific administration protocols for multimodal analgesia and nerve blocks during LC surgery still require further study. We also look forward to future larger-scale randomized controlled trials (RCTs) to validate the optimal preemptive analgesia approach for LC surgery.