Non-Opioid Analgesic Gets Another Poor Grade for Pain Relief

By Pat Anson, PNN Editor

An expensive analgesic drug that’s often touted as a safer alternative to opioids is not reliable or effective as a pain reliever, according to a new study.

Exparel is an injectable form of liposomal bupivacaine, a non-opioid local anesthetic used for post-operative pain and as a nerve block to numb parts of the body during surgery.

Because Exparel is a proprietary formulation of bupivacaine, Pacira BioSciences has priced it 10 times higher than generic bupivacaine. A 20 milliliter vial of Exparel costs about $376, compared to $38 for a same size vial of bupivacaine.

Some anesthesiologists have questioned whether Exparel is actually worth the higher cost, saying its effectiveness in relieving post-operative pain is “clinically unimportant” and no different than other local anesthetics.  

To see if they might be right, researchers at the Medical University of Vienna recruited 25 healthy volunteers for a blinded clinical study in which participants received two nerve blocks about a month apart, one with plain bupivacaine for pain control and the other with liposomal bupivacaine (Exparel).

"Since the combination of both forms of bupivacaine is recommended, little was known about the effectiveness of the use of liposomal bupivacaine alone in pain therapy during and immediately after surgery," wrote lead author Peter Marhofer, MD, a Professor of Anesthesia and Intensive Care Medicine at MedUni Vienna.

The study findings, recently published in the journal Anesthesiology, show that Exparel alone blocked pain in less than a third of the volunteers, compared to everyone who received plain bupivacaine.

“Given complete sensory blockade in merely 32% of cases, as compared to 100% with plain bupivacaine, liposomal bupivacaine does not emerge from our study as a suitable ‘sole’ local anesthetic for intraoperative regional anesthesia,” said Marhofer.

Those who did get pain relief from Exparel say it reduced their post-operative pain for up to 3.5 days. But because its effects varied widely from subject to subject, researchers don’t consider it a reliable analgesic when used alone.

"Our study showed unpredictable effects of liposomal bupivacaine in terms of nerve block and associated pain relief. Based on our findings, the substance cannot currently be recommended for use in pain therapy during and after surgery," said co-author Markus Zeitlinger, MD, an Associate Professor of Clinical Pharmacology at MedUni Vienna.

Pacira did not respond to a request from PNN for comment on the study. In the past, the company has aggressively promoted Exparel and used hardball tactics to silence critics.

In 2021, Pacira filed a lawsuit against the American Society of Anesthesiologists for publishing “false and misleading conclusions” in the journal Anesthesiology that said Exparel worked no better than other bupivacaine products. The lawsuit was later dropped.

In 2014, Pacira took the unusual step of filing a lawsuit against the FDA, after the agency sent a warning letter to Pacira for off-label marketing of Exparel. Pacira won that case in an out-of-court settlement when the FDA withdrew its warning letter and approved the use of Exparel for more types of post-operative pain.

Over the years, Pacira has paid nearly $34 million to doctors to help promote Exparel, according to Open Payments. That strategy backfired In 2020, when Pacira paid $3.5 million to settle allegations that it gave kickbacks to doctors in the form of fake research grants.

Pacira has also been active politically, spending over $3 million on lobbying and campaign donations since 2018, according to OpenSecrets. In 2019, the company hired former New Jersey governor Chris Christie as a consultant for $800,000 and lucrative stock options. Christie had recently chaired President Trump’s opioid commission, which issued a report recommending that hospitals use more non-opioid pain relievers.

Pacira is also bankrolling Voices for Non-Opioid Choices, an advocacy group that is lobbying the Biden administration for early implementation of the NOPAIN Act. Passed by Congress in late 2022, the law requires Medicare and Medicaid to pay for Exparel and other non-opioid treatments in outpatient surgical settings, starting in 2025. Supporters of the bill want the timetable moved up to 2024, which would generate millions of dollars in additional revenue for Pacira. 

Patients Who Received Opioids During Surgery Had Better Outcomes

By Pat Anson, PNN Editor

As pressure grows on the Biden Administration to implement the NOPAIN Act and require Medicare to pay higher costs for non-opioid pain relievers during surgery, a new study shows that restricting the use of opioids during surgical procedures may do more harm than good.

Researchers at Massachusetts General Hospital (MGH) analyzed the health records of over 61,000 patients who had surgery under general anesthesia at MGH, and found that those who received opioids were less likely to experience post-operative pain and needed fewer opioids during recovery.

The study findings, published in in JAMA Surgery, showed that surgery patients who were given the opioids fentanyl and hydromorphone had less pain, lower rates of persistent opioid use, and fewer opioid prescription refills. They were also less likely to have chronic pain 12 months after surgery.

Researchers were particularly surprised to find that patients who received higher doses of fentanyl had fewer chronic pain diagnoses and needed fewer opioid prescriptions 30, 90 and 180 days after surgery.

“We were surprised by the extent to which intraoperative administration of opioids was associated with medium- and long-term outcomes. This may relate to the fact that if inadequate amounts of opioids are administered in the operating room, patients may emerge from general anesthesia in pain, a phenomenon that has a known association with persistent postsurgical pain,” wrote lead author Patrick Purdon, PhD, Department of Anesthesia, Critical Care, and Pain Medicine at MGH.

“The main implication of this study is that in the drive toward overall reduction of opioid usage in surgical pain management in the US, the role of intraoperative nociception in determining postoperative pain may have been overlooked to the detriment of patient outcomes.”

Researchers say their findings underscore the importance of ensuring that patients don’t emerge from general anesthesia in pain, not only for their short-term wellbeing, but to prevent long-term opioid use.

“The opioid crisis is a major motivator for mitigating the risks of opioid usage,” said co–first author Laura Santa Cruz Mercado, MD, an anesthesiology resident at Beth Israel Deaconess Medical Center and former research fellow at MGH. “But appropriate opioid administration in the operating room may reduce total opioid usage after surgery.”

Lobbying for Early Implementation of NOPAIN

Although previous studies have found that the risk of opioid misuse or overdose after surgery is rare, pressure on U.S. hospitals to reduce their use of opioids has resulted in a 50% decrease in opioid prescribing after surgery.  

Supporters of the NOPAIN Act would like it to decrease further and faster. Passed by Congress late last year, the Act requires the Centers for Medicare and Medicaid Services (CMS) to expand reimbursement policies for non-opioid treatments in outpatient surgical settings, starting in 2025. Supporters of the bill have launched a campaign to have the timetable moved up to 2024.

“Healthcare leaders must help CMS understand the inevitable damage that will result if the agency does not implement the policy in 2024. Millions of Americans will be put needlessly at risk of opioid addiction for another year,” Nirav Amin, MD, an orthopedic surgeon at Pomona Valley Hospital in Pomona, CA, wrote in a recent op/ed in Healthcare Dive. “The policy will incentivize greater use of non-opioids by creating separate reimbursements for the administration of these therapies.”

Unmentioned in Amin’s column is that he’s been paid over $360,000 in recent years as a consultant for Pacira BioSciences, a company that stands to directly benefit from the NOPAIN Act. Pacira makes Exparel, an expensive injectable formulation of bupivacaine, a non-opioid analgesic used to treat post-operative pain.

Bupivacaine is a generic drug that only costs about $35 a vial, while Exparel is priced 10 times higher, at $365 a vial. According to two recent studies that Pacira claimed were “false and misleading,” Exparel works no better than the much cheaper bupivacaine products.

Pacira has made over $32 million in various payments to Amin and other doctors to help promote Exparel, according to Open Payments, a CMS database that tracks industry payments to healthcare providers. Pacira is also bankrolling Voices for Non-Opioid Choices, an advocacy group that is leading the campaign for early implementation of the NOPAIN Act.

Pacira is also very active politically, spending over $2.6 million on lobbying and campaign donations since 2018, according to OpenSecrets. In 2019, Pacira hired former New Jersey governor and current presidential candidate Chris Christie as a consultant for $800,000 and lucrative stock options. At the time, Christie had recently chaired President Trump’s opioid commission, which recommended that Medicare and Medicaid reimbursement policies be changed to encourage hospitals to use more non-opioid pain relievers.

Did Pacira Lie to Investors or a Federal Judge?

By Pat Anson, PNN Editor

The war of words between Pacira BioSciences and the American Society of Anesthesiologists (ASA) continues to escalate, with new allegations that the drug company either lied to its investors or a federal judge.

New Jersey-based Pacira filed a lawsuit in April over three articles in the ASA journal Anesthesiology that disparaged Pacira’s flagship product Exparel, an injectable non-opioid analgesic used for postoperative pain. An editorial and two peer-reviewed research articles said Exparel worked no better than other bupivacaine products, even though it costs 10 times more.

Pacira filed a libel complaint against the ASA in federal court seeking a retraction and damages for “significant pecuniary harm.” The company said “multiple existing customers” had either stopped using Exparel or were considering it because of the journal articles.

If true, that would be a significant blow to Pacira, since Exparel accounted for 96% of the company’s revenues in 2020.

The ASA filed a motion last week asking a federal judge to dismiss the case, calling the lawsuit “an egregious and unjustified public relations campaign that seeks to chill scientific research and debate.”

‘Nothing to Worry About’

The ASA motion quotes a statement from a May 4 earnings call, in which Pacira CFO Charlie Reinhart told analysts that “we don’t have anything to worry about” and “actually things are going very, very well,” despite the negative reviews of Exparel in the medical journal.

In a preliminary report released last week, Pacira even boasted about sales of the drug. “Exparel sales continue to significantly outperform the elective surgery market recovery, with May marking our fourth consecutive month of sequential growth in average daily sales,” the company said in a statement that didn’t mention the lawsuit.

“In other words, Pacira is lying either to a federal judge or its investors,” the ASA said in a press release Monday.  

A Pacira spokesperson declined to respond to the ASA statement, telling PNN that “our corporate policy is not to comment on pending litigation.”

Exparel was first approved by the FDA in 2011 as a local anesthetic for post-operative pain in adults.  Its use has since been expanded to include children and as a nerve blocking agent.  Pacira says over 8 million patients have been treated with Exparel. The drug is primarily sold to hospitals and ambulatory surgical centers. One of the biggest purchasers is the U.S. Department of Defense.

In the past, Pacira has gone to great lengths to promote Exparel and silence critics.  In 2014, the company filed a lawsuit against the FDA after the agency sent a warning letter to Pacira for off-label marketing of Exparel. In 2020, Pacira agreed to pay $3.5 million to resolve allegations that it gave kickbacks to doctors to promote Exparel in research articles.

Legal Fight Brews Over Non-Opioid Pain Reliever

By Pat Anson, PNN Editor

Competition between drug companies can get so intense that some resort to bare knuckle tactics to preserve market share. Such is the case for Pacira BioSciences, which filed a lawsuit against the American Society of Anesthesiologists (ASA) last month for “false and misleading conclusions” about the effectiveness of Pacira’s flagship product Exparel, an injectable non-opioid analgesic used for postoperative pain.

In February, the ASA published two research articles and an editorial in its journal Anesthesiology saying Exparel works no better than other bupivacaine products on the market. New Jersey-based Pacira considered that libelous, and filed a complaint in federal court seeking a retraction and damages for lost business.

Now comes word that Pacira’s attorneys withdrew their motion for a retraction after the ASA asked the court for a prompt hearing “to expose flaws in Pacira’s claims.”

“It is vitally important that we defend and stand behind these three works and the integrity and scholarship of those who contributed to them,” said Evan Kharasch, MD, editor-in-chief of Anesthesiology. “These authors are leading physicians and researchers in the fields of anesthesiology and clinical studies. Physicians and patients must have trusted information on which to base clinical decisions and care, and that information needs to be unaffected by commercial interests.”

It is not yet clear if Pacira will withdraw the rest of its libel case. “Our corporate policy is not to comment on pending litigation,” a spokesperson told PNN.

This is not the first time Pacira has used aggressive tactics to promote Exparel or fend off criticism. In 2014, the company filed a lawsuit against the FDA after the agency sent a warning letter to Pacira for off-label marketing of Exparel. The FDA said Pacira promoted Exparel for “surgical procedures other than those for which the drug has been shown safe and effective.”

Pacira won that case in an out-of-court settlement after the FDA backed down, withdrew its warning letter and changed Exparel’s label to say that it can be used for more types of post-operative pain.

In addition to doubts about Exparel’s effectiveness, some have questioned its cost. A 2015 STAT story pointed out that a vial of Exparel cost $285 and provided no better pain relief than a $3 vial of generic bupivacaine. 

In 2016, Pacira funded a report by an expert panel at the Jefferson College of Population Health that called for greater use of non-opioid medication for post-operative pain. One of the non-opioids recommended by the panel was Exparel. Pacira’s funding of the project was only noted at the end of the report.

In 2020, Pacira agreed to pay $3.5 million to resolve federal allegations that it gave kickbacks to doctors in the form of fake research grants that promoted Exparel.

Pacira has also been active politically, spending over $1.7 million on lobbying and campaign donations since 2018, according to OpenSecrets.org.

In 2019, Pacira hired former New Jersey Gov. Chris Christie as a consultant for $800,000 and lucrative stock options. The move was controversial, because Christie had just chaired President Trump’s opioid commission, which recommended that Medicare and Medicaid reimbursement policies be changed to encourage hospitals to use more non-opioid painkillers.

All this suggests that Pacira won’t back down easily from a fight. But it doesn’t sound like the ASA will either.

“Although Pacira started this lawsuit, ASA will not shy away from refuting Pacira’s claims and from exposing the important issues with Pacira’s controversial drug,” the ASA said in a news release.

Zynrelef Approved

Pacira is about to get more competition in the post-operative pain market. San Diego-based Heron Therapeutics says it has received FDA approval for Zynrelef, an extended-release analgesic for use by adults up to 72 hours after a bunionectomy, hernia repair and total knee replacement surgery.

Zynrelef combines bupivacaine with a low dose of the nonsteroidal anti-inflammatory drug (NSAID) meloxicam. In clinical studies, the company says the synergy between the two drugs resulted in patients experiencing significantly less pain with less use of opioids compared to bupivacaine alone.

"The first three days after surgery are when patients experience the most severe postsurgical pain and are most likely to receive opioids to manage that pain. With the impressive reduction in pain and opioid use demonstrated by Zynrelef, we now have an important new option to help many patients achieve an opioid-free recovery," said Roy Soto, MD, an anesthesiologist at Beaumont Health System who consults with Heron. 

The company expects Zynrelef to be available by July. Patients are advised not to take the drug if they are allergic or have side effects from NSAIDs. The most common side effects of Zynrelef are constipation, vomiting and headache.

Hospira Recall

Pfizer’s Hospira division is voluntarily recalling a single lot of bupivacaine and a lot of lidocaine due to mislabeling that caused some of the vials to be incorrectly labeled as the other product. Both drugs are used to treat surgical pain. The mislabeling was identified after a customer complaint.

Hospira assessed the potential risk to patients if the mislabeled products were used to be “moderate to high severity.” If the mislabeled lidocaine was administered to a patient instead of bupivacaine, the patient may not get enough pain relief. If the bupivacaine was administered instead of lidocaine, the outcome could be even worse: an overdose of bupivacaine may occur, which could lead to seizures, respiratory problems, irregular heartbeat and cardiac arrest.

The recalled lots were distributed nationwide to wholesalers and hospitals in the United States, Puerto Rico and Guam from December 29, 2020 to April 15, 2021.

Hospira has not received reports of any adverse events associated with the mislabeling. The company did not respond to a request to explain how the mislabeling occurred or how it went undetected for nearly five months.

Study: Opioids Not Always in Patient’s Best Interest

By Pat Anson, Editor

An industry funded report is calling for greater use of non-opioid medication for post-surgical pain to combat what it calls the “frightening reality” of the opioid epidemic.

The report by an expert panel convened at the Jefferson College of Population Health in Philadelphia claims that relieving a patient’s acute pain with opioids is expensive and “not always in their best interest” because it could lead to addiction.

“The added costs attributable to misuse and abuse of opioid prescriptions originating in the acute care setting are considerable. With steadily increasing numbers of surgical procedures being performed, even small increments in the percentage of chronic opioid users will create an unsustainable societal burden,” wrote lead author Janice Clark, RN, Jefferson College of Population Health.

The report also endorsed efforts to have Medicare eliminate a requirement that hospitals ask patients about the quality of their pain care in patient satisfaction surveys.

“Patient satisfaction has been associated with greater inpatient use, higher health care and prescription drug use and expenditures, and increased mortality. Clearly, giving patients what they want, or think they need, is not always in their best interest,” wrote Clark and her two co-authors.  

“There is so much wrong with this article it is hard to know where to start,” says Janice Reynolds, a patient advocate and retired nurse who specialized in pain management and oncology. She called the report “opiophobic” and unethical.

“It is unconscionable these people say the person in pain cannot say whether his pain was well managed or not,” said Reynolds. “Pain is what the person says it is, existing when he says it does.  It is subjective.  Only the person experiencing it knows if treatment was effective or not, as well as whether he was treated in a compassionate, empathic manor. “

The report’s recommendations -- which are being published in the journal of Population Health Management -- are very similar to guidelines released last month by the American Pain Society, which also promote the use of non-opioid medication for post-surgical pain.

“A wide variety of effective alternatives to opioids for pain management are available and patients need to be educated on what strategies are most appropriate for their procedure,” wrote Clark, who said in an email to Pain News Network the Jefferson College report did undergo peer review prior to publication.

The report calls for greater use of acetaminophen, non-steroidal anti-inflammatory drugs (NSAID’s) and preglabin (Lyrica) for post-surgical pain, as well as an injectable bupivacaine delivery system called Exparel that was developed by Pacira Pharmaceuticals, a New Jersey drug maker. 

The report was sponsored by Pacira and the company’s vice-president of medical health sciences, Richard Scranton, MD, was one of its co-authors.

At times the report reads like a promotion for Exparel, calling it an “innovative delivery system” that achieves “effective pain relief at substantially smaller doses.”

“In the acute pain space, where patients now ask for drugs by name, there is unprecedented risk of overprescribing, overuse, and misuse—particularly of opioid drugs. Exparel is an opioid alternative with equivalent pain control that reduces the need for postsurgical opioids and devices,” the report says.

“There should have been a disclosure up front that the company sponsoring the study makes Exparel,” said Reynolds.   

There is an acknowledgement on Page 2 of the 12-page report that Pacira Pharmaceuticals sponsored it, but the company is not identified as the maker of Exparel, which accounts for virtually all of the company's revenue.

Pacira Pharmaceuticals received a warning letter from the Food and Drug Administration in 2014 for its off-label promotion of Exparel, which was initially only approved for pain caused by bunion or hemorrhoid surgery. The U.S. Justice Department also subpoenaed the company for documents related to its marketing and sales of Exparel. 

“These additional materials suggest an extensive promotional campaign by Pacira to promote the use of Exparel in surgical procedures other than those for which the drug has been shown safe and effective,” the FDA letter states.

Pacira filed a lawsuit against the FDA claiming its first amendment rights were being violated. In an out-of-court settlement late last year, the FDA withdrew the warning letter and Exparel’s label was updated to state that it can be used for other types of postsurgical pain. The case was widely seen as a defeat for the FDA that could greatly expand the use of off-label marketing by drug companies.

A recent story by Stat questioned whether a $285 vial of Exparel provided any better pain relief than a $3 dose of bupivacaine after knee surgery.  The article also points out that other post-operative pain studies were conducted by researchers who received funding from Pacira.