Researchers seeking to reduce the duration of postoperative pain and opioid consumption in patients undergoing orthopedic surgery recently reported some promising findings: In a phase 3 trial designed to meet FDA standards for approval, investigators demonstrated that liposomal bupivacaine (Exparel, Pacira) administered as a single-injection nerve block significantly reduced pain and decreased or eliminated opioid consumption 48 hours after surgery in patients undergoing shoulder surgery.
“There is a significant difference in the pain experience through those first 48 hours,” said study co-author Jeffrey Gadsden, MD, associate professor of anesthesiology at Duke University School of Medicine, in Durham, N.C. “If you summed it all up, there was a roughly 46% reduction in pain intensity in the treatment group versus the placebo group.”
Moreover, there was a 77% reduction in opioid consumption over 48 hours among patients who received liposomal bupivacaine compared with those who received placebo. Dr. Gadsden referred to this as “a huge issue now in the era of the opioid crisis,” noting the value of any interventions that can potentially reduce opioid use.
Wanted: Longer, Safer Pain Relief
The duration of pain relief provided by traditional nerve blocks is limited, and there are other shortcomings. “Brachial plexus block works really well for shoulder surgery; it’s the gold standard for how we manage pain,” Dr. Gadsden said. But, he added, “single-shot blocks don’t last very long; the pain outlasts the block. Catheter techniques work well, but catheters have problems—they get displaced, they fall out, they kink.”
Opioids have been prescribed to provide additional postoperative pain relief when nerve blocks wear off, but the risks for opioid abuse and addiction have prompted researchers to seek other ways to control postoperative pain in outpatients.
Liposomal bupivacaine combines bupivacaine with a proprietary delivery technology that releases the medication over a desired period of time, providing longer lasting analgesia after surgery than bupivacaine alone. Liposomal bupivacaine is approved for administration into soft tissue surrounding the surgical site via infiltration. Last year, the drug’s developer submitted a supplemental New Drug Application (sNDA) to the FDA seeking approval for its use in nerve blocks based on promising phase 3 data in patients who received the drug as a single-injection nerve block for total knee arthroplasty or shoulder surgery.
Dr. Gadsden presented the current findings on liposomal bupivacaine at the New York School of Regional Anesthesia 2017 Annual Symposium on Regional Anesthesia, Pain and Perioperative Medicine (abstract NYS25). This phase 3, multicenter, randomized, double-blind, placebo-controlled trial included adult patients undergoing primary unilateral total shoulder arthroplasty or rotator cuff repair at 17 sites in Belgium, Denmark and the United States. All patients had an ASA physical status of I, II or III, and were randomly assigned 1:1:1 to receive liposomal bupivacaine (133 or 266 mg) administered as an ultrasound-guided single-injection brachial plexus block at least one hour before surgery, or placebo.
Following an interim pharmacokinetic analysis that demonstrated the efficacy of the 133-mg dose, investigators decided to randomly assign all future patients to receive the lower dose. One hundred forty patients were included in the final efficacy and safety analyses (n=69, 133 mg of liposomal bupivacaine; n=71, placebo); the 15 patients who received 266 mg of liposomal bupivacaine were included in the safety and pharmacokinetic analyses.
Liposomal bupivacaine significantly reduced pain intensity through 48 hours post-surgery—the primary outcome of the study—by 46% compared with placebo (P<0.0001), as measured by the mean area under the curve of visual analog scale pain intensity scores. Additionally, significantly more patients who received liposomal bupivacaine had no pain in the PACU compared with patients who received placebo (18 vs. two, respectively; P<0.0001), a trend that also was significant at 24 and 48 hours post-surgery (four vs. zero for both time points; P=0.04 for both).
Postoperative opioid consumption through 48 hours—a secondary study end point—was reduced significantly (by 77%) in recipients of liposomal bupivacaine versus placebo (P<0.0001). Time to first opioid rescue was significantly longer among patients who received liposomal bupivacaine compared with those who received placebo (4.2 vs. 0.6 hours, respectively; P<0.0001). Significantly more patients who received liposomal bupivacaine remained opioid-free at 24 hours (16 vs. one; P=0.0001) and 48 hours (nine vs. one; P=0.008) compared with patients who received placebo. Statistical significance was not maintained at 72 hours (four vs. one; P=0.16).
Safety and tolerability profiles of liposomal bupivacaine were comparable with placebo. Sensory function returned to baseline within 60 hours after surgery in patients who received liposomal bupivacaine, with most patients experiencing only a transient loss of sensation. Motor function resolved within 48 hours post-surgery in both the liposomal bupivacaine and placebo groups.
Conclusion: To Be Continued …
The study authors concluded that “liposomal bupivacaine can address an unmet need for a single-injection local anesthetic that provides prolonged post-surgical analgesia and mitigates opioid use.”
“And I think, personally,” Dr. Gadsden added, “from an investigator and a clinician point of view, that this is going to be a game changer for shoulder surgery.”
However, some anesthesiologists who reviewed the study were more cautious. Adam W. Amundson, MD, an anesthesiologist at Mayo Clinic, in Rochester, Minn., noted that, although the drug has potential, the findings of this study are not definitive.
“It is difficult to say that you have prolonged analgesia when only 6% [four of 69] of patients had no pain at 24 hours, and, of all the patients blocked, a mere 50% was the maximum number of patients who demonstrated a change in sensation over the shoulder [at approximately six hours post-surgery].”
Furthermore, he added, “although this study shows that liposomal bupivacaine is better than placebo, I want to know how it compares to a free bupivacaine interscalene brachial plexus block, with the most up-to-date adjuvants in a multimodal analgesic pathway. In an ideal world, a better study would have compared liposomal bupivacaine with its true competitor, which is free bupivacaine and not placebo.”
Despite this, Dr. Amundson said, “I like the study because it opens the door for further exploration and discussion on long-acting local anesthetics.” He speculated that a combination of periarticular injection and nerve block with liposomal bupivacaine may provide the best outcomes. “The opioid epidemic is a real problem, and we need to do everything we can to treat surgical pain in an opiate-sparing manner,” he added.
Kenneth Cummings, MD, MS, FASA, medical director of pre-anesthesia clinics at the Cleveland Clinic, in Ohio, agreed that opioid consumption is a clinically relevant study outcome, and pointed to the need for further studies.
“All we’ve learned here is that liposomal bupivacaine provides better pain relief than placebo. This would be a much more informative study if it were an active comparator trial. I think clinicians will want to see ‘real-world’ comparison studies with commonly used doses of local anesthetics and adjuvants as comparison groups.”
Dr. Cummings also challenged the data on duration of sensory block. “The rather low percentage of patients with cutaneous anesthesia over the shoulder—combined with the relatively short time to opioid rescue [4.2 hours]—leads me to wonder whether the concentration of free bupivacaine was sufficient to provide adequate sensory block and pain relief.”
Given the cost of liposomal bupivacaine and the small number of active–comparator trials published to date (e.g., Reg Anesth Pain Med 2017;42:334-341), Dr. Cummings questioned how these findings might translate into clinical practice.
“Compared with our current best single-shot nerve blocks, will liposomal bupivacaine spare patients enough exposure to opioids to mitigate their side effects? Will we prevent any patients from becoming chronic opioid users? Will the increased cost be worth the benefits?” These are questions that must be answered, he said.
Dr. Gadsden agreed with the need for further studies of liposomal bupivacaine versus an active comparator. He added, “While this is exciting preliminary work, what is really going to change clinical practice is the comparison of a single-injection block with liposomal bupivacaine versus a single-injection or continuous technique with plain bupivacaine.”
The FDA is considering the issue: the Anesthetic and Analgesic Drug Products Advisory Committee voted 6 to 4 not to recommend approval of the sNDA for liposomal bupivacaine on February 15. The FDA is expected to complete its review on April 6.