Abstract

Background

Postoperative pain remains a significant issue with poor perioperative pain management associated with an increased risk of morbidity and mortality. Liposomal bupivacaine is an analgesic consisting of bupivacaine hydrochloride encapsulated within multiple, non‐concentric lipid bi‐layers offering a novel method of sustained release.

Objectives

To assess the analgesic efficacy and adverse effects of liposomal bupivacaine infiltration peripheral nerve block for the management of postoperative pain.

Search methods

We identified randomised trials of liposomal bupivacaine peripheral nerve block for the management of postoperative pain. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), Ovid MEDLINE (1946 to January Week 1 2016), Ovid MEDLINE In‐Process (14 January 2016), EMBASE (1974 to 13 January 2016), ISI Web of Science (1945 to 14 January 2016), and reference lists of retrieved articles. We sought unpublished studies from Internet sources, and searched clinical trials databases for ongoing trials. The date of the most recent search was 15 January 2016.

Selection criteria

Randomised, double‐blind, placebo‐ or active‐controlled clinical trials of a single dose of liposomal bupivacaine administered as a peripheral nerve block in adults aged 18 years or over undergoing elective surgery at any surgical site. We included trials if they had at least two comparison groups for liposomal bupivacaine peripheral nerve block compared with placebo or other types of analgesia.

Data collection and analysis

Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. We performed analyses using standard statistical techniques as described in the Cochrane Handbook for Systematic Reviews of Interventions, using Review Manager 5. We planned to perform a meta‐analysis, however there were insufficient data to ensure a clinically meaningful answer; as such we have produced a 'Summary of findings' table in a narrative format, and where possible we assessed the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation).

Main results

We identified seven studies that met inclusion criteria for this review. Three were recorded as completed (or terminated) but no results were published. Of the remaining four studies (299 participants): two investigated liposomal bupivacaine transversus abdominis plane (TAP) block, one liposomal bupivacaine dorsal penile nerve block, and one ankle block. The study investigating liposomal bupivacaine ankle block was a Phase II dose‐escalating/de‐escalating trial presenting pooled data that we could not use in our analysis.

The studies did not report our primary outcome, cumulative pain score between 0 and 72 hours, and secondary outcomes, mean pain score at 12, 24, 48, 72, or 96 hours. One study reported no difference in mean pain score during the first, second, and third postoperative 24‐hour periods in participants receiving liposomal bupivacaine TAP block compared to no TAP block. Two studies, both in people undergoing laparoscopic surgery under TAP block, investigated cumulative postoperative opioid dose, reported opposing findings. One found a lower cumulative opioid consumption between 0 and 72 hours compared to bupivacaine hydrochloride TAP block and one found no difference during the first, second, and third postoperative 24‐hour periods compared to no TAP block. No studies reported time to first postoperative opioid or percentage not requiring opioids over the initial 72 hours. No studies reported a health economic analysis or patient‐reported outcome measures (outside of pain). The review authors sought data regarding adverse events but none were available, however there were no withdrawals reported to be due to adverse events.

Using GRADE, we considered the quality of evidence to be very low with any estimate of effect very uncertain and further research very likely to have an important impact on our confidence in the estimate of effect. All studies were at high risk of bias due to their small sample size (fewer than 50 participants per arm) leading to uncertainty around effect estimates. Additionally, inconsistency of results and sparseness of data resulted in further downgrading of the quality of the data.

Authors' conclusions

A lack of evidence has prevented an assessment of the efficacy of liposomal bupivacaine administered as a peripheral nerve block. At present there is a lack of data to support or refute the use of liposomal bupivacaine administered as a peripheral nerve block for the management of postoperative pain. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Author(s)

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

Abstract

Plain language summary

Liposomal bupivacaine as a nerve block to treat pain after surgery

Authors' conclusions

There is currently a lack of evidence around the use of liposomal bupivacaine as a nerve block to treat pain after surgery. Further large studies are required to see if there is a role for liposomal bupivacaine to treat pain after surgery.

Background and objectives

Pain after surgery is a significant concern, with poor pain management linked to an increased risk of complications. One method to treat pain is to inject a painkiller around the nerves that transmit pain (sensory nerves) from the surgical site; this is called a nerve block. A new drug called liposomal bupivacaine has been developed consisting of multiple small parcels of bupivacaine (a commonly used painkiller), and it has been designed to release the painkiller over a long time. This review assessed how good liposomal bupivacaine sensory nerve blocks are at treating pain after surgery, and whether there are any risks associated with their use.

Study characteristics and key results

In January 2016, we found seven studies that assessed liposomal bupivacaine nerve block. Three studies were listed as completed but had not reported results. This left four studies involving 299 participants for this review. Two studies investigated liposomal bupivacaine given between two of the layers of abdominal muscles to block the nerves supplying sensation to that area (known as a transversus abdominus plane (TAP) block); one study investigated liposomal bupivacaine given around the nerves that supply sensation to the penis (dorsal penile nerve block); and one study investigated the ankle (ankle block).

We did not identify any studies that reported our primary outcome cumulative pain score between 0 and 72 hours or pain‐centred secondary outcomes. Two studies reported cumulative opioid (a strong painkiller) use with inconsistent results. We looked for results about side effects but none were reported, however no participants dropped out of the studies due to side effects. Overall, the lack of evidence, due to the small number of trials each reporting different outcomes, prevented a full assessment of the role of liposomal bupivacaine administered as a nerve block for the management of pain after surgery in adults.

Quality of the evidence

Due to the small number of trials, and small number of participants in these trials, the quality of evidence was very low. As such, further research is required to evaluate the role of liposomal bupivacaine as a nerve block to treat pain after surgery.

Author(s)

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

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

A lack of evidence has prevented a quantitative assessment of the efficacy of liposomal bupivacaine administered as a peripheral nerve block. At present there is a lack of data to support or refute the use of liposomal bupivacaine administered as a peripheral nerve block for the management of postoperative pain. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

For people with postoperative pain

The current data cannot support or refute the use of liposomal bupivacaine administered as a peripheral nerve block to reduce postoperative pain. Further evidence is required.

For clinicians

The current data cannot support or refute the use of liposomal bupivacaine administered as a peripheral nerve block to reduce postoperative pain. Further evidence is required.

For policy makers

The current data cannot support or refute the use of liposomal bupivacaine administered as a peripheral nerve block to reduce postoperative pain. Further evidence of clinical, as well as cost effectiveness, is required.

For funders

This review has highlighted the need for further evidence to establish if there is a role for liposomal bupivacaine administered as a peripheral nerve block for the management of postoperative pain. Currently (March 2016) liposomal bupivacaine is not licensed for administration as a peripheral nerve block, and several ongoing studies have yet to report (see Characteristics of ongoing studies table). It is likely that the results of these ongoing studies will provide further evidence as to the clinical and cost effectiveness of liposomal bupivacaine and that this evidence will highlight areas for further research.

Implications for research 

General implications

Further trials are required to establish the clinical and cost effectiveness of liposomal bupivacaine as a peripheral nerve block in the management of acute postoperative pain. Trials should be conducted across a range of surgical sites, with a range of block types, with the results stratified and interpreted in a block and procedure‐specific manner. Trials should be focused on surgeries that are known to be associated with significant postoperative pain, particularly surgeries where inadequate pain control may be associated with increased morbidity (i.e. pneumonia following thoracotomy) or delayed hospital discharge (i.e. total knee replacement). Prior to conducting large‐scale pragmatic trials, further work is required to establish the optimum dose of liposomal bupivacaine for administration as a peripheral nerve block.

Design

Future trials should be parallel arm, active comparator RCTs. Trials should be well designed and adequately powered, involving more than 200 participants per arm, to reduce the risk of bias. Inclusion criteria for future trials should be broad such that results are applicable to the general population.

Measurement (endpoints)

The gold standard outcome measure for postoperative recovery following surgery has yet to be established. In addition to the absence of pain, people also value the absence of nausea and sedation as well the ability to mobilise and perform self care highly. In addition to the clinical outcome measures of pain scores, opioid usage, and cost‐effectiveness outcome measures, future studies should also evaluate patient‐reported functional outcome measures, which are likely to be surgery specific, as these outcome measures will provide further informational about the effectiveness of any intervention from the person's perspective.

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