Transversus Abdominis Plane Block as a Strategy for Effective Pain Management in Patients with Pain during Laparoscopic Cholecystectomy: A Systematic Review

Laparoscopic cholecystectomy (LC), unlike laparotomy, is an invasive surgical procedure, and some patients report mild to moderate pain after surgery. Transversus abdominis plane (TAP) block has been shown to be an appropriate method for postoperative analgesia in patients undergoing abdominal surgery. However, there have been few studies on the efficacy of TAP block after LC surgery, with unclear information on the optimal dose, long-term effects, and clinical significance, and the analgesic efficacy of various procedures, hence the need for this review. Five electronic databases (PubMed, Academic Search Premier, Web of Science, CINAHL, and Cochrane Library) were searched for eligible studies published from inception to the present. Post-mean and standard deviation values for pain assessed were extracted, and mean changes per group were calculated. Clinical significance was determined using the distribution-based approach. Four different local anesthetics (Bupivacaine, Ropivacaine, Lidocaine, and Levobupivacaine) were used at varying concentrations from 0.2% to 0.375%. Ten different drug solutions (i.e., esmolol, Dexamethasone, Magnesium Sulfate, Ketorolac, Oxycodone, Epinephrine, Sufentanil, Tropisetron, normal saline, and Dexmedetomidine) were used as adjuvants. The optimal dose of local anesthetics for LC could be 20 mL with 0.4 mL/kg for port infiltration. Various TAP procedures such as ultrasound-guided transversus abdominis plane (US-TAP) block and other strategies have been shown to be used for pain management in LC; however, TAP blockade procedures were reported to be the most effective method for analgesia compared with general anesthesia and port infiltration. Instead of 0.25% Bupivacaine, 1% Pethidine could be used for the TAP block procedures. Multimodal analgesia could be another strategy for pain management. Analgesia with TAP blockade decreases opioid consumption significantly and provides effective analgesia. Further studies should identify the long-term effects of different TAP block procedures.


Introduction
Laparoscopic cholecystectomy (LC) is a minimally invasive technique that causes mild postoperative discomfort in the parietal, visceral, incisional, and referred regions [1]. In these patients, multimodal approaches [2], epidural analgesia, and intraperitoneal injection of local anesthetics (LA) are often used in conjunction with patient-controlled intravenous analgesia. Transversus abdominal plane (TAP) block is a well-known procedure for postoperative analgesia during laparoscopic abdominal surgery as part of this approach [3]. TAP block is safe; it reduces or eliminates the need for analgesics and has fewer side effects such as postoperative nausea and vomiting (PONV) [4]. In addition, several physicians are actively improving the precision of LA absorption by ultrasound [5][6][7][8]. Thus, this innovative approach has demonstrated the analgesic efficacy of laparotomy and laparoscopic procedures [9].
Rafi [10] pioneered the TAP block in 2001 as a historically guided practice for achieving a field block through the petit triangle. In this procedure, a solution (LA) is injected further

Methods
This review was prepared in accordance with the 2020 PRISMA (Preferred Reporting Items for Systematic Review and Meta-analysis) guidelines [51].
Intervention: Postoperative pain management using TAP block or in combination with adjutants. 7.
Outcomes: Postoperative use of analgesia use if they reported a visual analogue scale (VAS) or numeric rating scale (NRS) outcome of postoperative pain after 24 h. 9.
Design: Randomized trials published in peer-reviewed journals.

Exclusion Criteria
Articles were considered ineligible if they were letters to the editor, commentary, not peer-reviewed papers (e.g., dissertations), case studies, were not published in full text (e.g., conference proceedings), or were non-experimental studies (e.g., qualitative studies). Furthermore, studies that did not include an active control group were also excluded.

Information Sources
The five electronic databases of PubMed, Academic Search Premier, Web of Science, CINAHL, and Cochrane Library were searched for randomized trials. The search was conducted primarily between 12 and 13 August 2022. A supplemental search was conducted in Google Scholar and trial registries (http://clinicaltrials.gov/, accessed on 15 August 2022). All registries and conclusions with the keywords "TAP block laparoscopic cholecystectomy", "postoperative pain in laparoscopic cholecystectomy", and "postoperative pain management in hospitalized patients undergoing laparoscopic cholecystectomy" were explored.

Search
We employed the keywords (search terms) transversus abdominis block OR transversus abdominal plane OR transversus abdominis plane AND laparoscopic cholecystectomy OR laparotomy. We limited the search to published articles from the beginning to the present. We considered articles that were published in English and had an abstract. The publication period ranged from inception to the present day. We also manually searched the reference lists for eligible studies.

Study Selection
Studies were selected using the PRISMA framework [51]. Results from the five databases were exported to Endnote Reference Manager, and duplicates were removed. The titles and abstracts were screened according to the eligibility criteria. Eligible studies for inclusion were identified after the full-text screening. Two independent reviewers (A.F.A. and D.S.) performed the screening independently, and a third reviewer (F.H.A.) was asked to clarify any discrepancies identified during the process.

Data Collection Process
Data were extracted from eligible studies and entered into a spreadsheet in Microsoft Excel. Two independent reviewers performed this task. A third reviewer was asked to clarify any discrepancies. The authors of the papers under consideration were contacted for queries or clarifications.

Data Items
Information on the study profile included participant demographics (i.e., gender and age), study design, population characteristics, sample size, study groups (intervention and control), and duration of follow-up. Components of the intervention include the setting in which it was delivered, the dose (frequency, duration, and course) of TAP, the total exposure in minutes to TAP, and the associated theories underlying the therapeutic effects of TAP as reported. For the outcomes, we extracted the mean (M) and standard deviation (SD) for VAS, NRS, and postoperative pain for all groups (i.e., intervention and control) at baseline, post-intervention, and follow-up. For accuracy, two reviewers (A.F.A. and D.S.) performed this task.

Risk of Bias in Individual Studies
Appraisals of the eligible studies were conducted using the Physiotherapy Evidence Database scale (PEDro scale). Because of its high construct validity, the PEDro scale was selected for evaluation in randomized controlled trials [52]. To obtain a PEDro total score, items 2-11 were summed. The Internal Validity subscale is scored with items 2-9, and the Statistical Reporting subscale is scored with items 10 and 11 [53,54]. The study is classified as moderate if it scores 4-5, good if it scores 6-8, and excellent if it scores 9-10 [55].

Summary of Measure and Synthesis of Results
The Cochrane Handbook for Systematic Reviews of Interventions was used as a guide for data processing [56]. A meta-analysis would be conducted in cases where more than two studies were eligible and measured the same outcomes at which data might be collected: T0 (baseline), T1 (immediately after intervention), and T2 (follow-up). We used a standardized approach in reporting results because different studies measured the same outcome differently. Given the differences in group means and variance within the study population, we determined the minimum clinically significant difference (MCID) using the distribution-based approach [57]. A small effect was described as 0.2, a medium effect as 0.5, and a large effect as 0.8, based on Cohen's d [58].

Results
As shown in Figure 1, a total of 758 results were generated from the five databases: CINAHL (n = 37), PubMed (n = 154), Web of Science (n = 183), Cochrane (n = 196), and Academic Search Premier (n = 183). Manual searches yielded five results (n = 5). After deduplicating 231 papers with endnotes and manual search, 527 papers were used for the title and/or abstract screening. After title and/or abstract screening, 77 records were selected for full-text screening. Twenty-nine records were removed after full-text screening for failure to meet the criteria. Forty-eight articles were included in the qualitative and quantitative synthesis.

Risk of Bias within Studies
As shown in Table 1, nineteen (39.6%) did not conceal the assignment of participants. Thirteen (27.1%), twenty-nine (60.52%), and thirty-one (64.58%) studies did not blind assessors, participants, and therapists, respectively. Twenty-six studies underwent an intention-to-treat analysis. In all studies, the dropout rate was less than 15%. All studies reported between-group statistical comparisons, point measures, and variability data. Overall PEDro ratings ranged from 4 to 10, with only one study rated as excellent and three as moderate, while the rest were of good quality. PMVD = point measures and variability data. Note: Each item was scored either Yes = 1 or No = 0. Items 2−11 are summed for a PEDro total score. The sum of items 2−9 yields the internal validity subscale score, while the sum of items 10 and 11 yields the statistical reporting subscale score. The PEDro total score was rated 0−3 = poor, 4−5 = moderate, 6−8 = good, and 9−10 = excellent.

Study Characteristics
As shown in Table 2, a total of 3651 subjects participated in the study, with the majority being female (n = 1822, 49.9%) and ages ranging from 18 to 80 years. The TAP block techniques ranges from ultrasound-guided transversus abdominis plane block, oblique subcostal transversus abdominis plane, posterior transversus abdominis plane block, erector spinae plane, subcostal Transversus abdominis, and transversus abdominis plane block. Other approaches were transversus abdominis plane block, oblique subcostal transversus abdominis, subcostal transversus abdominis, subcostal block, subcostal transversus abdominis plane block, quadratus lumborum, laparoscopic transversus abdominis plane, rectus sheath block, blocking the branches of intercostal nerves at the level of mid-axillary line, and laparoscopic subcostal TAP. Infiltration of the surgical site was 10 mL, 15 mL, 16 mL, 20 mL, 30 mL, 40 mL, and 100 mLand either unilateral or bilateral or to the respective or conventional port sites using local anesthetics or other relevant agents. Eighteen (37.5%) of the studies reported the use of patient-controlled analgesia (PCA) or patient-controlled intravenous analgesia (PCIA). The Visual Analogue Scale is the most commonly used outcome measure (n = 30, 62.5%).

Objective #1. The Optimal Dose of TAP Block Anesthesia for Laparoscopic Cholecystectomy
As already shown in Table 2, the minimum dose of local anesthetic for transversus abdominis plane blockade could be 20 mL for US-TAP and US-OSTAP and 0.4 mg/kg for port infiltration. However, the agents and their concentration may vary.

a.
Comparison of different approaches to ultrasound-guided blockade of the transversus abdominis plane

Analgesic Efficacy of Ultrasound-Guided Transversus Abdominis Plane Block Versus General Anesthesia Only
As shown in Table 3, Morphine consumption was greater in the control compared to the intervention group. Notably, the mean change in the intervention group from the start to the end of laparoscopic cholecystectomy was 9.6, p < 0.005, and the control group had a mean change of 20.5, p < 0.005 [59]. Between the first 20 min and 24 h postoperative, the two US-TAP groups using 0.25% and 0.5% Levobupivacaine reported lower postoperative pain scores of 3.3 to 1.6 and 3.2 to 1.3, respectively, compared with those receiving anesthesia alone (8.6 to 4.4) [7]. In addition, analgesic requirements between 20 min and 12 h postoperative were higher in the control group (−4.2 to −0.7) than in patients receiving 0.25% Levobupivacaine (−1.7 to −0.5) and 0.5% Levobupivacaine (−1.9 to −0.5) [7]. Similarly, the control group appeared to have higher pain scores between 0 and 24 h postop (2.35 to 1.3) compared to those who received posterior US-TAP block (1.2 to 0.8) and subcostal US-TAP block (0.85 to 0.15) [6]. Analgesic requirement between 0 and 12 h is also higher in the control group (−1.0 to −0.6) than in the posterior US-TAP block (−0.4 to −1.0) and subcostal US-TAP block (−0.7 to −0.65) [6]. Moreover, pain perception between 10 min and 24 h postoperative was higher in the control group at rest (6.6 to 2.1) than in the US-TAP group (4.2 to 2.1) and during cough (7.5 to 3.0 and 4.7 to 2.9, respectively [61]. The need for analgesics between 10 min and 6 h was also higher in the control group (−4.5 to −1.2) than in US-TAP (−1.8 to −1.8) [61].

Control
Nausea: none (n = 11), mild (n = 1), moderate (n = 3), severe (n = 0), and shoulders pain (n = 1). Houben (2019) [79]    Opioid consumption was found to be lower in those receiving US-TAP block with 0.25% Bupivacaine 2.1(0.5) and Bupivacaine 0.25% plus Magnesium Sulfate 0.5 g, 2.2(0.5) compared with those receiving general anesthesia alone 2.8(0.6) [65]. Compared with the control group, the first need for rescue analgesics was delayed in the US-TAP and US-TAP (Dexamethasone) groups (403.0, 436.0 versus 152.3, p < 0.01). Patients in the US-TAP and US-TAP (perineural Dexamethasone) groups had lower pain scores on the numeric rating scale (p > 0.01) and used fewer postoperative analgesics (p < 0.01) [67]. The need for analgesics was higher in the control group than in the group US-TAP [68]. The number of patients requiring additional analgesics (Morphine and Ketorolac) was higher in the group of patients receiving US-TAP block with in situ indwelling catheters than in the control group and the group of patients receiving US-TAP block + PCA [71]. There was a significant reduction in pain perception with US-TAP block (4.4 to 1.4) when compared with the control group (6.4 to 2.2) [96]. Again, the mean analgesic requirement between the first 2 and 24 h after surgery was found to be higher in the control group (−42 to −1.0) than in the US-TAP group (−3.0 to −0.5) [96].
Comparing the unilateral and bilateral US-TAP block with the control group, both strategies appear to be effective. Pain perception at rest and during coughing was lower with the unilateral (right) US-TAP (3.10 to 1.23 and 3.37 to 1.8, respectively) and the bilateral US-TAP block (3.33 to 1.23 and 3.47 to 1.57, respectively), compared with the control group (6.03 to 2.10 and 6.33 to 3.07) [100]. Analgesic requirements between 1 and 12 h postoperative both at rest and during cough were higher in the control group

Analgesic Efficacy of Ultrasound-Guided Transversus Abdominis Plane Block versus Port SITES Infiltration
Between the onset of surgery and 24 h after surgery, the demand for opioids (Morphine) was slightly higher in the US-TAP block group (14.6) than in the port infiltration group (14.4) [20]. This demand pattern continued after 24 h with 11.1 for the US-STAP block group and 9.6 for the port group [20]. However, there seems to be no difference in the need for hydrocodone [20]. The port infiltration group appears to have a higher need for diclofenac (0.65), Paracetamol (21.0), and Fentanyl (3.1) compared with the US-STA block group (diclofenac (0.58), Paracetamol (16.0), and Fentanyl (3.0) [60]. In the US-TAP group and the local infiltration group, the 24 h Morphine requirements (mean) were 34.57 mg and 32.76 mg, respectively (p = 0.688). A total of eight patients in the US-TAP group and 16 patients in the local infiltration group required additional fentanyl intra-operatively (p = 0.028). In the immediate postoperative period, local infiltration levels were significantly higher at rest and during cough (p = 0.034 and p = 0.007, respectively) [66]. Patients who received subcostal US-TAP block had a statistically significant reduction in postoperative pain within the first 24 h after surgery compared with port infiltration. In the subcostal TAP block group, opioid consumption was lower over 24 h (125 mg versus 175 mg p < 0.001). US-TAP block and local infiltration had significantly different postoperative pain scores (VAS) at 0, 2, 6, 12, and 24 h [101]. The VAS score is significantly higher in the local infiltration group than in the US-TAP block group (p < 0.001) [101].
It is noteworthy that a similar pattern of changes, in which the US-TAP block group had a lower pain experience and analgesic requirement compared with the port infiltration groups, was observed in a study by Khandelwal, Parag, Singh, Anand, and Govil [82] and by Arık, Akkaya, Ozciftci, Alptekin, and Balas [86]. A similar pattern of changes was observed and the time to rescue analgesia was equally longer in patients receiving subcostal US-TAP block (3.63 h) compared to the port infiltration group (1.73 h, p = 0.0002) [87].
Uniquely, Liang, Chen, Zhu, and Zhou [88] used different concentrations of Ropivacaine (0.5% and 0.25%) plus 1 mcg/kg Dexamethasone in addition to preoperative administration of solution at the trocar site before surgery (group LAI), with additional US-TAP block in the TL group, while the TR group received rectus sheath block in addition to US-TAP block; however, the three groups did not differ in pain scores at any time point within the 48 h period.

Analgesic Efficacy of Ultrasound-Guided Transversus Abdominis Plane Block before Induction of Anesthesia and after Surgery
Although there does not appear to be a significant difference between the two groups, mean meperidine consumption (mg) was higher in those receiving US-TAP block (after surgery) (34.21) than in those receiving US-TAP block (induction) (32.11) [102]. Postoperative pain perception in the first 30 min to 24 h was also higher in those who received a US-TAP block (post-surgery) (4.96 to 4.63) compared to US-TAP block (pre-induction) (3.18 to 3.47) [95]. Likewise, analgesic requirements in the first 30 min to 12 h after surgery were higher for the US-TAP block group (post-surgery) (−0.33 to −0.08) compared with the US-TAP block group (pre-induction) (0.29 to −0.06) [95]. On the contrary, time to first analgesic request was shorter for US-TAP blockade group (after surgery) (2.22, p = 0.089) than for US-TAP blockade group (induction) (5.80, p = 0.089) [102].

Analgesic Efficacy of Ultrasound-Guided Transversus Abdominis Plane Block Using Different Concentrations of Local Anesthetics
It appears that the higher the concentration of anesthetics used for the US-TAP block, the lower the experience of pain. Of note, Ra et al. [7] used 0.25% and 0.5% Levobupivacaine differently; however, patients who received 0.5% had less pain in the first 20 min to 12 h after surgery. In contrast, the need for a analgesics in this group seems to be higher in the first 20 to 60 min after the procedure [7]. Interestingly, patients who received US-TAP block with 0.25% Levobupivacaine reported a high need for analgesia (−1.0) compared to those receiving 0.5% Levobupivacaine (−0.1) six hours later [7]. Similarly, the mean pain experience at 24 h was higher for those who received US-TAP block with 0.25% Levobupivacaine (1.6) compared to 0.5% Levobupivacaine (1.3) [7]. After 10, 30, and 60 min, patients receiving ultrasound-guided TAP blocks (0.375% Ropivacaine) had significantly lower pain scores than patients receiving US-TAP blocks (0.25% bupivacaine) [69]. The median [interquartile range] of postoperative analgesic requirements and cumulative rescue analgesic requirements were the same for both drugs (0.75% bupivacaine for US-TAP block versus 0.375% Ropivacaine for US-TAP block, p = 0.366) [69].

Comparison of Analgesic Efficacy of Ultrasound-Guided Oblique Subcostal Transversus Abdominis Block versus Transversus Abdominis Plane Block
Because US-OSTAP is a relatively new technology that is essentially the same as TAP block procedures, we compared the analgesic efficacy of ultrasound-guided oblique subcostal transversus abdominis block with transversus abdominis plane block. Intraoperatively, there appears to be no difference between the US-TAP and US-OSTAP blocks in terms of Ketorolac consumption; however, the two groups differ in terms of intraoperative fentanyl consumption (US-TAP: 72.4 and US-OSTAP: 78.1) and postoperative Nalbuphine consumption (US-TAP: 7.3 and US-OSTAP: 8.0), with US-TAP block reporting less consumption [61]. In contrast, the US-TAP block group consumed more fentanyl postoperatively (US-TAP: 10.0 and US-OSTAP: 6.7) [61]. Mean postoperative pain scores between 10 min and 24 h at rest/coughing were also higher in the US-TAP group (4.3 to 2.1)/(4.7 to 2.9) than in the US-OSTAP (2.3 to 1.3)/(2.9 to 2.1) [61]. In addition, comparing the effects of the US-OSTAP procedure with only general anesthesia, the VAS pain scores at rest and upon movement were significantly lower in the OSTAP group on arrival at PACU and 2 h postoperative [62]. Total postoperative Tramadol requirements were significantly lower in the OSTAP group at 0-2 h (31.6) and 2-24 h (126.3) than in the control group at 0-2 h (80.3) and 2-24 h (267.1) [62]. In addition, a high proportion of patients who received US-OSTAP block (17, 85%) did not require additional analgesia compared with the US-TAP group (11, 55%) [68].
The US-OSTAP block (Ropivacaine) had a low fentanyl consumption of 122 mcg intraoperatively compared to US-OSTAP (normal saline) block (126.19 mcg [83]. Opioid consumption at PACU within the first 8 h after surgery was higher for the US-OSTAP (normal saline) block (9.52 mg) compared with the US-OSTAP (Ropivacaine) block (4.64 mg) [83]. In contrast, the US-OSTAP (Ropivacaine) block appears to have a higher opioid requirement between 8 and 16 h but not after 24 h [83].

Analgesic Efficacy of Ultrasound-Guided Subcostal Transversus Abdominis Plane versus Quadratus Lumborum Blocks
The time for first analgesic consumption using the US-TAP block was 63.72 min compared with the quadratus lumborum block at 70.00 min [78]. Similarly, Tramadol consumption (mg) was higher in the quadratus lumborum 86.66 mg than in the US-TAP block 83.43 [78]. Using the VAS scale, with the exception of 12 h postoperative, pain perception seems to be higher in the US-TAP block group (1.33 to 0.47) compared to quadratus lumborum (1.03 to 0.42) from 0 to 6 h [78]. However, this seems to differ in 12 and 24 h for the US-TAP block group (0.20 and 0.11) compared to the quadratus lumborum (0.22 to 0.09) [78]. In other words, pain perception using the DVAS scale appeared to be the same at 0 h but was higher in the US-TAP block group at 1 h (1.94) and at 12 h (1.00) [78]. In contrast, this pattern of change was observed in the quadratus lumborum after 6 h (1.50) and after 12 h (0.46) [78].

b.
Comparison of different approaches to laparoscopic-assisted transversus abdominal blockade

Comparison of Analgesic Efficacy Analgesic Efficacy of Laparoscopic-Assisted Transversus Abdominal Block with Bupivacaine versus Normal Saline
In the LAP-TAP group (Bupivacaine + periportal saline injection), numerical pain assessment scores were significantly decreased after 1, 3, and 6 h of rest (p = 0.025, p = 0.03, and p = 0.007, respectively) as compared to normal saline [63].

Analgesic Efficacy of Laparoscopic-Assisted Transversus Abdominal Block versus Port Sites Infiltration
Compared to port site infiltration, there seems to be no change in LAP-TAP block for pain at rest between the first 3 and 6 h postoperative [94]. However, it appears that the port infiltration group had more pain 24 h postoperative (3.0) and at discharge (2.0) [94]. In addition, a significant mean change was observed between the two groups in pain upon cough 6 h postop (LAP-TAP: 4.0, port site infiltration: 5.0) and on discharge (LAP-TAP: 1.5, port site infiltration: 3.0) [94]. On the contrary, the LAP-TAP block participants experienced higher pain scores (p = 0.043) and opioid requirements (p = 0.021) at 6 h than port infiltration group participants [84].

Analgesic Efficacy of Laparoscopic-Assisted Infiltration Using Different Doses of Local Anesthetic versus Normal Saline
The results of this review show that patients who received 0.9% normal saline for infiltration during laparoscopy reported a high need for rescue analgesia both in the ward (21, 70%) and at PACU (13, 43.3%) [88]. Compared with the other two groups, a higher proportion of those who received Ropivacaine at low concentrations (0.25%) required rescue anesthesia in the ward (5 (16.7%) [88]. The values of the control group VAS were significantly higher than those of the groups TAI, TAPB, and IPLA after 1, 2, 4, 6, 12, and 24 h [90]. In addition, the VAS values of the IPLA group were significantly higher than those of the LAI and TAPB groups at 1, 2, 4, 6, 12, and 24 h [90]. VAS values at 1, 2, 4, 6, and 24 h were not significantly different between TAI and the TAPB group. A significant difference was observed between the TAI and TAPB groups in terms of VAS values at 12 h [90]. c.
Other known techniques When bilateral double transversus abdominis plane blockade (BD-TAP) was compared with sham control, higher pain sensation was observed postoperatively in the control group at rest (2 h), during coughing (2, 6, and 48 h), and during walking (2, 6, and 48 h), with no change between the two groups at 24 h [91]. Ultrasound-guided modified BRILMA block (US-BRILMA) was compared with US-TAP block (subcostal), and it was found that postoperative Morphine consumption was higher in the US-BRILMA group (5.67 mg) than in the US-TAP block group (5.17 mg) [93]. The time to request rescue analgesia was higher in the US-BRILMA group (845) than in the US-TAP group (759.33) [93]. The efficacy of erector spinae block and oblique subcostal transversus abdominis block was compared, and the mean pain of the two groups between 2 and 24 h differed, with the OSTAP block group reporting more pain experience (2.27 to 0.70) [92]). The US-TAPB block group had significantly lower resting VAS values than the two groups receiving PCIA with Sufentanil and Nalbuphineat 2, 6, 12, 24, and 48 h postop (p < 0.05) (Han et al., 2022). Postoperatively, dynamic VAS was significantly lower in the US-TAPB block group (p < 0.05) than in the two groups receiving PCIA with Sufentanil and Nalbuphine [98].

Long-Term Effects
As shown in Table 3, all studies examined participants between 0 and 48 h or on the first postoperative day, with only one study examining pain intensity one week postop. Therefore, we cannot infer from this study that TAP block anesthesia has a long-term effect.

Objective #4. Clinical Significance of TAP Block
As shown in Table 4, the minimal clinically significant differences between the US-TAP block and port infiltration groups all had a large effect size index; however, the US-TAP block group had a higher effect.

Discussion
To our knowledge, this is the first review to comprehensively compare the analgesic efficacy of different procedures for laparoscopic cholecystectomy.
Evidence from this study has shown that US-TAP blockade in addition to general anesthesia is more effective than general anesthesia alone for postoperative pain management [59]. Use of the US-TAP block is associated with a reduced need for analgesics within the first 24 h postoperative [7]. In addition, using US-TAP block before induction of anesthesia and after the surgery might be associated with less need for analgesics within the first 24 h after laparoscopic cholecystectomy, although the two groups do not differ significantly [95]. The lower the concentration of local anesthetics used for laparoscopic infiltration, the higher the need for rescue analgesics [7]. Similarly, the higher the concentration of the solution used for US-TAP block, the lower the need for intra-operative or postoperative analgesia [7,72,98].
Apparently, the addition of 20 mL of normal saline to 0.5% bupivacaine for the US-TAP block might be associated with a lower need for analgesics than in patients who received 10 mL of normal saline to 0.5% bupivacaine [72]. US-TAP blockade with 0.375% Ropivacaine plus 2 mL Dexamethasone is more effective in relieving pain than US-TAP blockade with the same concentration of Ropivacaine or general anesthesia alone [67]. However, the addition of a lesser amount of Dexamethasone 1 mcg to 0.5% Ropivacaine does not result in any significant change [88]. Again, the same concentration of 0.2% Ropivacaine with an additional 4 mg/kg Dexamethasone was used for different TAP block procedures, and the US-ESP group had less postoperative pain and required fewer opioids than the OSTAP block group [92]. The addition of 0.5 mg/kg Esmolol to the local anesthetic for TAP block infiltration is more effective for pain management than the addition of 0.9% normal saline [89]. Again, administration of a local anesthetic percutaneously or subcutaneously or between obliquus internus and transversus abdominis or in the sub-diaphragmatic and pericholecystic areas is more effective than normal saline. In another development, the addition of 0.4% Ropivacaine to 100 mL of 0.9% saline and 10 mg/kg Tropisetron for US-TAP blockade could provide better pain relief than the addition of 2 mg/kg Sufentanil or Nalbuphine via PCA [98]. Patients receiving 0.5 mcg/kg Dexmedetomidine over 0.375% Ropivacaine consumed fewer opioids and took longer to request initial analgesia than patients receiving 2 mL of 0.9% saline over 0.375% Ropivacaine [75]. Magnesium Sulfate (0.5 g) was added on top of 0.25% Bupivacaine and achieved a reduction pain and in intra-operative opioid consumption [65]. The addition of 5 mcg Epinephrine to 0.375% Levobupivacaine is associated with lower postoperative and total opioid consumption [79]. Ketorolac (180 mg) was administered in combination with Oxycodone (40 mg) in addition to 100 mL of 0.9% saline, compared with patients receiving 20 mL of 0.2% Ropivacaine and those receiving additional patient-controlled analgesia; however, patients without local anesthetic had a greater need for analgesia than the others [71]. It was found that the addition of 2 mL of Sufentanil to 0.5% Bupivacaine prolonged the time to the first analgesia request in 24 h compared with patients who received 2 mL of normal saline or normal saline alone in addition to Bupivacaine [64].
US-TAP blockade with 2 mLof Sufentanil on 0.5% Bupivacaine might be associated with a lower opioids requirement than the use of 2 mL of 0.9% saline on 0.5% Bupivacaine or normal saline alone [64]. Uniquely, US-TAP blockade with 1% of Pethidine (40 mL) in addition to general anesthesia was found to be more effective for pain than US-TAP blockade with normal saline [70]. In particular, it is associated with lower intra-operative Fentanyl consumption and lower postoperative Morphine requirements [70].
Postoperative opioid consumption differs for the different types of blocks, with US-TAP consuming more Fentanyl and US-OSTAP consuming more Nalbuphine [61]. Although US-OSTAP was a relatively new technology, the results seemed consistent with US-TAP. Notably, when comparing the analgesic efficacy of the US-OSTAP and US-TAP block procedures, there appears to be no intra-operative difference between the two procedures in terms of Ketorolac (NSAID) consumption; however, US-OSTAP consumed more Fentanyl (opioids) than US-TAP block [61]. In contrast, more Fentanyl (opioids) was consumed postoperatively during the US-TAP block than during the US-OSTAP block [61]. However, Nalbuphine (opioids) consumption was higher in US-OSTAP block than in US-TAP block [61].
US-OSTAP blockade with Ropivacaine is more effective against pain and requires fewer analgesics than normal saline during and after surgery and at PACU [83]. In particular, US-OSTAP blockade appears to be associated with less pain and less need for opioids 2 h postop and at PACU compared with US-TAP [83]. US-TAP Subcostal block is associated with less pain experience and opioid consumption compared with quadratus lumborum [78]. Between 0 and 6 h postop, the US-TAP subcostal block appeared to be associated with higher pain perception; in contrast, the quadratus lumborum was perceived as more painful between 12 and 24 h [97]. To view it differently, quadratus lumborum reportedly had lower pain perception, lower cumulative daily Morphine consumption, and longer median time to first analgesic request compared with US-TAP block [97]. Therefore, further quantification is needed to clarify the pattern of analgesic consumption during different TAP blockade procedures.
Laparoscopically assisted TAP blockade with Bupivacaine plus Periportal injection of normal saline is associated with pain reduction between 1 and 6 h postoperative compared with those who received saline TAP blockade with a periportal injection of Bupivacaine [63]. The use of normal saline for LAP-TAP correlates with a higher need for rescue analgesia both in the ward and at PACU [88].
The port infiltration group seems to have a higher need for analgesics than the US-STA or US-TAP groups [94]. Notably, in the US-TAP block group, there seems to be a delay in requesting the first analgesics compared to the port infiltration group [94]. Within 3-6 h postoperative and at discharge, there appeared to be no significant difference between LAP-TAP and the port infiltration group; however, at 24 h, the port infiltration group had a greater demand for analgesia [94]. In contrast, the LAP-TAP group had a greater need for opioids and greater pain perception 6 h postoperative [94].
Subcostal US-TAP blockade is associated with lower postoperative opioid consumption compared with US-BRILMA [93]. Likewise, the time to request rescue analgesia was higher with the US-BRILMA blockade than with the US-TAP subcostal blockade [93]. In addition, US-ESP blockade was found to result in less pain between 2 and 24 h postoperative compared with OSTAP blockade [77]. Moreover, the bilateral double blockade of the transversus abdominis plane with Ropivacaine was associated with less pain perception at 2 h at rest and at 2, 6, and 48 h during walking and coughing, compared with the sham control group with normal saline [91].
The optimal dose means that symptoms and side effects can be most effectively controlled with the lowest dose of a drug [103]. From this study, we can infer that the optimal dose of local anesthetic for the blocks US-TAP or US-OSTAP could be 20 mL of Ropivacaine, Bupivacaine, or Levobupivacaine and 0.4 mL/kg for port site infiltration (Table 4). This is because we recorded a low number of side effects, adverse events, and complications (Table 4). However, caution should be exercised in using these data because of insufficient evidence. Overall, the effects of the interventions in this study were shortterm effects, and we could not find evidence of long-term effects because in most cases, the studies assessed outcomes between 0 and 24 h, and very few studied subjects 48 h or a week postoperative.
Corroborating the extant literature, our study confirmed the reduction in analgesic consumption 24 h after laparoscopic surgery with TAP blockade or general anesthesia with TAP blockade compared with general anesthesia or no TAP blockade or placebo treatment, with analgesic consumption also reduced after 24 h [45]. Consistent with the results of our study, Kalu et al. [104] submitted that postoperative opioid consumption was influenced by the use of the US-TAP block procedure both preoperatively and postoperatively. Notably, there was no significant difference between groups in opioid consumption, but the US-TAP blockade reduced postoperative pain in both groups. From this review, the higher the concentration of local anesthetic used for local infiltration, the greater the effect on pain. Notably, this study found that 30 mL of 0.5% Levobupivacaine was more effective than 0.2% at 6 h postoperative; El-Dawlatly et al. [59] also used 30 mL of 0.5% Bupivacaine for US-TAP procedures and achieved a reduction in opioid consumption for 24 h postoperative. Similarly, 0.375% Ropivacaine was equally more effective against pain compared with 0.25% between 10 and 60 min after surgery when administered by the same route [69]. The route of local anesthetic administration has been controversial; however, in previous studies, different routes of administration of Ropivacaine were found to be more effective than Bupivacaine [105,106]. Although Bupivacaine and Ropivacaine have been compared at various concentrations in the context of different surgical procedures, there appears to be a paucity of evidence comparing these local anesthetics in US-TAP blockade for laparoscopic cholecystectomy. Therefore, future studies should compare the analgesic efficacy of Ropivacaine and Bupivacaine in different routes of administration for laparoscopic cholecystectomy.
The modified BRILMA block has been used and was found to reduce intra-operative Fentanyl consumption and postoperative Morphine consumption in supra-umbilical open surgeries such as cholecystectomy and gastrectomy [107]. OSTAP block was found to reduce postoperative pain scores more than intravenous multimodal analgesics, and TAP for laparoscopic cholecystectomy [68]. In a similar study, Basaran et al. [62] showed significant improvement in respiratory function and postoperative pain with OSTAP blockade. As our study shows, the OSTAP block reduced postoperative Tramadol consumption significantly more than the ESP block; however, the ESP block did not reduce postoperative Tramadol consumption as significantly as the OSTAP block.
Opioid consumption varies by plane block procedure. While there are no intraoperative differences between US-TAP and US-OSTAP for Ketorolac, the US-OSTAP group consumed more Fentanyl, while the US-TAP group consumed more Nalbuphine postoperatively using 0.375% of Ropivacaine 40 mL [61]. However, there is contradictory evidence in the literature. It is worth noting that the US-TAP block reduced intra-operative consumption of Remifentanil or Sufentanil when 30 mL of Bupivacaine or Levobupivacaine was used [7,59]. Ortiz et al. [20] used 30 mL of 0.5% Ropivacaine and achieved lower intraoperative consumption of Morphine and Fentanyl compared to the port site infiltration. In addition, analgesic consumption and the need for rescue analgesia were reduced [7,59]. To look at it another way, 20 mL of Ropivacaine was previously found to reduce pain when coughing but not at rest [21]. US-TAP blocks following general anesthesia were significantly associated with lower Morphine consumption in the 24 h following surgery compared with patients receiving general anesthesia alone [59]. Therefore, future studies should be designed to clarify the analgesic efficacy of different block procedures using similar dosages.
The results of this review have shown that the use of adjuvant in addition to local anesthetics for TAP block procedures could be effective for pain management in laparoscopic cholecystectomy. To improve recovery after surgery and reduce postoperative opioid consumption, opioid-sparing techniques are increasingly used in anesthesia. Evidently, it was found that local anesthetics may be improved, and additional analgesics need to be administered less frequently when Dexmedetomidine is added to local anesthetics during central neuraxial blocks and peripheral nerve blocks [108]. Additionally, a study has shown that postoperative Fentanyl requirements were significantly lower in patients in the Esmolol group [109]. Perineural Dexamethasone combined with posterior TAP block was found to have a prolonged analgesic effect [110]. The pharmacokinetics of Ropivacaine were studied after the addition of Epinephrine for abdominal trunk blocks; however, this was found to attenuate the systemic absorption of Ropivacaine [111]. Previous studies have shown that multimodal analgesia with TAP blockade in combination with Nalbuphine PCIA is likely to be more beneficial for hemodynamic stability than Sufentanil or Nalbuphine PCIA, which is in line with this study outcome [112]. In abdominal TAP procedures, Magnesium Sulfate in addition to Bupivacaine reduced opioid requirements, duration of anesthesia, and pain intensity without adverse effects [113]. For OSTAP blockade, Pethidine was used in comparison with Bupivacaine and normal saline, and it proved to be as effective as Bupivacaine. The result is consistent with previous studies on the efficacy of US-OSTAP blocks in laparoscopic cholecystectomy [47,60].
Study results by McDonnell et al. [114] and [115] suggest that local anesthetics in TAP are cleared only after 36 to 48 h, possibly because TAP has fewer blood vessels compared to other body regions. Because there are no blood vessels in TAP, there is less risk of systemic toxicity from local anesthetics, which can occur when blood vessels are punctured, a common complication of peripheral nerve blocks. An effective method for relieving abdominal pain is to block the abdominal wall nerves (intercostal nerves, T7-T12, and ilioinguinal and iliohypogastric nerves, L1) [7]. There are two nerves that cross the intercostal plane between the obliquus internus muscle and the transversus abdominis muscle [7]. TAP blocking eliminates the pain caused by abdominal distension due to pneumoperitoneum during four accesses to laparoscopic cholecystectomy, even though the gallbladder is a supra-umbilical organ [69]. Unlike conventional blind techniques, ultrasound allows direct visualization of the target plane, virtually eliminating the limitations of anatomic and marker access. In patients with limited cardiac status, TAP blockade has also been used as an effective analgesic during abdominal surgery [116,117].
A few studies have contributed to the understanding of the modulation of postoperative pain by Esmolol, although its role in modulating pain still remains unclear [89]. Analgesic effects of beta-adrenergic antagonists are mediated by G proteins that are activated in isolated cell membranes [108]. Clonidine, which also acts on G proteins, produces central analgesia by activating these proteins [108]. Clinical studies have shown that the use of Magnesium Sulfate as an adjunct to local anesthetics is effective for pain in regional procedures [7,21,59]. However, the mechanism by which it acts remains unclear. It has been postulated that it may potentiate analgesic effects through local or systemic actions [65]. For magnesium to exert analgesic effects, it must block calcium influx into nerve fibers and block the NMDA (n-methyl D-aspartate) receptors [118][119][120]. These effects may interfere with the release of neurotransmitters at synaptic junctions or enhance the effects of local anesthetics [121]. There are many sites in the body where this NMDA receptor is found, including nerve endings, and it plays a well-defined role in modulating pain and various other functions [122][123][124]; therefore, blocking NMDA receptors could prevent peripheral nociceptive stimuli from causing central sensitization [125]. Specifically, as magnesium prevents NMDA receptor activation, calcium and sodium influx into the cell and potassium outflow into space activate peripheral nociceptive stimulation, resulting in central sensitization and enhancement [65].
The mechanism by which Dexamethasone might affect pain management also remains unclear; however, the lack of local blood vessels makes the TAP blockade lasts a long time because of the slow breakdown of local analgesia [114,126]. Aside from that, the literature has shown that different approaches to TAP blockade affect nerves differently [38,127]. In the past, Dexamethasone prolonged intercostal nerve blockade in sheep when added to Bupivacaine microspheres [128]. In addition, blockade of the sciatic nerves was induced in rats with Dexamethasone microspheres added to Bupivacaine [129]. Increasing systemic absorption and intraneural clearance of local anesthetics may be decreased because the vasoconstrictive effects of Epinephrine antagonize their inherent vasodilator effects and they may be redistributed intraneurally [130]. With shorter-acting agents, Epinephrine significantly prolongs both infiltration anesthesia and peripheral nerve blockade; it may also increase blockade somewhat, but with Bupivacaine, it prolongs epidural or peripheral blockade only slightly [131]. Research has shown that the use of different analgesics for multiple targets can result in satisfactory postoperative pain management [98]. There are several previous studies indicating a reduction in postoperative pain scores and opioid consumption after classic mid-axillary blocks US-TAP; a sensory blockade occurs between dermatomes T6 and T10 when TAP subcostal is reached [132,133]. As a result, OSTAP is used in the upper abdomen to relieve pain [134].

Limitations
The present systematic review has some limitations. Although all included studies were searched from different countries, we are subject to publication bias because this systematic review includes studies published in English only. Because of the lack of sufficient data, we could not draw conclusions about the clinical significance of the various TAP block procedures. We were also unable to provide information on the long-term effects of the TAP blockade procedures because of a lack of evidence. There were numerous RCTs whose data were not suitable for meta-analysis, either because of a pictorial representation of the data, different methods of measuring outcomes, or inappropriate statistical analysis (e.g., reporting median and mean values with a range) or the lack of baseline data. Furthermore, the ASA grade and BMI in the baseline data of patients could have an impact on the tolerance of local anesthetics. Again, the broader inclusion criteria and overall objective may be a limiting factor to consider when planning further studies. In view of these problems, it is advisable to not generalize conclusions from this study to broader clinical settings. However, further studies are needed to clarify the analgesic efficacy of different TAP block procedures at similar doses. The optimal long-term effect of local anesthetics in TAP blockade procedures and the toxicity of local anesthetics should be further investigated.

Conclusions
Four different types of anesthetics (Bupivacaine, Ropivacaine, Levobupivacaine, and Lidocaine) have been reported to be used in concentrations ranging from 0.2% to 0.375% for LC procedures. Ten different types of drugs (normal saline, Dexamethasone, Dexmedetomidine, Magnesium Sulfate, Oxycodone, Ketorolac, Epinephrine, Esmolol, Tropisetron, and Sufentanil) were reportedly used as supportive agents in addition to local anesthetics for LC. Although concentrations of LA may vary, 20 mL is probably the optimal dose for TAP block procedures and 0.4 mg/kg for port infiltration. However, further quantification is needed to clarify the optimal dose for different anesthetic concentrations. US-TAP blockades performed in addition to general anesthesia were more effective for pain than port infiltration or general anesthesia alone. Postoperative pain perception and opioid consumption were higher in those who received a US-TAP block after surgery than in those who received a block before induction; however, it took a shorter time for those who received a US-TAP block after surgery to require the first analgesics. US-TAP block with normal saline reportedly had higher opioid consumption in 24 h compared with those with Bupivacaine over normal saline or Bupivacaine over Sufentanil. It appears that the higher the concentration of the anesthetic used for US-TAP blockade, the lower the pain sensation, and that an adjuvant to LA could enhance its analgesic effect. Evidently, those who received Ropivacaine at low concentrations required rescue anesthesia in the ward. There seems to be no significant difference between the US-TAP and US-OSTAP. Time to first analgesic intake/request was higher in the groups with US-TAP block compared with quadratus lumborum. However, pain perception between 12 and 24 h was lower in the US-TAP group than in the quadratus lumborum group. This should be clarified in further studies. Compared with the port infiltrations, the LAP-TAP block group reportedly had less pain at rest in the first 3-6 h after surgery. The minimal clinically significant differences for both TAP block procedures and port infiltration appeared to have a large effect size index, but this should be taken with caution because of insufficient evidence. Subcostal US-TAP blockade may be correlated with lower postoperative opioid consumption and reduced need for rescue analgesics compared with US-BRILMA. US-ESP proved to be more effective than US-OSTAP block for postoperative pain within 24 h. Finally, multimodal analgesia could be another strategy for pain management. Analgesia with the TAP blockade significantly reduces opioid consumption and also provides effective analgesia.