Liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain Stable (no update expected for reasons given in 'What's new')

Abstract

Abstract Background

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.

Objectives

To assess the analgesic efficacy and adverse effects of liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain.

Search methods

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 We obtained clinical trial reports and synopses of published and unpublished studies from Internet sources, and searched clinical trials databases for ongoing trials.

Selection criteria

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.

Data collection and analysis

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.

Main results

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 (I2 = 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.

Authors' conclusions

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.

Author(s)

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

Abstract

Plain language summary

Liposomal bupivacaine at the site of surgery to treat pain

Bottom Line

Liposomal bupivacaine administered at the site of surgery appears to reduce postoperative pain when compared to placebo (salt water). At present there is limited evidence as to how effective it is compared to other painkillers, such as bupivacaine hydrochloride. Further large studies are required to see if there is a role for liposomal bupivacaine in this area.

Background

Despite painkillers, three in four people report pain following surgery. One method to treat pain is for the surgeon to inject a painkiller at the site of surgery to block the nerves that send pain signals to the brain. A new drug called liposomal bupivacaine has been developed which has been designed to release the painkiller over a much longer time and provide prolonged pain relief. This review has been designed to look at how good liposomal bupivacaine injected at the site of surgery is at treating pain and also to look at whether there are any risks associated with its use.

Study characteristics and key results

In January 2016, we found nine studies (10 reports) involving 1377 people that assessed liposomal bupivacaine following five different types of operation: total knee replacement; haemorrhoidectomy; inguinal hernia repair; bunionectomy and breast augmentation. The results suggested that compared to placebo (salt water) liposomal bupivacaine was better at reducing pain when injected at the site of surgery and also reduced both the overall requirement for, and duration before needing, additional, opiate‐based (strong), painkillers. However, the limited evidence did not suggest that liposomal bupivacaine was better than the currently used painkiller bupivacaine hydrochloride. Overall across all the included studies no‐one dropped out due to drug‐related side effects.

Quality of the evidence

Due to the small number of studies and some limitations in the quality of these trials, we ranked the quality of evidence as moderate to very low. Further research is required to evaluate the role of liposomal bupivacaine infiltration at the surgical site to treat pain after surgery.

Author(s)

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

Reviewer's Conclusions

Authors' conclusions

Implications for practice General Implications

Liposomal bupivacaine does appear to have efficacy in reducing postoperative pain compared to placebo when infiltrated at the surgical site, however, at present the limited evidence does not demonstrate superiority to bupivacaine hydrochloride. We assessed the quality of the evidence as moderate to very low and as such our confidence in the effect estimate is limited and the true effect may be substantially different from our estimates.

For people with postoperative pain

The current data do not support or refute the use of liposomal bupivacaine infiltration at the surgical site to reduce postoperative pain.

For clinicians

Further evidence as the clinical and cost effectiveness of liposomal bupivacaine infiltration at the surgical site is required as, due to the quality of evidence, the current data do not support or refute the use of liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain.

For policymakers

The current data do not permit firm estimates of effect size due to the low quantity and quality. As such the current data do not support or refute the use of liposomal bupivacaine infiltration at the surgical site to reduce postoperative pain. Further evidence of clinical, as well as cost‐effectiveness, is required.

For funders of the intervention

Currently the limited evidence does not demonstrate superiority to bupivacaine hydrochloride, however due to the quality of the evidence our confidence in the effect estimate is limited and the true effect may be substantially different from our estimates. The current data do not support or refute the use of liposomal bupivacaine infiltration at the surgical site to reduce postoperative pain and further evidence of clinical, as well as cost‐effectiveness, is required.

Implications for research General implications

Good quality, large, active comparator randomised controlled studies are required to establish the clinical and cost effectiveness of liposomal bupivacaine infiltration at the surgical site for the management of postoperative pain. Studies should be conducted across a range of surgical sites with the results stratified and interpreted by site. Studies should be focused on surgeries that are known to be associated with significant postoperative pain, particularly surgeries where improved pain control may deliver significant clinical benefits through reduced morbidity, or cost‐effectiveness benefits through faster rehabilitation and discharge (i.e. total knee replacement).

Design

Future studies should be parallel‐arm, active comparator randomised controlled trials with broad inclusion criteria, such that results are applicable to the general population. Studies should be well designed and adequately powered, involving more than 200 participants per arm, to reduce the risk of bias.

Measurement (end points)

This review focuses on the management of postoperative pain however it is important to note that recovery following surgery is multi‐factorial, with patients highly valuing the absence of nausea and sedation as well the ability to mobilise and perform self‐care, as well as other factors. A gold standard outcome measure for postoperative recovery following surgery has yet to be established however it is prudent that in addition to the clinical outcome measures of pain scores and opioid usage, future studies should also evaluate patient‐reported functional outcome measures, which are likely to be surgery‐specific, as these outcome measures will provide further information about the effectiveness of any intervention from the patient perspective.

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