A 2015 review evaluated the impact of volume expansion on the efficacy and pharmacokinetics of liposomal bupivacaine (Exparel) and found no evidence of a concentration-efficacy relationship across Phase II and III clinical studies, in which varying concentrations (0.22% to 1.33%) and volumes were used for surgical site infiltration. Analysis of pooled clinical data demonstrated that higher concentrations were not associated with improved pain control, and in some cases lower concentrations produced comparable or greater reductions in pain intensity, with similar opioid consumption and analgesic outcomes observed regardless of dilution. Additionally, a prospective study comparing identical doses administered at different volumes (266 mg/20 mL vs 266 mg/40 mL) showed no meaningful differences in postoperative pain scores or opioid use. Preclinical pharmacokinetic data further indicated that variations in concentration, dose, and injection volume did not alter systemic exposure profiles. Overall, the available evidence suggests that dilution of liposomal bupivacaine with saline to increase volume does not enhance analgesic efficacy or pharmacokinetic behavior, although it allows flexibility in covering larger surgical areas. [1]

A 2017 review of liposomal bupivacaine in total joint arthroplasty reports that the formulation may be diluted with normal saline and expanded to volumes up to 300 mL without loss of efficacy, with the stated rationale of increasing soft tissue coverage depending on surgical-site size. The authors note that greater volume expansion is believed to allow more thorough infiltration of periarticular tissues, where the drug must remain to exert its effect, and that technique, including multiple small-volume injections across tissue planes, is considered important for optimizing distribution. However, the same review emphasizes that liposomal bupivacaine may not diffuse through tissues as readily as standard bupivacaine, necessitating more injection sites, and that outcomes in the literature are inconsistent and often attributed to variability in infiltration technique rather than formulation or dilution alone. Importantly, while dilution and increased volume are described as methods to enhance tissue coverage, the review does not present definitive evidence that more dilute solutions or higher-volume mixtures (with saline or additional bupivacaine) result in superior pain control or nerve blockade; rather, it concludes that existing data are heterogeneous and insufficient to establish clear clinical benefit related to these factors. [2]

A 2023 retrospective cohort study evaluating liposomal bupivacaine dilution in shoulder arthroplasty investigated the effect of administering a fixed dose (20 mL; 266 mg) diluted with increasing volumes of normal saline (total volumes of 40 mL, 60 mL, and 80 mL) on postoperative pain and opioid consumption. The study reported that all dilution strategies provided effective analgesia with low opioid utilization; however, the 80 mL dilution group demonstrated significantly lower pain scores at postoperative day 7 compared to the 40 mL and 60 mL groups, with no statistically significant differences in opioid consumption across groups. The authors noted a trend toward reduced opioid use in the higher-volume (80 mL) cohort. The study further describes that liposomal bupivacaine may be diluted up to 300 mL to expand tissue coverage, with recommended administration involving diffuse infiltration across a broad surgical field to optimize analgesic distribution. Additionally, the findings reference existing clinical and preclinical evidence indicating that volume expansion does not adversely affect pharmacokinetics and may improve analgesic effectiveness by increasing surface area coverage, although intergroup differences were not consistently statistically significant. Overall, the data suggest that higher dilution volumes may be associated with improved pain control at certain time points, while all tested dilutions remain effective for postoperative analgesia. [3]

A 2025 phase I, open-label, dose-escalation study evaluated the pharmacokinetics, pharmacodynamics, and safety of liposomal bupivacaine administered via ultrasound-guided popliteal sciatic nerve block, either alone or admixed with immediate-release bupivacaine hydrochloride, in adults undergoing bunionectomy. Participants received predefined fixed-dose and fixed-volume formulations (20 to 30 mL total volume depending on cohort), including liposomal bupivacaine 266 mg or 133 mg with or without bupivacaine HCl 50 mg, or bupivacaine HCl 100 mg alone; no variations in dilution volume beyond these study-specific preparations were evaluated. Admixture with bupivacaine HCl resulted in biphasic plasma concentration profiles with an early and delayed peak, but did not reduce time to onset of sensory or motor block compared with non-admixed formulations. Sensory block onset was similar across all cohorts (median approximately 18 to 29 minutes), while liposomal bupivacaine, whether alone or admixed, produced substantially prolonged sensory block duration (median 119 to 167 hours) compared with bupivacaine HCl alone (67 hours). The study did not evaluate differences in tissue dispersion, injection volume expansion beyond protocol-defined volumes, or the impact of increased dilution with saline or additional local anesthetic on analgesic efficacy or nerve blockade characteristics. [4]