09/7/21

It Doesn’t Seem Right

Back in October of 2020 Purdue Pharma signed an $8 billion-plus settlement with the U.S. Department of Justice. Purdue agreed to plead guilty to three federal criminal charges for its role in creating the nation’s opioid epidemic and shut down the company. The charges included conspiracy to defraud the U.S. government. The Daily Beast reported Purdue will admit it impeded the DEA by falsely representing it had maintained an adequate program to stop drug diversion while the company’s internal system was beginning to sound an alarm. Purdue will also admit to violating antikickback laws by inducing doctors to write more prescriptions for opioids through a paid speaker program.

Some states objected to the settlement. CNN Business reported that while the $8 billion plus agreement would be a record settlement paid by a pharmaceutical company, it is only a fraction of the cost to federal, state and local governments fighting the opioid crisis. State lawsuits throughout the country have filed claims for over $2 trillion. State attorneys general and members of Congress objected to the settlement, saying it does not hold the Sackler family and Purdue properly accountable. The Connecticut Attorney General said: “The federal government had the power here to put the Sacklers in jail, and they didn’t. Instead, they took fines and penalties that Purdue likely will never fully pay.”

If the only practical consequence of your Department’s investigation is that a handful of billionaires are made slightly less rich, we fear that the American people will lose faith in the ability of the Department to provide accountability and equal justice under the law.

Members of the Sackler family withdrew more than $10 billion from Purdue Pharma and placed it in family trusts, as the company faced growing scrutiny related to its role in the opioid epidemic. A statement from the family said, “Members of the Sackler family who served on Purdue’s board of directors acted ethically and lawfully, and the upcoming release of company documents will prove that fact in detail.”

The New York Times (NYT) reported a Purdue Pharma proposal to restructure itself as a nonprofit company was put to a vote and approved by huge majority of its creditors. The restructuring plan would protect the company from further legal action over opioids. It also includes a blanket release from civil lawsuits for the Sackler family, who argued if the plan is confirmed, they should be covered by the same release from all present and future lawsuits as their company would be. “Neither the company, nor the Sacklers, would admit to wrongdoing in connection with these lawsuits.”

Under the plan, the Sacklers would surrender control of Purdue. The company would receive a new name and be run by an independently appointed board. The Sackler family would also pay at least $4.5 billion of their personal funds over nine years. That is in addition to the $225 million from a separate civil settlement with the DOJ.

According to the plan, the reconstituted, as-yet unnamed company would fund about a half-dozen trusts, including separate ones for tribes, adults and children. Proceeds from the sales of the nonprofit’s overdose-reversing medications as well as from moderate quantities of OxyContin would continue to be pumped into these trusts.

In July 2021, NPR said fifteen states, including Massachusetts, New York, Pennsylvania, Colorado and Illinois dropped their opposition to the Purdue bankruptcy plan, according to documents filed by a court mediator. Federal bankruptcy judge Shelley Chapman said in the legal filing, “The negotiations were difficult and hard-fought, with the outcome uncertain.” Chapman was appointed to mediate a settlement the opposing states could accept. The settlement is all but certain to be finalized. In addition to members of the Sackler family, the settlement would shelter many of their associates from future opioid lawsuits.

Under the mediation agreement, Purdue agreed to release more than 30 million documents to a public repository, including private communications with lawyers. Although those documents are expected to expose the full story of the company’s and the Sackler family’s complicity in selling OxyContin, they will be shielded from any further legal action by the Purdue restructuring plan. Members of Congress have introduced legislation to close a loophole in the bankruptcy code that permitted Purdue Pharma to declare bankruptcy, while its owners—the Sacklers—did not. They will remain as one of the richest families in the U.S. Even if the legislation passes, the Purdue plan will have been long since resolved.

The hearing before the U.S. House of Representatives’ Judiciary’s Subcommittee on Antitrust, Commercial and Administrative Law took place as Democratic members of the House and Senate introduced legislation aimed at reforming areas of bankruptcy law relevant to the Sackler family and Purdue situation.

The Nondebtor Release Prohibition Act of 2021 would prohibit litigation shields for owners or insiders of bankrupt companies. Though not included in the legislation, Wednesday’s hearing also focused on potential reforms to limit the ability of bankrupt companies to select judges they think will be favorable to them.

According to Reuters, the trial over the Purdue Pharma settlement began on August 12^th and was supposed to take two weeks. The settlement is supported by all but nine states, including Connecticut (where Purdue is headquartered), California, Maryland and Washington. Washington’s attorney general said he could not in good conscience accept the terms of Purdue’s deal. “The latest settlement plan ‘allows the Sacklers to walk away as billionaires with a legal shield for life.’” Adding insult to injury, he said “they don’t even have to apologize.”

Purdue says the deal is worth more than $10 billion. If the settlement is approved, Purdue assets will be transferred to the new company. The company will be governed by a new independent board, “who will operate in a responsible and sustainable manner taking into account long-term public health interests related to the opioid crisis.” The Sackler family will have no involvement in the new company, and will end their involvement in pharmaceutical companies worldwide.

Critics of the settlement oppose the “third-party releases” that would provide legal protections to the Sacklers. The company has said that without the releases, the entire settlement, including billions of dollars for state and local opioid abatement programs, would collapse.

On September 1^st, The NYT reported the settlement agreement was provisionally approved and Purdue Pharma was dissolved. The presiding judge said the case was a B-I-T-T-E-R result, spelling out the word. He was incredibly frustrated that so much of the Sackler money was in offshore accounts. He had wished for and expected a higher settlement. The costs of further delay and the benefits of the agreement with its focus on lessening the impact of the opioid epidemic influenced his decision.

Just last month, Dr. Richard Sackler, a former president and cochairman of the board for Purdue, testified that neither the family, the company nor its products bore any responsibility for the opioid epidemic. Other Sacklers struck a more conciliatory note, saying they were horrified that a medication intended to alleviate pain had, in fact, caused pain to so many. But neither apologized nor took personal responsibility.

So, there it is. It appears that the full story of how OxyContin helped fuel the opioid epidemic will only become known when it is too late for any legal actions to be taken against individuals from Purdue Pharma or the Sackler family. The company, but no persons will be found guilty of federal crimes; no one will apologize or be held accountable for their actions. And that doesn’t seem right.

For other articles on this issue, see: “What Purdue and the Sackler Family Treasure,” “Giving an Opioid Devil Its Due,” The Tale of the OxyContin Lie,” and more.

12/4/18

The Bondage of Buprenorphine

It’s not often that a patent award creates a media storm, but it happened recently when a patent was awarded for a novel oral formula of buprenorphine, the opioid in Suboxone and its generic cousins. The new formula is a buprenorphine-wafer that is proposed for MAT (medication assisted therapy) with opioid addicts as well as for treating chronic pain. The wafer formula is said to be more “diversion and/or abuse-resistant” than the existing ones, which are tablets (ie., Subutex and Zubsolv) and sublingual film (i.e., Suboxone). It just so happens that one of the six listed inventors of the buprenorphine wafer is Richard Sackler; and Purdue Pharma LP was the original assignee for the patent. Members of the Sackler family and Purdue Pharma are currently facing hundreds of lawsuits that claim they played a role in the birth and growth of the opioid crisis.

The connection of the Sackler family and Purdue Pharma to the opioid crisis is tellingly documented by Barry Meier in his book, Pain Killer, which was recently released in a second, updated edition. Read: “Giving an Opioid Devil Its Due” for an overview of Meier’s book, with links to two NYT articles he wrote as Pain Killer was published in May of 2018. Also see “The Tale of the OxyContin Lie,” “Greed with OxyContin is NOT Good,” and “Doublespeak in the Opioid Crisis, Part 2” for more on the connection of Purdue Pharma and the Sackler family to the opioid crisis.

Among the media outlets describing the Sackler and Purdue connection to the buprenorphine-wafer patent was STAT News and The Washington Post. Both news outlets noted how several critics are outraged that the Sacklers and Purdue are positioning themselves to benefit financially from the opioid epidemic they are seen as having facilitated in the first place. Luke Nasta, the director of a New York-based drug and alcohol addiction treatment center said the Sackler family “shouldn’t be allowed to peddle any more synthetic opiates—and that includes opioid substitutes.” He added: “It’s reprehensible what Purdue Pharma has done to our public health.”

The patent application for the buprenorphine-wafer said there is a need for “other diversion and/or abuse-resistant dosage forms of buprenorphine, which can be used in drug substitution therapy.” Additionally, the preparation would also provide “efficient analgesia” when used for pain relief.

It is an object of the present invention to provide an oral pharmaceutical dosage form of the active agent buprenorphine that is less prone to diversion and/or abuse in drug substitution therapy. It is another object of the present invention to provide an oral dosage form of the active agent buprenorphine that can be used for drug substitution therapy and/or pain treatment.

The patent does not seem to only envision using the wafer technology with buprenorphine. It points out how “the invention and its various embodiments which are set out below, can be extended to any opioid or analgesic whose preferred route of administration is oral, preferably sublingual, as is the case for buprenorphine.” One embodiment of the wafer is also said to release buprenorphine or other “pharmaceutically acceptable salt” in less than three minutes, and perhaps as quickly as one or two minutes.

Even more preferably, substantially all of the buprenorphine or said pharmaceutically acceptable salt thereof will be released within less than thirty seconds, twenty seconds, ten seconds or even within less than five seconds after oral, preferably sublingual, application of the dosage form.

Reflect for a moment on how rapid, “instant” absorption of a drug intravenously or nasally is often the preferred method of drug ingestion by an addict because the euphoria is more immediate. The good news here is the wafer technology will seemingly restrict diversion, but the bad news is it may initiate another rapid ingestion method for individuals looking for an opioid high. The biochemical nature of buprenorphine is said to have a “euphoric ceiling” that limits its long-term abuse potential, but the same is not true for other addictive “pharmaceutically acceptable salts.”

Another red herring in the patent application is describing how drug addicts take prescription drugs for replacement therapy “under the close supervision of medical parishioners.” This means that the slower absorption of buprenorphine in the other formulas, taking five to ten minutes to dissolve, could result in drug addicts trying “to divert these sublingual buprenorphine tablets by removing them from the mouth when the supervising healthcare professional’s attention is directed to other activities.” Methadone, which is only used within a medical setting in the U.S., did have these kinds of problems years ago so the formula was changed from a tablet to a liquid form. Ingesting buprenorphine in MAT is NOT supervised in a medical setting in the U.S. The patient gets a prescription and takes the medication without any medical supervision, so the supposed advantage of the rapidly absorbed buprenorphine wafer in limiting diversion is nonexistent.

Also in the news about the Purdue Pharma debacle is the role of Rudy Giuliani, who acted as legal counsel for Purdue in the mid-2000s. FiercePharma, The Hill and others reported that two Democratic Senators are requesting documents detailing information about Purdue Pharma’s interactions with the Department of Justice and the Drug Enforcement Agency when Purdue was under investigation for its OxyContin promotions. They are trying to determine whether or not Giuliani “secured leniency for opioid maker Purdue Pharma through conflicts of interest.” At the same time he was representing Purdue Pharma in its dealings with the Department of Justice over a probe of Purdue’s marketing of OxyContin, Giuliani’s firm worked for the DOJ under a $1 million contract to provide advice on reorganizing its major drug investigations. FiercePharma said:

According to the letters, Giuliani convinced political appointees at the Department of Justice to reject career prosecutors’ recommendations in the opioid marketing case. As a result, the company entered a guilty plea to “misbranding” OxyContin, its powerful painkiller. Under the deal, the senators also said Giuliani convinced DOJ to assign fault to Purdue Frederick, a holding company, to allow Purdue Pharma to continue to do business with the federal government. Purdue paid $640 million under the agreement in 2007.

The bottom line is it seems Giuliani helped Purdue keep OxyContin on the market after 2007. Top Justice Department officials in 2006 failed to follow their Virginia prosecutors’ recommendations to indict Purdue Pharma executives on felony charges instead of the lesser misdemeanor charges and no jail time they ultimately received. Even with this sweet plea deal in hand, the night before the plea agreement was set to expire—meaning the company would face charges—a senior Justice Department official (“at a Purdue lawyer’s request”) phoned John Brownlee, the U.S. Attorney pursuing the indictment, at his home in an attempt to convince him to extend the deadline and give Purdue more time. It didn’t work.

By the time the negotiations were complete, Purdue’s holding company, Purdue Frederick, would plead guilty to a single misbranding felony and the company’s executives to misdemeanor charges of misbranding the drug. Ultimately, though, it was the holding company, not Purdue Pharma, that was banned from doing business with public health programs, a Giuliani-arranged deal that allowed OxyContin sales to continue growing—and the epidemic to continue festering, largely unchecked.

Another factor to remember in the pursuit of Sackler and others to bring their buprenorphine wafer to market is the anecdotal reports of individuals withdrawing from buprenorphine. Regularly in my years of experience working with opioid addicts, those who used and/or abused buprenorphine reported how buprenorphine was harder for them to “kick” than heroin, methadone or any other opioid. Could we be looking at the creation of an entire population of individuals who are physically dependent on buprenorphine without the ability to discontinue the drug once they use it for an extended time period? See Pain Killers or the Politico article, “They Were All Lawyered Up and Rudy Giuliani’d Up” for more on how Giuliani fought for Purdue. Politico also unpacks some of the back-story to the 2007 plea agreement reached with Purdue by the DOJ.

06/8/18

Doublespeak in the Opioid Crisis, Part 2

Last year The New York Times reported drug overdoses were now the leading cause of death for Americans under the age of fifty. The nationwide total for drug-related deaths was around 64,000 in 2016. According to Vox, this is more than the number of soldiers killed during the entire Vietnam War (an estimated 55,000); more than the 43,000 Americans who died in car crashes at the peak of auto-related deaths in 1972; and more than the 43,000 who died of HIV/AIDS in 1995 at the height of that epidemic. A CDC infographic using data from the National Survey on Drug Use and Health (NSDUH) for 2011-2013 reported that individuals who are addicted to opioid painkillers are forty times more likely to be addicted to heroin. Let this last statistic sink in: Today’s heroin addict often begins as someone who first used opioids for pain relief.

In Part 1 of “Doublespeak in the Opioid Crisis” we saw how the misuse of a 1980 letter published in the New England Medical Journal helped to generate these statistics. Here we will look closer at how the accelerated rate in opioid prescribing and one of the players in that increase contributed to the current opioid crisis. Purdue Pharmaceuticals will be shown to have played a crucial role in the birth and growth of the opioid problem in the U.S.

In the Annual Review of Public Health, Kolodny et al. gave the following information in: “The Prescription Opioid and Heroin Crisis.” Since 2000, the consumption of hydrocodone more than doubled and the consumption of oxycodone increased by almost 500%. Parallel to this, the OPR-related overdose death rate increased almost fourfold. Between 1997 and 2011, emergency rooms saw a 900% increase of individuals seeking treatment for addiction to OPRs (opioid pain relievers). “The correlation between opioid sales, OPR-related overdose deaths, and treatment seeking for opioid addiction is striking.” See chart below taken from “The Prescription Opioid and Heroin Crisis.”

In 1986 a paper by Portenov and Foley, “Chronic Use of Opioid Analgesics in Non-Malignant Pain,” concluded that pain patients could be treated safely on a long-term basis with OPRs. “Despite its low-quality evidence, the paper was widely cited to support expanded use of opioids for chronic non-cancer pain.” Along with the misquoting and misuse of Hershel Jick’s 1980 letter in the NEMJ, the stage was being set for the coming increase in the prescription and consumption of opioids. The gradual upward trend of opioid use that began in the 1980s accelerated rapidly after the introduction of OxyContin to the OPR market in 1995.

Between 1996 and 2002, Purdue Pharma funded more than 20,000 pain-related educational programs through direct sponsorship or financial grants and launched a multifaceted campaign to encourage long-term use of OPRs for chronic non-cancer pain. As part of this campaign, Purdue provided financial support to the American Pain Society, the American Academy of Pain Medicine, the Federation of State Medical Boards, the Joint Commission, pain patient groups, and other organizations. In turn, these groups all advocated for more aggressive identification and treatment of pain, especially use of OPRs.

In 1995 the American Pain Society introduced a campaign entitled: “Pain is the Fifth Vital Sign.” Health care professionals were encouraged to assess pain with the same zeal as they do with other “vital signs”; and become more willing to use opioids to treat non-cancer pain. Before the introduction of OxyContin, physicians were reluctant to prescribe OPRs on a long-term basis for common chronic pain conditions, as they were concerned with their patients developing tolerance, physiological dependence and addiction. Opioid manufacturers, including Purdue, had physician-spokespersons publish papers and give lectures on ‘opiophobia,’ claiming the medical community has been confusing addiction and ‘physical dependence,’ which they said was “clinically unimportant.”

In “The Promotion and Marketing of OxyContin,” Art Van Zee said from 1996 to 2001 Purdue conducted more than 40 national pain management and speaker-training conferences at resorts in Florida, Arizona and California. “More than 5,000 physicians, pharmacists, and nurses attended these all-expenses-paid symposia, where they were recruited and trained for Purdue’s national speaker bureau.” In 2001 alone Purdue spent $200 million in a variety of approaches to market and promote OxyContin. Using data on the prescribing patterns of physicians nationwide, Purdue targeted physicians who were the highest prescribers of opioids across the country.

They specifically went after primary care physicians, encouraging a more liberal use of opioids. By 2003, almost half the physicians prescribing OxyContin were primary care physicians. Some experts became concerned that primary care doctors were not sufficiently trained in pain management or addiction issues. Those who worked within a managed care environment of time constraints had the least amount of time to evaluate and follow up on patients with complicated chronic pain.

There was a bonus system in place to encourage sales representatives to increase the sales of OxyContin in their territories. Physicians with high rates of opioid prescriptions received a large number of visits. In 2001, Purdue paid out almost $240 million in sales incentive bonuses to its sales representatives. From 1996 to 2000 Purdue increased its sales force from 318 to 671 sales representatives. The company also had a starter coupon program that provided patients with a 7- to 30-day supply of OxyContin. “By 2001, when the program was ended, approximately 34,000 coupons had been redeemed nationally.”

Branded promotional items like OxyContin fishing hats and stuffed plush toys were distributed. There was even a compact music disc: “Get in the Swing With OxyContin.” The breadth and scope of such marketing was unprecedented for a Schedule II opioid.

Purdue “aggressively” promoted the use of opioids for use in the “non-malignant pain market.” A much larger market than that for cancer-related pain, the non–cancer-related pain market constituted 86% of the total opioid market in 1999. Purdue’s promotion of OxyContin for the treatment of non–cancer-related pain contributed to a nearly tenfold increase in OxyContin prescriptions for this type of pain, from about 670,000 in 1997 to about 6.2 million in 2002, whereas prescriptions for cancer-related pain increased about fourfold during that same period.

Kolodny et al. indicated that in addition to minimizing the risks of OPRs, opioid manufacturers and pain organizations exaggerated the benefits of long-term OPR use. “In fact, high-quality, long-term clinical trials demonstrating the safety and efficacy of OPRs for chronic non-cancer pain have never been conducted.” Surveys of patients with chronic non-cancer pain receiving long-term OPR treatment suggested that most patients continued to experience significant chronic pain and dysfunction. “The CDC and some professional societies now warn clinicians to avoid prescribing OPRs for common chronic conditions.”

Although increased opioid consumption over the past two decades has been driven largely by greater ambulatory use for chronic non-cancer pain, opioid use for acute pain among hospitalized patients has also increased sharply. A recent study found that physicians prescribed opioids in more than 50% of 1.14 million nonsurgical hospital admissions from 2009 to 2010, often in high doses. The Joint Commission’s adoption of the Pain is the Fifth Vital Sign campaign and federally mandated patient satisfaction surveys asking patients to rate how often hospital staff did “everything they could to help you with your pain” are noteworthy, given the association with increased hospital use of OPRs.

Van Zee indicated in “The Promotion and Marketing of OxyContin” that a consistent feature in Purdue’s promotion and marketing of OxyContin was a systematic effort to minimize the risk of addiction when using opioids to treat chronic non-cancer-related pain. In the literature and audiotapes of their promotional campaign for physicians, and on its “Partners Against Pain” website, Purdue claimed the risk of addiction from OxyContin was extremely small. Purdue trained its sales force to affirm that the risk of addiction was “less than one percent.” They cited the 1980 NEMJ letter to the editor by Jick (see Part 1 of this article for more information on this) and other studies to minimize the risk of addition. “Misrepresenting the risk of addiction proved costly for Purdue,” to the tune of $634 million in fines:

On May 10, 2007, Purdue Frederick Company Inc, an affiliate of Purdue Pharma, along with 3 company executives, pled guilty to criminal charges of misbranding OxyContin by claiming that it was less addictive and less subject to abuse and diversion than other opioids.

While research showed OxyContin was simply comparable to other available opioids in safety and efficacy, Purdue’s marketing made it into a blockbuster product. Sales escalated from $44 million in 1996 to almost $3 billion over 2001 and 2002. Prescriptions increased from 316,000 to over 14 million.

The remarkable commercial success of OxyContin, however, was stained by increasing rates of abuse and addiction. Drug abusers learned how to simply crush the controlled-release tablet and swallow, inhale, or inject the high-potency opioid for an intense morphine-like high. There had been some precedence for the diversion and abuse of controlled-release opioid preparations. Purdue’s own MS Contin had been abused in the late 1980s in a fashion similar to how OxyContin was later to be; by 1990, MS Contin had become the most abused prescription opioid in one major metropolitan area. Purdue’s own testing in 1995 had demonstrated that 68% of the oxycodone could be extracted from an OxyContin tablet when crushed.

Purdue Pharmaceuticals and its subsidiary companies are privately owned by the Sackler family, named in 2016 by Fortune Magazine as the 19^th richest family in the US. None of the Sackler family has even been charged in the past litigation against Purdue. Although family members are not involved in the day-to-day operations of Purdue Pharma companies today, several Sacklers are current board members of Purdue Pharma. In “Meet the Sacklers,” Joann Walters pointed out how the Sackler family has a reputation for its cultural and academic philanthropy to institutions such as Harvard, Yale, MIT, Columbia, Cornell, Stanford and other universities in the US; as well as the Guggenheim Museum, the Smithsonian, the Serpentine Sackler Gallery, the Royal Academy in Britain and others.

Allen Frances said in his article for The Guardian there is no Pablo Escobar Wing at New York’s Metropolitan Museum of Art (there is a Sackler Wing); and no El Chapo Guzman gallery at the Guggenheim (there is a Sackler Center for Art Education). Oxford would no longer be Oxford if it had one of its libraries named in honor of the Cali cartel (but there is a Sackler Library). “The Sackler name is emblazoned on, and disgraces, dozens of the world’s greatest museums, universities, and performing arts centers. So far, none has turned down their donations, none has returned their money already given.” He thought a solution was for institutions to elicit and receive permission from the family members to remove their name, “without any quid pro quo requirement for returned funding.”

I’m not sure about that idea, but I could definitely support two other ones he suggested. First, the family should use its fortune to provide “free treatment for the people they addicted.” Second, they should mount “a reverse marketing campaign to undo their previous brainwashing of doctors and patients.” But I don’t think those ideas will ever happen.

While Purdue announced it halved its sales force and will no longer send out field representatives to promote OxyContin to health professionals in the U.S., there is no indication that the same approach will be taken by its overseas subsidiaries, such as Mundipharma. In “OxyContin Goes Global,” the LA Times noted where a network of international companies owned by the Sackler family are expanding into Latin America, the Middle East, Africa and other regions. “In this global drive, the companies known as Mundipharma, are using some of the same controversial marketing practices that made OxyContin a pharmaceutical blockbuster in the U.S.”

If you’re interested in more information on Purdue Pharma, the Sacklers and OxyContin, also look at: “The Tale of the OxyContin Lie” and “Greed With OxyContin Is NOT Good.”

05/29/18

Doublespeak in the Opioid Crisis, Part 1

How did we get to the place where overdose deaths from opioids were five times higher in 2016 than 1999? On average, 115 Americans die every day from an opioid overdose. An estimated 66% of all the drug overdose deaths in 2016 involved an opioid. From 1999 to 2016, more than 630,000 people died from a drug overdose. And there is evidence that a 1980 one-paragraph letter published in the New England Medical Journal was used to get us there.

The above statistics were from a CDC page on opioid overdose called, “Understanding the Epidemic.” The article showed a graphic representation of three waves in the rise in opioid overdose deaths. The first wave began in the 1990s with increase of overdose deaths from prescription opioids. “The second wave began in 2010, with rapid increases in overdose deaths involving heroin.” The third wave began in 2013 and is associated with illicitly manufactured fentanyl.

The letter was co-written by Dr. Hershel Jick, a drug specialist at Boston Medical Center. A Boston Globe article reported that Dr. Jick said his letter only referred to hospital patients getting opioids for a short period of time, not long-term outpatient use. He said: “I’m essentially mortified that that letter to the editor was used as an excuse to do what these drug companies did.” In his book, Pain Killer, Barry Meier noted years after the publication of his 1980 letter Dr. Jick said that he and his coauthor submitted their statistics about opioid use as a letter “because they were not robust enough to merit a study.” He added that nothing could be concluded about the long-term use of opioids from his study.

A team of Canadian researchers demonstrated the connection between Jick’s letter and the opioid epidemic. Their analysis of this connection was published in an editor’s note for the New England Medical Journal: “A 1980 Letter on the Risk of Opioid Addiction.” The original 1980 letter is in an appendix for the June 2017 editor’s note by Juurlink et al. in the NEMJ. It is quoted here in its entirety:

Recently, we examined our current files to determine the incidence of narcotic addiction in 39,946 hospitalized medical patients who were monitored consecutively. Although there were 11,882 patients who received at least one narcotic preparation, there were only four cases of reasonably well-documented addiction in patients who had no history of addiction. The addiction was considered major in only one instance. The drugs implicated were meperidine [Demerol] in two patients, Percodan in one, and hydromorphone in one. We conclude that despite widespread use of narcotic drugs in hospitals, the development of addiction is rare in medical patients with no history of addiction.

Dr. David Juurlink, who led the analysis, was quoted by the Boston Globe as saying: “It’s difficult to overstate the role of this letter. . . . It was the key bit of literature that helped the opiate manufacturers convince front-line doctors that addiction is not a concern.” The NEMJ said its readers should be aware Jick’s letter was heavily and uncritically cited as evidence addiction was rare with opioid therapy. “People have used the letter to suggest that you’re not going to get addicted to opioids if you get them in a hospital setting. We know that not to be true.”

Here’s what Juurlink and his colleagues did. They identified 608 citations of the 1980 letter “and noted a sizable increase after the introduction of OxyContin (a long-acting formulation of oxycodone) in 1995.” Of the articles citing the 1980 letter, 80.8% (491) cited it as “evidence that addiction was rare in patients treated with opioids.” Additionally, 80.8% (491) of the 608 articles did not point out the patients who were described by Jick in his letter were hospitalized at the time they received the prescription. Affirmational citations of the article began to decrease after 2002. See the NEMJ article for a chart illustrating this.

Now let’s look at this trend from another perspective. The Joint Commission (formerly The Joint Commission on the Accreditation of Healthcare Organizations or JCAHO) published a document titled: “The Joint Commission’s Pain Standards: Origins and Evolution.” In 1990 the President of the American Pain Society wrote an editorial criticizing the lack of improvement in pain assessment and treatment since 1970. He said the failure was because patients didn’t tell their doctors and nurses about their pain, nurses weren’t able to adjust doses, and doctors were reluctant to use opioids. Pain, he said, was often invisible. “Pain relief has been nobody’s job.”

In addition to his recommendations to help “make pain visible,” he emphasized the received wisdom of the day that “therapeutic use of opiate analgesics rarely results in addiction.” This wisdom “was based on only a single publication that lacked detail on how the study was done.” That “study” was the one done by Dr. Hershel Jick and the citation was his 1980 article in the NEMJ. The next year the American Pain Society released quality of assurance standards for the relief of both acute pain and cancer pain. The recommendations followed the previous recommendations of its President. The Joint Commission followed suit and announced new standards for health care organizations to improve pain management in 2000.

Recall that the CDC marked the beginning of the first wave of overdose deaths as beginning in 1999. In “Understanding the Epidemic” a CDC chart tracked the number of drug overdose deaths since 1999. It noted the initial wave of overdose deaths was due to increased prescribing of opioids (natural and semi-synthetic opioids) beginning in the 1990s; with the second wave of heroin beginning in 2010; and synthetic opioids coming as the third wave in 2016. Below is a CDC data brief apparently used to compile the CDC’s three-wave chart.

The Joint Commission standards were lauded by pain management specialists and called “A rare and important opportunity for widespread and sustainable improvement in how pain is managed in the United States.” However, some raised concerns that the new standards would encourage the inappropriate use of opioids. Total opioid prescriptions had been steadily increasing in the U.S. since 1991, which the Joint Commission attributed to the efforts of advocacy work by pain experts. From 1997 the acceleration for opioid prescribing seems to have become more rapid. “Some of this acceleration in the rate of increase in opioid prescribing may have been due to the 1995 approval of the new sustained-release opioid OxyContin.”

The FDA had approved labeling for OxyContin which said that iatrogenic addiction was “very rare” and that the delayed absorption from the sustained-release formulation in OxyContin “reduced the abuse liability of the drug.” These claims were used by Purdue Pharmaceuticals in marketing campaigns to physicians and in more than 40 national pain-management and speaker training conferences; all expense paid ones, that is. In 2001 the FDA required Purdue to remove these unsubstantiated claims form the OxyContin labeling. But the damage was done. “However, the concept that iatrogenic addiction was rare and that long-acting opioids were less addictive had been greatly reinforced and widely repeated, and studies refuting these claims were not publish until several years later.”

So a one-paragraph 1980 letter became a kind of doublespeak, misused by Purdue Pharmaceuticals and others to change popular and medical thinking about pain management. And the first wave of the opioid epidemic was the result.

Updated with additional information on Dr. Jick’s 1980 letter on 6/8/2018

12/12/17

Greed with OxyContin is NOT Good

The health insurer Cigna announced that effective January 1, 2018, it will no longer cover OxyContin as a preferred medication. The company is in the process of notifying customers with current OxyContin prescriptions and their doctors of the upcoming change. Individuals who have begun using OxyContin for hospice care or cancer treatments will continue to be covered through 2018. If a doctor believes the use of OxyContin is medically necessary, Cigna will consider approving coverage. Needless to say, Purdue Pharmacy, the manufacturer of OxyContin, disagrees with the Cigna decision.

Cigna will offer an oxycodone equivalent medication with abuse deterrent properties, Xtampza ER with Collegium Pharmaceuticals. Collegium signed a “value-based contract” with Cigna, which will hold the company financially accountable if average daily dosage strengths of Xtampza ER prescribed for Cigna customers exceed a specific threshold. If the threshold is exceeded, Collegium will reduce the cost of the medication. “Linking financial terms to dosage metrics may encourage more education to prevent overprescribing.”

The Fix reported a Purdue spokesperson said there were few differences between OxyContin and Xtampza ER. “Unfortunately, Cigna’s decision limits the tools prescribers can use to help address the opioid crisis as both products are formulated with properties designed to deter abuse.” Cigna responded by saying the point is to change prescription practices. “The insurer hopes that doctors will begin to prescribe drugs like Xtampza ER ‘in lesser quantities and for lesser amounts of time.’”

Cigna’s decision comes in the midst of increasing pressure on Purdue Pharmacy for their aggressive, and at times illegal marketing practices of OxyContin. The pharmaceutical company came under scrutiny partly because of a series of investigative reports by the LA Times that noted a series of issues. The issues including how Purdue Pharma knew pain relief with OxyContin did not last the 12 hours as it claimed; but the company continued to insist the drug did last, in part, to protect its revenue. When doctors complained about the duration, Purdue instructed them to prescribe stronger, not more frequent doses. “OxyContin’s market dominance and premium price hinge on its 12-hour duration.” Purdue allegedly knew of this issue for more than twenty years.

For years, Purdue Pharma lied to federal regulators and the public about the addictiveness of OxyContin and countless patients got hooked on this deadly painkiller. We need to know if Purdue once again lied about the longevity of OxyContin’s pain-relieving properties and hold Purdue accountable.

Additionally, Purdue knew OxyContin was being overprescribed and illegally trafficked, but in many cases, did nothing about it. With one such operation, Lake Medical, Purdue did not stop supplying OxyContin and did not tell authorities what it knew for several years until the clinic was out of business and its leader indicted. By that time, 1.1 million pills has been put on the street.

A Los Angeles Times investigation found that, for more than a decade, Purdue collected extensive evidence suggesting illegal trafficking of OxyContin and, in many cases, did not share it with law enforcement or cut off the flow of pills. A former Purdue executive, who monitored pharmacies for criminal activity, acknowledged that even when the company had evidence pharmacies were colluding with drug dealers, it did not stop supplying distributors selling to those stores.

In 2015 Kentucky received $24 million from Purdue to settle the state’s 2007 against the company over their allegedly illegal promotion of OxyContin. As is usual in cases where pharmaceutical companies settle outside of court, they requested the records gathered in the court case be sealed and destroyed. In this case, there were 17 million pages of documents, including a deposition of Dr. Richard Sackler, the former president of Purdue Pharma and a member of the family who owns the privately held company. As part of the agreement, the Kentucky attorney general destroyed its copies of the documents provided by Purdue. However, copies of several key documents, including the Sackett deposition, filed under seal at the Pike County court, were not destroyed.

STAT News learned of the existence of these documents and filed a motion in March of 2016 to unseal the documents. In May of 2016 a Kentucky judge ordered that the documents be unsealed by June 12^th. The judge said he would stay the release of the records if there was an appeal filed before then. As of June of 2017, the documents were still not released. Purdue appealed the ruling to the Kentucky Court of appeals and although the appeals court said it expected to rule on the matter by the end of August, there was still no announcement by the middle of October.

The President of the Kentucky state Senate planned to file a motion to support the efforts by STAT to unseal the documents, saying that shielding the records from public view was “inappropriate.” He acknowledged his request to intervene could be unsuccessful, and it seems that it was. He thought the documents could help evaluate whether the $24 million payment from Purdue was a good settlement for Kentucky. “Two prior attorneys general valued the case at between $100 million and $1 billion.” Senate President Robert Stivers was concerned the state settled for “pennies on the dollar.”

Purdue was already pivoting to go overseas with its marketing strategy by 2011. With the growing concern over the opioid crisis in the U.S. and the awareness of the role OxyContin played in it, prescriptions fell by almost 40% since 2010, meaning billions in lost revenue for Purdue. Again, the LA Times documented this market expansion by Purdue in a December 2016 article, “OxyContin Goes Global.” Using a network of international companies owned by the Sackler family, Purdue Pharma is moving rapidly into Latin America, Asia, the Middle East, Africa and other regions. “In this global drive, the companies known as Mundipharma, are using some of the same controversial marketing practices that made OxyContin a pharmaceutical blockbuster in the U.S.”

In 2011, operations were started in China, Russia, Turkey, Hong Kong and South Africa. 2013 saw activity in Indonesia, Vietnam, Thailand and Taiwan. Dubai, Brazil, Columbia and Spain came on board in 2014. Lebanon and Portugal opened operations in 2015; Argentina in 2016. Chile, Ecuador, Peru, Uruguay and Venezuela plan to launch operations in the near future. There is an interactive map on “OxyContin Goes Global” that graphically illustrates this expansion.

In Brazil, China and elsewhere, the companies are running training seminars where doctors are urged to overcome “opiophobia” and prescribe painkillers. They are sponsoring public awareness campaigns that encourage people to seek medical treatment for chronic pain. They are even offering patient discounts to make prescription opioids more affordable.

Like the initial marketing of OxyContin in the U. S., some Mundipharma representatives and promotional material minimize the risks that patients will become addicted to opioid medications. While U.S. public health officials were warning of the growing pain killer threat in 2015, a Mundipharma executive in Seoul South Korea was saying doctors there worry too much about addiction: “Many studies have shown that it’s almost impossible for those with chronic or severe pain to become addicted to narcotics, as long as the drug is used for pain relief.” The opioid problem in the U.S. is said to be largely due to recreational abuse of the drugs.

“That is exactly the same thing they were teaching U.S. physicians when they launched OxyContin in this country,” said Sharon Walsh, an addiction expert who advises the FDA on risks from pain medications.

Mundipharma uses consultants (referred to as thought leaders in the U.S.), as did Purdue and other pharma companies, to overcome this opiophobia among doctors reluctant to prescribe narcotics. Top company officials have said their success in new markets depends on defeating this mind-set.

In Spain, Mundipharma used a series of actors, musicians and models in a campaign against chronic pain. “Ebélate contra el dolor (Rebel against the pain).” The ads did not recommend a specific medication, but urged viewers to seek out a healthcare professional (call your doctor?). “The campaign is part of a strategy to redefine back pain, joint aches and other common conditions as a distinct malady — chronic pain — that doctors and patients should take seriously.” Mundipharma sales were up seven-fold since 2007.

Around the world, Mundipharma companies cite statistics suggesting there is a great unmet need for their products. Opening an office in Mexico in 2014, Mundipharma officials declared that 28 million citizens were suffering from chronic pain. In Brazil, the company cited a figure of 80 million. In Colombia last year, a company news release said 47% of the population — about 22 million people — were afflicted by ‘this silent epidemic.’”

Meanwhile, back in the US, the lawsuits against Purdue Pharma just keep on coming. In May of 2017 the NYT reported Purdue and three current and former executives pleaded guilty in federal court to criminal charges “that they misled regulators, doctors and patients” about the drug’s addiction risk and potential for abuse. In order to resolve criminal and civil charges stemming from the drug’s “misbranding,” Purdue agreed to pay $600 million, one of the largest amount ever paid by a drug company in such cases. Three executives, including its president and its top lawyer pleaded guilty as individuals to misbranding, which is a criminal violation. “They agreed to pay a total of $34.5 million in fines.”

Purdue Pharma acknowledged in the court proceeding today that “with the intent to defraud or mislead,” it marketed and promoted OxyContin as a drug that was less addictive, less subject to abuse and less likely to cause other narcotic side effects than other pain medications.

Reuters reported that New Hampshire announced in the beginning of August of 2017 that it was suing Purdue for engaging in deceptive marketing practices. The lawsuit followed similar cases against Purdue and other pharmaceutical companies by Oklahoma, Mississippi, Ohio and Missouri and several cities and counties in California, Illinois, Ohio, Oregon, Tennessee and New York.

A week later, South Carolina filed suit against Purdue Pharma, according to Reuters. Again the company is accused of unfair and deceptive marketing of opioid painkillers. South Carolina had been part of a 2007 settlement when Purdue and three executives pleaded guilty to federal charges of misbranding OxyContin. In the August 2017 lawsuit, “South Carolina claimed that since the 2007 settlement, Purdue has continued to engage in misleading opioid marketing practices rather than reforming them to conform with the law.”

In the 1987 movie Wall Street, Michael Douglas as Gordon Gekko famously said, “Greed, for lack of a better word, is good.” He went on to claim that greed captured the essence of the evolutionary spirit. “In all of its forms; greed for life, for money, for love, knowledge has marked the upward surge of mankind.” At the end of his speech, he was applauded. The greed of Purdue Pharma and the Sackett family, which privately owns Purdue Pharma and OxyContin, is not good. Their unrestrained greed has contributed to the current opioid epidemic in the U.S., despite the denials of the company. And now they want to export the same drug and marketing strategy to the world.

07/19/16

The Tale of the OxyContin Lie

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 (1920-2017). 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 OxyContin, 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 Pharmaceuticals. 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.”

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: Purdue Pharmaceuticals