Impact of Intraoperative Clonidine on Postoperative Opioid Use in Patients With Endometriosis: A Randomized Controlled Trial

Manager Save my selection Original Clinical Research Report Impact of Intraoperative Clonidine on Postoperative Opioid Use in Patients With Endometriosis: A Randomized Controlled Trial Birkebæk, Stine MD1; Lundsgaard, Louise M. PhD2; Seyer-Hansen, Mikkel PhD1,3; Uhrbrand, Camilla G. MD1; Uhrbrand, Peter G. PhD2; Nikolajsen, Lone DMSc1,2 From the 1Department of Clinical Medicine, Aarhus University 2Department of Anesthesiology and Intensive Care 3Department of Gynecology and Obstetrics, Aarhus University Hospital, Aarhus, Denmark. Accepted for publication September 4, 2025. The authors declare no conflicts of interest. Funding: This work was funded by Novo Nordisk Foundation (grant reference number NNF21OC0071111). Clinical Trial Registration Number: NCT05560230. EudraCT number: 2022-001810-21. Address correspondence to Stine Birkebæk, MD, Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Palle Juul-Jensens Blvd 99, Aarhus N 8200, Denmark. Address e-mail to [email protected]. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Patients with endometriosis undergoing surgery are at risk of moderate-to-severe postoperative pain. Clonidine, an alpha-2 agonist with analgesic properties, may improve multimodal pain management in these patients.

We conducted a randomized, blinded, placebo-controlled trial to investigate the effect of a single intraoperative dose of clonidine on postoperative opioid consumption and pain intensity. Patients undergoing endometriosis surgery at Aarhus University Hospital, Denmark, were randomized 1:1 to receive either intravenous clonidine (150 µg) or placebo intraoperatively. Our primary outcome was cumulative opioid consumption (intravenous morphine equivalents) 3 hours after surgery. Secondary outcomes included opioid consumption at 6 hours, pain intensity at rest and during coughing, shivering, postoperative nausea and vomiting, and sedation within the first 2 postoperative hours. The length of stay in the postanesthesia care unit was also recorded.

A total of 120 women (mean ± standard deviation [SD] age 37 ± 7 years) were included in the final analysis, with 57 receiving clonidine and 63 receiving placebo. Mean (interquartile range [IQR]) postoperative intravenous morphine consumption during the first 3 hours was lower in the clonidine group with 5 mg (0–10) compared to 10 mg (0–16.5) in the placebo group (P = .032). Shivering was less frequent in the clonidine group (3 vs 18 patients, P = .001). Sedation was more common in the clonidine group (21 vs 12 patients, P = .029). No differences were found between groups for pain intensity at rest and during coughing, postoperative nausea and vomiting, or length of stay in the postanesthesia care unit (PACU).

A single intraoperative dose of clonidine is hemodynamically safe in patients undergoing endometriosis surgery and is associated with reduced postoperative opioid consumption and shivering, but increased sedation. KEY POINTS Question: What is the effect of a single dose of intraoperative clonidine on postoperative opioid consumption in patients undergoing endometriosis surgery? Findings: A single intraoperative clonidine reduces postoperative opioid consumption and shivering in patients undergoing surgical treatment for endometriosis. However, it was associated with increased sedation and had no effect on postoperative pain intensity. Meaning: Intraoperative clonidine may be a useful adjunct in multimodal pain management for certain patients undergoing surgery. Acute postoperative pain is a major and common concern for surgical patients, and moderate-to-severe pain remains common despite advancements in multimodal pain management.1 Unrelieved pain can reduce patient satisfaction, prolong hospital stays, and increase the risk of persistent pain.2,3 While multimodal pain management strategies aim to minimize acute postoperative pain, opioids continue to be the first-line treatment for moderate-to-severe pain. However, their use is associated with a risk of side effects.4,5 Patients with endometriosis undergoing surgery are at an increased risk of experiencing moderate-to-severe acute postoperative pain, as chronic pain is a common symptom in these patients.6,7 Additionally, gynecological surgeries have a high incidence of postoperative nausea and vomiting (PONV), which is further exacerbated by opioids.8–11 Consequently, identifying alternative analgesics is crucial to enhance multimodal pain management to minimize opioid use and opioid-related complications. Clonidine, an alpha-2 agonist, has demonstrated potential as an adjunct in multimodal pain management because of its analgesic properties. Today, clonidine is used mainly for managing postoperative pain, opioid withdrawal symptoms, and menopausal flushing.12 Clonidine exerts its effects by binding to alpha-2 adrenergic receptors and inhibiting the release of noradrenaline. Its analgesic mechanism is believed to involve the activation of these receptors and pain-modulating pathways at both the spinal and supraspinal levels.13,14 When administered intravenously, clonidine reaches peak plasma concentration within 10 minutes and has an elimination half-life of 6 to 23 hours, making it favorable for perioperative pain management.14–17 However, side effects may include bradycardia, hypotension, and sedation.12,14,15,18 Previous studies have suggested that perioperative intravenous (IV) clonidine reduces postoperative opioid consumption and pain intensity.16,17,19,20 However, a knowledge gap persists, primarily due to the small sample sizes, heterogeneous study designs, and variations in administration routes. To address this gap, we conducted a randomized, blinded, placebo-controlled trial to evaluate the effects of a single intraoperative dose of clonidine on postoperative opioid consumption, pain intensity, and side effects in patients undergoing surgery for endometriosis.

Trial Design This single-center trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP) guidelines and was monitored by the GCP unit at Aarhus University Hospital, Denmark. This manuscript adheres to the applicable CONSORT guidelines. Approval was obtained from the Danish Medicines Agency (EudraCT number: 2022-001810-21) and the Danish Data Protection Agency (ID 1-16-02-311-22). Ethical approval (ID 2209269) was granted by the Danish Research Ethics Committee. Before patient enrollment, the trial was registered on clinicaltrials.gov (ID number NCT0556023) on September 26, 2022, and the protocol was published for transparency at the initial trial stage.21 Patients Patients scheduled for endometriosis surgery at the Department of Gynecology and Obstetrics, Aarhus University Hospital, Denmark, were selected for participation in this study. The exclusion criteria were as follows: age <18 years, American Society of Anesthesiologists Physical Status IV or V, allergy to clonidine, inability to provide informed consent, severe renal insufficiency, severe bradyarrhythmia, pregnancy/lactation, daily opioid use for at least 7 days leading up to surgery, and pain intensity >5 on the numeric rating scale (NRS, 0–10, where 0 = no pain, and 10 = severe pain) for more than half of the time in the past month as these patients received perioperative ketamine infusion as a standard procedure at our department. Oral and written informed consent were collected before the inclusion. Intervention, Randomization, and Blinding Patients were randomly allocated in a 1:1 ratio to receive a single intraoperative IV dose of either clonidine (150 µg) or placebo (0.9% saline). Randomization was stratified according to surgery type to ensure a balanced allocation between the groups. Patients were categorized as having undergone either minor surgery (removal of superficial lesions and/or deep infiltrated endometriosis affecting organs close to the pouch of Douglas) or major surgery (deep infiltrating endometriosis requiring bowel resection and intestinal anastomosis). Randomization was performed using blocks of 4 and 6 patients. The randomization list and preparation of the study drug were managed by the Hospital Pharmacy at Aarhus University Hospital to ensure blinding and allocation concealment. Each study drug package was handed out in sealed packages with identical outer appearances and labeled with a consecutive randomization number. Each package contained either clonidine (Clotaxip, 1 mL × 150 µg/mL, 2care4) or 0.9% saline (NaCl, 10 mL × 9 mg/mL, Fres. Kabi) and a 100 mL bag of 0.9% saline. A nurse not involved in the study mixed the contents from the vial into a 100 ml saline bag before administration. The study drug was administered after intubation by an anesthetist. All the parties involved remained blinded to the treatment allocation. The randomization list was kept concealed until the completion of the statistical analysis and the initial draft of the manuscript. Anesthesia and Analgesia Anesthesia, surgery, and postoperative pain management were performed according to standard institutional procedures. Surgery was conducted using a laparoscopic approach. General anesthesia was induced and maintained with propofol and remifentanil. The study drug (clonidine or placebo) was infused over 5–10 minutes immediately after intubation. At induction, fentanyl (200 µg) was administered, followed by a bolus dose of 75 µg/h during the surgery. Additional intraoperative analgesics included a single dose of methadone (0.2 mg/kg), paracetamol (1000 mg), and wound infiltration with bupivacaine with adrenaline (2.5 mg/mL and 5 µg/mL, respectively) by the surgeon before closure. Supplemental fentanyl (1 µg/kg) was administered if the baseline parameters increased: mean arterial pressure >10 mm Hg, heart rate >10 bpm, or peak airway pressure >5 cm H2O. Given the high risk of PONV in these patients, the majority received ondansetron (4 mg), droperidol (0.25 mg), and cyclizine (25 mg) according to Danish guidelines.22 Patients categorized as having minor surgery also received dexamethasone (8 mg) and ketorolac (30 mg). Hypotension was treated with fluids and/or vasopressors, whereas bradycardia was managed with atropine, in both cases if the anesthetist deemed treatment necessary. Both hypotension and bradycardia were recorded if treatment occurred from the administration of the study drug until 6 hours postoperatively. Postoperatively, patients reporting pain intensity ≥7 at rest on the NRS (0–10) received either IV alfentanil (0.006 mg/kg) combined with morphine (0.1 mg/kg), or fentanyl alone (1 µg/kg). For NRS scores of 4 to 6, IV morphine (0.05–0.01 mg/kg) was administered and repeated as needed until NRS ≤3. If morphine was not tolerated owing to severe side effects, IV oxycodone was given. All opioid administrations were registered in the electronic patient journal. Outcomes The primary outcome was cumulative opioid consumption (IV morphine equivalents in mg) within the first 3 hours after arrival at the postanesthesia care unit (PACU). Secondary outcomes included postoperative opioid consumption within the first 6 hours after arrival at the PACU and pain intensity at rest and during coughing, assessed using NRS (0–10) at 0, 30, 60, 90, and 120 minutes or discharge from the PACU if discharged before 120 minutes. Additional outcomes included shivering (yes/no), PONV (yes/no), and sedation levels measured on the Ramsay Sedation Scale (1–6, where 1 indicates agitation, 2 represents a tranquil state, and 3 to 6 reflects increasing sedation levels) recorded by the nurse from the PACU at 0, 60, and 120 minutes or discharge from the PACU. The length of PACU stay was also recorded. Patients reported their current abdominal pain intensity using the NRS (0–10) and provided details about their pain treatment during the 24 hours before surgery (Table 1). Postoperative opioid administration data were collected from the electronic patient journal and converted into IV morphine milligram equivalents by using the following conversion ratios: oxycodone (1.3:1), fentanyl (0.1:1), and alfentanil (10:1).23 Neuropathic pain treatment includes gabapentin, tricyclic antidepressants, and duloxetine. Abbreviations: ASA, American Society of Anesthesiologists; BMI, body mass index; IQR, interquartile range; NRS, Numeric Rating Scale; NSAIDs, nonsteroidal anti-inflammatory drugs. aMean (standard deviation); n (%); median (IQR [range]). Sample Size The sample size calculation was based on a pretrial pilot study of 50 endometriosis patients conducted at our department, which showed that 150 µg clonidine reduced postoperative opioid consumption by 40% compared with standard care. We estimated that a single dose of 150 μg clonidine would reduce the mean IV morphine consumption by 30% from 30 mg, with a standard deviation of 15 mg (primary outcome). Accordingly, 58 patients in each arm were required to reach a power of 90% (β = 0.1) and a significance level of 0.05 (α = 0.05). To account for potential dropouts, 60 patients were planned in each group, resulting in a total study population of 120 patients. Statistical Analysis Data collection and management were performed using REDCap electronic data capture tools.24 Statistical analyses were performed using Stata software version STATA/SE 18.0 (StataCorp). Normally distributed numerical data are presented as the mean (±standard deviation [SD]). Nonnormally distributed numerical data and ordinal data (pain intensity) were reported as median (interquartile range [IQR]) and compared using the Mann-Whitney U test. Categorical data are expressed as n (%) and analyzed using the X2 test or Fisher exact test, as appropriate. Aligned Rank Transform ANOVA was used to examine the interaction effect between intervention group and time on repeated measures of pain intensity scores.25 Two-sided P values <0.05 were considered statistically significant.

Patients Patient enrollment occurred between October 3, 2022 and August 13, 2024. In total, 290 patients scheduled for endometriosis surgery were screened for eligibility. After excluding 166 patients (Figure 1), 124 were randomized to receive either clonidine (60 patients) or a placebo (64 patients). Four patients were excluded after randomization for 3 reasons (Figure 1). Data from 120 patients were analyzed: 57 in the clonidine group and 63 in the placebo group. The baseline characteristics of the 2 groups are shown in Table 1 and were similar between the groups. The intraoperative characteristics are presented in Table 2. CONSORT flowchart diagram. CONSORT indicates Consolidated Standards of Reporting Trials. Primary and Secondary Outcomes The median (IQR [range]) IV morphine equivalent consumption in the first 3 postoperative hours was lower in the clonidine group 5 mg (0–10 [0–40.2]) vs 10 mg (0–16.5 [0–40.5]) in the placebo group (P = .032). Similarly, the median IV morphine consumption within the first 6 hours was 5 mg (0–14 [0–45.4]) in the clonidine group compared to 11 mg (3.9–17 [0–40.5]) in the placebo group (P = .036) Pain intensity (NRS) at rest and during coughing was comparable between the clonidine and placebo groups at all measured time points (Figure 2). Interaction effects between intervention group and time on pain intensity at rest and during coughing were not significant (P = .384 and P = .286, respectively). Two patients in the placebo group received a transverses abdominal plane block during their PACU stay because of insufficient pain control with opioids. Upon arrival at the PACU, shivering was less frequent in the clonidine group than in the placebo group (3 vs 18 patients, P = .001) (Table 3). The duration of PACU stay did not differ between groups, with a median of 125 minutes (105–150 [68–1065]) in the clonidine group vs 120 minutes (95–140 [68– 350]) in the placebo group (P = .34). In patients undergoing minor surgery, the median IV morphine equivalent consumption within the first 3 postoperative hours was 0 mg (0–10 [0–40.2]) in the clonidine group and 5 mg (0–19 [0–40.5]) in the placebo group (P = .084). In patients undergoing major surgery, the median IV morphine equivalent consumption was 6 mg (4–20 [0–31]) in the clonidine group compared to 14 mg (7–15.5 [0–27.5]) in the placebo group (P = .167). Table 3. - Secondary Outcomes and Side Effects in the Perioperative Period Hypotension is defined when it requires treatment with either fluid therapy or vasopressors. Bradycardia is defined when it requires treatment with atropine. Abbreviations: PACU, postanesthesia care unit; PONV, postoperative nausea and vomiting. aData are presented as numbers (n). bDenotes Fisher exact test. cDenotes χ2 test. Side Effects and Severe Adverse Events No difference in the incidence of PONV was observed between the clonidine and placebo groups during the observation period at the PACU (Table 3). On arrival at the PACU, a greater proportion of patients in the clonidine group had a Ramsay Sedation Scale >2 compared to the placebo group (21 vs 12 patients, P = .0290) (Table 3). Hypotension was treated in 12 clonidine and 7 placebo patients, with no difference between groups (P = .136). Most cases occurred intraoperatively (11 clonidine vs 5 placebo), with 2 postoperative cases observed in the PACU in each group. Intraoperative bradycardia was treated in 2 patients in the clonidine group and in none in the placebo group. One patient developed severe arrhythmia (ventricular tachycardia) and desaturation during surgery. Although this patient received clonidine, the clinical team determined that the episode was caused by air embolism.

In this randomized trial, we demonstrated that a single intraoperative dose of 150 µg clonidine in patients undergoing endometriosis surgery reduces postoperative opioid consumption within the first 3 hours, with the effect sustained after 6 hours. However, clonidine did not reduce pain intensity at rest or during coughing in the PACU. Our findings are consistent with 2 similar studies that tested a single dose of clonidine. Samantaray et al reported that a preoperative dose of 3 µg/kg clonidine reduced cumulative fentanyl use at 180 and 240 minutes in 60 patients undergoing thoracic surgery, corresponding to a 20% reduction in IV fentanyl in the clonidine group vs placebo (120 µg vs 150 µg). Pain scores during coughing were reduced within the first 120 minutes, although not beyond that period.19 Similarly, Deyne et al found reduced postoperative opioid consumption with a preoperative dose of 3 µg/kg clonidine in 60 patients undergoing laparoscopic abdominal surgery. Patients receiving clonidine required 46% less IV piritramide than patients receiving placebo (7.4 ± 6.64 mg vs 13.8 ± 3.8 mg).26 Four studies examined the opioid-sparing effect of clonidine when administered as a loading dose followed by continuous infusion. Marinangeli et al examined 3 intraoperative doses (5, 3, and 2 µg/kg) with a postoperative infusion of 0.3 µg/kg/h for 12 hours compared to a placebo in spine surgery patients.20 They observed dose-dependent reductions in IV morphine use (5.6 ± 2.1 mg, 12.2 ± 4.2 mg, 21.4 ± 5.3 mg, and 32.6 ± 9.1 mg). Pain scores were reduced at the 2 highest doses (5 and 3 µg/kg) compared to the lowest dose and placebo. The highest dose (5 µg/kg) provided better analgesia but increased sedation and hypotension.20 De Kock et al, in a study of 200 patients undergoing major abdominal surgery, found a lower IV morphine consumption during the first 12 postoperative hours (19.7 ± 11.1 mg vs 27.6 ± 18.1 mg) with a loading dose of 4 µg/kg and an intraoperative infusion of 2 µg/kg/h compared to a placebo.16 Similarly, Bernard et al found reduced intramuscular morphine consumption in patients who received a loading dose of 5 µg/kg and infusion of 0.3 µg/kg/h for 11 hours.17 In contrast, Striebel et al found no opioid-sparing effect (150 µg loading dose and 150 µg infusion) in women undergoing cholecystectomy.27 Our trial reflects real-life clinical practice and supports the use of intraoperative clonidine in endometriosis patients. The observed 5 mg difference in IV morphine may be considered modest, potentially below the minimal clinically important difference. However, a prior study on hip or knee arthroplasty found a 6 mg median difference in IV morphine use between patients with no vs mild opioid-related side effects, suggesting even small reductions may have clinical relevance.28 In our study, clonidine provided an opioid-sparing effect in addition to multimodal pain management with paracetamol, ketorolac, methadone, fentanyl, dexamethasone, and local infiltration analgesia. This was achieved with a fixed dose of 150 µg, corresponding to approximately 2-3 µg/kg, which is lower than in several previous studies. Whether a higher, weight-based dose would have yielded a greater opioid reduction remains unclear. This is particularly relevant, as Mariangeli et al demonstrated a dose-dependent analgesic effect of clonidine. Nevertheless, a fixed dose was chosen because of patient homogeneity and the practicality of clinical implementation. Although continuous infusion of clonidine may offer additional benefits, we decided not to use it as this trial was designed to minimize opioid use in the PACU to facilitate early hospital discharge, which would have been challenging with a continuous postoperative infusion. Our results elucidate that clonidine has opioid-sparing effects in patients undergoing endometriosis surgery, supporting its potential role in multimodal pain management. Unlike previous studies, we found no significant difference in pain intensity with intraoperative clonidine. However, it would have been possible to reveal a significant difference between the clonidine and placebo group as pain intensity at rest in the placebo group was 3 (0–6) on PACU arrival and 3.5 (1–5) after 30 minutes. Our findings support previous studies showing that intraoperative clonidine prevents shivering,12 a clinically relevant effect, as shivering can cause discomfort, exacerbate pain and increase oxygen consumption. Effective management of shivering is important for enhancing recovery after surgery.29 Clonidine was associated with increased sedation on arrival at the PACU, which may limit its clinical use. However, the PACU stay was not prolonged in patients receiving clonidine. While Samantaray, De Kock, and Bernard found that clonidine was not associated with sedation during PACU stay,16,17,19 Mariangeli et al observed increased sedation at doses of 5 and 3 µg/kg compared with 2 µg/kg and placebo.20 Our study found no difference in treatment-required hypotension between groups, which aligns with some other studies reporting no increase in hypotension in patients receiving clonidine.16,19,26,27,30 Our study has several limitations. First, external validity may be limited, as 166 of 290 eligible patients were excluded. However, given the various reasons for their exclusion, we believe that our sample remains representative, with the exception of patients at high risk for severe postoperative pain, such as those with daily opioid use or persistent pain.7 The exclusion of these high-risk patients is a major limitation of our study, as they are most likely to benefit from optimized postoperative pain management. Moreover, our study does not address whether clonidine is safe or an effective option in these high-risk patients, who may also be at risk of increased opioid requirements and delayed discharge from the PACU. This limits the applicability of our findings to patients at high risk of severe postoperative pain. Second, a patient-reported outcome measure, such as pain intensity, may have been a more appropriate primary outcome, as it better reflects patient experience than opioid consumption. Third, another major limitation of this study is the heterogeneity among patients regarding both the anatomical location of endometriosis lesions and the extent of surgery. Some patients underwent excision of superficial lesions on the peritoneum, rectovaginal area, or endometriotic cysts, whereas others underwent more extensive surgeries, including hysterectomy or bowel resection. This variability complicates comparison between patients, as both surgical extent and the location of surgery are known to influence postoperative pain and analgesic requirements. To address variability in surgical extent, randomization was stratified into major and minor surgery. Due to heterogeneity in the anatomical location of endometriosis, stratification by location was not feasible. It is possible that clonidine may be more effective in patients undergoing extensive surgery, but our study was not powered to assess such subgroup effects. Finally, differences in surgery duration may have influenced the analgesic timing of clonidine, potentially reducing its efficacy in some patients.

This randomized, blinded, placebo-controlled trial confirmed that intraoperative clonidine is hemodynamically safe in young patients undergoing endometriosis surgery. Intraoperative clonidine demonstrated a reduction in postoperative opioid consumption and likely helps with shivering. While pain scores and PACU discharge times were unaffected, this study establishes the feasibility for future studies to examine clonidine in patients with endometriosis who are at high risk of severe postoperative pain. ACKNOWLEDGMENTS The authors would like to thank the anesthetic nurses and nurses in the postanaesthesia care unit for their help with registering data and outcomes in the trial. This manuscript was handled by: Anna Woodbury, MD.

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