Liposomal Bupivacaine Incisional Infiltration for Postoperative Analgesia After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy: A Randomized Placebo-Controlled Trial

Abstract

Moderate-to-severe postoperative pain is common after cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Evidence that liposomal bupivacaine provides clinically important advantages over conventional local anesthetics is inconsistent, and evidence in CRS + HIPEC remains limited. This trial evaluated the incremental efficacy and safety of liposomal bupivacaine incisional infiltration added to patient-controlled intravenous analgesia (PCIA) compared with saline infiltration plus PCIA. In this single-center, randomized, participant- and assessor-blinded, placebo-controlled trial, adults aged 18–65 years scheduled for elective CRS + HIPEC were assigned 1:1 to standardized PCIA plus liposomal bupivacaine incisional infiltration (PCIA-LB) or PCIA plus normal saline infiltration (PCIA-NS). The primary endpoint was the incidence of moderate-to-severe movement-evoked incisional pain (numeric rating scale > = 4) within 72 h. The prespecified primary efficacy analysis used the per-protocol set (PPS), with a conservative intention-to-treat (ITT) sensitivity analysis. PCIA followed an institutional standard operating procedure. Monitoring was continuous in the intensive care unit (ICU); after transfer to the ward, pulse oximetry was continued through postoperative day 3, with intermittent electrocardiography and noninvasive blood pressure monitoring. The PPS included 94 patients (PCIA-NS, n = 48; PCIA-LB, n = 46). Moderate-to-severe movement-evoked pain within 72 h was less frequent with PCIA-LB than with PCIA-NS (19.6% versus 70.8%, P < 0.001). The conservative ITT sensitivity analysis supported the same conclusion (26.0% versus 68.0%, P < 0.001). PCIA-LB also produced a modest reduction in cumulative 72-h study-recorded oral morphine milligram equivalents (556.8 [473.4, 600.0] versus 600.0 [557.4, 630.0] mg, P = 0.002) and reduced rescue analgesia (30.4% versus 54.2%, P = 0.020). QoR-15 scores did not differ significantly. Overall analgesia-related adverse events occurred in 23.9% and 10.4% of the PCIA-LB and PCIA-NS groups, respectively (P = 0.143). No participant required naloxone, emergency airway intervention, or ventilatory support for a clinically recognized opioid-related respiratory event, and no local anesthetic systemic toxicity, incisional infection, or fat liquefaction was observed. Compared with saline infiltration, liposomal bupivacaine incisional infiltration reduced early movement-evoked incisional pain and rescue analgesia and produced a statistically significant but quantitatively modest reduction in 72-h opioid consumption captured by the study records after CRS + HIPEC. It did not improve QoR-15. These findings do not establish superiority over plain bupivacaine, ropivacaine, or catheter-based regional techniques, and the study was not powered to establish safety. Chinese Clinical Trial Registry, ChiCTR2500100826. Registered at 00:00 on 15 April 2025, before enrollment of the first participant later the same day. Patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy often experience substantial pain during the first few days after surgery. Opioid-based patient-controlled intravenous analgesia is widely used, but it may not fully control pain and can cause adverse effects. Liposomal bupivacaine is a long-acting local anesthetic formulation designed to release bupivacaine gradually at the wound site. In this randomized placebo-controlled trial, patients received the same institutional patient-controlled intravenous analgesia pathway and were additionally assigned to either liposomal bupivacaine or normal saline infiltration along the abdominal incision. Patients who received liposomal bupivacaine had less moderate-to-severe movement-evoked incisional pain and required fewer rescue analgesic interventions during the first 72 h; the reduction in opioid consumption captured by the study records was statistically significant but modest. Overall recovery quality measured by the 15-item Quality of Recovery score at 72 h was similar between groups. Analgesia-related adverse events were numerically more frequent in the liposomal bupivacaine group, although the difference was not statistically significant, and no severe local-anesthetic-related event was observed. Because the study did not include plain bupivacaine or ropivacaine as an active comparator, it cannot determine whether liposomal bupivacaine is superior or cost-effective compared with less expensive conventional local anesthetics.