EC₅₀ and EC₉₅ of Epidural Ropivacaine for Intraoperative Analgesia During High-Intensity Focused Ultrasound for Adenomyosis: A Prospective Double-Blind Up-and-Down Concentration-Finding Study

Introduction

Adenomyosis, a benign estrogen-dependent uterine disorder, is characterized by ectopic endometrial glands and stroma within the myometrium, inducing reactive hyperplasia of adjacent smooth muscle.¹ Its clinical hallmarks—progressive dysmenorrhea, menorrhagia, chronic pelvic pain, and infertility—severely impair quality of life and reproductive potential.² The pathophysiology, though not fully elucidated, involves abnormal tissue invasion and inflammation, contributing to pain and abnormal uterine bleeding. As a common gynecological condition affecting 10%-30%³ of reproductive-aged women, its diagnosis and management present ongoing clinical challenges.

Therapeutic options range from pharmacologic agents such as NSAIDs, combined oral contraceptives, progestins, and GnRH agonists to procedural interventions including uterine artery embolization, high-intensity focused ultrasound (HIFU), and myomectomy or hysterectomy. However, each treatment modality carries its own advantages and limitations. Pharmacotherapy often provides symptomatic relief but is limited by side effects—such as hormonal disruption, breakthrough bleeding, and metabolic alterations—and high relapse rates after discontinuation.⁴ While hysterectomy remains the definitive treatment for refractory cases, fertility-sparing surgical options (eg, adenomyomectomy) entail considerable risks of hemorrhage, postoperative adhesion formation, and uterine rupture, making them less ideal for young patients wishing to preserve fertility.⁵

HIFU, a noninvasive thermoablative technique, has emerged as a promising alternative by using focused ultrasound waves to generate localized thermal energy, thereby selectively ablating ectopic endometrial tissue while preserving uterine integrity.⁶ This image-guided approach minimizes tissue damage and promotes faster recovery. The technique involves bundling high-intensity ultrasound waves through specialized transducers to focus energy on a specific spot, resulting in localized thermal ablation and coagulation necrosis within the target tissue. However, prolonged or high-intensity thermal energy may cause skin burns, and the thermal effect can potentially injure adjacent nerves near the focal point. Consequently, HIFU imposes two essential demands on anesthetic management: first, the patient must remain perfectly static to prevent movement-induced targeting errors; second, and critically, the patient must retain a level of consciousness and sensory acuity sufficient to immediately report early warning sensations, such as cutaneous burning or radiating leg pain. An ideal analgesic regimen must, therefore, reconcile profound analgesia with preserved communicative capacity.

Despite its growing adoption, optimal intraoperative analgesia during HIFU remains underexplored. While general anesthesia with endotracheal intubation or subarachnoid block can effectively achieve pain relief and patient immobility, the partial or complete sensory loss may prevent timely feedback on cutaneous burning or radiating neuropathic pain. The conventional midazolam-fentanyl regimen presents significant clinical challenges in HIFU settings, such as individual variations in drug metabolism and the cumulative nature of midazolam complicate dosage titration, excessive sedation causes respiratory depression and abolishes the patient’s ability to report paresthesia, while insufficient sedation leads to patient discomfort and movement that disrupts treatment precision. This delicate balance between respiratory safety and procedural efficacy adds to the difficulty in sedation management for HIFU procedures.⁷

Epidural anesthesia, particularly with low-concentration ropivacaine, offers a potential solution. Its sensory-motor dissociation profile provides potent analgesia with minimal motor blockade—a well-established advantage in obstetric anesthesia.⁸ When combined with sufentanil, this epidural regimen enhances analgesic efficacy through synergistic action without compromising hemodynamic stability, as evidenced in cesarean delivery cohorts.⁹ We posit that similar benefits may extend to HIFU for adenomyosis, where precise ablation demands both patient immobility and preserved respiratory function. The dural puncture epidural (DPE) technique further optimizes drug spread and onset, offering a reliable means of achieving such balanced anesthesia.

This prospective, double-blind, sequential allocation trial aimed to determine the median effective concentration(EC₅₀) and 95% effective concentration (EC₉₅) of epidural ropivacaine when co-administered with sufentanil (0.5 µg/mL) for intraoperative analgesia during HIFU treatment of adenomyosis using a DPE-verified technique. Establishing the optimal dosage may help standardize care and enhance patient comfort during this noninvasive therapy, and provides a rational starting dose for future studies.

Material and Methods

Study Design

This prospective, double-blind, sequential allocation trial was designed to determine the EC₅₀ and EC₉₅ of epidural ropivacaine for analgesia during HIFU ablation of adenomyosis. The study was rigorously registered with the Chinese Clinical Trial Registry (ChiCTR2400091541) and received full approval from the Institutional Review Board of Suining Central Hospital (Approval No. KYLLkS20240137). The trial was conducted in strict adherence to the ethical principles of the Declaration of Helsinki. A comprehensive written informed consent process was undertaken with all prospective participants, during which the nature of the study, potential risks and benefits, and alternative anesthesia options were explained in detail.

Participant Selection and Enrollment

A total of 34 female patients were screened for eligibility between November 1, 2024, and June 1, 2025. The inclusion criteria encompassed women aged 18 to 65 years, classified as American Society of Anesthesiologists (ASA) physical status I or II, who were scheduled for elective HIFU ablation of symptomatic adenomyosis confirmed by preoperative magnetic resonance imaging (MRI). To ensure patient safety and data integrity, stringent exclusion criteria were applied. These included: skin ulceration or infection at the planned HIFU treatment site on the lower abdomen; concurrent acute pelvic inflammatory disease or active genital tract infection; any contraindication to neuraxial anesthesia (eg, significant spinal deformity, coagulopathy defined as an International Normalized Ratio (INR) greater than 1.5 or a platelet count less than 100×10⁹/L, or therapeutic anticoagulation); severe obesity (Body Mass Index greater than 40 kg/m²) which could compromise both epidural technique and HIFU beam penetration; and any history of chronic pain syndrome, long-term opioid use, or inability to comprehend and use the Visual Analog Scale (VAS) for pain assessment. Of the 34 screened patients, five were excluded: three declined to participate due to withdrawing consent, and two did not meet the inclusion criteria. Consequently, 29 patients completed the study and were included in the final analysis (Figure 1).

Figure 1 Study flow diagram.

Blinding Protocol

This study was a double-blind, prospective, sequential allocation study. Anesthesiologist A performed all epidural catheterizations using a standardized technique (L2-L3 interspace, 18-gauge Tuohy needle).

Anesthesiologist B, blinded to the ropivacaine concentration, managed intraoperative anesthesia. Research Assistant C, trained in pain assessment and unaware of group allocation, recorded outcomes. Nurse D, independent of clinical care, prepared study drugs (ropivacaine at varying concentrations combined with sufentanil 0.5 µg/mL) in identical syringes labeled with sequential allocation codes. The allocation code was sealed in opaque envelopes accessible only to the statistician, with emergency unblinding permitted for critical events, such as severe allergic reaction or total spinal anesthesia.

Anesthesia Protocol

No preoperative medication was administered before entering the room. Upon entering the operating room, patients received supplemental oxygen via face mask while peripheral venous access was established. Standard monitoring included non-invasive blood pressure (NIBP), heart rate (HR), pulse oximetry (SpO₂), and electrocardiography (ECG). Patients were then placed in the left lateral position. After preliminary ultrasound localization of the L2-L3 interspace, the epidural space was confirmed via loss-of-resistance to saline. A 23-gauge spinal needle was then advanced to intentionally puncture the dura mater, with free cerebrospinal fluid (CSF) flow observed. No intrathecal medication was administered. An epidural catheter was inserted cephalad 5 cm into the epidural space, followed by negative aspiration and a test dose (5 mL solution containing ropivacaine and sufentanil 0.5 µg/mL). Patients were subsequently repositioned supine. Ten minutes after the test dose, a 15-mL bolus of the ropivacaine-sufentanil solution (prepared by Nurse D per the sequential allocation scheme) was administered, with subsequent 10-mL maintenance doses every 40-minute interval. HIFU ablation commenced 20 minutes after the initial bolus. Ropivacaine concentrations were adjusted using an up-and-down sequential method, with the initial concentration set at 0.06% based on extrapolation from previous studies: 0.0625% ropivacaine-sufentanil provided effective labor analgesia¹⁰ and analgesia for major abdominal surgery,¹¹ while an EC₅₀ of 0.062% was documented for ropivacaine-dexmedetomidine epidural analgesia.¹² Intraoperative pain intensity (assessed every 5 minutes by VAS) guided concentration adjustments: VAS ≥ 4 prompted a 0.005% increase for subsequent patients; VAS < 4 prompted a 0.005% decrease.

Procedural failures (puncture failure, vascular puncture, catheter malfunction, or unilateral block) required repeating the same concentration for the next patient. Inadequate analgesia (intraoperative VAS ≥ 4) triggered rescue therapy (midazolam 0.5 mg combined with fentanyl 50 µg IV). The concentration gradient was fixed at 0.005%, and the study concluded after six sequential reversals.

Research Assistant C assessed bilateral lower limb motor blockade using the Bromage scale at 10-minute intervals. Postoperative rescue analgesia included diclofenac sodium suppositories, NSAIDs, and other non-opioid analgesics. Hypotension (defined as either a >30% decrease from pre-anesthetic systolic blood pressure or systolic blood pressure <90 mm Hg) was treated with intravenous ephedrine 6 mg plus crystalloid fluid. Bradycardia (<55 bpm) received intravenous atropine 0.5 mg. Nausea and vomiting were managed with symptomatic treatment.

Measurements

General patient information, including age, BMI, and ASA physical status, was recorded. NIBP, HR, SpO₂ were monitored. Pain intensity was assessed every 5 minutes using a VAS (0 = no pain, 10 = worst imaginable pain). Motor blockade was evaluated bilaterally every 5 minutes using a modified Bromage scale (4 = the patient can move the knee and foot; 3 = the patient can move the knee freely; 2 = the patient cannot bend the knees, but the feet can move; and 1 = knees and feet cannot move). The duration of postoperative hospital stay and the consumption of rescue analgesics were also documented. All complications were meticulously recorded. Complications related to epidural anesthesia included hypotension, bradycardia, respiratory depression, nausea and vomiting, urinary retention, and infection at the puncture site. Complications related to HIFU therapy included nerve injury, skin burns, and injury to adjacent organs.

Determination of EC₅₀ and EC₉₅ Using Up-and-Down Sequential Allocation

The EC₅₀ and EC₉₅ of epidural ropivacaine were determined using an up-and-down sequential allocation method followed by probit regression. The concentration of ropivacaine administered to a given patient was determined by the analgesic response of the preceding patient. Effective analgesia was defined as a VAS score < 4 at 30 minutes after epidural injection. When effective analgesia was achieved, the ropivacaine concentration for the subsequent patient was decreased by one gradient (0.005%); when ineffective, the concentration was increased by the same gradient. The study continued until at least six independent crossover points (transitions from effective to ineffective analgesia, or vice versa) were observed, a standard stopping rule that provides stable estimates of the EC₅₀ with a limited sample size.¹³ The primary outcome was binary (effective vs. ineffective analgesia); therefore, probit regression was used to model the dose-response relationship. The EC₅₀ and EC₉₅ values, along with their 95% confidence intervals (CIs), were derived by fitting the observed response data to a probit regression model.

Statistical Analysis

According to the literature, cohorts of 20–40 participants provide robust estimates of the EC₅₀ when at least six crossover points are observed.^13,14 Our cohort of 29 patients achieved six reversals, satisfying these criteria. All statistical analyses were performed using SPSS 24 (IBM Corp., Armonk, NY, USA) and GraphPad Prism 8.0 (GraphPad Software, San Diego, CA, USA). The normality of continuous data was assessed using the Shapiro–Wilk test. Normally distributed continuous variables are expressed as mean ± standard deviation (mean ± SD) and were compared between groups using the independent-samples t-test. Non-normally distributed continuous variables are expressed as median (M) and interquartile range (IQR) and were compared using the Mann–Whitney U-test. Categorical variables are expressed as number (%) and were compared using the χ²-test or Fisher’s exact test, as appropriate. A two-sided P value < 0.05 was considered statistically significant. The EC₅₀ and EC₉₅ values with their 95% CIs were calculated using probit regression.

Results

A total of 34 patients with adenomyosis were initially enrolled in this study. Of these, five patients were excluded: three for not meeting the inclusion criteria and two due to refusal to provide informed consent. Consequently, 29 patients were ultimately included in the analysis, with the allocation process resulting in six independent up-down deflections for dose assessment, as illustrated in the sequential allocation plot (Figure 2).

Figure 2 Up-and-down sequential allocation of epidural ropivacaine with sufentanil 0.5 µg/mL. The X-axis represents patient number, the Y-axis represents ropivacaine concentration (%). Solid circles represent effective analgesia (VAS < 4), whereas open circles denote ineffective analgesia.

The demographic and clinical characteristics of the patients, including age, BMI, ASA physical status classification, and duration of surgery, were comparable between those who achieved successful analgesia and those who did not. No statistically significant differences were observed between the two groups (P > 0.05, Table 1).

Table 1 Patient Characteristics

Effective analgesia, VAS score of <4 during the procedure, was achieved in 13 patients, while 16 patients experienced unsuccessful analgesia (VAS ≥ 4). The distribution of patients across the different ropivacaine concentration groups and the corresponding success rates for each group are detailed in Table 2.

Table 2 Percentages of Patients Who Had Effective Analgesia

A dose-response curve for ropivacaine was constructed using probit analysis (Figure 3). For ropivacaine combined with sufentanil to provide effective analgesia during HIFU treatment of adenomyosis, the estimated median effective concentration (EC₅₀) was 0.079% (95% CI, 0.075–0.084%), and the estimated effective concentration for 95% of patients (EC₉₅) was 0.089% (95% CI, 0.084–0.118%).

Figure 3 Dose-response curves for epidural ropivacaine. For epidural ropivacaine combined with sufentanil 0.5 µg/mL, probit regression analysis of the relationship between ropivacaine concentration and the probability of effective analgesia. The EC50 and EC95 values with 95% confidence intervals are indicated.

Adverse Events

There were no occurrences of local anesthetic toxicity or puncture-related complications.

Discussion

This prospective sequential allocation trial determined the effective concentrations of epidural ropivacaine, combined with sufentanil, for analgesia during high-intensity focused ultrasound (HIFU) treatment of adenomyosis. The EC₅₀ was 0.079% (95% CI, 0.075–0.084%), and the EC₉₅ was 0.089% (95% CI, 0.084–0.118%). These data help define the dose–response relationship for epidural analgesia in this procedural context, which has not previously been formally quantified.

Epidural anesthesia has been used for HIFU treatment in several clinical settings. For adenomyosis, Lee et al found that epidural analgesia provided better pain control and higher ablation rates than monitored anesthesia care.¹⁵ For HIFU treatment of liver tumors, a randomized study reported satisfactory epidural blockade with ropivacaine.¹⁶ However, none of these studies formally determined the minimum effective concentration required for this procedure. The choice of ropivacaine concentration has therefore remained empirical, which is concerning because inadequate analgesia may lead to patient movement, whereas excessive dosing may cause unnecessary motor blockade and hypotension. The EC₉₅ of 0.089% identified by our up-down sequential allocation method provides a scientifically derived starting concentration for this population.

Compared with the concentrations typically used for epidural labor analgesia, our EC₅₀ and EC₉₅ values are slightly lower. When ropivacaine is used alone for the initiation of labor analgesia, 0.20% is considered to provide better analgesia than 0.15% or 0.10%.¹⁷ For the 0.15% concentration, Zhong et al found that ropivacaine alone produced analgesia comparable to that of ropivacaine combined with sufentanil, with fewer adverse effects.¹⁸ Ran et al reported that in a PIEB regimen, 0.1% ropivacaine combined with 0.5 μg/mL sufentanil at 40-minute intervals provided effective analgesia in 90% of parturients.¹⁹ Using an up-down sequential allocation design, Cai et al determined that the EC₅₀ of epidural ropivacaine combined with 0.3 μg/mL sufentanil for labor analgesia was 0.09687% (95% CI, 0.08944%–0.1043%), which exceeds our EC₉₅ of 0.089%.²⁰ The efficacy observed at this low concentration can be interpreted from several perspectives. Technically, the DPE technique facilitates enhanced caudal and rostral spread of the local anesthetic through a controlled transdural conduit, improving epidural distribution and block quality.^21,22 Pharmacologically, the synergy between ropivacaine and sufentanil is central: sufentanil potentiates sensory blockade via spinal opioid receptor agonism, allowing a reduction in local anesthetic concentration without worsening motor impairment.²³ The nature of the pain itself also contributes. Although HIFU and labor analgesia involve overlapping spinal dermatomes, HIFU thermocoagulation produces persistent deep visceral burning,²⁴ whereas labor pain is intermittent, intense, and somatic.²⁵ These differences in nociceptive quality and temporal pattern may lead to divergent local anesthetic requirements. The relative contribution of each factor cannot be determined from our data, and alternative explanations such as population differences or unmeasured confounders cannot be excluded.^26,27 Nonetheless, this anesthetic strategy achieved the clinical goal of conscious immobility: effective visceral analgesia was obtained while motor function and proprioception were preserved, allowing patients to comply voluntarily with positioning requirements. Most importantly, clear verbal communication was maintained throughout the procedure, ensuring that patients could immediately report aberrant thermal sensations such as radiating leg pain or cutaneous burning, which is the overriding safety requirement of HIFU treatment.

In summary, this study is the first to determine the effective concentration of epidural ropivacaine combined with sufentanil for HIFU treatment of adenomyosis, with an EC₉₅ of 0.089%. This evidence-based concentration can help anesthesiologists avoid empirical titration. However, it must be emphasized that individual titration based on real-time patient feedback and the extent of adenomyotic lesions remains essential. While this concentration appears capable of meeting the dual demands of analgesia and preserved responsiveness under the conditions of this study, its generalizability and definitive clinical impact require validation through appropriately designed multicenter randomized trials.

Our study has several limitations. First, this is a single-center investigation that employed an up-and-down sequential allocation methodology, which is efficient for estimating the EC₅₀ and offers the advantage of requiring a small sample size; however, the trade-off of this small sample size is limited estimation precision, particularly for the EC₉₅. It is well-documented that up-and-down designs are suboptimal for estimating extreme quantiles. Furthermore, this design introduces statistical dependency between consecutive observations, as each dose assignment is contingent upon the outcome of the preceding patient. This dependency may amplify individual variability and introduce potential bias compared to a parallel-group trial. Second, we did not assess patient satisfaction. While the varying epidural ropivacaine concentrations administered across patients preclude meaningful between-group comparisons, this represents a design limitation; patient satisfaction should have been collected as a descriptive secondary outcome. Such data, though not suitable for confirmatory hypothesis testing in this dose-finding design, would have provided valuable insights into the overall acceptability of the regimen and informed the design of future parallel-group randomized trials. Finally, the external validity of our EC estimates is limited. These findings are specific to patients undergoing HIFU for adenomyosis. Compared with patients undergoing HIFU for uterine fibroids or liver cancer, differences in pain nature and location preclude direct extrapolation of our findings to other indications.

Future research could go in a few directions. First, we need larger, multicenter studies to properly assess safety and efficacy. Future studies should incorporate a validated standardized satisfaction scale to comprehensively evaluate patient perspectives on different anesthetic regimens. Also, if small sample sizes remain desirable for efficiency, we could use a biased-coin design combined with isotonic regression analysis. This approach can give us more reliable EC₉₅ estimates and confidence intervals. In addition, future multi-center studies should include patients with different HIFU indications (eg, uterine fibroids, liver tumors) to confirm the generalizability of our findings Second, it is worth asking whether adding other adjuncts could further lower the required concentration of ropivacaine. For example, several studies have shown that dexmedetomidine works well as an adjuvant, producing a clear synergistic analgesic effect. Finally, we should include long-term follow-up assessments. How this anesthetic strategy affects the long-term efficacy of HIFU treatment remains to be seen. If better analgesia and improved intra-operative cooperation lead to more complete tumor ablation, and in turn lower recurrence rates, the clinical value would be substantial. Therefore, future studies should collect imaging follow-up data at 3–6 months or longer, systematically tracking outcomes like complete ablation rate, local recurrence, and other relevant endpoints.

Conclusion

In conclusion, this study defines the EC₅₀ and EC₉₅ of epidural ropivacaine combined with sufentanil for analgesia during HIFU treatment of adenomyosis, providing valuable guidance for clinical practice. This optimized epidural regimen provides a valuable dose reference that may help improve patient comfort and facilitate stable procedural conditions during HIFU treatment for adenomyosis.