When attempting to control post-operative pain, which drug is better — bupivacaine, at a price of about $2.80 per vial, or the liposomal bupivacaine formulation trade-named Exparel, at about $285 per vial?

For the price, Exparel should be lights-out better. But it's not clear if Pacira Pharmaceuticals' flagship pain medication is even slightly superior at controlling post-op pain than conventional local anesthetics. An examination of Exparel's clinical trial data, the FDA's evaluation of those data and a patchwork of post-approval studies show very little difference between the performance of liposomal bupivacaine and standard bupivacaine.

"And at $285 for a dose of Exparel versus $2.80 for a shot of bupivacaine, there should be a difference," says orthopedic surgeon William Schroer, MD, of the St. Louis Joint Replacement Institute.

If true, then surgical facilities may have been paying too much for pain relief and patients may have experienced more post-op pain than necessary once they've been discharged home.

Three years after Exparel entered the surgical market with a big splash, there's ample reason to doubt that it's added significantly to the pain-control armamentarium. In the surgical community, the drug has its fans, but doubts are growing. And federal government agencies like the FDA and the Department of Justice are taking a hard look at whether Pacira, the drug's maker, promoted the drug appropriately.

A promising idea
Exparel was born in the labs of Skyepharma, an English pharmaceutical maker specializing in novel drug delivery systems. In 2006, Skyepharma spun off the business unit in charge of SKY 042 and Pacira, a new pharmaceutical company, was born.

In the prospectus for the company's public offering in 2010, officials wrote: "We believe Exparel will address a significant unmet ... need for a long-acting non-opioid postsurgical analgesic, resulting in simplified postsurgical pain management and reduced opioid consumption. ... We estimate there are approximately 24 million surgical procedures performed annually in the United States where Exparel could be used."

Undoubtedly the principals truly believed SKY 042 would improve post-operative pain control. But early Phase 2 testing of the drug against straight bupivacaine, a drug that had been on the market for more than 2 decades, produced results that could not have thrilled them. Early tests indicated that Exparel's advantage over bupivacaine was weak or even non-existent.

A double-blind, active-control trial of 108 total knee patients, designed to figure out the best dose of Exparel, compared the drug at several dose levels to bupivacaine HCl 150 mg. The researchers found no appreciable differences in visual analog pain scores until they cranked up the dosage of Exparel to 533 mg, more than double the dosage of the control. At that level, Exparel patients experienced a very high level of adverse events — 78% experienced nausea, 48% experienced hemorrhagic anemia and 20% experienced anemia. Exparel's ultimate approval was for no more than 20 mL, or 266 mg, and that is what comes in each $285 vial.

A study of 136 breast augmentation patients randomized to bupivacaine or Exparel appears to have produced a slight edge for Exparel in a measurement called "area under the curve." Exparel patients' pain scores were about 6% lower than bupivacaine's, but the authors admit that the study was "underpowered." And in the study, Exparel test subjects received a 300 mg dose, whereas bupivacaine controls received only a 100 mg dose.

"These were not robust trial results," says an anesthesiologist with knowledge of Exparel's development program who spoke on the condition of anonymity, "and a number of trials had negative findings."

With Phase 2 complete, the company moved on to Phase 3 studies, which it would use to prove safety and efficacy to the FDA. Unlike most earlier studies, FDA reviewers vetted the results of these studies. Here are the 3 studies and what they found:

• A study pitting Exparel against saline in hemorrhoidectomy surgery found that Exparel was more effective than saline at controlling pain for up to 24 hours, at which point its efficacy was indistinguishable from placebo. "The analgesia derived from Exparel does not differ from placebo, at least not in a clinically meaningful way, beyond 24 hours," wrote FDA reviewer Arthur Simone, MD, PhD.
• A study pitting Exparel against saline in bunionectomy surgery found that Exparel was more effective than saline for 12 hours. Somewhere between 12 and 24 hours, the differences became statistically insignificant. Both Exparel and saline performed poorly in this group, with patients experiencing moderate pain throughout the study period.
• A study pitting Exparel against bupivacaine HCl for hemorrhoidectomy resulted in a tiny edge for straight bupivacaine; it performed better in 2 out of 60 measurement points. In the sponsor's own study, the old $2.80 standby beat the $285 one.

From his comments, it appears that Dr. Simone was far less than impressed. He points out that "the duration of Exparel's analgesic effect appears to be no more than 24 hours and not longer than that of bupivacaine hydrochloride. The last study failed to show a difference between [Exparel] and [bupivacaine]."

PRECISE ADMINISTRATION Exparel's extended-release feature means you must infiltrate it in a very specific manner.

On to market
On the strength of its performance against saline, however, Exparel won FDA approval late in 2011. The approval simply stated that the drug was for "single-dose administration into the surgical site to produce postsurgical anesthesia." The FDA's Dr. Simone may have had his opinions, but Pacira apparently disagreed with him, and wasted no time pressing the case for what it thought its new drug could do.

In what would become a familiar refrain in Pacira promotion and sales presentations, a Pacira press release trumpeted the assessment of Harold Minkowitz, MD, a Texas anesthesiologist and Pacira consultant. "Typically, the first 48 to 72 hours after surgery are the most difficult from a pain-management perspective, so a product like Exparel, which can provide pain relief with reduced opioid consumption for up to 72 hours, represents a significant, much-needed addition to the currently available postsurgical pain management options."

Pacira's ad campaign featured a happy young patient perched in a wicker chair. "Patient-Focused Pain Control That Lasts for Up to 72 Hours," the headline read. It continued: "The only single-dose local analgesic to reduce or eliminate opioids with pain control for up to 3 days."

The company recruited a team of anesthesiologists, orthopods, pharmacists and other professionals to perform studies and talk up the drug on the lecture circuit — a not-at-all unusual step for a pharmaceutical company. In 2013, the only year data are available to date, Pacira spent close to $800,000 on consulting fees, grants, travel and other items for physicians.

Perhaps coincidentally, articles began to be published that were laudatory of Exparel.

In 2015, a 7-doctor "consensus" group published recommendations on injecting Exparel for total hips and total knees. In 2013, Pacira paid 6 of the authors a total of more than $46,000.

In 2015, anesthesiologist Jacob Hutchins, MD, and colleagues published an article lauding Exparel for transversus abdominal plane (TAP) blocks in hysterectomies. Pacira paid and provided benefits for Dr. Hutchins totaling more than $48,000 in 2013.

At least 2 retrospective (as opposed to prospective) studies found that Exparel works as well or even slightly better than femoral blocks for pain control, and ambulation is quicker.

Currently underway is a "case control" study pitting bupivacaine against Exparel in total knee cases, by Texas surgeon John Barrington, MD. His study so far has shown a slight edge for Exparel in pain scores (2.48 for bupivacaine vs. 1.98 for Exparel), a slight decrease in length of stay for Exparel patients (0.29 days) and a better Press-Ganey score (98.3% vs. 96.7%). Dr. Barrington presented the results at the American Academy of Orthopedic Surgeons, but his study has not been published and so it is apparently not peer-reviewed. It is a single-center study. It's not known whether the investigators or patients were blinded. No information is available on how the patients were selected. And Dr. Barrington also has a consulting relationship with Pacira.

Another single-center 60-patient study awaiting publication pits 0.25% bupivacaine against Exparel for subcostal TAP blocks for hysterectomy. The study showed that the Exparel patients used only half the opioids that the bupivacaine patients did — 3 Percocet per day instead of 6 — and also showed that they had lower minimum and maximum pain scores. But the controls received less than two-thirds of the medication that the study patients did. Average pain scores weren't reported. The study is small. And once again, it was designed by a Pacira consultant.

Many surgeons became enthusiastic about Exparel, and many still are. By the end of 2014, Pacira had sold $189 million worth of Exparel, more than doubling the $76 million the drug had brought in the year before.

Storm clouds
But trouble was on the horizon. Other studies, particularly those whose authors had no relationship with Pacira, were critical.

A review by 5 pharmacists published in Hospital Pharmacy in 2014 was highly skeptical of Exparel's value. The authors said Exparel's clinical trials had shown no statistical differences in pain scores. "The use of a new product is justifiable when it fulfills an unmet need or the increased cost is offset by improved outcomes over current standard," says the study. "However, based on the available data, bupivacaine liposomal does not meet such a need."

In 2015, a study in Pharmacotherapy testing Exparel against no drug in a multimodal setting in total knee patients found no statistical difference in pain scores between the group that received Exparel and the group that did not. The Exparel group did take fewer opioids than the control group.

Also in 2015, urologic surgeons performed a randomized prospective study of Exparel against 0.25% bupivacaine in laparoscopic urologic surgery patients. The researchers found no difference in pain scores or opioid consumption between the 2 groups.

Several institutions have conducted their own private studies of Exparel and found little benefit.

Last December, Baptist Health System in San Antonio, Texas, removed Exparel from its formulary, saying in a memo to the medical staff that after 2 years of evaluation, "no additional benefit could be attributed to Exparel ... compared to the use of other pain medications."

Rothman Orthopaedic Specialty Hospital in suburban Philadelphia also removed Exparel from its formulary earlier this year after using it in hip and knee replacement surgeries for close to 2 years. "The surgeons were not seeing the projected block of 72 hours. It was much less than what was expected: 36 hours, if that," says John R. Karwoski, RPh, MBA, of JDJ Consulting, which provides pharmacy services to Rothman, the Philadelphia region's largest orthopedic specialty group. "We went back to plain bupivacaine."

Duke University re-searchers tested Exparel on 150 total knee patients. Finding that the effects of the drug didn't last as long as expected, the hospital discontinued the study and returned to nerve blocks.

Anesthesiologist Vince Kasper, MD, the director of regional anesthesia at United Anesthesia Services in the Philadelphia area, calls Exparel "an attempt at a shortcut: a very expensive, non-efficacious shortcut. The results are not predictable. The only thing predictable about the drug is its instability."

Dr. Schroer, who performs 700 total knees per year, says he was curious about Exparel and had no pre-formed opinions about it. But he had observed that there were "no prospective, randomized, controlled studies by someone who has no financial relationship with Pacira that show that liposomal bupivacaine is any better than plain bupivacaine injections." So he conducted his own. His soon-to-be published study in The Journal of Arthroplasty compares periarticular injections with liposomal bupivacaine versus plain bupivacaine in 111 total knee arthroplasty patients. Exparel went 0-for-3 in the study. There was no significant difference in pain scores recorded twice daily during hospitalization, opioid use during hospitalization and hospital length of stay. Opioid use actually increased in Exparel patients after discharge, which Dr. Schroer says may represent a rebound phenomenon.

"This study," says Dr. Schroer, "does not justify the routine use and cost of liposomal bupivacaine as part of a multimodal pain management program."

In 2014, the FDA also denied Pacira's application to get liposomal bupivacaine approved as a single-shot nerve block. In a company-sponsored study of 180 patients, the drug also failed to show a consistent benefit. A 14-patient Pacira-funded study by anesthesiologist Brian Ilfeld, MD, MS, of the department of anesthesiology at the University of California San Diego, showed that the drug works unpredictably for regional blocks. Dr. Ilfeld's study showed that the drug lasted for more than 24 hours, but the magnitude of the blocks varied widely. Strangely, the higher the dosage, the lesser the effect.

More trouble was ahead. Last September, after examining the company's advertising, the FDA issued a warning letter to Pacira, calling Exparel a "misbranded" product and forcing the company to redact claims in print advertisements that the drug offered 72-hour pain relief when in fact it was only deemed effective for a 24-hour period. The FDA took the very unusual step of forcing Pacira to run full-page correction ads in all the journals in which the company had advertised Exparel, including Outpatient Surgery. In an awkward confession, Pacira was forced to admit that a clinical study that demonstrated that Exparel significantly reduced pain intensity compared to placebo for up to 24 hours also demonstrated that "there was minimal to no difference between Exparel and placebo treatments on mean pain intensity" between 24 and 72 hours after Exparel was administered.

The FDA also said Pacira had subtly promoted the use of Exparel in surgical procedures other than those for which the drug has been shown to be safe and effective. The agency "is concerned with Pacira's suggestions, made in an array of professionally-directed promotional materials that Exparel has been demonstrated to be safe and effective in various other surgical procedures." The FDA listed as examples: knee arthroplasty, gastric sleeve, open hysterectomy, lumbar interbody fusion and abdominoplasty.

This spring, Pacira got more bad news when the U.S. Department of Justice subpoenaed a broad range of documents related to the marketing and promotion of Exparel. It is not known what the DOJ has in mind or what it will find. Potentially the investigation may turn up nothing, or it could be existential. Pacira says it is cooperating. Erol Onel, MD, Pacira's vice president of clinical research and medical information, declined to discuss the investigation further. Earlier DOJ investigations of big pharma companies resulted in fines of $2.3 billion for Pfizer, $950 million for Merck, $3 billion for Glaxo and $2.2 billion for J&J.

What's next?
The controversy hasn't stopped many surgeons from using Exparel — and insisting that it controls surgical pain.

Some orthopedic surgeons "swear by this product. Are they blinded by the new, fashionable, sparkly product, or are they right and we are wrong and it truly does make a difference and the studies were not designed well enough to show the difference?" asks anesthesiologist Sergio Bergese, MD, chief of neuroanesthesia and director of clinical research at Ohio State University in Columbus, Ohio. "Does the published data reflect clinical outcomes? No. It just reflects data."

Pacira's Dr. Onel says that's because the drug does work. "If you just look at pain scores, you're missing the boat," he says. With a long-acting analgesic like Exparel, he says, pain studies can be deceptive because they don't account for the impact that opioids and other pain medications have on subjective pain scores over time among study participants. Dr. Onel says the pain scores of patients who've received Exparel "normalize" with those who receive bupivacaine, saline or nothing at all at around 24 hours — the point at which non-Exparel study patients likely received additional pain medication, while Exparel patients received nothing more.

Dr. Onel also says pain studies don't always measure such key benchmarks as patient satisfaction, opioid usage and discharge time.

"When you look at the studies that have shown Exparel led to a decrease in discharge, the question becomes: Will you spend a couple hundred dollars to save a couple thousand dollars?" says Dr. Onel.

An anesthesiologist who was involved with the earlier studies agrees in part. He says, "I think the drug probably performs better than some of the trials suggest."

Another theory has it that Exparel's showing in studies might relate to how precisely you must infiltrate it. Exparel's high-tech designer drug delivery molecule, which encloses bupivacaine in the vesicles of an artificial glob of fat so that the medication will trickle out over time rather than being flushed by the circulatory system, makes it highly dependent on how it's injected. It doesn't diffuse, so it works best when it's infiltrated into the surgical wound in a very specific manner.

"Technique is critical," says orthopedic surgeon Thomas Meade, MD, of Allentown, Pa. "If it's not done correctly, the results are not that good. You have to think like a sniper, not a shotgun."