Laparoscopically guided transversus abdominis plane block versus local wound infiltration analgesia in laparoscopic surgery for peritoneal endometriosis: A prospective randomized controlled double-blinded LTAP-trial

Introduction Endometriosis patients often suffer from more severe pain in association with surgical procedures. The aim of this study was to investigate whether laparoscopically guided transversus abdominis plane block (LTAP) offers an opioid-sparing effect compared to local wound infiltration (LWI) analgesia in laparoscopic surgery performed for suspected peritoneal endometriosis.

In this single-center prospective, randomized, controlled, double-blinded clinical study, 46 patients were randomized to receive either levobupivacaine inserted in the four quadrants of the abdomen at LTAP points and saline at trocar sites (n = 23) or saline at the LTAP points and levobupivacaine at trocar sites (n = 23). The study size was based on a power calculation. The primary outcome, opioid consumption 24 h postoperatively, was measured using patient-controlled analgesia pumps. Secondary outcomes included postoperative pain scores and other enhanced recovery after surgery (ERAS) measures, as well as patient outcome questionnaires at six months after surgery. Statistical analyses were performed on an intention-to-treat basis. The study was prospectively registered in Clinicaltrials.gov, ID: NCT04735770, Jan 19, 2021; https://clinicaltrials.gov/study/NCT04735770?term=LTAP&rank=2.

There was no significant difference in the mean opioid consumption (iv morphine equivalents) between the study groups: 31.8 ± 25.5 mg in the LTAP group and 27.5 ± 19.3 mg in the LWI group (mean difference 4.3 mg, 95% CI −9.2 to 17.7, p = 0.52). No significant differences were found in the postoperative pains scores, mean operation times, mean total blood loss, or mobilization between the study groups. 17 (73.9%) patients in each group received histological diagnosis of peritoneal endometriosis of the samples obtained during surgery. Times to discharge were 24.4 ± 4.3 (LTAP) and 28.1 ± 14.8 h (LWI), p = 0.25. No complications related to LTAP or LWI were reported.

In this study performed on women suffering from long-term abdominal pain preoperatively, no significant differences were found between LTAP and LWI as regards to postoperative opioid consumption, postoperative pain, ERAS factors, or safety. Abbreviations | | | |---|---| | | | | | | | | | Key message No significant differences were found between LTAP and LWI as regards to postoperative opioid consumption, pain scores, mobilization, or complications. 1 INTRODUCTION Endometriosis is a chronic, inflammatory disease that affects up to 10% of women during their fertile years. The symptoms include cyclic or chronic pelvic pain, dysmenorrhea, deep dyspareunia, dysuria, dyschezia, and infertility.1-3 The mechanisms underlying endometriosis pain are complex and not fully understood. Endometriosis implants cause peritoneal inflammatory response and may lead to peripheral and, finally central sensitization of pain pathways.4, 5 Conservative hormonal medication is the primary treatment option, and based on current knowledge, no surgical verification of endometriosis is needed before starting treatment.6 However, hormonal treatment may be insufficient in symptom control, or the patients may suffer from side effects or contraindications that prevent successful use of hormonal treatments. Hence, there is also need for surgical treatment of peritoneal endometriosis.6 Chronic pain, dysmenorrhea, and endometriosis have been shown to be associated with increased postoperative pain.7, 8 Local wound infiltration (LWI) analgesia in laparoscopy may often be insufficient in patients with substantial preoperative pain symptomology, and even the use of epidural analgesia has been common practice in our clinic. However, epidural analgesia carries a risk of potentially harmful complications9 and may also hinder enhanced recovery after surgery (ERAS) and prolong the time to discharge.10 Furthermore, increasing postoperative opioid consumption associated with inadequate pain control predisposes patients to complications such as nausea, vomiting, and respiratory depression.11 Dorsally inserted transversus abdominis plane block (TAP) was introduced at the beginning of the 21st century. A local anesthetic agent is inserted between the internal oblique and transversus abdominis muscles, blocking the sensory nerves of the abdominal wall unilaterally between the costal margin and the inguinal ligament (T6–L1), providing analgesia to the parietal peritoneum, muscles, and abdominal skin accordingly. When inserted in a blind fashion, it carries a risk of peritoneal perforation. Thus, to avoid complications, ultrasound-guided transversus abdominis plane block technique (UTAP) was adopted by anesthesiologists.12 TAP may also be inserted under laparoscopic visualization (LTAP), blocking the sensory nerves T10–T12 supplying mainly the infraumbilical area of the abdominal wall.12 Meta-analyses have shown the efficacy of TAP blocks concerning either reduced opioid consumption and/or reduced postoperative nausea and vomiting (PONV) in laparoscopic cholecystectomies, colorectal, and bariatric surgery13-15 with the results of laparoscopically guided transversus abdominis plane block (LTAP) comparable to those of UTAP in minimally invasive colorectal surgery.16 The results of previously published studies on the efficacy of TAP in laparoscopies performed for gynecological indications have, however, been somewhat inconsistent.17-20 The aim of this study was to investigate whether LTAP provides an opioid-sparing effect in comparison to LWI after gynecological organ-sparing laparoscopic surgery for suspected peritoneal endometriosis. 2 MATERIAL AND METHODS This was a prospective, randomized, controlled, double-blinded clinical study conducted at a single tertiary university-affiliated hospital with a multidisciplinary center specialized in endometriosis care. For a detailed description of the collection of the study population and study execution, we refer to the peer-reviewed, published study protocol.21 2.1 Study population The study population consisted of patients aged 18–50 years undergoing laparoscopic surgery for suspected peritoneal endometriosis based on pain-related symptoms. Deep infiltrating endometriosis (DIE) was excluded preoperatively by transvaginal ultrasound and/or pelvic magnetic resonance imaging. The exclusion criteria were: American Society of Anesthesiologists' (ASA) Physical Status Classification >3, previous diagnosis of sleep apnea, contraindications to opioids or NSAIDs, or continuous preoperative opioid intake. Informed consent was obtained during the preoperative outpatient visit. The patients were recruited between January 2021 and September 2023 and operated on between May 2021 and December 2023. Randomization at the patient level was done with an allocation ratio of 1:1. The active LTAP group (n = 23) received levobupivacaine administered at LTAP points and saline infiltrated at the sites of laparoscopic trocars. The LWI group (n = 23) received saline at LTAP points and levobupivacaine at the trocar sites. The opaque, sealed randomization envelope was opened, and the syringes were prepared accordingly in the operating room by the OR nurses before the surgeon entered the room. The patient and the surgeon remained blinded to the allocated group. The OR nurses did not participate in the postoperative care of the patients. Postoperative outcomes were assessed by the healthcare professionals working in the inpatient ward, who did not participate in the study. 2.2 Anesthesia and postoperative analgesia The patients received total intravenous anesthesia with endotracheal intubation using propofol and remifentanil infusions and relaxation with rocuronium. No inhalation anesthetics were used. All patients received dexamethasone 5 mg iv to prevent postoperative nausea and vomiting (PONV). At the end of the procedure, 50 mg of dexketoprofen iv and fentanyl 0.5 μg/kg iv were administered as remifentanil infusion was discontinued. In the recovery room, a patient-controlled analgesia (PCA) pump (Deltec CADD Legacy®, Steripolar) was initiated with oxycodone 3 mg/mL (with 1.5 mg boluses, 10-min lock out period and a maximum of 4 doses per hour). If needed, iv oxycodone was administered in addition to the PCA pump as rescue analgesia. In the case of PONV, ondansetron 4 mg and dehydrobenzperidol 0.5 mg were given iv. Paracetamol 1 g × 3 and ibuprofen 600 mg × 3 po were started, with early mobilization and other ERAS protocols implemented. No indwelling catheters were used. However, the bladder may have been emptied during surgery using a disposable catheter if deemed necessary to maintain a safe surgical view and space. Patients were primarily scheduled for non-outpatient surgery because of the 24-h PCA pump follow-up designed specifically for this study. However, same-day discharge was not contraindicated if the postoperative pain could be managed perorally and other discharge criteria were fulfilled. 2.3 Surgery All the surgeries were performed by either of two experienced laparoscopists (S.K. or A.M.T.). A 12 mm laparoscopic camera port was placed on the lower rim of the umbilicus, and three 5 mm laparoscopic ports on the lower abdomen. Entry was performed using a Veress needle, and 10 mmHg intra-abdominal pressure was maintained throughout the surgery (UHI-4® insufflator, Olympus). All visible peritoneal endometriosis implants in the pelvic area were resected using a monopolar hook. For patients with no visible endometriosis implants, a random biopsy was taken from the left-side peritoneal area in the Fossa Douglas. Bipolar energy instruments were used to ensure hemostasis where needed. For the 12 mm camera port, fascial closure was performed using a single slowly absorbable (PDS® 2–0, Ethicon) suture. All skin incisions were closed using absorbable (Monosyn® 2–0, B. Braun) sutures. 2.4 Intervention Injections into abdominal wall were performed at the beginning of surgery. The LTAP group received 10 mL of levobupivacaine 2.5 mg/mL at each of the LTAP sites in each quadrant of the abdomen and 2.5 mL of saline at each of the trocar sites. The LWI group received 10 mL of saline at each of the LTAP sites and LWI at the four trocar sites with levobupivacaine 5 mg/mL, 10 mL in total. The injections were performed under direct visualization: first bringing the 21-gauge needle into the preperitoneal space and then retracting it between the transversus abdominis and internal oblique muscles, the injection resulting in the so-called internal Doyle's bulge22 at the LTAP sites at the brim of the transversus abdominis muscle at approximately mid-axillary line (Supporting Information, Video S1), and at the marked trocar sites (Figure 1). 2.5 Sample size Sample size was calculated based on the assumption that LTAP would decrease postoperative opioid consumption by 50%, which was deemed to be a clinically relevant difference. The calculation was based on previous literature showing a 15.4 mg ± 9.2 mg postoperative opioid consumption after local wound analgesia after laparoscopy.23 With 80% power and a 0.05 alfa-error, a sample size of 46 (23 + 23) was obtained. 2.6 Outcomes The primary outcome was the overall postoperative opioid consumption in 24 h compared between the LTAP and LWI groups. All patients filled out two questionnaires, first preoperatively and again at six months postoperatively: NRS pain inquiry covering 11 different pain sites, scaled from 0 to 10 (0 meaning no pain and 10 meaning “worst imaginable pain”), and the endometriosis health profile EHP-30,24, 25 containing 30 questions covering five subscores: “Pain” (11 questions), “Control and powerlessness” (6 questions), “Emotional well-being” (6 questions), “Social support” (4 questions), and “Self-image” (3 questions). The total score, as well as the subscores, vary between 0 and 100, higher score representing greater worsening impact of endometriosis on the quality of life. Minimal clinically important differences for the subscores vary between 7.6 for “Emotional well-being” and 35.2 for “Control and powerlessness”.24 Secondary outcomes included (1) the maximum postoperative pain using the NRS questionnaire at the recovery room and at the ward every six hours up to 24 h (if the patient was discharged before 24 h, they were requested to fill in the NRS at home), (2) factors related to the surgery and ERAS (operation time, blood loss, nausea/vomiting, peroral intake, mobilization, complications, time of discharge, readmission to hospital), and (3) a six-month postoperative follow-up using the NRS pain inquiry and EHP-30 questionnaires sent to participants. 2.7 Statistical methods Statistical analyses were performed on an intention-to-treat (ITT) basis using the programs SPSS (IBM Corp. Released 2021. IBM SPSS Statistics for Windows, Version 28.0. Armonk, NY: IBM Corp) and SAS (version 9.4, SAS Institute Inc., Cary, NC, USA). Per protocol (PP) analyses were performed where needed. Continuous variables were described as mean with standard deviation (SD) or as median with 25th–75th percentiles, and categorical variables as numbers and percentages. Comparisons between study groups were performed using the Student's t-test or Mann–Whitney U test for continuous variables and Chi-square test for categorical variables. Continuous variables with measurements both pre- and postoperatively were analyzed using a linear regression model with the preoperative score as an adjusting factor. Sensitivity analyses were also performed using a linear regression model. The difference between means with 95% confidence intervals (95% CI) was presented as a result of the t-test and regression model. Repeatedly measured postoperative pain was analyzed using linear mixed model (LMM), where time, group and time × group interaction were set as fixed factors and patient set as a random effect. Statistical significance was set at a two-sided p-value < 0.05. 3 RESULTS A flow chart of the enrollment of the study population is presented in Figure 2. There were no withdrawals of participation after consent, and all patients in each of the study groups primarily received the allocated treatment. One patient in the LWI group received an epidural block postoperatively in the recovery room due to inadequate analgesia. 3.1 Background characteristics The background characteristics of the study groups are presented in Table 1. The study groups were comparable considering the mean age, BMI, education, smoking, ASA classification, overall comorbidities, the usage of hormonal medications for endometriosis, and the preoperative mean NRS and EHP-30 scores, as well as EHP-30 subgroup scores. However, patients in the LTAP group were less parous (8.7% vs. 34.8%), had more previous abdominal surgeries (34.8% vs. 8.7%) and had higher usage of medications for chronic pain (43.5% vs. 13%) compared to the LWI group. | LTAP (n = 23) | LWI (n = 23) | | |---|---|---| | Age, mean ± SD | 25.9 ± 8.24 | 27.1 ± 6.38 | | BMI, mean ± SD | 26.0 ± 5.49 | 25.8 ± 6.21 | | Education, secondary or higher, n (%) | 19 (86.4)a | 20 (87.0) | | Smoking, yes, n (%) | 4 (17.4) | 3 (13.0) | | Comorbidities, n (%) | 20 (87.0) | 19 (82.6) | | Pain diagnosis, n (%) | 14 (60.9) | 11 (47.8) | | Migraine, n (%) | 9 (39.1) | 9 (39.1) | | Parous, n (%) | 2 (8.7) | 8 (34.8) | | Amenorrhea on medication, n (%) | 16 (69.6) | 10 (43.5) | | Previous abdominal surgeries, n (%) | 8 (34.8) | 2 (8.7) | | NSAID usage, n (%) | 22 (95.7) | 22 (95.7) | | Occasional codein/tramadole usageb, n (%) | 10 (43.5) | 5 (21.7) | | Medication for chronic pain, n (%) | 10 (43.5) | 3 (13.0) | | Usage of pain medication, days/month, median [range] | 15 [2–30] | 12 [2–30] | | Absenteism from work, days/month, median [range] | 2 [0–30] | 0.5 [0–30] | | Preoperative dymenorrhea, NRS, mean ± SD | 8.0 ± 1.41 | 7.4 ± 2.76 | | Preoperative pelvic pain, NRS, mean ± SD | 7.4 ± 1.50 | 6.4 ± 2.52 | | Preoperative EHP-30, mean ± SD | 56.1 ± 2.67 | 58.1 ± 3.16 | | Hormonal treatment | || | No, n (%) | 1 (4.3) | 2 (8.7) | | Monotherapy, n (%) | 15 (65.2) | 13 (56.5) | | Multiple hormonal medications, n (%) | 7 (30.4) | 8 (34.8) | | ASA 1, n (%) | 9 (39.1) | 11 (47.8) | - Abbreviations: ASA, American Society of Anesthesiologists Physical Status Classification System; BMI, body mass index, kg/m2; EHP-30, endometriosis health profile; LTAP, laparoscopically guided transversus abdominis plane block; LWI, local wound infiltration; NRS, numeric rating scale; NSAID, non-steroidal anti-inflammatory drugs; SD, standard deviation. - a Information on education missing = 1 in the LTAP group. - b Regular opioid usage was an exclusion criterion in the study. Occasional use of weak opioids (tramadol or codeine in a paracetamol-containing combination preparation for exacerbated pain) was, however, allowed. 3.2 Primary outcome There was no significant difference in the mean opioid consumption (iv morphine equivalents) in the ITT analyses between the study groups: 31.8 25.5 mg in the LTAP group and 27.5 19.3 mg in the LWI group (mean difference 4.3 mg, 95% CI -9.2 to 17.7, p = 0.52) (Table 2) during the first 24 h postoperatively. In addition, PP analyses on opioid consumption were performed (LTAP, n = 23; LWI, n = 22; LWI and epidural block n = 1). However, the difference between the groups remained statistically insignificant. | LTAP (n = 23) | LWI (n = 23) | Difference (95% CI)b | p | | |---|---|---|---|---| | Opioid consumptiona, mg, mean ± SD | 31.8 ± 25.5 | 27.5 ± 19.3 | 4.3 (−9.2 to 17.7)b | 0.52 | | Operation time, minutes, mean ± SD | 52.8 ± 9.4 | 52.4 ± 16.4 | 0.4 (−7.6 to 8.4)b | >0.90 | | Total blood loss, mL, mean ± SD | 4.4 ± 11.6 | 5.0 ± 12.0 | −0.7 (−7.7 to 6.4)b | 0.85 | | Time to discharge, hours, mean ± SD | 24.4 ± 4.3 | 28.1 ± 14.8 | −3.7 (−10.2 to 2.7)b | 0.25 | | Histological diagnosis of endometriosis, n (%) | 17 (73.9) | 17 (73.9) | 0 (−24.5 to 24.5)c | >0.90 | - Note: Students t-test, chi-square test. - Abbreviations: CI, confidence interval; LTAP, laparoscopically guided transversus abdominis plane block; LWI, local wound infiltration; NRS, numeric rating scale; SD, standard deviation. - a Morphine equivalents. - b Difference between means (95% CI). - c Difference in %-unit (95% CI). 3.3 Secondary outcomes The mean postoperative NRS scores are presented in Figure 3, with no significant differences between the study groups. There was no difference in the mean operation times (52.8 9.4 min vs. 52.4 16.4 min, p = 0.92) or mean total blood loss (4.4 11.6 mL vs. 5.0 12.0 mL, p = 0.85). 17 (73.9%) patients in each group received histological diagnosis of peritoneal endometriosis of the samples obtained during surgery (Table 2). In addition to these, three patients in each group received a visual diagnosis of endometriosis, even though histology remained negative or suggested fibrosis. Nausea was reported by four and four patients in the recovery room, six and four patients at six hours, and two and zero patients at 24 h postoperatively for LTAP and LWI groups, respectively (p = 0.03). Peroral intake of fluids already at the recovery room was reported for 14 patients in the LTAP group and seven patients in the LWI group (p = 0.04). No differences in mobilization were found between the study groups. Times to discharge were 24.4 4.3 and 28.1 14.8 h for the LTAP and LWI groups, respectively (mean difference − 3.7, 95% CI −10.2 to 2.7, p = 0.25) (Table 2). One patient in the LTAP group was diagnosed with postoperative urinary tract infection. Nine patients (39%) in the LTAP group and four patients (17%) in the LWI group visited the gynecological outpatient ward in the first 30 days postoperatively (p = 0.19). One patient in the LWI group was readmitted to the hospital for abdominal pain with no specific findings within 30 days postoperatively. No complications related specifically to the LTAP or LWI procedures were reported. 3.4 Secondary outcomes at six months postoperatively Six-month follow-up data were available for 19 patients (82.6%) in each group. The six-month EHP-30 mean scores were 45.2 and 39.3 for the LTAP and LWI groups, respectively (mean difference 5.9, 95% CI −9.1 to 20.9, p = 0.43). When adjusted for the preoperative score, the difference between the groups remained statistically not significant (mean difference 9.2, 95% CI −2.9 to 21.3, p = 0.13). All the postoperative EHP-30 subscores were lower compared to the preoperative scores in both LTAP and LWI groups, although no significant differences between the groups were found at six months postoperatively (Table 3a). | EHP-30 scores | |||||||| |---|---|---|---|---|---|---|---|---| | Preoperative | 6 months postoperative | ||||||| | LTAP, n = 23, mean (SD) | LWI, n = 23, mean (SD) | LTAP, n = 19, mean (SD) | LWI, n = 19, mean (SD) | Mean difference, (95% CI), crude | p, crude | Mean difference, (95% CI), adjusted* | p, adjusted* | | | Total | 56.1 (12.8) | 58.1 (15.2) | 45.2 (24.6) | 39.3 (20.9) | 5.9 (−9.1 to 20.9) | 0.43 | 9.2 (−2.9 to 21.3) | 0.13 | | Pain | 52.7 (12.6) | 57.8 (11.9) | 42.3 (21.3) | 34.8 (22.3) | 7.5 (−6.8 to 21.9) | 0.30 | 13.1 (−0.4 to 26.6) | 0.057 | | Control/Powerlessness | 71.9 (14.7) | 68.8 (20.1) | 54.6 (29.2) | 48.9 (30.8) | 5.7 (−14.1 to 25.4) | 0.56 | 2.0 (−14.7 to 18.79) | 0.81 | | Emotional well-being | 48.0 (15.7) | 47.4 (19.6) | 37.9 (22.4) | 30.7 (20.9) | 7.2 (−7.0 to 21.5) | 0.31 | 9.4 (−2.4 to 21.2) | 0.11 | | Social support | 48.9 (17.1) | 53.4 (20.6) | 40.5 (29.3) | 36.2 (26.7) | 4.3 (−14.2 to 22.7) | 0.64 | 13.2 (−1.4 to 27.8) | 0.076 | | Self-image | 59.1 (22.2) | 58.0 (28.9) | 51.3 (33.3) | 47.4 (25.2) | 3.9 (−15.5 to 23.4) | 0.68 | 3.5 (−12.9 to 19.9) | 0.67 | - Note: Students t-test and linear regression model. - Abbreviations: CI, confidence interval; EHP-30, endometriosis health profile; LTAP, laparoscopically guided transversus abdominis plane block; LWI, local wound infiltration. - * Adjusted for the preoperative score. For the six-month NRS scores, no significant differences were found between the study groups (Table 3b). | NRS scores | ||||||| |---|---|---|---|---|---|---|---| | Preoperative | Postoperative | |||||| | LTAP, n = 23, mean (SD) | LWI, n = 23, mean (SD) | LTAP, n = 19, mean (SD) | LWI, n = 19, mean (SD) | Mean difference (95% CI) | p crude | p adjusted* | | | Menstrual pain | 8.00 (1.41) | 7.35 (2.76) | 5.77 (3.7) | 4.71 (3.62) | 1.01 (−1.69 to 3.82) | 0.44 | 0.052 | | Pelvic pain | 7.39 (1.50) | 6.41 (2.52) | 6.42 (2.04) | 5.53 (3.06) | 0.90 (−0.81 to 2.61) | 0.30 | 0.65 | | Dyspareunia | 6.81 (2.14) | 6.25 (2.71) | 4.71 (3.62) | 4.28 (3.14) | 0.43 (−1.90 to 2.75) | 0.71 | 0.58 | | Pain defecating | 5.09 (3.27) | 5.82 (3.05) | 4.74 (3.66) | 3.95 (3.21) | 0.79 (−1.48 to 3.06) | 0.48 | 0.30 | | Full bladder pain | 5.74 (3.43) | 5.05 (3.20) | 5.26 (3.30) | 3.47 (3.10) | 1.79 (−0.32 to 3.89) | 0.93 | 0.21 | | Pain urinating | 4.65 (3.49) | 3.91 (3.12) | 4.32 (2.96) | 3.00 (3.30) | 1.32 (−0.75 to 3.38) | 0.20 | 0.28 | | Upper abdominal pain | 5.48 (3.15) | 5.45 (3.17) | 5.05 (2.80) | 3.74 (3.80) | 1.32 (−0.88 to 3.51) | 0.23 | 0.22 | | Lower back pain | 6.17 (2.76) | 5.55 (2.99) | 5.79 (2.57) | 4.47 (2.86) | 1.32 (−0.47 to 3.10) | 0.14 | 0.21 | | Upper back pain | 3.83 (2.66) | 3.91 (3.31) | 2.68 (3.47) | 3.11 (3.02) | −0.42 (−2.56 to 1.72) | 0.69 | 0.69 | | Shoulder pain | 5.09 (2.35) | 5.59 (3.23) | 3.26 (3.31) | 3.26 (3.63) | 0.00 (−2.29 to 2.29) | 1.00 | 0.83 | | Leg pain | 3.78 (3.30) | 4.55 (3.74) | 4.00 (3.37) | 3.95 (3.70) | 0.05 (−2.28 to 2.38) | 0.96 | 0.74 | - Note: Student's t-test and linear regression model. - Abbreviations: LTAP, laparoscopically guided transversus abdominis plane block; LWI, local wound infiltration; NRS, numeric rating scale. - * Adjusted for the preoperative score. A mean of 1.4 (LTAP) and 1.2 (LWI) contacts (visits or phone calls) to the Department of Gynecology were recorded during the six-month follow-up per patient (p = 0.51). 4 DISCUSSION LTAP provided no opioid-sparing effect compared to LWI in this randomized, prospective, double-blinded controlled study. In addition, no significant differences in postoperative pain scores or other secondary postoperative outcomes were found. Our results are in line with the only previous study available, performed on the endometriosis population: an Iranian RCT compared three groups, LWI with placebo LTAP (n = 21), LTAP with placebo LWI (n = 24) and placebo LWI with placebo LTAP (n = 25) in laparoscopic endometriosis resection. Both active LTAP and active LWI reduced pain scores significantly compared to placebo, but no differences in effect were found between LTAP and LWI.17 The patients in the study by Kargar et al.17 had various endometriosis stages, mostly deep endometriosis, and the operation times were three hours or more. Our results also agree with a previous study investigating TAP blocks in the hysterectomy population: an RCT from the United States compared UTAP administered by the anesthesiologist (n = 45) and LTAP administered by the surgeon (n = 43) to LWI administered on the contralateral side to the TAP block at the end of minimally invasive hysterectomy. No improvements on pain scales were found for either of the TAP blocks compared to LWI.18 Our study provides a novel perspective compared to Kargar et al.17 and El Hachem et al.18 with our homogenous patient population, standardized LTAP insertion, and opioid consumption measured with a PCA-pump as the primary outcome. In contrast with these studies, an RCT from the United States found UTAP (n = 31) to be associated with decreased opioid intake and better quality of recovery compared to LWI (n = 31) 72 h postoperatively in patients undergoing laparoscopic or robot-assisted laparoscopic hysterectomies.26 Two meta-analyses report conflicting results on the use of the TAP block in gynecological surgery. No difference in opioid consumption or postoperative pain scores was found between laparoscopic/robot-assisted laparoscopic hysterectomy patients receiving TAP block compared to placebo or no block in a meta-analysis based on 9 RCTs. The TAP blocks varied in timing, location, and guidance method (laparoscopic visualization/ultrasound) between the studies included.19 In contrast, a recent meta-analysis based on 10 RCTs comparing TAP (both ultrasound- and laparoscopically guided) to LWI in gynecological procedures (both laparoscopy and -tomy) reported TAP to result in lower pain scores up to 24 h after surgery. In addition, TAP was associated with significantly reduced postoperative opioid consumption, although no difference in the incidence of PONV was found.20 A recent Cochrane review found no difference in opioid consumption between TAP block and local anesthetic (two RCTs) in women undergoing laparoscopic or robotic gynecological surgery, whereas postoperative pain was slightly reduced for TAP (six RCTs), which is largely in accordance with our results.27 It is notable that previous literature on TAP blocks presents high variability in the techniques, locations and timing of the inserted blocks, as well as the indications and techniques of the surgeries, making comparisons somewhat challenging. Many studies report that UTAP and LTAP provide comparable results.28-30 Considering the locations of a TAP block, the more posterior the approach, the more central it is in the nervous system; thus, a wider area can be anesthetized. Posterior LTAP inserted in the area of the petit triangle has been shown to decrease opioid intake compared to lateral LTAP.31, 32 Among patients undergoing minimally invasive hysterectomies, there was no difference in opioid consumption between pre- and postoperatively inserted TAP blocks, although preoperative TAP was associated with significantly reduced time to discharge in a single-center retrospective cohort.33 Our study was conducted in a patient population suffering from long-term preoperative pain, with perhaps peripheral and central sensitization involved in their symptom presentation. These patients are known to be at risk of increased surgery-associated pain. Preoperative chronic pain doubled the risk for higher pain intensity in a German cohort of gynecologic surgery patients.7 Furthermore, endometriosis surgery was associated with an increased risk for moderate to severe postsurgical chronic pain in a large prospective European multicenter observational cohort.34 Endometriosis diagnosis has been shown to be associated with a failure of preplanned outpatient surgery,35 as well as an increased opioid consumption up to two weeks after hysterectomy.8 In addition, endometriosis patients had higher postoperative pain scores despite their high use of opioids,8 which might indicate that opioids were not an effective medication for the type of pain the patients had. In our study, the opioid consumption was surprisingly high in both study groups, in accordance with the patients' preoperative pain status, but postoperative NRS scores were low, indicating that the response to perioperative opioid treatment was sufficient. The high overall opioid consumption may in part be explained by the use of patient-controlled analgesia, as previous studies have demonstrated that PCA is associated with increased opioid consumption alongside improved analgesia and higher patient satisfaction compared with conventional nurse-administered opioid regimens.36 The background characteristics of the study groups in our study might offer some explanation as to why LTAP did not bring benefits compared to LWI. Despite the randomization, women in the LTAP group were less parous, had more often previous abdominal surgeries, and higher usage of medications for chronic pain. Thus, it could be argued that they were more prone to increased postoperative pain. These differences in the background factors are probably explained by chance, considering the limited study size. Sensitivity analyses were conducted in three different models adjusting either for parity, for the use of chronic pain, or the occasional use of mild opioids. However, in these models no significant differences between the LTAP and LWI groups concerning the primary outcome were found (Table S1). LTAP patients reported more nausea during the first 24 h postoperatively. This might be explained by their early peroral fluid intake already in the recovery room. Overall, the reported nausea rates were high, despite maximal preventative efforts. Nausea may be a side effect of the high doses of opioids used, or simply a sign of visceral pain that could be difficult for the patient to recognize or name and cannot be managed by LTAP or LWI blocks. There was a trend of lower early postoperative NRS and earlier time-to-discharge for the LTAP group, although no statistically significant differences were found. No complications related to LTAP or LWI were reported, which is reassuring, considering that multimodal pain management, including regional techniques, is recommended to be implemented in gynecologic surgery.37 Furthermore, in our study, the patients in the LTAP group reported slightly worse scores in the six-month follow-up questionnaires compared to the patients in the LWI group (although statistically not significant). It is likely that the results at six months do not reflect LTAP or LWI technique per se but are more a reflection of the preoperative status. Adjusting the results with the preoperative scores did not change the statistical significance. There are certain limitations to our study. The study size is rather small, although based on a power calculation. It would have been optimal to estimate opioid consumption with a more similar group of patients with long-term preoperative pain, but no such data was available for power calculation. This may have resulted in optimistic effect size estimations. The high use of opioids in both study arms may have diluted possible differences between LTAP and LWI. Unfortunately, we were not able to include a stress test, such as coughing, in our evaluation of postoperative pain. In addition, we didn't ask in which specific abdominal region the postoperative pain was located. It could be pelvic pain, and since pelvic floor innervation originates from lumbar and sacral roots, it could not be reached well by TAP block. Furthermore, it needs to be considered that our study material consisted of women experiencing long-term pain preoperatively with DIE excluded. Thus, our results may not be generalizable to a more diverse population, either healthier pain-wise or with findings of DIE. The strengths of our study include the randomized, prospective, double-blinded, controlled design, minimizing reporter- or observer-derived bias. We had a standardized anesthesia protocol to ensure an equal outset for every patient and used PCA to avoid bias caused by possible underdetection of postoperative pain. In addition, the setting in a tertiary endometriosis care center provides similarity in indications for surgery and the surgical procedures across the study population. A vast majority of the operated patients received an endometriosis diagnosis. We collected meticulous background data, including the validated endometriosis-related quality-of-life questionnaire, and provide high coverage on the six-month follow-up data. 5 CONCLUSION In this study performed on women suffering from long-term abdominal pain preoperatively, we found no significant differences between LTAP and LWI regarding to postoperative opioid consumption, postoperative pain, ERAS factors, or safety. AUTHOR CONTRIBUTIONS All authors participated in the study design, Anna M. Terho and Sari Koivurova performed the surgeries, Pasi Ohtonen conducted the statistical analyses, Anna M. Terho and Terhi Puhto prepared the manuscript, and all authors contributed to the revisions, as well as approved the final version of the manuscript. ACKNOWLEDGMENTS Anne Parviainen and Hanna-Mari Pyrrö, the endometriosis nurses at OUH, have played a significant role in taking care of these patients and organizing the surgeries. We also express our gratitude to all other staff members at OUH for making this study possible. Finally, we express our gratitude to all the women who consented to take part in this study. Credit for Figure 1 goes to Mr Jussi Saarela, which is gratefully acknowledged. Open access publishing facilitated by Oulun yliopisto, as part of the Wiley - FinELib agreement. FUNDING INFORMATION Funding was obtained from the Finnish Cultural Foundation (personal grant to AMT) and the Finnish state research grant (2023). The funding sources were not involved in the design or the execution of the study, nor in interpreting or reporting the results. ETHICS STATEMENT Study permission was obtained from the Ethics Committee of the North Ostrobothnian Hospital District (152/06.00.00/2020) on July 14, 2020, and from the Finnish Medicines Agency (Fimea) and the European Union Drug Regulating Authorities Clinical Trials Database: Eudra-CT 2020-004353-80 both on October 12, 2020. The study was prospectively registered in ClinicalTrials.gov, ID: NCT04735770, Jan 19, 2021. The study protocol was published in a peer-reviewed journal.21 DATA AVAILABILITY STATEMENT Under Finnish privacy laws and the study permission obtained, the underlying data cannot be shared. The statistical output, however, may be shared upon reasonable request to the authors.