“Current but limited literature does suggest that […] a transversus abdominis plane block with liposomal bupivacaine might provide benefit over plain bupivacaine.”

Optimizing postoperative analgesia with multimodal, opioid-sparing analgesic protocols is crucial to promote enhanced recovery after surgery. The incorporation of regional anesthetic techniques in those protocols can improve the quality of analgesia and facilitate patient recovery. Fascial plane blocks have been shown to provide useful analgesic benefit after abdominal surgery.  The duration of analgesia is, however, limited with the use of traditional plain local anesthetics in single shot blocks. Extending the duration of analgesia is desired to prolong the benefits of these blocks. While this can be achieved by using continuous catheter techniques, catheter-based techniques are technically more challenging; require additional time, equipment, and monitoring; incur additional costs; and are associated with leakage and accidental disconnections or dislodgements. Finding ways to prolong the duration of single injection regional blocks has therefore been of interest and includes the addition of adjuncts such as dexamethasone and the use of sustained-release preparations of local anesthetics. Liposomal bupivacaine was approved by the U.S. Food and Drug Administration (Silver Spring, Maryland) in 2011 and promised prolonged analgesia after a single injection. Evidence for its superior analgesic efficacy over plain local anesthetic formulations has, however, been challenged.

In this issue of Anesthesiology, Hussain et al.  perform a systematic review and meta-analysis of randomized trials that compared liposomal bupivacaine with plain local anesthetics for fascial plane blocks in patients undergoing a variety of abdominal surgeries. The authors chose a primary endpoint of the standardized mean difference in the area under the curve (AUC) for pain scores at rest from 24 to 72 h postoperatively. They also analyzed several secondary outcomes including pain scores at rest at 1, 6, 12, 24, 48, and 72 h, opioid consumption on the first, second, and third postoperative days, time to first analgesic request, and length of hospital stay as well as side effects. They included 16 studies with 667 patients receiving liposomal bupivacaine and 620 receiving plain local anesthetics. All included studies investigated transversus abdominis plane blocks, except for one that used quadratus lumborum block. For the primary outcome, four studies posted results on clinicaltrials.gov, with three appearing not to have completed the original target enrollment (one was recently published the other three not published), six studies reported no benefit of liposomal bupivacaine, and three studies reported benefit. Using the conservative Hartung-Knapp-Sidik-Jonkman method for random effects, the authors report no benefit of liposomal bupivacaine over plain bupivacaine in the primary outcome when pooling the results of 13 studies or in any of the secondary outcomes. The results were robust to several sensitivity analyses.

The time frame of the primary outcome chosen by the authors is appropriate, given that the suggested benefit of liposomal bupivacaine is to extend the duration of analgesia beyond the first postoperative day. They also chose to assess the AUC to allow for evaluation of the potential analgesic benefit from 24 to 72 h, rather than focusing on just one time point. However, only three time points were available for the included studies, so relatively few pain scores contributed to the AUC. The authors also only included pain scores at rest and did not assess pain scores on movement or maximum pain scores, despite this being reported in many of the included studies. Pain scores on movement can better assess the efficacy of an analgesic intervention and are more likely to show a benefit from a fascial plane or regional block if one exists.5  Other limitations of the meta-analysis include adding studies that have not been peer-reviewed, the significant statistical and more importantly clinical heterogeneity of included studies, and the inadequate power for the primary outcome, which becomes even more significant with the multiple sensitivity analyses that were performed to account for the significant heterogeneity.

Meta-analyses provide a powerful tool for summarizing and evaluating the evidence for an intervention. Including appropriate studies in a meta-analysis is, however, crucial to reliably answer the research question. It is therefore important to examine closely the studies included in this meta-analysis. Specifically, when comparing the efficacy of liposomal bupivacaine with plain bupivacaine for transversus abdominis plane blocks, it is important to choose a surgical model for which a transversus abdominis plane block would provide adequate coverage and therefore analgesic benefit. Models where transversus abdominis plane blocks cover only part of the surgical incision may not be the optimal surgical model to answer this research question. The only study included in this meta-analysis that had a placebo arm in addition to the liposomal and plain bupivacaine arms reported no analgesic benefit from the two active arms over the placebo arm and no difference between the two bupivacaine arms at any of the time points, which included day of surgery up to 7 days postoperatively after open ventral hernia repair. This suggests that the transversus abdominis plane blocks were not effective and that the model used in that study might not be a suitable model to compare the two preparations of bupivacaine. Another negative study included in this meta-analysis used a subcostal transversus abdominis plane block for a lower abdominal midline incision for open abdominal hysterectomy. The subcostal approach, which covers mainly T9–11 dermatomes would be more suitable for an upper abdominal surgery and a posterior approach to the transversus abdominis plane block or a rectus sheath block might have been more appropriate blocks to use and compare the two preparations of bupivacaine in this surgical model. Other included studies that used abdominally based breast reconstruction may also not be the best models to evaluate transversus abdominis plane blocks, as these blocks would not likely cover the entire surgical area.

Optimizing multimodal analgesic protocols and ensuring correct placement of the fascial plane blocks are crucial for analgesic efficacy. For instance, in a study comparing liposomal bupivacaine with plain bupivacaine for transversus abdominis plane blocks in women undergoing cesarean delivery there was a significant reduction in opioid consumption and pain scores in the liposomal bupivacaine group over the first 72 h postoperatively when the analysis included protocol-compliant patients. However, after excluding patients with incorrect transversus abdominis plane block placement (as assessed by a review of the ultrasound images by an independent review committee), those with nonadherence to the study’s multimodal analgesic protocol, or local anesthetic dosing, a post hoc analysis found no benefit of liposomal bupivacaine over plain bupivacaine, with the lack of efficacy attributed mainly to incorrect transversus abdominis plane block placement. Transversus abdominis plane blocks cover only incisional pain, and compliance with an adequate multimodal regimen is essential to cover visceral pain. More importantly, for a transversus abdominis plane block to work optimally, the local anesthetic must be deposited in the correct plane, so adequate training and expertise are needed. The transversus abdominis plane, for all its apparent simplicity, is often challenging to “open up,” and technical challenges frequently lead to ineffective patterns of sensory loss over the lower abdomen, and potentially a “failed” block.  Compounding this is the fact that—unlike unencapsulated local anesthetics—multivesicular liposomes do not cross fascial planes. The implication is that if plain bupivacaine is placed incorrectly within the transversus abdominis or internal oblique muscle, the transversus abdominis plane block may still partially work because of diffusion; however, the same is unlikely to be true when liposomal bupivacaine is used. Fascial plane blocks with liposomal products demand a very high degree of precision, and clinicians using this formulation must have the proper training in ultrasound-guided block techniques.

What can we conclude from the meta-analysis by Hussain et al., and from the current literature? This meta-analysis suggests no benefit of liposomal bupivacaine over plain bupivacaine when used for (primarily) transversus abdominis plane blocks for abdominal surgeries. It does, however, pool data from studies, some of which might not be optimal to answer this research question, so the results need to be interpreted with caution. Current but limited literature does suggest that when performed by experienced providers in select surgeries that are amenable to coverage with transversus abdominis plane blocks, and with meticulous attention to multimodal analgesic protocol adherence, a transversus abdominis plane block with liposomal bupivacaine might provide benefit over plain bupivacaine.  Future well-conducted studies in appropriate surgeries are needed to conclusively determine whether there is a place for liposomal bupivacaine in fascial plane blocks for abdominal surgery.