Spinal Fusion Patients Immobilized by Pain
by John Fauber, Reporter
Milwaukee Journal Sentinel/MedPage Today
September 18, 2011
Tom Engel goes on a ventilator at night because the opioid painkillers he takes for his back pain cause central sleep apnea. Hidden under Tom Engel's skin is a small device that around the clock pumps a morphine-like drug into his spinal column and ultimately into his brain.
Without it, his back pain would be unbearable.
Before getting the pump, Engel underwent two surgeries in which a product known as Infuse (bone morphogenetic protein-2 or BMP-2) was implanted in his spine in an effort to relieve his back pain.
The first surgery, in 2002, used the product according to the label indications approved by the Food and Drug Administration. The second, in 2004, used the product in an unapproved "off-label" way.
A Pain that Knows No End
"He doesn't even go to church anymore," said his wife, Rita. "We went to church all our lives. He can't walk that far and the drugs put him to sleep."
Engel's experience puts him at the center of a growing medical controversy surrounding the product and Medtronic, the company that markets it.
The product's growth to $700 million a year in sales was built on questionable research by doctors with financial ties to Medtronic, relationships that were not always fully disclosed in articles published in medical journals.
Now, the company faces investigations by the U.S. Justice Department, a U.S. Senate committee and a group of reformed-minded surgeons.
The Senate investigation and an unprecedented scientific and financial expose of the product in the Spine Journal in June were prompted in part by stories published in the Milwaukee Journal Sentinel and MedPage Today.
Engel, with his wife, Rita, has undergone two spinal fusions with Infuse, including an off-label surgery in 2004. Those articles found that as Medtronic paid out tens of millions of dollars in royalties to prominent spine surgeons around the country, those doctors produced favorable articles for medical journals. In those published studies, the authors often failed to link the product to serious complications, including the formation of unwanted bone in the spinal canal, dissolving bone, radiating leg and arm pain, infections, cancer risk and sterility in men.
None of the royalties were for Infuse.
Infuse was approved in for narrow use. It seemed like a triumph of biotechnology that would spare patients from a minor operation to harvest a small amount of their own bone for use in spinal fusion surgery.
But today, as much as 80% of its sales reflect unapproved uses (uses that were neither rigorously tested nor proven to be safe and effective, studies show).
More than 500,000 people have gotten Infuse implants since the product came on market in 2002. Doctors say many of them have benefited from it. But others have suffered.
Engel, who lives in the Milwaukee area, can attest to how such surgeries led to unrelenting pain. He now has what is known as Failed Back Surgery Syndrome, according to his doctor, Don Harvey MD.
It is a common condition at pain clinics around the country, said Harvey, a pain specialist with Advanced Pain Management in Sheboygan, Wisc.
"We have a national epidemic of that," said Harvey, who was not involved in Engel's spine surgeries.
He said 10% to 15% of the patients he sees have failed spinal fusions.
Harvey said many orthopedic surgeons were quick to start using Infuse because the medical literature was filled with reports of how well it worked, articles that often were authored by doctors who had financial relationships with Medtronic.
"This is an ugly story for the practice of medicine," he said. "An awful lot of really good (doctors) are probably second-guessing themselves as to having used Infuse."
In Engel's case that tale became a cruel irony: The morphine pump in his abdomen also is made by Medtronic.
They Won't Be Doing Testimonials
John Lane, his wife, Kathleen, and their two sons. The family lives in O'Fallon, Mo. Like Engel, John Lane, of O'Fallon, Mo., is not likely to show up in patient testimonials for Medtronic.
In an x-ray Lane's neck looks bionic (a series of rods, screws and other hardware affixed along his spine).
Lane, now 46, already had undergone surgery on his neck without Infuse when he went to see Timothy Kuklo, MD, a confident orthopedic surgeon and West Point graduate who had come to Washington University in St. Louis from Walter Reed Army Medical Center.
Though the first fusion surgery in 2006 failed to relieve Lane's pain, Kuklo was reassuring. According to Lane, Kuklo told him there was a 95% chance that he would get at least 90% pain relief.
"He basically said, 'I can fix you,'" Lane said. "'This is no big deal. You are going to be well.'"
Kuklo's remedy: Perform another cervical fusion, this time with Infuse, using it in an off-label and potentially risky manner that, months earlier, had been the subject of an FDA warning.
In 2009 (just a few months after he operated on Lane) Kuklo would be making headlines nationally as the subject of an ethics investigation.
Kuklo was accused of a number of ethics violations, chief among them were allegations that he forged the signatures of several co-authors on a positive 2008 study involving the use of Infuse on severe shinbone fractures in combat soldiers injured in Iraq. Kuklo came to Washington University as a retired Army orthopedic surgeon.
In March, 2009, James Scott, the editor of the Journal of Bone and Joint Surgery, the British medical journal that published Kuklo's 2008 study, took the unusual step of retracting the paper from the scientific literature and banning Kuklo from publishing future research in the journal.
Washington University later found that Kuklo had committed research misconduct, but it failed to find sufficient evidence that he falsified data.
In news accounts at the time, Medtronic acknowledged paying Kuklo about $800,000 between 2001 and 2009. The company would not confirm that figure for this story.
Kuklo, who now practices at the Colorado Comprehensive Spine Institute in Englewood, Colo., declined to comment.
His attorney, Henry Dane, said the Army's investigation of Kuklo was one-sided and based largely on unsubstantiated allegations by a junior colleague. He said Kuklo was not allowed to obtain a lawyer to represent him.
"Despite the unfortunate fall out from his relationship with Medtronic, Dr. Kuklo is a distinguished and dedicated medical researcher and clinician who has published 120 peer-reviewed journal articles and chapters," Dane said.
A letter obtained by Journal Sentinel and MedPage Today indicates that as of June 22, Medtronic's activities with Kuklo and other doctors still were being investigated by a federal grand jury in Boston.
The letter was sent by Secretary of the Army John McHugh to U.S. Sen. Chuck Grassley (R-Iowa) as the ranking member of Senate's Committee on the Judiciary.
In June, Grassley, also the senior member of the Senate Committee on Finance, and Sen. Max Baucus (D-Mont.), chairman of that panel, began an investigation of whether complications with Infuse were not reported in journal articles co-authored by doctors with financial relationships with Medtronic.
McHugh wrote that a criminal investigation unit of the Army was supporting the federal grand jury investigation and that other agencies and federal investigative units were interviewing witnesses and reviewing documents.
Breaking the Doctor-Patient Bond
A scan of Lane's cervical spine shows past surgeries. He underwent an off-label fusion with Medtronic's Infuse in 2009. Lane said he was not aware of Kuklo's extensive ties to Medtronic when Kuklo operated on him, nor was he aware of the various ethics questions.
At first, Lane said, he did well after the surgery. When stories began to surface about Kuklo's ethical problems at Walter Reed and Washington University, Lane defended him. He even wrote a letter to a newspaper attacking the coverage of Kuklo.
But his condition worsened after a few months, as more and more troubling developments unfolded.
Lane said bone spurs formed in his neck and new bone pressed on his spinal cord. The pain, he said, now is indescribable and unrelenting.
He has undergone three surgeries since the Kuklo operation to help relieve the pain.
Lane said he is troubled that Kuklo did not tell him that he would be undergoing an off-label surgery and that there were options other than using Infuse.
"If they were going to use me as an experiment or a guinea pig, I would have like to had options and the facts," he said.
Dane said his client, Kuklo, would not have said there was a 95% chance of the operation's success or "anything approaching that expectation. I have no idea where Mr. Lane got those numbers."
He noted that off-label use of medical devices is both permissible and common.
Nothing Kuklo did contributed to Lane's worsening condition and Infuse was not the root of his problem, Dane said.
In January, Lane filed a lawsuit against Kuklo. The suit was dismissed on what his attorney said were procedural grounds. They intend to refile it.
During an interview in August, as Lane sat at his kitchen table, his left hand is shaking. His arm, he said, is numb and weak. He tells the visitor that he would rather be in bed.
Lane takes two different kinds of narcotic painkillers, a muscle relaxer, a sleeping pill, another type of pain medicine and an antidepressant.
"The medicine doesn't make the pain go away," he said. "All it does is drug you. If I didn't have it, I wouldn't be able to get out of bed ever."
Even with the painkillers, "I can't do much of anything," he said.
He spends much of his day lying in bed on his right side with a laptop.
"I watch Netflix a lot," he said.
Lane spends a lot of time in bed because of on-going pain after spinal surgery. Lane, who owned and operated a window and siding business before his surgeries, said he no longer can work.
When his two sons, ages 12 and 8, want to play catch, he struggles to toss the ball and later he pays a price in pain.
"We went from being really independent people who did not need help to needing a lot of help," said his wife, Kathleen.
Doctors say the rapid acceptance of Infuse by spine surgeons was due partly to the fact that it made spinal fusion surgery easier.
In the past, getting a successful fusion required more surgical skill, but Infuse worked so well at growing bone that the operation became simpler, said Rahul Vaidya, MD, an orthopedic surgeon at Detroit Medical Center, who has done research on problems with Infuse.
And although Infuse was approved for a specific type of fusion surgery, surgeons were eager to try it in other unapproved and less-tested ways, partly because of all the hype in the medical literature.
"It's a great product," Vaidya said. "It was just badly brought to market. The orthopedic industrial complex jumped on the product and everyone thought they would make money. And maybe they weren't as judicious or ethical as we would have liked them to be."
A scar from one of several surgeries done on Lane's neck. It is a familiar story.
Once a medical device or drug gets on the market it is not uncommon for doctors to use it in ways for which its safety and effectiveness are not established and approved through a rigorous clinical trial. While some patients may benefit from off-label use of a new medical technology, such use also exposes them to the potential for greater hazard because the safety of the product in those situations is not completely known.
That's especially true when a product is not just an improvement on an existing therapy but entirely new technology like Infuse.
Compounding the problem is the fact that Infuse or BMP-2 really is a drug, but technically it is classified as a device.
For years, spine surgeons primarily worked with hardware such as screws, plates, rods and cages. Suddenly they were being asked to administer a clear, biologically active liquid and to keep it confined to a small space between vertebrae.
Medtronic spokeswoman Marybeth Thorsgaard said the company has been clear in warning that Infuse is not indicated for use in the cervical spine.
She said that in 2005 a warning regarding cervical complications was added to the package insert for Infuse and the company also warned doctors about the complications.
"Patient safety is always front and center for Medtronic," she said.
For example, she noted that Medtronic contracted with Yale University to conduct two independent systematic reviews of the safety and effectiveness of Infuse. The company took the action following publication of the Spine Journal expose.
Another Infuse Warning
Lane and his wife, Kathleen, talk about how his pain and disability increased after undergoing cervical spine surgery with the Medtronic product known as Infuse in 2009.
Last October independent ear, nose and throat specialists at the Henry Ford School of Medicine in Detroit published a damning study about Infuse when used in off-label cervical spine procedures from the front.
The study, which did not get much attention, looked back at 260 Infuse patients and found a substantially higher incidence of acute airway obstruction due to inflammation when compared with 515 patients who underwent similar operations without Infuse.
As a result, unplanned intubations and tracheotomies after the spine surgery were needed nearly four to five times more often in the Infuse patients. Respiratory failure occurred more than three times more often than in their non-Infuse peers.
In addition, use of Infuse in the cervical spine was linked to deaths in 4.2% of patients, compared with 1.7% of patients who did not receive Infuse.
It also had significant cost with an average hospital charge of $129,483 in Infuse patients and $74,974 in non Infuse patients.
Lead author Kathleen Yaremchuk, MD, chairman of the department of otolaryngology, head and neck surgery at Henry Ford, said she believes use of Infuse in the cervical spine remains common in the U.S, despite the all the concerns.
"The purpose of this was patient safety," she said in an interview. "There are more reports saying it is dangerous than it's not. And there is nothing to show it improves outcomes."
A Promising Start
Tom Engel, the Milwaukee patient who relies on a tiny implanted device to keep his pain at bay, first encountered Infuse in 2002 shortly after it the FDA approved it.
It was an on-label fusion in his lumbar spine performed by Arvind Ahuja, MD, a surgeon at Aurora St. Luke's Medical Center. Two years later Ahuja did an off-label surgery with Infuse.
Ahuja, who does not have a financial relationship with Medtronic, said he now is doing about half the spinal fusions with Infuse that he did just a few years ago. He said he also is using about half the dose.
The reason: complications that were not reported in the medical literature started showing up in his patients.
"We owe to the patients and ourselves to be truthful about the science," he said.
In retrospect, undergoing fusion surgery in the first place was a mistake, the Engels said. Engel said he agreed to it hoping that it would provide a more normal life and relief from his ailing back.
Instead, it led to a downward spiral.
The beds of Rita and Tom Engel sit next to each other on the first floor of their pleasant condominium, though his mattress is elevated because of breathing problems when he sleeps.
Before the couple turns off the lights at night, Engel must flip a different kind of switch.
It's in his throat.
With all the narcotic painkillers flowing into his body, Engel has developed central apnea in which his brain essentially tells his lungs to stop breathing many times a night. Besides ruining his sleep, the condition puts him at risk for a variety of life-threatening conditions, including high blood pressure, stroke, and heart failure.
If he drove, his risk of having a car accident would be five times greater than the risk for a healthy driver.
So in 2009 doctors performed a tracheostomy in which a tube and inflatable cuff were surgically placed in his windpipe. Before he goes to sleep, he hooks the tube up to a ventilator next to his bed and it takes over his breathing.
It just another device that's been implanted into his 65-year-old body over the last decade. A morphine pump in his abdomen; rods, screws, small metal cages and Infuse in his spine.
"It's not a good life," said Phil DeTrana, MD, the physician and sleep specialist who implanted the tracheostomy tube in Engel.
But it gives him a much better night's sleep, more energy during the day, and it helps keep him alive.
"Knowing what we know now, we would have never went for the surgery," Rita added. "He was a healthy man except for a very bad back."
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