The University of Minnesota Medical Center is betting big on an off-label use of a new anesthetic, hoping doctors can use it to relieve postoperative pain without the need for addictive opioids.
But some doctors worry that the hospital is pushing beyond government and hospital safety protocols and being influenced by the pharmaceutical industry.
The controversy centers on Exparel, which won federal approval in 2011 for use during operations, when it is injected by a surgeon into a patient’s surgical wounds to manage their pain. Led by Dr. Jacob Hutchins, a group of university anesthesiologists has gone a step further: They inject the drug into patients before surgery to reduce their pain while in recovery.
This off-label approach may one day prove superior at managing postoperative pain and reducing patients’ needs for opioid painkillers, which are so addictive and heavily prescribed that they have contributed to an alarming increase in overdose deaths. Just last week, the state Department of Health reported that 216 Minnesotans died from prescription opioid overdoses in 2015, a tenfold increase since 2000.
On the other hand, the U.S. Food and Drug Administration already rejected this use of Exparel, and there is little proof that it is safer or controls pain better than alternatives.
No other Twin Cities’ hospital system uses Exparel in this way as a “peripheral nerve block,” an injection that blunts key nerves that transmit pain signals from an injury site to the brain.
Experimentation is part of the mission of an academic medical center, but skeptics point out that U anesthesiologists are using Exparel off-label without making patients part of a controlled study.
Two doctors, speaking to the Star Tribune on the condition of anonymity, said this use of Exparel has prompted some anesthesiologists to leave the university. Two other anesthesiologists confirmed that they left the university but declined to comment on why.
One of the concerned doctors, who still works at the U, said the “unknown risk” of the off-label approach outweighs the “questionable benefit.”
Another, who has since left, acknowledged that off-label prescribing is an everyday practice in medicine. But he said there is a difference between using drugs in ways the FDA hasn’t yet reviewed, and using them in ways the FDA rejected.
“That’s not off-label anymore,” he said. “You have to come up with a new term.”
The doctors also expressed concern about Hutchins’ role as a paid adviser to Pacira, the New Jersey-based manufacturer of Exparel. According to Medicare federal open-payment records, he received $189,020 from Pacira in 2014 for consulting and speeches along with the requisite travel, lodging and meal expenses. That was the second-highest sum paid by the company to any U.S. physician for non-research purposes.
Asked about the potential for conflict, Hutchins said he always discloses his relationship with Pacira to patients and in publications.
Hutchins said the relationship benefits patients and doctors because it allows him to pass on his clinical observations — that many patients receiving off-label Exparel enjoy shorter hospital stays, less nausea, and improved pain control with fewer opioids.
“The work I do … actually allows me to help patients all across the country,” he said.
The influence of industry money has been a sticky subject, nationally and locally. Critics questioned the millions of dollars that Medtronic PLC paid a decade ago to Dr. David Polly, a U spinal surgeon, for his work with the company’s Infuse bone grafting product. And a long-running controversy regarding the 2004 suicide of a schizophrenia research subject had its roots in a U study funded by drugmaker AstraZeneca.
The U has since adopted ethics reforms to limit conflicts while maintaining private funding, which is considered important in an era of dwindling public grants.
Dr. Michael Wall, anesthesiology chairman at the U, said Hutchins’ work complies with those policies. He praised Hutchins’ work as part of an effort to upgrade the amount of grant funding and the quality of research and residency training in a department which 10 years ago was placed on probation by its accrediting body for academic deficiencies.
Blessing and a curse
Postoperative pain is often treated with bupivacaine, which is administered via a catheter to inhibit pain signals that nerves transmit to the brain. Exparel contains bupivacaine, but is formulated for slow release and longer effectiveness; as a result, an Exparel injection stays in the area around the nerves longer and doesn’t require a patient to be tethered to a catheter.
The blessing of Exparel might also be its curse, because the long-acting drug doesn’t clear out of the body quickly.
“If there is a complication or something is going wrong, it’s there,” said Dr. John Mrachek, an anesthesiologist at Allina Health’s Abbott Northwestern Hospital in Minneapolis. “You can’t go back in and suck that drug out.”
Allina doctors do not use Exparel off-label, he said.
Surgeons at Mayo Clinic use Exparel, but its anesthesiologists do not use it off-label, said Mayo’s Dr. J.P. Abenstein, past president of the American Society of Anesthesiologists.
Abenstein said he wouldn’t use the drug off-label unless as part of a clinical study approved by Mayo’s institutional review board. However, he understands the appeal; a long-acting pain reliever without a catheter can hasten patients’ mobility, which aids recovery. “If it works for 36 hours,” he said, “that’s a day and a half of a happy patient.”
The current and former U doctors said a concern with Exparel is its potential toxic effect on nerves, which can cause prolonged weakness, numbness, tingling and anxiousness for recovering patients. A toxic reaction is a rare concern when any form of bupivacaine is used, Hutchins replied, which is why an antidote is on hand throughout the hospital. (Its effect on Exparel has been poorly studied to date, though.)
Due to concerns about off-label prescribing in a way that the FDA rejected, Hutchins said he checked with the agency. E-mails from January 2015 show he also checked with the university’s associate general counsel, Ruth Flynn. She replied that doctors should inform patients of the off-label use, document that such a conversation occurred, and give patients handouts about the risks of off-label drugs.
Even after receiving this information, most patients say ‘Yeah, give me the drug that lasts longer so I have less pain,” Hutchins said.
Wall added that many drugs in anesthesiology are used off-label without this level of information. “This is the only [anesthesia] drug I know of where we’re gaining consent to use it off-label,” he said.
Exparel had a controversial emergence in the U.S., because federal regulators accused Pacira of inappropriately marketing it for purposes beyond the two procedures for which it had been closely tested. Pacira subsequently sued the FDA, and reached a settlement last December that permitted the company to market Exparel for wider uses.
Hutchins was among the first researchers to publish results using Exparel for a certain kind of nerve block called TAP, which relieves pain after abdominal surgeries. It also was considered off-label until the FDA court settlement.
His February 2015 report in the International Journal of Gynecological Cancer reviewed 60 patients after hysterectomies and found less postoperative pain and quicker discharges among those who received TAP blocks with Exparel.
“I do believe it is only a matter of time until this is approved for peripheral nerve blocks as well,” he said.
Hutchins is not alone nationally in using Exparel for nerve blocks, but most of the completed research to date on the drug traces back to the manufacturer.
Six orthopedic specialists from Texas and Pennsylvania reported this March that they stopped using traditional painkillers after knee replacements because off-label Exparel worked equally well and reduced opioid prescriptions. Five have financial relationships with Pacira, which helped write the report.
More independent analysis is upcoming, though. Among 48 ongoing trials with Exparel listed on the federal clinical trials website, only five are industry sponsored.