Mega-liposuction, also known as large-volume liposuction, is defined as the removal of ≥ 5 L of aspirate in a single procedure and has gained popularity recently [1,2]. Despite advances in anesthetic techniques, patients undergoing liposuction frequently experience moderate-to-severe postoperative pain, which may impair early recovery, prolong hospital stay, and reduce overall satisfaction [3]. Although the tumescent technique involves infiltration of dilute lidocaine to provide local anesthesia during liposuction procedures, its analgesic effect may be insufficient for extensive or prolonged procedures such as large-volume liposuction [4-6].

This pain is mainly attributed to extensive subcutaneous tunneling, tissue trauma, and irritation of peripheral sensory nerves caused by repeated cannula movements within the adipose tissue [7]. It typically peaks within one week postoperatively [4]. Since acute postoperative pain may predict the development of chronic pain, establishing an effective perioperative pain control strategy is essential [8].

Historically, conventional pain management strategies have depended significantly on opioids. However, while these medications can be effective, they are linked to adverse effects and the risk of dependence, which has led to growing concerns about their long-term use and the need for alternative pain management approaches [9]. Consequently, during the transition to multimodal analgesia, adjuvant medications have gained increasing attention through targeting various pain pathways to improve analgesia and reduce the need for opioids. Accordingly, many anesthesiologists adopt preemptive analgesia using various medications and techniques to prevent injury-induced hypersensitivity and pain pathway activation, including the use of drugs such as pregabalin, which can effectively modulate pain responses [5,10].

Pregabalin, a structural derivative of the inhibitory neurotransmitter, gamma-aminobutyric acid, exhibits antihyperalgesic, anticonvulsant, anxiolytic, and sleep-modulatory properties. It interacts with the presynaptic β12δ subunit of calcium channels, consequently diminishing calcium entry and attenuating the secretion of excitatory neurotransmitters within pain pathways [11]. Duloxetine hydrochloride is an antidepressant that is used to treat anxiety and severe depressive disorders. It is a potent and selective serotonin-norepinephrine reuptake inhibitor with minimal dopaminergic reuptake. It has been hypothesized that duloxetine elicits analgesic effects by modulating the descending inhibitory pain pathways in the central nervous system. Additional proposed mechanisms include inhibition of N-methyl-D-aspartate receptors or sodium channels and enhancement of the endogenous endorphin system [12].

Although both agents have demonstrated beneficial effects in terms of postoperative analgesia in various surgical settings [13-16], the possible synergistic effects of combining these agents during surgery, particularly in procedures involving extensive tissue damage, such as mega-liposuction, have not been sufficiently studied. Consequently, evidence regarding the safety and efficacy of their simultaneous application in high-pain procedures such as mega-liposuction is insufficient.

We hypothesized that the simultaneous perioperative administration of duloxetine and pregabalin would improve postoperative pain control and reduce opioid use, while maintaining a similar rate of complications in patients undergoing liposuction. Therefore, the aim of this study was to evaluate the efficacy and safety of a perioperative protocol involving duloxetine and pregabalin, with particular attention paid to postoperative pain management and opioid use, in patients undergoing mega-liposuction procedures under general anesthesia.

This prospective, double-blind, randomized clinical investigation was approved by the Institutional Ethics Committee (No. N-39-2021) of the Faculty of Medicine at Cairo University, Cairo, Egypt, and registered on ClinicalTrials.gov (NCT04862845). All the participants provided written informed consent. Patients aged 18-50 years, classified as having American Society of Anesthesiologists (ASA) physical status I-II and scheduled to undergo elective mega-liposuction under general anesthesia, were enrolled in the study. Patients who refused consent or had contraindications or allergies to the study drugs were excluded. Additional exclusion criteria included severe psychiatric disease, severe organ disease or dysfunction, history of prolonged opioid or anticonvulsant therapy, or analgesic use within the preceding 24 h.

The sample size was determined based on a preliminary pilot study evaluating postoperative morphine consumption in three groups, conducted using the same perioperative multimodal analgesic protocol as in the present trial. The pilot study included 30 patients (10 per group), with mean ± standard deviation (SD) values of 24.60 ± 8.44 mg for Group I (pregabalin + duloxetine), 35.50 ± 10.98 mg for Group II (pregabalin + placebo), and 44.40 ± 12.93 mg for Group III (placebo). The pooled SD was 10.94 mg, yielding an effect size (Cohen’s f) of 0.74. Utilizing G*Power software (version 3.1) with an alpha of 0.05 and 90% power, 27 patients per cohort were required (total of 81). To accommodate possible attrition, an additional 10% of participants were recruited, yielding a final sample size of 90. The allocation was randomized using a computer-generated sequence, which was then deposited in sealed opaque containers to ensure concealment. The sequence was generated by an independent statistician with no other involvement in the trial.

The study drugs were prepared in identical empty capsules (Arab Gelatin and Pharmaceutical Products). Based on the randomization list, the hospital pharmacy packaged the capsules, and the access to the allocation was restricted to clinical pharmacists. The hospital pharmacy transferred pregabalin 75 mg (Lyrica®, Pfizer), duloxetine 60 mg (Cymbalta®, Lilly del Caribe Inc.), or placebo (sugar-filled) from original containers into empty capsules and labeled them. The final preparation was performed by an anesthetist (WSW) who was not involved in the study or data collection. Both patients and medical teams were blinded to the capsule contents. All procedures were performed by the same surgical team, using standardized techniques.

Twenty-four hours before the surgical procedure, all patients underwent ambulatory evaluation, including medical history, physical examination, and routine laboratory evaluations (comprehensive blood count, coagulation panel, aspartate aminotransferase, alanine aminotransferase, urea, and creatinine). The study protocol, medications, and anesthesia techniques were explained to all the participants. The participants were instructed to use the Visual Analog Scale (VAS; 0 = no pain and 10 = worst imaginable pain). They also learned about the Quality of Recovery Questionnaire-40 (QoR-40) [17], a validated patient-reported outcome measure that assesses recovery after surgery across five domains: physical comfort, emotional state, psychological support, physical independence, and pain. The total score ranged from 40 (poor recovery) to 200 (excellent recovery). The study emphasized voluntary participation and the right to withdraw at any time without affecting care. On the day of surgery, demographic data (age, sex, body mass index [BMI], ASA score, and comorbidities) and baseline VAS and QoR-40 scores were recorded. Randomization envelopes were then opened, and medications were administered as follows: Group I (n = 30) received pregabalin 300 mg in conjunction with duloxetine 60 mg orally 90 min before surgery, followed by pregabalin 75 mg every 12 h combined with a daily dose of 60 mg duloxetine for three days after surgery. Group II (n = 30) received pregabalin 300 mg plus placebo preoperatively and subsequently pregabalin 75 mg every 12 h alongside the placebo once daily for 3 days. Group III (n = 30) received placebo capsules preoperatively, followed by placebo every 12 h and once daily postoperatively for three days. The selected dosing regimen was based on previous randomized trials demonstrating the analgesic efficacy of the study drugs [13-15].

The participants were then transferred to the preoperative holding area. A 20-G intravenous (IV) cannula was inserted, and 0.01 mg/kg midazolam, 8 mg ondansetron, 40 mg pantoprazole, 8 mg dexamethasone, 30 mg IV ketorolac, 1 g IV paracetamol, and 2 g prophylactic cefazolin were administered. An infusion of 100 ml of 0.9% sodium chloride containing 40 mg/kg magnesium was initiated and infused over 10 min before anesthesia induction. These medications were administered as part of a standardized multimodal analgesic regimen that was applied consistently across all study groups to ensure uniform perioperative pain management. Upon entry into the operating theater, conventional monitoring modalities were implemented, including non-invasive blood pressure measurement, oxygen saturation (SpO₂), and electrocardiography. Baseline vital signs and tympanic membrane temperature were documented with a thermometer (FT 65, Beurer®).

All patients received standardized general anesthesia. Anesthesia was initiated with IV propofol (2 mg/kg), ketamine (0.5 mg/kg), and lidocaine (1 mg/kg). Morphine sulfate (0.1 mg/kg) was subsequently administered until the eyelid reflex was absent. Rocuronium, 0.60 mg/kg, was administered to facilitate endotracheal intubation. All concentrations were determined based on the ideal body weight of the patient.

Mechanical ventilation was used to maintain the end-tidal carbon dioxide partial pressure within a range of 30 to 35 mmHg. Anesthesia was maintained with sevoflurane in an air/oxygen mixture, with the end-tidal concentration titrated to maintain the heart rate (HR) and mean arterial pressure (MAP) within 20% of the baseline values. Rocuronium was administered as a continuous infusion at 0.01 mg/kg/min. If the HR or MAP increased by more than 20% from baseline without signs of inadequate depth of anesthesia (e.g., movement or sympathetic responses), IV morphine boluses (0.05 mg/kg) were administered as rescue analgesia. Hypotension (MAP < 50 mmHg) or bradycardia (HR < 50 beats/min) was treated with 10 mg of ephedrine or 1 mg of atropine, respectively.

Intraoperative hypothermia was mitigated with a heat-and-moisture exchange filter, warmed IV fluids, and maintenance of the operating room temperature between 22°C and 24°C. Following induction, the abdomen, hips, quadriceps, and back were infiltrated with a tumescent fluid comprising 1 L of Ringer’s lactate combined with 20 ml of 1% lidocaine, 20 ml of sodium bicarbonate, and 1 ml of 1:1,000 adrenaline. Liposuction was performed through a 7-mm incision for pre-tunneling, followed by a 4-mm cannula for fat extraction, and the fat volume from each side was recorded. Upon completion of the surgical procedure, the residual neuromuscular blockade was reversed with sugammadex at a dose of 2-4 mg/kg, and extubation was performed upon restoration of consciousness. Following the procedure, the patients were transported to the post-anesthesia care unit and provided with a cotton blanket, and the recovery room temperature was maintained at the same level as that of the operating room.

Postoperative management was standardized across all groups and consisted of oral ketorolac (30 mg every 12 h) and oral paracetamol (1 g every 6 h) for 3 days. Upon patient request for analgesia (VAS score > 3), 3 mg of IV morphine was initially administered, followed by the implementation of a patient-controlled analgesia (PCA) device (Rhythmic Evolution Organizer 100, Micrel Medical Devices S.A.) programmed to deliver 50 mg of morphine. The PCA was configured to provide 1-mg bolus doses with a 10-min lockout period.

During PCA, HR, MAP, respiratory rate (RR), and SpO₂ were monitored. If morphine-related adverse events occurred, including nausea, vomiting, hypotension (MAP < 25% of baseline), bradycardia (HR < 25% of baseline), or respiratory depression (RR < 10 breaths/min or SpO₂ < 95%), PCA was discontinued. Management included ondansetron 1.5 mg/kg for nausea or vomiting, ephedrine 10 mg for severe hypotension, atropine 1 mg for severe bradycardia, and naloxone 0.04 mg IV with 3 L/min oxygen for severe respiratory depression until RR exceeded 12 breaths/min.

The collected intraoperative data included blood loss, blood transfusion requirements, intraoperative fluid volume, tumescent fluid volume, urine output, and total liposuction volume. The average surgical duration was defined as the time from tumescent infiltration to port site skin closure. Duration of anesthesia was defined as the time from induction to extubation. Extubation time was defined as the interval between discontinuation of anesthetic agents and removal of the endotracheal tube. Recovery time was defined as the time to achieve a modified Aldrete score ≥ 9.

The principal endpoint was cumulative postoperative morphine consumption throughout the first 72 h after surgery. Secondary outcomes included total morphine consumption (intraoperative and postoperative), time to the initial analgesic request, postoperative sedation evaluated using the Modified Ramsay Sedation Scale [18], and postoperative pain evaluated using the VAS at 6, 12, 24, 48, and 72 h. Additionally, intraoperative complications and drug- or opioid-related adverse effects or toxicities, including sedation, blurred vision,nausea and vomiting, and dizziness, were recorded. At 72 h postoperatively, the patients completed the QoR-40 questionnaire and assessed their satisfaction with postoperative analgesia using a 4-point Likert scale (1 = poor, 2 = fair, 3 = good, and 4 = excellent).

The Consolidated Standards of Reporting Trials (CONSORT) flow chart illustrates the participant progression in this study. Of the 105 participants assessed for eligibility, 15 were excluded, and 90 were randomly allocated to the three study groups. Each group included 30 participants who received the assigned interventions with no loss to follow-up or discontinuation. All the enrolled participants were included in the analysis (Fig. 1).

The baseline characteristics were comparable across the three groups, with no statistically significant differences in age, BMI, sex distribution, ASA physical status, comorbidities, or preoperative QoR-40 scores (all P > 0.050) (Table 1).

The intraoperative and recovery parameters were similar across groups. No statistically significant differences were identified in tumescent fluid volume, liposuction volume, operative duration, extubation time, anesthesia duration, intraoperative fluid or colloid administration, estimated blood loss, transfusion volume, urine output, or recovery room stay (all P > 0.050). In contrast, intraoperative sevoflurane consumption differed significantly, increasing from Group I (31.90 ± 4.00 ml) to Group II (37.93 ± 5.75 ml) and Group III (45.40 ± 6.87 ml) (P < 0.001) (Table 2).

Group I showed the most effective opioid-sparing effect, with intraoperative morphine consumption of 7.20 ± 1.45 mg, which was significantly lower than that of Group II (9.57 ± 2.95 mg) and Group III (14.13 ± 3.81 mg). Postoperative morphine use over three days was lower in Group I (19.40 ± 2.51 mg) than in Group II (24.07 ± 3.14 mg) and Group III (33.90 ± 4.74 mg), resulting in a total morphine consumption of 26.60 ± 3.18 mg, which was significantly lower than that of the other groups (all P < 0.001). Moreover, Group II required significantly less morphine than Group III during the intraoperative, postoperative, and overall periods (all P < 0.001). The time to first analgesia in Group I was 2.39 ± 0.72 h, which was significantly longer than that in Group II (1.89 ± 0.61 h) and Group III (0.95 ± 0.52 h). Group II had a significantly longer time to first analgesia than Group III (Table 3).

The VAS scores were significantly lower in Group I than in Groups II and III at the immediate postoperative, 6-h, and 12-h time points (P < 0.001; Fig. 2). Group II demonstrated substantially lower scores than Group III at the corresponding time points (P < 0.001). At 24, 48, and 72 h, both Groups I and II exhibited markedly reduced VAS scores compared with those in Group III (P < 0.001), with no statistically significant differences observed between Groups I and II.

Comparison of postoperative outcomes showed that Group I had the highest patient global QoR-40 (183.10 ± 4.85) and satisfaction scores (3.47 ± 0.68), both of which were significantly higher than those of Group II (181.10 ± 4.50 and 2.90 ± 0.76) and Group III (178.57 ± 5.51 and 2.23 ± 0.97), with P = 0.003 and P < 0.001, respectively. All the groups were equivalent in terms of physical comfort, physical independence, emotional well-being, and psychological support. However, Group I showed significantly better pain domain scores (33.03 ± 1.54) than Group II (31.50 ± 3.09) and Group III (27.80 ± 2.41) (P < 0.001). The Modified Ramsay Sedation Score was comparable among the groups, with a median of 2 and no statistically significant difference (P = 0.108). The occurrence of intra- and postoperative complications and adverse events was comparable, exhibiting modest rates and no statistically significant differences (all P > 0.050) (Table 4).

In this prospective, double-blind, randomized controlled trial, 90 patients scheduled to undergo elective mega-liposuction under general anesthesia were enrolled to assess the efficacy and safety of perioperative administration of duloxetine and pregabalin. Demographic and operative characteristics at baseline were comparable across all groups, except for notably higher sevoflurane consumption in Groups II and III compared with Group I. The combination of 300 mg pregabalin with 60 mg duloxetine (Group I) significantly reduced total morphine consumption (intra- and postoperative) compared with pregabalin alone (Group II) and placebo (Group III). Furthermore, this combination significantly extended the time to initial analgesia request, enhanced recovery outcomes and patient satisfaction, and improved postoperative pain scores. The administration of both drugs was safe, with no significant increase in perioperative complications, including bradycardia, hypotension, nausea, vomiting, dry mouth, sedation, or dizziness. These findings indicate that adding duloxetine to pregabalin provides superior perioperative analgesia, reduces opioid requirements, and improves postoperative recovery without compromising hemodynamic stability or safety. These findings support the role of multimodal analgesia in reducing opioid-related adverse effects and enhancing postoperative recovery. However, the higher sevoflurane consumption observed in Groups II and III may reflect increased anesthetic requirements in patients receiving less effective adjuvant analgesia; it should not be considered as a direct surrogate marker of nociception. In the present study, the depth of anesthesia was titrated according to hemodynamic responses rather than bispectral index monitoring. Therefore, differences in sevoflurane consumption should be interpreted cautiously because several factors, including hemodynamic targets and anesthesiologist-directed titration, may also influence anesthetic requirements. Overall, the duloxetine-pregabalin regimen was well tolerated and may represent an effective opioid-sparing strategy that enhances postoperative comfort and recovery, supporting its role as part of multimodal analgesia in extensive liposuction procedures.

Postoperative pain involves multiple mechanisms at various neural locations [19]. Therefore, the use of multimodal analgesics can effectively reduce pain. Although opioids are typically preferred for moderate-to-severe pain, their use may cause adverse effects and increase pain sensitivity [20], which can complicate postoperative recovery and necessitate alternative pain management strategies. Multimodal analgesia combines different drugs and techniques to achieve synergistic pain relief, allowing for the use of lower doses of each agent and reduction of individual drug side effects [21].

Pregabalin and duloxetine operate through distinct mechanisms and their combination may yield improved analgesia through synergistic effects, especially during procedures such as mega-liposuction. To the best of our knowledge, this is one of the first randomized trials to evaluate the combined perioperative use of duloxetine and pregabalin in mega-liposuction. This demonstrates that duloxetine, a serotonin-norepinephrine reuptake inhibitor, and pregabalin, a gabapentinoid, can be used together perioperatively. This suggests that they can be used for indications beyond the treatment of neuropathic and chronic pain syndromes [22].

Evidence for the use of this combination in liposuction is limited, although it has been effective in reducing neuropathic pain in patients with diabetic neuropathy and fibromyalgia [23-25]. Numerous studies have indicated that duloxetine can alleviate acute postoperative pain and expedite recovery after various surgical procedures. A thorough meta-analysis of 29 studies showed that oral perioperative administration of duloxetine, compared with placebo, significantly reduced pain scores at 24 and 48 h, decreased opioid use in the first 24 h, and delayed the time to the first rescue analgesic [26]. However, evidence for its routine use in acute postoperative pain remains low to moderate because of the heterogeneity in surgical procedures, patient populations, and dosing protocols, which complicates the generalizability and establishment of standardized treatment guidelines [27-29]. This variability underscores the necessity for additional studies to determine optimal dosing strategies and specific patient populations that may derive the greatest benefit from duloxetine for the management of postoperative pain.

Numerous studies have demonstrated the effectiveness of pregabalin in reducing postoperative pain and opioid consumption [30-32]. Mishriky et al. [33] reported that, regardless of the dose or schedule, pregabalin decreases pain scores and opioid consumption in various postoperative settings. Meta-analyses of high-quality evidence comparing pregabalin to placebo rated the evidence as low-to-moderate quality owing to methodological limitations arising from differences in surgical types, treatment protocols, and follow-up durations [34-36], suggesting that further research is needed to establish more definitive conclusions about the effectiveness of pregabalin in postoperative pain management.

A recent randomized trial of knee fracture surgery demonstrated that duloxetine 60 mg/day is a safe and effective perioperative substitute for pregabalin 150 mg/day. Both medications were equally effective in alleviating pain. However, duloxetine resulted in a slight increase in opioid consumption within the initial 24 h and did not necessitate additional pain management between 24 and 48 h. This discrepancy may be ascribed to the delayed onset of duloxetine compared with that of pregabalin [37]. A subsequent clinical trial in lower limb trauma surgery demonstrated that pregabalin 150 mg/day and duloxetine 60 mg/day provided equivalent pain management, as evidenced by analogous VAS scores, latency to initial rescue analgesia, and total rescue analgesic consumption within the initial 72 h [38].

The limitations of the current trial include the single-center design, relatively limited sample size derived from pilot data, evaluation of only short-term outcomes, and exclusion of patients with ASA physical status III-IV or substantial comorbidities, thereby restricting its applicability to high-risk populations. Furthermore, the depth of anesthesia was not regulated by bispectral index monitoring, and sevoflurane titration was determined by hemodynamic parameters, potentially influencing the interpretation of variations in anesthetic consumption.

Perioperative administration of duloxetine 60 mg combined with pregabalin 300 mg significantly enhanced postoperative analgesia, reduced morphine requirements, and improved quality of recovery after mega-liposuction without increasing sedation or adverse effects. The incorporation of this regimen into multimodal analgesia protocols may lead to better patient outcomes and support opioid-sparing strategies for extensive liposuction. However, further multicenter trials with larger populations and longer follow-up durations are required to validate these findings.