How it became America’s most widely abused prescription drug
BY HARRIET RYAN
LISA GIRION AND
LOS ANGELES TIMES
TRIBUNE NEWS SERVICE
The drugmaker Purdue Pharma launched OxyContin two decades ago with a bold marketing claim:
One dose relieves pain for 12 hours, more than twice as long as generic medications.
Patients would no longer have to wake up in the middle of the night to take their pills, Purdue told doctors. One OxyContin tablet in the morning and one before bed would provide “smooth and sustained pain control all day and all night.”
On the strength of that promise, OxyContin became America’s bestselling painkiller.
But OxyContin’s stunning success masked a fundamental problem: The drug wears off hours early in many people, a Los Angeles Times investigation found. OxyContin is a chemical cousin of heroin, and when it doesn’t last, patients can experience excruciating symptoms of withdrawal, including an intense craving for the drug.
The problem offers new insight into why so many people have become addicted to OxyContin, one of the most abused pharmaceuticals in U.S. history.
Claims by Purdue
The Times investigation, based on thousands of pages of confidential Purdue documents and other records, found that:
Purdue has known about the problem for decades. Even before OxyContin went on the market, clinical trials showed that many patients weren’t getting 12 hours of relief. Since the drug’s debut in 1996, the company has been confronted with additional evidence, including complaints from doctors, reports from its own sales reps and independent research.
The company has held fast to the claim of 12-hour relief, in part to protect its revenue.
OxyContin’s market dominance and its high price – up to hundreds of dollars per bottle – hinge on its 12-hour duration. Without that, it offers little advantage over less expensive painkillers.
When many doctors began prescribing OxyContin at shorter intervals in the late 1990s, Purdue executives mobilized hundreds of sales representatives to “refocus” physicians on 12-hour dosing.
Purdue tells doctors to prescribe stronger doses, not more frequent ones, when patients complain that OxyContin doesn’t last 12 hours. That approach creates risks of its own. Research shows that the more potent the dose of an opioid such as OxyContin, the greater the possibility of overdose and death.
More than half of long-term OxyContin users are on doses that public health officials consider dangerously high, according to an analysis of nationwide prescription data conducted for The Times.
Over the past 20 years, more than 7 million Americans have abused OxyContin, according to the federal government’s National Survey on Drug Use and Health.
The drug is widely blamed for setting off the nation’s prescription opioid epidemic, which has claimed more than 190,000 lives from overdoses involving OxyContin and other painkillers since 1999.
Decades of data
The internal Purdue documents reviewed by The Times are from sealed court files. They span three decades, from the conception of OxyContin in the mid-1980s to 2011, and include emails, memos, meeting minutes and sales reports, as well as testimony by executives, sales reps and other employees.
The documents provide a detailed picture of the development and marketing of OxyContin, how Purdue executives responded to complaints that its effects wear off early, and their fears about the financial impact of any departure from 12-hour dosing.
Reporters also examined Food and Drug Administration records, Patent Office files and medical journal articles, and interviewed experts in pain treatment, addiction medicine and pharmacology.
‘Recipe for addiction’
Experts said that when there are gaps in the effect of a narcotic like OxyContin, patients can suffer body aches, nausea, anxiety and other symptoms of withdrawal. When the agony is relieved by the next dose, it creates a cycle of pain and euphoria that fosters addiction, they said.
For people in whom it wears off early, OxyContin taken at 12-hour intervals could be “the perfect recipe for addiction,” said Theodore J. Cicero, a neuropharmacologist at the Washington University School of Medicine in St. Louis and a leading researcher on how opioids affect the brain.
Patients can suffer both a return of their underlying pain and “the beginning stages of acute withdrawal,” Cicero said. “That becomes a very powerful motivator for people to take more drugs.”
Peter Przekop, a neuroscientist and physician who oversees the treatment of painkiller addicts at the Betty Ford Center in Rancho Mirage, said that repeated episodes of withdrawal from OxyContin “absolutely” raise the risk that patients will abuse the medication.
“You are messing with those areas of the brain that are involved in addiction, and you are going to get the person dependent on it,” he said.
The Times sought comment from Purdue’s scientists and executives. At the company’s request, the newspaper submitted detailed questions in writing. Purdue responded with a one-page statement noting that the FDA approved OxyContin as a 12-hour drug.
“Scientific evidence amassed over more than 20 years, including more than a dozen controlled clinical studies, supports FDA’s approval of 12-hour dosing for OxyContin,” said Purdue’s chief medical officer, Dr. Gail Cawkwell.
As a Los Angeles Police Department officer, Ernest Gallego was fearless. He broke up bar fights and street brawls. During a torrential rainstorm in 1980, he waded into a flooded intersection to rescue two motorists.
He was on duty in Echo Park seven years later when a tow truck slammed into his patrol car, leaving him with a career-ending back injury. He had several surgeries and tried various pain medications over the next two decades.
By 2012, he was on OxyContin. His parents and siblings watched and worried as the strong, fastidiously neat man they knew became wobbly on his feet and unkempt. His father, an attorney, wrote letters on his law office letterhead pleading with his son’s doctor to take him off the drug, and his mother hid any OxyContin bottles she found, Gallego’s sister, Kathryn Galvan, recalled.
“He was having car accidents, fender benders. Very groggy all the time,” she said. He spent much of his day sleeping. When confronted, “He would say, ‘I have it under control. I know what I’m doing.’”
When his mother died in 2012, Gallego showed up at the funeral disheveled and confused.
A month and a half later, a police officer found him slumped over the steering wheel of his car in a convenience store parking lot and took him to the hospital. The next evening, he lay down on the floor of his father’s living room, as he often did to relieve his pain. He never awoke. He was 58.
A toxicology test showed lethal levels of oxycodone in his blood. The label on an OxyContin bottle directed Gallego to take an 80-milligram pill every 12 hours, according to the coroner’s office.
Based on the date Gallego filled the prescription, there should have been 44 pills left. There were seven.
Purdue developed OxyContin as a cure for pain –– and for a financial problem.
The company’s owners were the Sacklers, a New York family of physicians and philanthropists who bought Purdue in 1952.
By the late 1980s, the patent on its main source of revenue, a morphine pill for cancer patients called MS Contin, was running out. Executives anticipated a huge loss of revenue as generic versions drove down the price of MS Contin, according to internal company correspondence from the period.
The company was focused on finding a new moneymaker. In a 1990 memo, Robert F. Kaiko, vice president for clinical research, laid out why it was important to develop a second painkiller.
“MS Contin may eventually face such serious generic competition that other controlled-release opioids must be considered,” Kaiko wrote.
Purdue already had developed a technique to stretch a drug’s release over time. In MS Contin, the technique made morphine last eight to 12 hours. Kaiko and his colleagues decided to use it on an old, cheap narcotic, oxycodone.
Sold under several names and formulations, including Percocet and Roxicodone, oxycodone controls pain for up to six hours.
With the delayed-release technique, executives theorized, the drug would last 12 hours – at least twice as long as generics and the high end of MS Contin’s range.
Over the next decade, Purdue sunk more than $40 million into development of OxyContin, Paul D. Goldenheim, then vice president of scientific and medical affairs, wrote in a 2003 court declaration.
Sales and marketing representatives gathered at the company’s headquarters, then in Norwalk, Conn., in March 1995 to start planning the roll-out of the new drug.
The first patients to use OxyContin were women recuperating from abdominal and gynecological surgery at two hospitals in Puerto Rico in 1989.
In the clinical study, designed and overseen by Purdue scientists and paid for by the company, 90 women were given a single dose of the drug while other patients were given short-acting painkillers or placebos.
None of the women were regular users of painkillers, so they were more susceptible to the effects of narcotics.
More patients, trials
Even so, more than a third of the women given OxyContin started complaining about pain in the first eight hours and about half required more medication before the 12-hour mark, according to an FDA analysis of the study.
The study found that OxyContin was safe, relieved pain and lasted longer than the short-acting painkillers.
Purdue moved ahead on two paths: seeking patents for its new drug and running additional clinical trials to secure FDA approval.
In a 1992 submission to the Patent Office, the company portrayed OxyContin as a medical breakthrough that controlled pain for 12 hours “in approximately 90 percent of patients.”
Applying for a separate patent a few years later, Purdue said that once a person was a regular user of OxyContin, it “provides pain relief in said patient for at least 12 hours after administration.”
Before 12th hour
Purdue’s researchers, meanwhile, were conducting at least half a dozen clinical trials, according to the company’s FDA application. In study after study, many patients given OxyContin every 12 hours would ask for more medication before their next scheduled doses.
The label for Purdue’s MS Contin, for example, recommends that doctors prescribe the drug every eight or 12 hours to suit the patient. The morphine tablet, Kadian, manufactured by Actavis, is designed to be taken once a day, but the label states that some patients may need a dose every 12 hours.
Despite the results of the clinical trials, Purdue continued developing OxyContin as a 12-hour drug.
It did not test OxyContin at more frequent intervals.
Approved in 1995
To obtain FDA approval, Purdue had to demonstrate that OxyContin was safe and as effective as other pain drugs on the market. Under agency guidelines for establishing duration, the company had to show that OxyContin lasted 12 hours for at least half of patients. Purdue submitted the Puerto Rico study, which showed that.
The FDA approved the application in 1995.
In a written statement, spokeswoman Sarah Peddicord said that although the FDA approved OxyContin for use every 12 hours, “it should be well understood by physicians that there will be some individual variability in the length of time that patients respond to this drug.’’
Purdue spent $207 million on the launch, doubling its sales force to 600, according to a court declaration. Sales reps pitched the drug to family doctors and general practitioners to treat common conditions such as backaches and knee pain. Their hook was the convenience of twice-a-day dosing.
With Percocet and other short-acting drugs, patients have to remember to take a pill up to six times a day, Purdue told doctors. OxyContin “spares patients from anxious ‘clock-watching,’” a 1996 news release said.
Sales reps showered prescribers with clocks and fishing hats embossed with “Q12h.” The company invited doctors to dinner seminars and flew them to weekend junkets at resort hotels, where they were encouraged to prescribe OxyContin and promote it to colleagues back home.
Rich got richer
By the third year, sales were more than double MS Contin’s peak, according to testimony by a Purdue executive. By the fifth, OxyContin was generating annual revenue of more than $1 billion.
Sales would continue to climb until 2010, when they leveled off at $3 billion.
Forbes magazine last year estimated the worth of Purdue’s owners – the Sackler family – at $14 billion, which, the magazine noted, put the family ahead of American dynasties such as the Mellons and Rockefellers.
Other drug companies began marketing their own narcotic painkillers for routine injuries.
By 2010, one out of every five doctor’s visits in the U.S. for pain resulted in a prescription for narcotic painkillers, according to a Johns Hopkins University study.
Rates of addiction and overdose have soared alongside the rise in prescriptions. News coverage of these problems in Appalachia in the late 1990s made OxyContin notorious. Purdue sent representatives to Kentucky, West Virginia and elsewhere to defend its drug. They blamed misuse of OxyContin and insisted that their pill was a godsend for pain sufferers when taken as directed.
“A lot of these people say, ‘Well, I was taking the medicine like my doctor told me to,’ and then they start taking them more and more and more,” Purdue senior medical director, Dr. J. David Haddox, told a reporter in 2001. “I don’t see where that’s my problem.”
The U.S. Justice Department launched a criminal investigation, and in 2007 the company and three top executives pleaded guilty to fraud for downplaying OxyContin’s risk of addiction. The case centered on elements of Purdue’s marketing campaign that suggested to doctors that OxyContin was less addictive than other painkillers.
In the years after the fraud case, Purdue funded programs to prevent pharmacy robberies and keep teenagers from stealing relatives’ pills. The company eventually rolled out a tamper-resistant version of the painkiller that was harder to crush and snort.
But in all the scrutiny of Purdue and OxyContin, the problem of the drug wearing off early was not addressed.
$97 to $630
Purdue charged wholesalers on average about $97 for a bottle of the 10-milligram pills, the smallest dosage, while the maximum strength, 80 milligrams, cost more than $630, according to 2001 sales data the company disclosed in litigation with the state of West Virginia.
By 2004, Purdue was seeing “a trend away from prescribing OxyContin” more frequently than every 12 hours, according to a company filing with the FDA.
In the training materials reviewed by The Times, little was said about the effect of higher doses on patient health. Those on higher doses of opioids are also more likely to overdose, according to numerous research studies.
An analysis of the medical records of more than 32,000 patients on OxyContin and other painkillers in Ontario, Canada, found that one in 32 patients on high doses fatally overdosed.
A ‘zombie’ patient
Patients began filing lawsuits in the early 2000s that accused Purdue of overstating OxyContin’s duration, among other complaints. One of the plaintiffs was a retired Alabama businessman named H. Jerry Bodie.
His doctor had Bodie on 30 milligrams of OxyContin every eight hours for chronic back pain. A Purdue sales rep persuaded him to switch Bodie to a higher dose every 12 hours, according to a judge’s summary of the evidence.
The doctor kept raising the dose, eventually putting Bodie on 400 milligrams a day. “I was more or less just a zombie,” Bodie said in a deposition.
Bodie’s lawsuit and hundreds of others filed by OxyContin users and their families never got before juries. Purdue got suits dismissed by asserting, among other defenses, a legal doctrine that shields drug companies from liability when their products are prescribed by trained physicians. Purdue settled other lawsuits on confidential terms.
West Virginia case
In the fall of 2004, in a remote courthouse in Appalachia, the 12-hour dosing issue came close to a public airing. The West Virginia attorney general was pressing a lawsuit against Purdue demanding reimbursement of “excessive prescription costs” paid by the state through programs for the poor and elderly. The state accused the company of deceptive marketing, including the 12-hour claim.
The judge hearing a motion for summary judgment in the case in McDowell County was Booker T. Stephens, the first African-American elected to the West Virginia circuit court.
The company tapped Eric Holder Jr. On Oct. 13, 2004, Holder argued that West Virginia prosecutors didn’t have sufficient evidence to warrant a trial.
Stephens disagreed. He ruled that there was enough evidence that a jury could find Purdue had made deceptive claims about OxyContin, including how long it lasted.
“Most of the patients in the clinical trials required additional medication, so called ‘rescue medications,’ that accompanied their 12-hour OxyContin dose,” the judge wrote in his Nov. 5, 2004 ruling. “Plaintiff’s evidence shows Purdue could have tested the safety and efficacy of OxyContin at eight hours, and could have amended their label, but did not.”
On the eve of the trial, Purdue agreed to settle the case by paying the state $10 million for programs to discourage drug abuse.
The settlement did not require Purdue to admit any wrongdoing or change the way it told doctors to prescribe the drug.
In the years that followed, attacks on the 12-hour claim largely dropped from the agenda of Purdue’s critics.
Class-action attorneys moved on to other drugs.
OxyContin is still hugely popular. Doctors wrote 5.4 million prescriptions for the painkiller in 2014, and according to a Purdue spokesman, 80 percent were for 12-hour dosing.
At the Times’ request, scientists at the University of Arkansas for Medical Sciences analyzed OxyContin prescriptions in a database of insurance claims covering about 7 million patients across the country.
In 2014, the analysis found, more than 52 percent of patients taking OxyContin longer than three months were prescribed doses greater than 60 milligrams a day, a level the CDC said last month doctors “should avoid” or “carefully justify.”
Dr. Debra Houry, director of the CDC’s National Center for Injury Prevention and Control and a leader of the agency’s response to the opioid epidemic, called the analysis “really concerning.” “The higher you go, the more likely you are to die,” she said.