Published: Dec 22, 2013
By John Fauber, Reporter, Milwaukee Journal Sentinel/ MedPage Today
For years following spine surgery, Anthony Fort suffered.
And like many with his condition, the 46-year-old gospel singer and former construction worker used a combination of medications to alleviate his pain.
But as he took more drugs, including narcotic painkillers, Fort was often groggy when awake. When he slept, he gurgled and snored so loudly that his fiancee recorded it so she could convince him he was using too much medication.
On May 18, 2011, he didn't wake up.
According to the Milwaukee County Medical Examiner Office he died of an accidental overdose of opioids.
Tramadol, a "Safe" Pain-Killer
Included in the mix were drugs well-known for their abuse and overdose potential -- hydrocodone and methadone -- and one that the medical world long had thought posed little threat: tramadol.
But doctors -- and the FDA, the agency charged with regulating drug safety -- may have gotten it wrong.
Recent research shows that tramadol has greater potential to be abused and to cause overdoses than was believed when it first appeared on the U.S. market in 1995.
A Journal Sentinel/MedPage Today investigation found that the FDA failed to heed a key piece of research indicating tramadol had the potential to be abused. Instead, the agency recommended not putting tramadol under the Controlled Substance Act. Restrictions on prescribing it are no more stringent than for Lipitor or Viagra.
The Controlled Substance Act places drugs into five progressively restrictive categories based on their abuse potential. At the top of the list are drugs such as heroin. At the other, are some cough medicines with limited amounts of codeine.
In approving tramadol, the FDA decision was based largely on research in which the drug was injected. The FDA also weighed evidence from Europe, where tramadol had been on the market for years.
But the FDA also had research showing that when given to opioid abusers orally in high doses, rather than being injected, it produced opiate-like effects that were similar to oxycodone, the narcotic in OxyContin, one of the most abused drugs in America.
The FDA did ask Ortho-McNeil, the company that marketed the tramadol, to fund a committee of paid consultants who were to watch for abuse problems that might require making it a controlled substance.
That never happened.
Emerging Danger
Now, after 18 years of less restrictive treatment, the U.S. Drug Enforcement Administration has proposed putting tramadol under the Controlled Substances Act. While that has not been done on the federal level, 10 states already have done so on their own.
An analysis by the Journal Sentinel and MedPage Today revealed that tramadol use has increased dramatically since 2008, rising from 25 million prescriptions that year to nearly 40 million in 2012, according to data from IMS Health, a market research firm.
In 2011, the drug was linked to 20,000 emergency department visits around the country.
In Florida alone, there were 379 overdose deaths involving tramadol in 2011, up from 106 in 2003.
In Milwaukee County, 20 people died of a drug overdose involving tramadol from 2010 through October 2013, according to records from the Medical Examiner's Office. In most of those cases, tramadol was one of several opioids that had been taken.
In May of 2011, Fort was found in bed not breathing by his fiancee, Latrice Wells Odom.
She said Fort started taking tramadol about 9 months before he died.
"I said, 'I don't like what it's doing to you,'" she said. "He said, 'Baby, I'm in so much pain.'"
Fort had been taking narcotic painkillers after injuring his back at a construction site several years earlier, Wells Odom said. A beam fell on his back, leading to surgery and the placement of 10 screws and a rod in his spine.
She said he never thought the tramadol might be dangerous.
"Tony's thing was, the doctor gave it to him so it must be safe," she said.
Tramadol was first introduced in Germany in 1977.
Evidence Overlooked
Data from Germany had suggested it was only about one-tenth as potent as morphine when injected. Other data showed that after years of use in Germany and other countries there was very little abuse of the drug.
However, in the early 1990s, researchers at Johns Hopkins University did a study in which high doses of the drug were given orally to opioid abusers. Taken that way, tramadol acted much differently than when injected.
At very high doses it produced opiate-like effects that were similar to high-dose oxycodone.
Taken by mouth, the drug is transformed in the liver to a metabolite known as M1, which is able to attach to and activate opioid receptors in the brain. It is that substance that is believed to produce the desirable, opiate-like effect.
In 1994, Ortho-McNeil, part of the R.W. Johnson Pharmaceutical Research Institute of Johnson & Johnson, sought approval from the FDA to sell Ultram, its brand name version of the drug in the U.S.
The Johns Hopkins study never was published but the company said it was provided to the FDA when it was reviewing the approval for tramadol.
"That paper certainly was accurate," said Thomas Kosten, MD, an addiction specialist and professor of psychiatry at Baylor College of Medicine. "You take enough of it, you can get high from it."
Sharon Walsh, PhD, an opioid researcher at the University of Kentucky College of Medicine, said the research provided important evidence that tramadol had the potential to be abused.
Given the findings of the Hopkins study, it is unlikely the FDA would approve tramadol today as a nonscheduled drug, said Walsh, director of the university's Center for Drug and Alcohol Research.
But in the early 1990s, when the FDA approved the drug, abuse of opioids such as heroin and morphine often was done by addicts who injected the drugs. In the years that followed, dramatic increases in abuse of pill-form opioids such as OxyContin and Vicodin would plague the country.
Following the Money
Journal Sentinel/MedPage Todayinvestigations have showed that opioid companies paid millions of dollars to doctors and nonprofit medical societies that pushed for more liberal use of the drugs in treating chronic, noncancer pain. Yet, rigorous studies never have shown that the drugs are safe and effective when used that way.
Morgan Liscinsky, a spokeswoman for the FDA, said she could not comment on the agency's decision-making process that led to the drug's approval as a noncontrolled substance. As tramadol's public health and abuse risks became more fully recognized, the FDA now has recommended making it a controlled substance, she said.
Liscinsky noted that, at the time, the FDA's advisory committee unanimously said the drug should not be put under the Controlled Substances Act.
Yet there was concern that abuse of the drug might occur in the U.S., which was why the FDA asked an "independent steering committee," to monitor the drug as part of the FDA's marketing approval. Ortho-McNeil paid for the committee's work and also paid consulting fees to its members.
Sidney Schnoll, MD, PhD, a former member of the committee, said he could not remember how much the committee members were paid. In total, the program cost Ortho-McNeil about $15 million a year, said Schnoll, now an executive with Pinney Associates, a Bethesda, Md. company that works with drug and opioid companies.
From early on, Ortho-McNeil's marketing plan for tramadol meant keeping it off the controlled substances list where it would have difficulty competing against other narcotic painkillers such as Tylenol 3 and Tylenol 4, Schnoll said in a 2009 interview. Both Tylenol products contain codeine and are schedule 3 drugs.
The interview was done with two professors, one from the University of Florida and one from Rensselaer Polytechnic Institute in New York, as part of a project at University of Michigan Substance Abuse Center.
"There were equally good products that were cheaper on the market," he said, according to a transcript of the interview. "So they really wouldn't have much of the market. They wanted to see if it would be possible to get the drug onto the market as a noncontrolled substance."
After a decade, the eight-member Ortho-McNeil committee dissolved itself in December 2005, without ever having recommended that tramadol be put under the Controlled Substances Act.
"There was absolutely nothing independent about this group," said Andrew Kolodny, MD, a New York addiction specialist and advocate of tighter controls on opioids.
In an email, Pam Van Houten, a spokeswoman for Johnson & Johnson, said no one from the company was on the committee and only committee members were allowed to attend its deliberations and monthly meetings. Van Houten did, however, add that there were occasional circumstances when company officials were invited to committee meetings.
Moreover, Van Houten said the committee's funding always was disclosed.
Tramadol "Trending"
Walsh, the University of Kentucky researcher, and others have done their own studies on oral tramadol showing that experienced opioid abusers like it as much or more than oxycodone.
In a 2012 study, they gave up to 400 mg of tramadol, about four times the normal single dose, and oxycodone to nine opioid abusers.
On the next day, the test subjects sat at a computer. They were told they would be given the drugs again in increments if they clicked a mouse to earn it. The mouse clicking progressively increased for each additional increment of the drug. To get all the drug, they would have to click the mouse 7,800 times.
Five of the nine test subjects clicked the mouse at least 5,300 times to get the high-dose tramadol, compared with only one who did so to get the high-dose oxycodone.
"That was really surprising to us," said lead author Shanna Babalonis, PhD, an assistant professor of behavioral science at the University of Kentucky.
The likability of oral tramadol can be seen in the large numbers of people who have used it recreationally.
In 2011, 2.6 million people ages 12 and older used tramadol for nonmedical purposes, according to the DEA. The DEA said the drug is most commonly abused by addicts, chronic pain patients, and health professionals.
Over the years, there had been indications that the drug was being abused, but Ortho-McNeil has fought efforts to make tramadol a controlled substance.
In 2006, the company argued that by making it a controlled substance, doctors would be less likely to prescribe it for chronic pain. It cited concerns about the stigma attached to opioids and what it called "opiophobia." The comments were made in a document filed with the FDA in response to an inquiry by the World Health Organization over whether tramadol should become a scheduled narcotic internationally.
Van Houten, the company spokesperson, said the company is reviewing the DEA's proposal to put tramadol under the Controlled Substances Act.
She said the company no longer actively promotes its tramadol product, Ultram, in the U.S.
"Tramadol has been and remains an important medicine used to treat moderate to moderately severe pain in adults," Van Houten said.
DEA Petitions
In 2005, the DEA received four petitions to put tramadol under the Controlled Substances Act in the U.S., three that asked that it be a schedule 3 drug.
Last month, the DEA recommended that it be put under schedule 4 of the act.
Similar concerns about tramadol abuse and overdoses have been raised recently in Great Britain.
In February, the country's Advisory Council on the Misuse of Drugs noted that deaths in which tramadol was mentioned on the death certificate nearly doubled between 2008 and 2011. Prescriptions for tramadol in England also increased from 5.9 million in 2005 in 11.1 million in 2012.
The council recommended that tramadol become a scheduled drug, which would make it a crime to use it or deal it without a prescription. It also said doctors should be given training regarding the drug's possible misuse by patients and the serious complications it can cause.
In the U.S., those who most often prescribe are likely to be on the front line of medicine.
A MedPage Today/Milwaukee Journal Sentinel analysis of IMS Health prescription data shows that over the last 2 years, the top prescribers of tramadol have been family practice doctors, internal medicine physicians, osteopaths, nurse practitioners, and physicians assistants.
More than two-thirds of tramadol prescriptions from 2012 through October, 2013 were written by those health professionals.
Walsh, the University of Kentucky opioid researcher, said she believes that many doctors who prescribe tramadol take their direction from whether a drug is a scheduled narcotic.
"I suspect they don't know about its abuse potential," she said.
Two years after Anthony Fort's death, his former fiancee still has the recording of his loud snoring and gurgling that she made on the day he died.
She was going to play it back to him later in hopes that it would make him realize that the medications he was taking were affecting his sleeping.
After making the recording, she went to the store. She said she only was gone about a half hour.
"I wanted him to listen to it because it scared me," she said. "But it was too late."
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