07/19/16

The Tale of the OxyContin Lie

© Jaroslaw Kilian | 123rf..com

© Jaroslaw Kilian | 123rf..com

To tell the tale of OxyContin, we should start with the Sackler family, named by Forbes Magazine as the 16th richest family in the U.S. for 2015 with an estimated net worth of $14 billion dollars. The Sacklers own 100% of Purdue Pharma, which generated more than $3 billion in sales for 2015, most of which came from OxyContin.  Separate Sackler-owned companies outside the U.S. with a similar product profile were said to generate as much money in sales to Europe, Canada, Asia and Latin America. In 2007 Purdue Pharma paid $600 million to settle charges it misbranded OxyContin as safer and less addictive than it actually was. Currently, Purdue faces a civil lawsuit in Kentucky with the potential to exceed $1 billion in damages. But I am getting ahead of the story. It all begins with the traditional American success story of an immigrant family who came to America in the early 20th century.

Isaac Sackler immigrated from what is now the Ukraine and Sophie Sackler came from Poland. They ran a grocery in Brooklyn and had three sons: Arthur (1913-1987), Mortimer (1916-2010) and Raymond (1920-). All three brothers became psychiatrists. Arthur Sackler was said by the New Yorker to be the “founder” of modern pharmaceutical advertising. His thinking inspired the marketing strategy that would be applied to Oxycontin after his death. The brothers bought a small drug manufacturer in 1952 that would eventually become Purdue Pharma, L.P.

Purdue Pharma initially sold products like laxatives and earwax remover. Then in 1972, the Contin® controlled drug-release system was developed. In 1987, MS Contin®, a controlled release morphine formula was launched. In 1991 Purdue Pharma L.P. was formed, with a focus on pain management. It currently manufactures pain medicines containing hydromorphone, oxycodone, fentanyl, codeine and hydrocodone. In 1993 Purdue established Partners Against Pain® to help alleviate unnecessary suffering of chronic pain care through education. Then in 1996, Purdue launched OxyContin®. In 2010 the reformulated version of OxyContin® was launched. In 2010 the company launched the Butrans® Transdermal system, a buprenorphine-based pain reliever. In 2012 it launched the Intermezzo® sublingual tablet. In 2015 Purdue launched Hysingla® ER, extended release hydrocodone tablets. Also in 2015, Purdue launched TeamAgainstOpioidAbuse.com.

The Contin® controlled drug-release system was marketed as having the potential to minimize or stymie abuse concerns with oxycodone by spreading the drugs effects over 12 hours. Before OxyContin®, oxycodone had only been used for pain relief with cancer patients. “Not long after OxyContin’s launch in 1995, primary-care doctors were prescribing it for an array of painful symptoms.” Mortimer Sackler’s obituary in the New York Times said that by 2001, sales of OxyContin had reached almost $3 billion and accounted for 80% of the Purdue Pharma revenue.

But OxyContin wasn’t as abuse-resistant as it claimed. Reporting for Forbes, Alex Morrell described how the pills could be crushed and the time release mechanism neutralized. Then the drug could be snorted (or dissolved in water and injected) for a heroin-like high. I’ve thought for years that the FDA should have a panel of opioid addicts review every newly proposed abuse-resistant pain medication to brainstorm about possible ways to work around the abuse-resistant technology. The company finally reformulated OxyContin in 2010, which has been speculated by some as contributing to the migration of prescription opioid users to the cheaper and more used heroin.

In 2007 Purdue Pharma, its president, top lawyer and former chief medical officer pleaded guilty to misleading the public about the drug’s risk of addiction. They agreed to pay a total of $635 million in fines. CNBC reported the plea agreement came two days after Purdue agreed to pay $19.5 million to 26 states and the District of Columbia to settle complaints the company had encouraged physicians to overprescribe OxyContin. The state of Kentucky launched an independent lawsuit against Purdue in 2007 alleging false marketing, which is just now coming before a judge. It has the potential for over $1 billion in damages.

Purdue learned from focus groups with physicians in 1995 that doctors were worried about the abuse potential of OxyContin. The company then gave false information to its sales representatives that the drug had less potential for addiction and abuse than other painkillers, the U.S. attorney said.

The LA Times did an investigation of Purdue Pharma and OxyContin and just recently printed their findings. They began by pointing out Purdue Pharma made a bold claim with OxyContin—that it would relieve pain for 12 hours, “more than twice as long as generic medications.” But it seems that for many people, the drug does not last that long and that Purdue knew it. “Even before OxyContin went on the market, clinical trials showed many patients weren’t getting 12 hours of relief.” Since the launch in 1996, Purdue was confronted with additional evidence from a variety of sources, including complaints from doctors, independent research and even reports from its own sales reps.

But Purdue persisted in its claim that OxyContin provided 12-hours of pain relief. It’s high price and huge market was based on this claim. “Without that, it offers little advantage over less expensive painkillers.” When doctors began prescribing OxyContin at shorter intervals than 12 hours, Purdue sent out sales reps to “refocus” doctors on 12-hour dosing. They suggested the doctors prescribe stronger doses, not more frequent ones. But this has the potential to increase the possibility of overdose and death.

Over the last 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.

The LA Times reviewed internal Purdue documents in its investigation spanning three decades, from the conception of OxyContin in the mid-1980s to 2011. The documents painted a clear picture of the development and marketing of OxyContin, how Purdue responded to the complaints about its product, “and their fears about the financial impact of any departure from 12-hour dosing.” Experts said the withdrawal symptoms from OxyContin’s less than 12-hours pain relief, followed by the next 12-hour dose created a cycle of pain and euphoria that fostered addiction. Theodore Cicero, a neuropharmacologist, and researcher into how opioids effect the brain, said this was “the perfect recipe for addiction.”

Now let’s return to the late 1980s. The patent for MS Contin, Purdue’s main source of income, was running out. Executives expected a significant drop in income when the patent ran out. A 1990 memo read: “MS Contin may eventually face such serious generic competition that other controlled-release opioids must be considered.” So they decided to use the Contin technology on oxycodone. Over the next ten years, the company put over $40 million into developing OxyContin.

Multiple clinical trials indicated that OxyContin wasn’t giving 12-hour pain relief. “In study after study, many patients given OxyContin every 12 hours would ask for more medication before their next scheduled dose.” This even happened in the study ultimately used by Purdue to get OxyContin approved as a 12-hour pain relief drug. The official who led the FDA’s review of OxyContin left the agency shortly after the drug’s approval. Within two years, he was working for Purdue in new product development.

Before Oxcontin, doctors were hesitant to prescribe narcotic painkillers, seeing them as dangerously addictive. Through organizations like Partners Against Pain doctors were re-educated to “alleviate the unnecessary suffering of chronic pain.” Before the drug’s debut, the minutes of a 1995 meeting indicated a Purdue marketing executive said: “We do not want to niche OxyContin just for cancer pain.” Sales reps urged doctors to try OxyContin with common conditions like backaches and knee pain. “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.”

Then came the 2007 lawsuits. Curiously, in all the inquiries into Purdue and OxyContin, the short acting problem was not looked at. Purdue drug reps reported that doctors said the drug didn’t last and many were prescribing it for use three or four times a day. Company officials worried that if OxyContin wasn’t seen as a 12-hour drug, hospitals and insurance companies would resist paying its premium price. So they trained sales reps to convince doctors OxyContin provided 12-hour pain relief. “Purdue held closed-door meetings to retrain its sales force on the importance of 12-hour dosing, according to training documents.”

If a doctor complained that OxyContin didn’t last, Purdue reps were to recommend increasing the strength of the dose rather than the frequency. There is no ceiling on the amount of OxyContin a patient can be prescribed, sales reps were to remind doctors, according to the presentation and other training materials.

There’s more to see in the LA Times article, but you get the sense of the issue. Purdue Pharma responded to the LA Times report, saying it was “long on anecdotes and short on facts.” And it was based on a “long-discredited theory.” They said scientific evidence amassed over more than 20 years supports the FDA’s approval of 12-hour dosing for OxyContin. “The OxyContin label has been updated more than 30 times and at no point did FDA request a change to the dosing frequency.” By the way the medication guide for OxyContin says: “Take your prescribed dose every 12 hours at the same time every day. Do not take more than your prescribed dose in 12 hours. If you miss a dose, take your next dose at your usual time.”

None of the Sackler family has ever been charged in the litigation against Purdue. These days, the family is not involved in the day-to-day running of the company. Throughout their history they have been philanthropic, with donations resulting in the Sackler Library at Oxford University; the Sackler Faculty of Medicine in Tel Aviv, Israel; the Sackler Institute of Biomedical Science at New York University; and the Sackler School of Graduate Biomedical Sciences at Tufts University. But the Sacklers may not be able to be as generous if they lose a major chunk of their $14 billion fortune. A Kentucky judge has ordered the unsealing of secret documents about the marketing of OxyContin in June of 2016, according to STAT.  But that’s a tale for another time.

02/9/15

Evolution of Synthetic Painkillers

The documentary, “American Addict” (available on Netflix) reported that 106,000 Americans die from prescription drugs each year. In the first six months of 2008, 67% of the oxycodone that was prescribed throughout the U.S. came out of Broward County Florida. What was going on? Mid Eastern states had a prescription drug-monitoring program; Florida didn’t.  Drug seekers from those states went south for their drugs.

By the end of the 1800s, a wide variety of “patent medicines” had come onto the market. They were called “patent” medicines because their formula was a secret; so the ingredients weren’t listed. “Some of the patent medicines were up to 50% morphine by volume. And no matter what ails you, if you take something that is 50% morphine by volume, you’re going to feel better.” And some people began to use opiated “cure-alls” as intoxicants. These cure-alls were popular among women. “The typical opiate user in the nineteenth century was a middle class, middle–aged, white woman living in the middle of the country,” according to Pat Morgan of UCLA.

When Congress passed the Pure Food and Drug Act of 1906, it required the patent medicine industry to label its ingredients. “As a result of these regulations, most of the patent medicines went out of business immediately.” Addiction decreased dramatically; as a result of Americans becoming aware of what these drugs could do, according to historian Cliff Schaffer. But heroin addiction was just coming into its own (See another article, “Legacy of the ‘Joy Plant’”).

By 1913, heroin replaced morphine as the leading cause of hospital admissions for narcotics problems in the US. It was the leading drug of abuse in New York City. In 1914 the federal government passed the Harrison Tax Act. This legislation required an opiate prescriber to get a license and pay a tax; and an opiate user had to be a patient of a licensed prescriber. It created an estimated 100,000 to 200,000 criminals out of users and addicts. Heroin eventually became an illicit substance in 1924 with the Heroin Act, which made it illegal to manufacture, possess or distribute heroin—even for medical use. But the chemists of the world were already working to develop synthetic substitutes.

Oxycodone was first synthesized in 1916 at the University of Frankfurt. It was hoped that it could be a less addictive substitute for morphine and heroin. By the 1920s, there were reports of “euphoric highs” in patients using oxycodone. It was first introduced to the US in 1939. In the early 1960s, the US classified it as a Schedule II drug.  In 1950, Percodan (oxycodone and aspirin), was put on the market by Endo Pharmaceuticals. In 1971, Percocet (oxycodone and acetaminophen) was launched by Endo Phrmaceuticals. In 1996, OxyContin, a time-release form of oxycodone became available from Purdue Pharmaceuticals.

The time-release mechanism that was supposed to make OxyContin more difficult to abuse was quickly and easily neutralized by crushing the tablet before snorting the powder or mixing it with water to inject it. Users compare the high from oxycodone to heroin. In 2010, an abuse-deterrent formulation of OxyContin was introduced. The intent was to make it more difficult to crush. The New England Journal of Medicine published an article, “Effect of Abuse-Deterrent Formulation of OxyContin” in July of 2012 that indicated the new formula did indeed decrease it as a drug of abuse. But 24% of those who had abused OxyContin reported they found a way to defeat the tamper-resistant properties. Sixty-six percent reported switching to another opioid, with heroin being the most common choice. Heroin is easier to use, cheaper and easily available. The article concluded “Abuse-deterrent formulations may not be the “magic bullets” that many hoped they would be.”

Not to be deterred by these conclusions, Purdue Pharmaceuticals recently received approval for Terginiq ER, a combination of oxycodone and naloxone, a drug that is supposed to block the euphoric effects of oxycodone if it is crushed (so it can’t be snorted or dissolved and injected). But if you simply swallow Teriniq ER, the naloxone is not activated. “When the pills are swallowed they are as addictive as pure oxycodone.” Nevertheless, the FDA sees the approval of abuse-deterrent medications like Targiniq ER as a positive step in its fight address the public health crisis of prescription drug abuse in the U.S.

Hydrocodone was first synthesized in 1920, of course, by Germans. In 1924, it was first sold by Knoll Pharmaceuticals in Germany as Dicodid. Knoll was also responsible for the introduction and marketing of oxycodone as Dinarkon in 1917, and Dilaudid (hydromorphone), in 1926. Through a series of mergers, Knoll became a part of Abbott Laboratories in June of 2002.

In 1929, the U.S. Bureau of Social Hygiene gave the National Research Council several million dollars to study various new compounds like hydrocodone, to see if there was a less addictive opioid than morphine or heroin. Nathan Eddy tested the safety, efficacy and side effects of 350 drugs, including morphine, codeine, Dilaudid and hydrocodone. His results showed that hydrocodone was an effective painkiller, with predicable side effects. It also “induced euphoria, and therefore there was a danger of addiction.” Eddy said that tolerance developed more slowly than with morphine or Dilaudid and the occurrence of abstinence syndromes were less severe than with other drugs. This suggested an individual could become dependent on it without knowing it until they are really hooked.

With the Controlled Substances Act of 1971, pure hydrocodone was classified as a Schedule II controlled substance, as was opium and morphine. But in combination with other drugs, it could be regulated as a Schedule III drug. In 1978, Knoll Pharmaceuticals introduced Vicodin, five milligrams of hydrocodone with 500 milligrams of acetaminophen. Generic Vicodin became available in 1983.

Hydrocodone had become the most prescribed medication in the U.S. “Since 2007, more U.S. prescriptions were written for hydrocodone + acteminophen than any other drug.” In 2012 alone, there were over 135 million prescriptions written.

In 2002, emergency room reports involving hydrocodone had increased by 500% since 1990. That same year, the FDA recommended tighter warnings on drugs containing acetaminophen because of the concerns it can cause liver damage. In October of 2014, Vicodin was reclassified as a Schedule II drug. The purpose of the change was to minimize its use as a recreational drug, while ensuring that patients with severe pain still have reasonable access.

A new hydrocodone painkiller called Zohydro, with 5 to 10 times the power of Vicodin, was approved by the FDA in October of 2013. This approval ignored the 11 to 2 vote AGAINST APPROVAL by its own advisory panel. Zohydro is pure hydrocodone. Melanie Haiken, a contributor to Forbes, wondered if we need a new opiate painkiller, given that we don’t seem to be able to prevent the ones we already have from ending up in the wrong hands. She commented: “The U.S., with just 5 percent of the world’s population, now accounts for 84 percent of global oxycodone (OxyContin) consumption and more than 99 percent of hydrocodone (Vicodin, Lortab) consumption. That’s a lot of painkillers.”