Thomas W Hamilton, Vassilis Athanassoglou, Stephen Mellon, Louise H Strickland, Marialena Trivella, David Murray, Hemant G Pandit

Despite multi-modal analgesic techniques, acute postoperative pain remains an unmet health need, with up to three quarters of people undergoing surgery reporting significant pain. Liposomal bupivacaine is an analgesic consisting of bupivacaine hydrochloride encapsulated within multiple, non-concentric lipid bi-layers offering a novel method of sustained-release analgesia. To assess the analgesic efficacy and adverse effects of liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain. On 13 January 2016 we searched CENTRAL, MEDLINE, MEDLINE In-Process, Embase, ISI Web of Science and reference lists of retrieved articles. We obtained clinical trial reports and synopses of published and unpublished studies from Internet sources, and searched clinical trials databases for ongoing trials. Randomised, double-blind, placebo- or active-controlled clinical trials in people aged 18 years or over undergoing elective surgery, at any surgical site, were included if they compared liposomal bupivacaine infiltration at the surgical site with placebo or other type of analgesia. Two review authors independently considered trials for inclusion, assessed risk of bias, and extracted data. We performed data analysis using standard statistical techniques as described in the Cochrane Handbook for Systematic Reviews of Interventions, using Review Manager 5.3. We planned to perform a meta-analysis and produce a 'Summary of findings' table for each comparison however there were insufficient data to ensure a clinically meaningful answer. As such we have produced two 'Summary of findings' tables in a narrative format. Where possible we assessed the quality of evidence using GRADE. We identified nine studies (10 reports, 1377 participants) that met inclusion criteria. Four Phase II dose-escalating/de-escalating trials, designed to evaluate and demonstrate efficacy and safety, presented pooled data that we could not use. Of the remaining five parallel-arm studies (965 participants), two were placebo controlled and three used bupivacaine hydrochloride local anaesthetic infiltration as a control. Using the Cochrane tool, we judged most studies to be at unclear risk of bias overall; however, two studies were at high risk of selective reporting bias and four studies were at high risk of bias due to size (fewer than 50 participants per treatment arm).Three studies (551 participants) reported the primary outcome cumulative pain intensity over 72 hours following surgery. Compared to placebo, liposomal bupivacaine was associated with a lower cumulative pain score between the end of the operation (0 hours) and 72 hours (one study, very low quality). Compared to bupivacaine hydrochloride, two studies showed no difference for this outcome (very low quality evidence), however due to differences in the surgical population and surgical procedure (breast augmentation versus knee arthroplasty) we did not perform a meta-analysis.No serious adverse events were reported to be associated with the use of liposomal bupivacaine and none of the five studies reported withdrawals due to drug-related adverse events (moderate quality evidence).One study reported a lower mean pain score at 12 hours associated with liposomal bupivacaine compared to bupivacaine hydrochloride, but not at 24, 48 or 72 hours postoperatively (very low quality evidence).Two studies (382 participants) reported a longer time to first postoperative opioid dose compared to placebo (low quality evidence).Two studies (325 participants) reported the total postoperative opioid consumption over the first 72 hours: one study reported a lower cumulative opioid consumption for liposomal bupivacaine compared to placebo (very low quality evidence); one study reported no difference compared to bupivacaine hydrochloride (very low quality evidence).Three studies (492 participants) reported the percentage of participants not requiring postoperative opioids over initial 72 hours following surgery. One of the two studies comparing liposomal bupivacaine to placebo demonstrated a higher number of participants receiving liposomal bupivacaine did not require postoperative opioids (very low quality evidence). The other two studies, one versus placebo and one versus bupivacaine hydrochloride, found no difference in opioid requirement (very low quality evidence). Due to significant heterogeneity between the studies (I(2) = 92%) we did not pool the results.All the included studies reported adverse events within 30 days of surgery, with nausea, constipation and vomiting being the most common. Of the five parallel-arm studies, none performed or reported health economic assessments or patient-reported outcomes other than pain.Using GRADE, the quality of evidence ranged from moderate to very low. The major limitation was the sparseness of data for outcomes of interest. In addition, a number of studies had a high risk of bias resulting in further downgrading. Liposomal bupivacaine at the surgical site does appear to reduce postoperative pain compared to placebo, however, at present the limited evidence does not demonstrate superiority to bupivacaine hydrochloride. There were no reported drug-related serious adverse events and no study withdrawals due to drug-related adverse events. Overall due to the low quality and volume of evidence our confidence in the effect estimate is limited and the true effect may be substantially different from our estimate.