Nociception-guided opioid administration within multimodal analgesia for laparoscopic endometriosis surgery: a randomized controlled trial

Women with endometriosis are at increased risk of severe postoperative pain due to nociceptive sensitization. While multimodal analgesia reduces opioid use, the added value of objective nociception monitoring remains unclear. This study evaluated whether NOL®-guided opioid titration improves perioperative outcomes within a standardized multimodal regimen. In this prospective, randomized, single-blinded trial, premenopausal women undergoing laparoscopic surgery for suspected endometriosis or adenomyosis were assigned to NOL®-guided analgesia or standard care based on clinical assessment. All patients received a standardized multimodal protocol. The primary outcome was total perioperative opioid consumption. Secondary outcomes included postoperative pain scores (NRS) and PACU length of stay. Exploratory analyses assessed the association between preoperative pain (Mankoski Pain Scale, MPS) and postoperative outcomes. A total of 111 patients were analyzed (NOL®: n = 54; control: n = 57). Total perioperative opioid consumption did not differ significantly between groups (adjusted mean difference = 14 μg for Fentanyl and 52 μg for Remifentanil; p = 0.8). Surgery duration was an independent predictor of opioid use (p < 0.001) and PACU length of stay (p = 0.01), whereas treatment group had no significant effect. Postoperative pain scores were comparable between groups at all time points. NOL®-derived metrics were not associated with opioid consumption or pain. Higher preoperative MPS scores independently predicted higher pain scores in the late PACU phase. NOL®-guided opioid titration did not reduce perioperative opioid consumption or improve early postoperative outcomes compared with standard multimodal analgesia in women undergoing laparoscopic surgery for endometriosis. Similar content being viewed by others 1 Background Adequate, patient-centered analgesia is a cornerstone of modern general anesthesia. Poorly controlled acute postoperative pain is associated with increased morbidity, delayed recovery, prolonged hospital stay, and a higher risk of developing chronic postsurgical pain [1,2,3]. Conversely, excessive intraoperative opioid administration carries well-recognized risks, including respiratory depression, postoperative nausea and vomiting, sedation, and opioid-induced hyperalgesia [4, 5]. Achieving balanced nociceptive control while minimizing unnecessary opioid exposure remains a central challenge in anesthetic practice [6, 7]. Traditionally, intraoperative analgesia has been guided by indirect clinical signs such as changes in heart rate and blood pressure, which reflect autonomic activation rather than nociception itself and require subjective interpretation [8, 9]. To address these limitations, objective nociception monitoring technologies have been developed. The Nociception Level (NOL®) index provides a multiparametric assessment of nociceptive balance by integrating physiological signals through a machine-learning–based algorithm [10,11,12]. Meta-analyses suggest that NOL®-guided opioid administration may reduce intraoperative opioid consumption in opioid-centered anesthetic regimens, although consistent improvements in clinically relevant outcomes remain uncertain [8, 13, 14]. In parallel, multimodal analgesia has become a key component of perioperative pain management. By combining agents that target different nociceptive pathways, such strategies reduce opioid requirements while maintaining effective analgesia [15,16,17,18]. In this context, it remains unclear whether the addition of nociception monitoring provides meaningful benefit when multimodal analgesia is already optimized. Women with endometriosis represent a population with increased pain vulnerability due to peripheral and central sensitization mechanisms [19,20,21]. As a result, they are at higher risk of severe postoperative pain, making individualized analgesic strategies particularly relevant [17, 22, 23]. We therefore conducted a prospective, randomized, single-blinded clinical trial comparing a standardized multimodal anesthetic regimen guided either by conventional clinical assessment alone or supplemented by NOL® index–guided opioid titration in patients undergoing laparoscopic surgery for endometriosis or adenomyosis. We hypothesized that NOL®-guided analgesia would reduce perioperative opioid consumption and improve early postoperative outcomes. Rather than seeking a decrease in opioid consumption as a primary therapeutic goal, the use of the NOL® index aimed to optimize titration by aligning opioid delivery more precisely with real-time nociceptive stimuli. This individualized approach seeks to maintain a more stable analgesic depth, potentially reducing the incidence of both opioid-induced side effects from over-medication and inadequate pain control from under-medication. The hypothesis of this study was generated from the premise that objective nociception monitoring could provide a more precise endpoint for opioid titration than conventional clinical surrogates. Given the heightened pain vulnerability of patients with endometriosis, we posited that more accurate ‘right-sizing’ of analgesia through the NOL® index would lead to reduced total opioid exposure and improved postoperative recovery metrics. This was balanced against a secondary hypothesis that a sufficiently robust multimodal analgesic baseline might minimize the incremental value of such monitoring. 2 Methodology 2.1 Ethics The trial was conducted in accordance with the ethical principles of the Declaration of Helsinki (2013 revision) [24], the International Conference on Harmonisation – Good Clinical Practice (ICH-GCP) guidelines [25], and all applicable Swiss regulatory requirements. The study protocol, informed consent forms, and all study-related documents were reviewed and approved by the Ethics Committee of the Canton of Zurich (BASEC No.: 2024–00822) before the enrolment of the first participant. The study was prospectively registered in a publicly accessible database (ClinicalTrials.gov Identifier: NCT06732050) before participant recruitment. The trial followed the CONSORT 2010 guidelines for the reporting of randomized controlled trials [26]. Eligible patients received both written and oral information about the study’s purpose, design, procedures, potential risks, and benefits during the preoperative anesthesiology consultation. Written informed consent was obtained from all participants before inclusion. Participation was voluntary, and patients were told that they could withdraw consent at any time without providing a reason and without any consequences for their medical treatment. All study data were coded and stored on secure, password-protected institutional servers at Spital Limmattal, Zurich, accessible only to authorized members of the research team. The data management process adhered to institutional and Swiss data protection regulations. No personal identifiers were used in any publication or data sharing. The Nociception Level (NOL®) monitor used in this study is CE-marked and approved for use during intraoperative procedures. All anesthetic interventions, including multimodal analgesia and opioid administration, were consistent with accepted clinical standards of care. The study did not expose participants to additional risks beyond routine anesthesia management. No financial or other incentives were provided for participation in the study. 2.2 Study design and population This was a prospective, randomized, controlled, single-blinded, single-center clinical trial conducted between August 2024 and September 2025 at Spital Limmattal, Zurich, Switzerland. The study compared a Nociception Level (NOL®) index–guided analgesic regimen with a standardized multimodal analgesic protocol in patients undergoing laparoscopic surgery due to endometriosis or adenomyosis. Subjects in this study were premenopausal women who were scheduled for laparoscopic surgery for suspected endometriosis or adenomyosis. All the patients were screened during their preoperative anesthesiology consultation, during which eligibility was checked, and baseline data were collected. Eligible participants were premenopausal, aged 18 years or older, and capable of providing written informed consent. The following data were recorded at the preoperative assessment for all eligible patients: demographic information, relevant medical history, and baseline pain levels. Pain levels and analgesic use were assessed using the Mankoski Pain Scale (MPS). To ensure a relatively homogeneous population and minimize the confounding effects of pre-existing opioid tolerance, patients with an MPS score of 6 or higher—indicating a clinical requirement for potent opioids (e.g., codeine) for analgesic relief—were excluded from the study. This functional threshold was chosen as a pragmatic proxy for identifying significant baseline opioid demand, which reflects the patient’s pain phenotype more accurately than a simple assessment of usage duration. No additional cut-off point regarding specific duration or frequency of opioid use was applied. Thus, patients were excluded from participating in this study if they had a history of chronic preoperative opioid use (defined functionally as MPS ≥ 6), contraindications for common analgesic medications, pregnancy or lactation, and any condition that would prevent the correct positioning of the Nociception Level (NOL®) sensor or adherence to study protocol, such as insufficient language proficiency. 2.3 Intervention protocol All patients in the study received a standardized multimodal analgesia regimen consisting of fentanyl, remifentanil, ketamine, clonidine, paracetamol (1 g) and metamizole (1 g) (Fig. 1). All anesthesia were conducted exclusively with target-controlled infusions (TCI) of propofol to eliminate any co-analgesic effects of volatile agents such as sevoflurane. To minimize the confounding effects of propofol-opioid synergy, depth of anesthesia was strictly standardized using BIS™ monitoring, with propofol TCI titrated to maintain a target range of 40–60 [27]. This ensured that the administration of hypnotics and analgesics was decoupled, with opioids titrated solely in response to nociceptive endpoints (NOL® or clinical assessment) while maintaining a stable hypnotic baseline across both study cohorts. Throughout the procedure, vital signs, respiratory parameters, and medication administration were continuously monitored and recorded. Intraoperative opioid management utilized a combination of fentanyl and remifentanil TCI, reflecting institutional practice to optimize perioperative coverage. While remifentanil offers superior intraoperative titratability, its rapid offset can result in insufficient postoperative analgesia [28, 29]. Consequently, fentanyl was administered (0.15 mg at induction and 0.15–0.3 mg at incision) to ensure residual analgesia in the post-anesthesia care unit (PACU) and to limit the risk of opioid-induced hyperalgesia associated with high-dose remifentanil [30, 31].Remifentanil was given via TCI with a target concentration of 2.5 ng/ml at induction and at start of operation with an intermittent reduction to 1.5 ng/ml. Patients were randomized 1:1 to either NOL®-guided or clinical judgment (control) groups. In both groups, a NOL® monitor was applied, but the display was blinded to the anesthesia team in the control group. - NOL®-Guided Group: Remifentanil and fentanyl were adjusted to maintain a NOL® index between 10 and 25. If NOL® > 25 for > 120 s, a fentanyl bolus (0.05–0.1 mg) was administered as the primary intervention to ensure PACU coverage. If NOL® remained > 25 after 5 min, the remifentanil TCI target was increased in 0.5 ng/ml increments to a maximum effector concentration (Ce) of 5 ng/ml. This ceiling was established to minimize remifentanil-related acute tolerance and hyperalgesia [3]. If NOL® 120 s, the remifentanil target was reduced by 0.5 ng/ml (minimum 0.5 ng/ml), Fig. 2. - Control Group ((standard multimodal care): Opioid titration was based on conventional clinical assessment (hemodynamics, lacrimation, etc.) without access to NOL® data. The remifentanil TCI target was prospectively capped at 5 ng/mL to prevent remifentanil-induced hyperalgesia and acute tolerance, which are associated with high-infusion-rate protocols [30, 31]. If nociception remained uncontrolled at this concentration, additional fentanyl boluses were utilized to provide more stable and persistent analgesia, reflecting a safer and more clinically standard approach to multimodal management [28, 29]. NOL®-guided titration was suspended for five minutes following vasopressor administration, except during continuous norepinephrine infusion, to avoid potential signal interference. Ketamine was administered either as intermittent boluses (0.5 mg/kg at induction followed by 0.25 mg/kg every 30–60 min; maximum cumulative dose 1 mg/kg) for standard procedures, or as a continuous infusion (0.5 mg/kg bolus followed by 0.2 mg/kg/h) for more extensive surgeries, based on anticipated surgical complexity. Clonidine was administered as a single dose of 150 µg (75 µg for patients < 50 kg) and omitted in patients with baseline heart rate < 60/min. All adjuncts were discontinued approximately 30 min before the end of surgery. Following surgery, all patients were observed in the Post-Anaesthesia Care Unit (PACU). Pain intensity was evaluated every 15 min using the Numeric Rating Scale (NRS, 0–10). All analgesic interventions, pain episodes, and adverse events were documented within 2 h of PACU arrival or until discharge, whichever occurred first. Postoperative rescue analgesia was standardized across both groups. Maintenance therapy consisted of oral oxycodone/naloxone (Targin®), with oral oxycodone (Oxynorm®) for breakthrough pain. In patients unable to tolerate oral medication, intravenous morphine was utilized. Non-opioid adjuncts, including ketamine and clonidine, were available for refractory pain as per the institutional protocol (Fig. 3). 2.4 Outcomes The primary outcome was total perioperative opioid consumption (intraoperative and up to 2 h in the PACU). Secondary outcomes included postoperative NRS scores and PACU length of stay. Preoperative pain burden was captured using the Mankoski Pain Scale (MPS) for exploratory analysis of pain phenotypes. The secondary outcome measures were postoperative pain severity, assessed using the Numeric Rating Scale (NRS, 0–10) at 15-min intervals during the PACU stay and length of stay in the PACU, measured from arrival to the time of discharge. 2.5 Randomization Participants were randomly assigned in a 1:1 ratio to either Nociception Level (NOL®)–guided analgesia or standard multimodal analgesia. Randomization was performed using a computer-generated sequence created with Sealed Envelope™ software [32]. Allocation concealment was ensured through centralized sequence generation, with group assignment revealed only after patient enrolment. The study followed a single-blind design, with patients blinded to treatment allocation. To maintain identical procedural conditions, a NOL® monitor was applied in both groups; however, in the control group the monitor display was concealed from the anesthesia team to prevent influence on intraoperative analgesic management. 2.6 Statistics All analyses were conducted using the per-protocol population, comprising randomized patients with valid intraoperative NOL® recordings and postoperative outcome data after specified exclusions. In addition to the per-protocol (PP) analysis, an intention-to-treat (ITT) sensitivity analysis was also performed, excluding patients with major protocol deviations, to assess the robustness of the primary outcome. Continuous variables are presented as mean ± standard deviation (SD) or median (with interquartile range, IQR) as appropriate, and categorical variables are presented as counts and percentages. Between-group comparisons were performed using the independent samples t-test or Mann–Whitney U test for continuous data and the χ2 or Fisher’s exact test for categorical data. Statistical significance was set at p < 0.05 (two-sided). The primary analysis compared total perioperative analgesic consumption between the NOL®-guided and standard multimodal groups. Linear regression models adjusted for relevant covariates (age, BMI, ASA physical status, baseline pain, and surgery duration) were used to estimate the adjusted mean difference with 95% confidence intervals (CIs). Total perioperative opioid requirement was assessed by recording the cumulative doses of fentanyl (μg) and remifentanil (μg) administered from induction until PACU discharge. To facilitate comparison and provide a global assessment of opioid burden, total consumption was also converted to Oral Morphine Equivalents (OME) using standard conversion ratios (e.g., 100 μg of fentanyl = 10 mg OME). To identify independent predictors of PACU length of stay, we employed a multivariable regression model adjusting for surgery duration, total intraoperative opioid dose, and preoperative pain phenotype (MPS). This allowed us to isolate the effect of treatment group allocation from surgical and baseline patient factors. Postoperative pain intensity (Numeric Rating Scale, NRS) was analyzed using a linear mixed-effects model with time (measured in 15-min intervals), treatment group, and their interaction as fixed effects, and patient ID as a random intercept. The length of stay in the PACU was compared using linear regression or, when non-normally distributed, quantile regression. Binary outcomes, such as the need for postoperative rescue analgesia, were analyzed with multivariable logistic regression, and results expressed as adjusted odds ratios (aOR) with 95% CIs. To explore within-patient nociceptive dynamics, the percentage of intraoperative time that the NOL® index was below ( 25) the target range was calculated for each patient. These continuous exposure variables were used to assess dose–response relationships between nociception control and key outcomes, including total fentanyl dose, postoperative NRS scores, and the need for rescue analgesia. Linear or logistic regression models were applied depending on the outcome type, and the association was expressed per 10% change in time spent below or above the range. A high-risk subgroup was defined a priori as patients who spent more than 50% of intraoperative time below the target NOL® range (“nociception-failure phenotype”). This subgroup was compared with the remaining cohort in terms of postoperative pain, intra- and postoperative opioid consumption, rescue analgesia, and length of PACU stay. Finally, the relationship between the preoperative Mankoski pain score and intra- and postoperative analgesic requirements was assessed using linear regression. This analysis examined whether preexisting pain severity predicted perioperative opioid demand and early postoperative pain levels, independent of group assignment. All analyses were performed using IBM SPSS Statistics (version 30). Emphasis was placed on effect estimates with 95% CIs and clinical interpretation rather than dichotomous significance testing. 2.7 Sample size and power The trial was prospectively powered for the primary outcome (total perioperative analgesic requirement). We assumed a large effect size (Pearson product correlation coefficient r = 0.5), which, with a two-sided α = 0.5 and power = 80%, required a sample size of N = 102 (51 per group). Allowing for 15% attrition, the final required sample size was N = 120. Secondary and exploratory outcomes (e.g., PACU NRS trajectory, interaction tests) were not specifically powered and are interpreted as hypothesis-generating. 3 Results 3.1 Study population A total of 111 patients were included in the final analysis (Intervention: n = 54; Control: n = 57). Baseline demographic and clinical characteristics were comparable between the groups (Table 1). One hundred and twenty-five patients were randomised in a 1:1 ratio to either the Nociception Level (NOL®)–guided analgesia group or the standard multimodal analgesia group. Fourteen patients were excluded from the final analysis due to surgery-related cancellation or deferral (n = 4), withdrawal of consent (n = 1), or post-randomization protocol violations (n = 9) (Table 2). The final study cohort, therefore, comprised 111 patients, including 54 in the NOL®-guided group and 57 in the control group. The flow of participants through the study is shown in the CONSORT diagram (Fig. 4). 3.2 Primary outcome Multiple linear regression analysis demonstrated no significant difference in total intraoperative opioid use between the NOL®-guided and the non-guided groups. Average total intraoperative fentanyl consumption was 350 μg (IQR = 150) in both the NOL®-guided group and the control group (Table 3). However, surgery duration was a highly significant and independent predictor of opioid use per minute (p < 0.001 for both fentanyl and remifentanil). Univariantlinear regression analysis revealed no significant association between the NOL®-derived metrics (% time in, above, or below range) and intraoperative opioid consumption. (Table 3). Neither the proportion of time below range nor the proportion of time within the range correlated significantly with total intraoperative fentanyl or remifentanil dose. Figures 5A and 5B illustrate the positive linear relationship between total intraoperative opioid consumption and surgery duration, stratified by intervention group (blue: control; red: guided). The regression lines demonstrate a steep positive slope for both groups, reflecting increasing opioid requirements with longer surgery, but no difference in gradient or total consumption between the groups. A per-protocol sensitivity analysis excluding patients with major protocol deviations (n = 14) yielded results consistent with the primary ITT analysis, with no significant differences observed between groups. 3.3 Secondary outcomes The median length of stay in the PACU did not differ significantly between the guided and non-guided groups. In a multiple regression model, surgery duration emerged as the only significant predictor of PACU stay (B = 0.16, p = 0.01). Neither the proportion of intraoperative time in or out of NOL® range nor the preoperative had a significant influence on PACU duration. Similarly, postoperative NRS pain scores showed no significant difference between the guided and non-guided groups at any time point during PACU observation. The NOL®-derived indices (% time below, in, or above range) were also not significantly correlated with maximal postoperative pain intensity. There were no significant differences between the NOL®-guided and control groups in the total dose of postoperative rescue opioids administered in the PACU (p = 0.76 for morphine) (Table 4). 3.4 Exploratory analyses The exploratory multivariate analysis assessing preoperative pain phenotype (Table 3), revealed that the preoperative MPS score was a significant independent predictor of postoperative pain in the later PACU phase. Higher preoperative MPS values were associated with higher NRS scores at 1.5 h (B = 0.35, p = 0.046) and 2 h (B = 0.55, p = 0.022) after PACU admission. A subgroup analysis restricted to patients with a high preoperative pain phenotype (MPS 4–5) showed no significant difference in postoperative NRS nor in opioid consumption between the guided and non-guided groups. In the multiple linear regression model, surgery duration was the only independent predictor of increased intraoperative fentanyl and remifentanil consumption (B = 601.6, β = 0.758, p < 0.001). Allocation to the NOL®-guided group was not a significant predictor of opioid consumption. An additional analysis converting cumulative fentanyl and remifentanil doses into OME using established conversion methods [33] found no significant association between total opioid consumption and NOL® derived metrics or postoperative pain scores. Surgery duration remained the only significant independent predictor of opioid consumption (B = 601.6, p < 0.001). 3.5 Safety and adverse events One serious adverse event was recorded during the study period. A patient required a postoperative blood transfusion (pod 4), which led to a non-specific transfusion reaction. This event was assessed as being unrelated to the study intervention or anesthesia protocol. No adverse events related to the use of the NOL® monitor, or the opioid titration protocol were reported. The incidence of common postoperative side effects, such as nausea and vomiting, was comparable between the two groups. 4 Discussion 4.1 Primary outcome In this randomized controlled trial, the NOL®-guided analgesia did not provide an additional reduction in intraoperative opioid consumption or postoperative pain intensity when compared with a standardized multimodal analgesic regimen. These results suggest that the current multimodal approach, incorporating ketamine, clonidine, opioid and non-opioid analgesics, is sufficiently robust to suppress nociception in laparoscopic endometriosis surgery. 4.2 Secondary outcomes Surgical duration emerged as the strongest independent predictor of both intraoperative opioid requirements and the length of stay in the PACU, regardless of treatment group. The preoperative pain phenotype, as measured by the Mankoski Pain Scale (MPS), was a significant independent predictor of postoperative pain intensity, underscoring the influence of baseline pain burden on perioperative outcomes. In contrast, NOL®-derived parameters, including the percentage of intraoperative time spent within, below, or above the target range, showed no meaningful association with opioid consumption, postoperative pain, or PACU recovery time. 4.3 Context within the literature Previous trials evaluating nociception monitors, including the NOL®, Surgical Pleth Index (SPI), and Analgesia Nociception Index (ANI), have shown inconsistent reductions in opioid use, often limited to contexts with higher nociceptive burden or lower baseline opioid dosing [14, 34, 35]. Our findings are consistent with reports from short-duration, low-to-moderate-intensity surgeries in which multimodal analgesia is routinely employed [13, 35]. These data suggest that the potential benefit of nociception monitoring is context-dependent, being most useful when analgesic regimens are tailored rather than standardized. 4.4 Mechanistic interpretation The lack of difference between the NOL® guided and non-guided groups likely stems from the high efficacy of the baseline multimodal protocol. By interrupting nociceptive signaling at multiple levels, including NMDA-receptors, α2-adrenoreceptors, and peripheral pathways, this regimen produces a stable state of analgesia. In combination with the fixed pre-incisional fentanyl boluses, this created an analgesic ceiling which effectively blunted nociceptive stimuli in laparoscopic surgery and left no room for further titration [18, 36, 37]. Under the given conditions, the NOL® index may lack the chance to guide further optimization, as the physiologic nociceptive response was already effectively suppressed. Whether the NOL® sensor could improve postoperative outcomes within a purely opioid-based regimen, without multimodal coverage, remain to be investigated. Exploratory analysis of the Mankoski Pain Scale Score (MPS) identified a preoperative pain vulnerability associated with higher NRS scores in the late PACU phase. This supports the classification of endometriosis patients into low and high-pain phenotypes and highlights those at risk for persistent pain even after the initial surgical peak subsides [38, 39]. Interestingly, even in patients with higher preoperative pain sensitivity (MPS 4–5), the addition of NOL®-guidance did not outperform the multimodal baseline. This suggests that the robustness of our protocol is sufficient to manage increased baseline sensitivity, leaving little room for the NOL® index to provide further benefit in this specific surgical setting. Despite the increased pain experienced with high MPS, MPS did not influence PACU duration. It should be noted that patients with an MPS ≥ 6 were not included in the study and therefore not included in this subgroup analysis. It therefore remains unclear whether the NOL® sensor would allow for more targeted analgesia and thus better postoperative pain management, particularly in patients with even more severe preoperative pain and chronic opioid use. 4.5 Clinical implications and limitations These findings support a shift from maximal to optimized, patient-centered analgesia, where nociception monitoring may be more useful for preventing overmedication than for escalating opioid delivery. In the present setting, however, the combination of multimodal analgesia and fixed opioid supplementation likely limited the ability of NOL® to demonstrate incremental benefit. This study has several limitations. First, the single-center, single-blind design and focused population of premenopausal women undergoing gynecologic laparoscopy may limit the generalizability of our findings. Second, the high efficacy of our baseline multimodal regimen likely resulted in a ceiling effect for opioid consumption, potentially masking any incremental benefit from NOL®-guided titration. Third, intraoperative pre-laparoscopic diagnostic procedures introduced variability in anesthesia duration, while pre-emptive opioid loading in shorter cases may have led to functional over-analgesia, further blunting the utility of the NOL® index. Fourth, the standardized PACU protocol lacked extended rescue options for high-pain outliers. In two instances, continuous ketamine infusions were initiated for refractory pain, leading to the exclusion of these patients from the per-protocol analysis. This variability in rescue management for high-pain outliers suggests that future studies should implement more comprehensive escalation tiers to better evaluate recovery in patients with severe preoperative pain phenotypes. The pharmacological protocol—combining fentanyl for baseline coverage with remifentanil for dynamic titration—was designed to optimize the transition to postoperative care and minimize remifentanil-related hyperalgesia [30, 31]. However, this approach likely created a robust analgesic floor. Future studies might explore whether the NOL® index provides greater utility in purely remifentanil-based regimens or in procedures with higher nociceptive variability where a fixed baseline is less effective. Finally, secondary analyses were exploratory and not powered to draw definitive conclusions. 5 Conclusion In conclusion, NOL®-guided analgesia did not reduce opioid consumption or improve recovery outcomes compared to standard multimodal care in women undergoing surgery for endometriosis. These findings suggest that multimodal analgesic strategies are sufficiently robust to maintain nociceptive balance in this population, potentially rendering real-time nociception monitoring redundant when such protocols are strictly followed. Although NOL® metrics did not predict recovery efficiency, the preoperative Mankoski Pain Scale was clinically valuable for identifying patients at risk of persistent postoperative pain. This underscores the need for early detection of pain phenotypes to better tailor analgesic strategies within fast-track protocols. Future research should investigate whether nociception-guided opioid administrations offer more significant value in opioid-centric regimens, high-risk populations, or opioid-tolerant patients where the protective threshold of multimodal analgesia is not already met. Data availability All data supporting the findings of this study are available within the paper and its Supplementary Information.

Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res. 2017;10:2287–98. https://doi.org/10.2147/JPR.S144066. Joshi GP, Ogunnaike BO. Consequences of Inadequate Postoperative Pain Relief and Chronic Persistent Postoperative Pain. Anesthesiol Clin N Am. 2005;23(1):21–36. https://doi.org/10.1016/j.atc.2004.11.013. Kehlet H, Jensen TS, Woolf CJ. Persistent postsurgical pain: risk factors and prevention. The Lancet. 2006;367(9522):1618–25. https://doi.org/10.1016/S0140-6736(06)68700-X. Butterworth JF. Morgan & Mikhail’s Clinical Anesthesiology. seventh edition. New York: McGraw-Hill LLC; 2022. 1 p. (McGraw-Hill’s AccessMedicine). McNicol E, Horowicz-Mehler N, Fisk RA, Bennett K, Gialeli-Goudas M, Chew PW, et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain. 2003;4(5):231–56. https://doi.org/10.1016/S1526-5900(03)00556-X. Frauenknecht J, Kirkham KR, Jacot‐Guillarmod A, Albrecht E. Analgesic impact of intra‐operative opioids vs. opioid‐free anaesthesia: a systematic review and meta‐analysis. Anaesthesia. 2019;74(5):651–62. https://doi.org/10.1111/anae.14582. Volkow ND, Collins FS. The Role of Science in Addressing the Opioid Crisis. N Engl J Med. 2017;377(4):391–4. https://doi.org/10.1056/NEJMsr1706626. Bornemann-Cimenti H, Lang-Illievich K, Kovalevska K, Brenna CTA, Klivinyi C. Effect of nociception level index-guided intra-operative analgesia on early postoperative pain and opioid consumption: a systematic review and meta-analysis. Anaesthesia. 2023;78(12):1493–501. https://doi.org/10.1111/anae.16148. Stomberg MW, Sjöström B, Haljamäe H. Routine intra-operative assessment of pain and/or depth of anaesthesia by nurse anaesthetists in clinical practice. J Clin Nurs. 2001;10(4):429–36. Ledowski T. Objective monitoring of nociception: a review of current commercial solutions. Br J Anaesth. 2019;123(2):e312–21. https://doi.org/10.1016/j.bja.2019.03.024. Edry R, Recea V, Dikust Y, Sessler DI. Preliminary Intraoperative Validation of the Nociception Level Index: A Noninvasive Nociception Monitor. Anesthesiology. 2016;125(1):193–203. https://doi.org/10.1097/ALN.0000000000001130. Martini CH, Boon M, Broens SJL, Hekkelman EF, Oudhoff LA, Buddeke AW, et al. Ability of the Nociception Level, a Multiparameter Composite of Autonomic Signals, to Detect Noxious Stimuli during Propofol-Remifentanil Anesthesia. Anesthesiology. 2015;123(3):524–34. https://doi.org/10.1097/ALN.0000000000000757. Sogut MS, Kalyoncu I, Karakaya MA, Manici M, Darçin K. Does Nociception Level Index-Guided opioid administration reduce intraoperative opioid consumption? A systematic review and meta-analysis. Anesth Analg. 2024;139(5):978–85. https://doi.org/10.1213/ANE.0000000000007180. Ma D, Ma J, Chen H, Mu D, Kong H, Yu L. Nociception monitors vs. standard practice for titration of opioid administration in general anesthesia: A meta-analysis of randomized controlled trials. Front Med. 2022;9:963185. https://doi.org/10.3389/fmed.2022.963185. Graff V, Grosh T. Multimodal Analgesia and Alternatives to Opioids for Postoperative Analgesia. Anesth Patient Saf Found. 2018;33(2):46–7. Wu CL, Raja SN. Treatment of acute postoperative pain. Lancet Lond Engl. 2011;377(9784):2215–25. https://doi.org/10.1016/S0140-6736(11)60245-6. (PubMed PMID: 21704871). Edwards DA, Hedrick TL, Jayaram J, Argoff C, Gulur P, Holubar SD, et al. American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on Perioperative Management of Patients on Preoperative Opioid Therapy. Anesth Analg. 2019;129(2):553–66. https://doi.org/10.1213/ANE.0000000000004018. (PubMed PMID: 30768461). Wick EC, Grant MC, Wu CL. Postoperative Multimodal Analgesia Pain Management With Nonopioid Analgesics and Techniques: A Review. JAMA Surg. 2017;152(7):691–7. https://doi.org/10.1001/jamasurg.2017.0898. Nnoaham KE, Hummelshoj L, Webster P, D’Hooghe T, De Cicco NF, De Cicco NC, et al. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril. 2011;96(2):366-373.e8. https://doi.org/10.1016/j.fertnstert.2011.05.090. Maddern J, Grundy L, Castro J, Brierley SM. Pain in Endometriosis Front Cell Neurosci. 2020;6(14):590823. https://doi.org/10.3389/fncel.2020.590823. Samuelsen PJ, Nielsen CS, Wilsgaard T, Stubhaug A, Svendsen K, Eggen AE. Pain sensitivity and analgesic use among 10,486 adults: the Tromsø study. BMC Pharmacol Toxicol. 2017;18(1):45. https://doi.org/10.1186/s40360-017-0149-2. Cetera GE, Merli CEM, Vercellini P. A Multimodal Approach to Symptomatic Endometriosis: A Proposed Algorithm for Clinical Management. Reprod Sci Thousand Oaks Calif. 2025;32(2):289–99. https://doi.org/10.1007/s43032-024-01763-w. (PubMed PMID: 39775786). As-Sanie S, Mackenzie SC, Morrison L, Schrepf A, Zondervan KT, Horne AW, et al. Endometriosis: A Review. JAMA. 2025;334(1):64–78. https://doi.org/10.1001/jama.2025.2975. World Medical Association. WMA Declaration of Helsinki – Ethical Principles for Medical Research Involving Human Participants. In: 75th WMA General Assembly. Helsinki: World Medical Association; 2024. European Medicines Agency. ICH E6 Good clinical practice - Scientific guideline [Scientific guideline]. London: European Medicines Agency (EMA); 2016. Scientific guideline EMA/CHMP/ICH/135/1995. Schulz KF, Altman DG, Moher D. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340(mar23 1):c332–c332. https://doi.org/10.1136/bmj.c332. van den Berg JP, Absalom AR, Venema AM, Kalmar AF, Van Amsterdam K, Hannivoort LN, et al. Comparison of haemodynamic- and electroencephalographic-monitored effects evoked by four combinations of effect-site concentrations of propofol and remifentanil, yielding a predicted tolerance to laryngoscopy of 90%. J Clin Monit Comput. 2021;35(4):815–25. https://doi.org/10.1007/s10877-020-00540-9. Scott LJ, Perry CM. Remifentanil: a review of its use during the induction and maintenance of general anaesthesia. Drugs. 2005;65(13):1793–823. https://doi.org/10.2165/00003495-200565130-00007. (PubMed PMID: 16114980). Beers R, Camporesi E. Remifentanil update: clinical science and utility. CNS Drugs. 2004;18(15):1085–104. https://doi.org/10.2165/00023210-200418150-00004. (PubMed PMID: 15581380). Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, et al. Acute Opioid Tolerance: Intraoperative Remifentanil Increases Postoperative Pain and Morphine Requirement. Anesthesiology. 2000;93(2):409. https://doi.org/10.1097/00000542-200008000-00019. Colvin LA, Bull F, Hales TG. Perioperative opioid analgesia—when is enough too much? A review of opioid-induced tolerance and hyperalgesia. The Lancet. 2019;393(10180):1558–68. https://doi.org/10.1016/S0140-6736(19)30430-1. Simple randomisation service | Sealed Envelope. 2026. Available from: https://www.sealedenvelope.com/simple-randomiser/v1/ Nielsen S, Degenhardt L, Hoban B, Gisev N. A synthesis of oral morphine equivalents (OME) for opioid utilisation studies. Pharmacoepidemiol Drug Saf. 2016;25(6):733–7. https://doi.org/10.1002/pds.3945. (PubMed PMID: 26693665). Jiao Y, He B, Tong X, Xia R, Zhang C, Shi X. Intraoperative monitoring of nociception for opioid administration: a meta-analysis of randomized controlled trials. Minerva Anestesiol. 2019;85(5):522–30. https://doi.org/10.23736/S0375-9393.19.13151-3. (PubMed PMID: 30735017). Snoek MAJ, van den Berg VJ, Dahan A, Boon M. Comparison of different monitors for measurement of nociception during general anaesthesia: a network meta-analysis of randomised controlled trials. Br J Anaesth. 2025;134(1):180–91. https://doi.org/10.1016/j.bja.2024.09.020. (PubMed PMID: 39609176). Brown EN, Pavone KJ, Naranjo M. Multimodal General Anesthesia: Theory and Practice. Anesth Analg. 2018;127(5):1246–58. https://doi.org/10.1213/ANE.0000000000003668. (PubMed PMID: 30252709; PubMed Central PMCID: PMC6203428). Hendrickx JFA, Eger EII, Sonner JM, Shafer SL. Is Synergy the Rule? A Review of Anesthetic Interactions Producing Hypnosis and Immobility. Anesth Analg. 2008;107(2):494. https://doi.org/10.1213/ane.0b013e31817b859e. Kanti FS, Allard V, Métivier AA, Lemyre M, Arendas K, Maheux-Lacroix S. Pain Phenotypes in Endometriosis: A Population-Based Study Using Latent Class Analysis. BJOG Int J Obstet Gynaecol. 2025;132(4):492–503. https://doi.org/10.1111/1471-0528.18021. (PubMedPMID:39627905;PubMedCentralPMCID:PMC11794060). Zondervan SKT. Endometriosis. N Engl J Med. 2020;382:1244–56. Funding JBE has received speaker’s fees from Medtronic (paid to institution) and is a board member of the European Society of Anaesthesiology and Intensive Care. All authors declare that they have no financial or personal relationships that could be perceived as potential conflicts of interest related to this work. No external commercial funding was received for this study. Institutional resources were used exclusively to support study conduct. Author information Authors and Affiliations Contributions All listed authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship. HTB: Conceptualization; Methodology; Investigation; Data curation; Formal analysis; Writing – original draft. JBE: Conceptualization; Methodology; Formal analysis; Supervision; Writing – review & editing. SZ: Investigation; Data curation; Writing – review & editing. PR: Investigation; Data curation; Writing – review & editing. TP: Investigation; Writing – review & editing. IM: Conceptualization; Methodology; Supervision; Project administration; Writing – review & editing. All authors approved the final version to be published and agree to be accountable for all aspects of the work, including the accuracy and integrity of the data and analyses. No individuals meeting criteria for non-author contributors or collaborators, as defined by the National Library of Medicine, were omitted from authorship. Corresponding author Ethics declarations Animal research This study did not involve animal subjects. Conflict of interest JBE has received speaker’s fees from Medtronic (paid to institution) and is a board member of the European Society of Anaesthesiology and Intensive Care. All authors declare that they have no financial or personal relationships that could be perceived as potential conflicts of interest related to this work. No external commercial funding was received for this study. Institutional resources were used exclusively to support study conduct. Clinical trial registration This clinical trial was prospectively registered prior to patient enrollment at ClinicalTrials.gov (Identifier: NCT06732050). The methods and outcomes reported in this manuscript are consistent with the registered protocol. Ethical approval and protection of human subjects This study was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and complied with Good Clinical Practice guidelines. The study protocol was reviewed and approved by the Ethics Committee of the Canton of Zurich (BASEC No. 2024–00822). Written informed consent was obtained from all participants prior to inclusion. Participant confidentiality was strictly maintained, and all data were de-identified prior to analysis. Ethical and scientific integrity The authors affirm adherence to ethical research conduct and scientific integrity. No fabrication, falsification, inappropriate authorship designation, or other forms of scientific misconduct occurred. The authors agree to cooperate fully with the Journal should any questions arise regarding ethical or scientific aspects of the work. Investigational drugs All medications administered in this study were used in accordance with established clinical practice and within accepted dosing ranges. No investigational drugs, neuraxial or perineural investigational drug administration, or pediatric drug use outside standard clinical indications were involved. Plagiarism and duplicate publication This manuscript represents original work that has not been published previously and is not under consideration for publication elsewhere. Preliminary data from this study were presented as a poster at Euroanaesthesia 2025 (Lisbon, Portugal). The authors affirm compliance with journal policies on plagiarism and duplicate publication. Use of generative artificial intelligence Generative artificial intelligence tools were not used to generate study data, results, or references. We used AI-assisted support (ChatGPT V5.2) during manuscript preparation, which was limited to language refinement and did not replace the authors’ intellectual contributions. Responsibility for the content of the manuscript rests entirely with the authors. Additional information Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Supplementary Information Below is the link to the electronic supplementary material. 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To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. About this article Cite this article Buis, HT., Berger-Estilita, J., Zirngast, S. et al. Nociception-guided opioid administration within multimodal analgesia for laparoscopic endometriosis surgery: a randomized controlled trial. J Clin Monit Comput (2026). https://doi.org/10.1007/s10877-026-01459-3 Received: Accepted: Published: Version of record: DOI: https://doi.org/10.1007/s10877-026-01459-3