02/1/22

Carrot-and-Stick Tactics of Purdue and the Sacklers

© kmiragaya |123rf.com The Metropolitan Museum of Art in Manhattan

In the aftermath of frustration with the bankruptcy settlement with Purdue Pharma that shielded the Sackler family from any future legal action, the Metropolitan Museum of Art and the Sackler family announced the Sackler name would be removed from seven exhibit spaces. The New York Times said this was a significant break between the world’s largest museum and one of the world’s biggest benefactors. The Sackler family said they thought it was in the best interest of the museum and the mission it serves. “The museum had already severed ties to the family’s funding, announcing in 2019 that it would no longer accept gifts from the Sacklers, given their links to the maker of OxyContin.” Then a week later, a federal judge overturned the settlement that legally shielded members of the Sackler family from future litigation.

Reuters reported that U.S. District Judge Colleen McMahon said the New York bankruptcy court did not have the authority to grant the Sacklers legal protection from future opioid litigation. Attorney General Merrick Garland agreed, and was pleased by the ruling. He said: “The bankruptcy court did not have the authority to deprive victims of the opioid crisis of their right to sue the Sackler family.”

McMahon raised questions about more than $10 billion that Purdue distributed to the members of the Sackler family over a ten-year period of time preceding the company’s filing for bankruptcy. A statement from the family about the transfer of funds 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 bankruptcy settlement was said to be worth $8 billion, a record payout by a pharmaceutical company. However, the Sackler family threatened to walk away and scuttle the settlement unless the legal protections were included. The family was to contribute over $4 billion of their personal funds to charitable assets over nine years as part of the settlement.

The Hill reported that in September 2021, U.S. Bankruptcy Judge Robert Drain approved the initial settlement plan. It would have led to the dissolution of Purdue Pharma and the transfer of its assets to a nonprofit company whose mission would be to fight the opioid crisis.

Representative Carolyn Maloney (D-N.Y.), Chair of the Committee on Oversight and Reform, said: “Today’s ruling striking down Purdue Pharma’s bankruptcy plan and its illegal releases for the Sacklers is a monumental step toward justice for the victims of the Sacklers’ cruel, deliberate plan to flood our communities with the highly addictive opioid, OxyContin.” She added,

The Sacklers must not be permitted to evade accountability by abusing our bankruptcy system, and I applaud the District Court for recognizing what I’ve long believed — that nonconsensual third-party releases are not only immoral and unjust, but also illegal.

Of course, Purdue will appeal the district court’s decision. Steve Miller, Purdue’s chairman, said:

While the district court decision does not affect Purdue’s rock-solid operational stability or its ability to produce its many medications safely and effectively, it will delay, and perhaps end, the ability of creditors, communities, and individuals to receive billions in value to abate the opioid crisis.

This sounds suspiciously like Purdue and the Sacklers are using a “carrot-and-stick” approach to their negotiations—the billions in settlement money as the carrot and the threat of rejecting the settlement without legal protection of the Sacklers from future opioid litigation as the stick.

Paul Pelletier, a former Department of Justice fraud chief and Beth Macy, a journalist and the author of Dopesick, wrote an opinion piece for STAT News. They noted that in late 2020, Purdue pled guilty to defrauding federal health agencies and violating anti-kickback laws. Although the Department of Justice won a $225 million civil settlement, it won’t collect on the $8.3 billion fine, as the company was already in bankruptcy. It failed to bring charges against any individuals for their roles in the company’s crimes. But the 2020 settlement did not close the door on criminal prosecution of Sackler family members.

Sacklers Avoiding Justice?

Fifteen years ago, prosecutors in western Virginia uncovered evidence of fraud and recommended multiple felony charges against the three top executives at Purdue. These charges included money laundering, conspiracy, misbranding, interstate wire and mail fraud. Pelletier and Macy said “the evidence of callous greed was chilling.” But political appointees at the DOJ, swayed by Purdue’s lawyers, refused to approve felony charges for the executives.

Purdue received a $600 million fine and pleaded guilty to “misbranding” OxyContin while marketing. The three executives pleaded to a misdemeanor “misbranding” charge, but did not admit any wrongdoing. The case was settled through a plea bargain and the evidence within the case forgotten until a copy of the Justice Department memo was leaked. For more information on this, see “Giving an Opioid Devil Its Due.”

The company had fired employees who tried to blow the whistle on its crimes and maneuvered to have reporters who were onto the story fired or removed from their beats. Sales reps were encouraged to allow doctors to believe — falsely — that morphine was stronger than OxyContin when executives knew the opposite was true. The company’s medical director, Dr. Paul Goldenheim, lied to Congress when he testified that executives hadn’t known until 2000 that OxyContin was being widely abused: in fact, they’d become aware of addiction-related abuse shortly after the drug’s introduction in 1996.

“A trial would have exposed the company’s OxyContin profits to forfeiture or prompted one of the executives to expose the magnitude of OxyContin scion Richard Sackler’s participation in the admitted crimes.”

Pelletier and Macy said after avoiding a legal trial related to the above investigation, they know the Sacklers and Purdue intensified their marketing of OxyContin. Purdue hired consultants to advise them how to “turbocharge” sales. They concentrated on well-known pill mills, and pushed the highest-dose pills. They also joined with other opioid makers to get around FDA regulators.

Beth Macy’s book, Dopesick was made into a television series. The show’s creator said it was “the trial that Purdue Pharma and the Sackler family never had.” As Pelletier and Macy pointed out, America is not supposed to rely on books and a movie for justice. “We pay taxes and give the Department of justice legal authority to enforce the law.” They said that Judge McMahon’s ruling was a win for accountability, “but it may not endure.”

So far, no criminal charges have been filed against any member of the Sackler family. But a new U.S. attorney for the federal district responsible for investigating the Sacklers has been sworn in. And Pelletier and Macy think he could be the perfect Special Prosecutor. We’ll have to wait and see if this makes a difference. Meanwhile, the Metropolitan Museum of Art continues to distance itself from the Sacklers and Purdue.

While the billionaire Sacklers may spend this holiday season ruminating on the ignominy of having their name removed from New York’s Metropolitan Museum of Art and other museums they showered with blood money, a million families across America will have to endure it without their children, spouses, parents, and friends whose lives were either eviscerated or cut short by opioids. It is shameful that, at least for now, they must live without justice, too.

For more information on the initial settlement, see: “It Doesn’t Seem Right.”

10/12/21

Unintended Consequences of COVID-19

On December 17, 2020, while the country’s attention was focused on the just-approved COVID vaccines, the CDC released a health advisory that noted substantial increases in drug overdose deaths across the U.S. Then, the report estimated that there were 81,230 drug overdose deaths in the 12-months ending in May 2020. This represented a worsening of the drug overdose epidemic in the U.S. and was the largest number of drug overdoses ever recorded for a 12-month time period. The CDC report said it appeared that drug overdose deaths accelerated during the COVID-19 pandemic. But then a new CDC report released in July of 2021 reported the number of overdose deaths had increased to 92,183 in December of 2020.

The July 2021 CDC report contains interactive figures showing the month-ending counts of overdose deaths by drug class and by states. From December of 2019 until December of 2020 California overdose deaths increased 45.9%; New York State, 37.3%; New York City, 36.6%. The states with the highest increases of overdose deaths were: Vermont, 57.6%; West Virginia, 55.6%; Kentucky, 53.7%; and South Carolina, 52.8%. The overall increase for the U.S. was 29.6%. See the July 2021 CDC report for more information.

A public health researcher for Brown University said to AP News this was a “staggering loss of human life.” While the nation was already struggling with a serious overdose epidemic, “COVID has greatly exacerbated the crisis.” Lockdowns and other restrictions during the pandemic made treatment harder to get. The increased deaths are most likely from people who were already struggling with addiction. Suspensions of evictions and extended unemployment benefits meant there was more money than usual to spend on drugs.

According to Shannon Monnat, a sociology professor at Syracuse University, what is really driving the surge in overdoses is an increasingly poisoned drug supply. “Nearly all of this increase is fentanyl contamination in some way. Heroin is contaminated. Cocaine is contaminated. Methamphetamine is contaminated.”

Reuters reported that during the pandemic, many drug programs were not able to operate. Restrictions meant therapy sessions were done by Zoom, which are not as impactful as in person face-to-face contact. Indirectly, pandemic lockdowns likely contributed to the increase in overdose deaths. The lockdowns intensified feelings of isolation, which is a factor in anxiety and depression, which leads to drug abuse. A health policy expert at John Hopkins Bloomberg School of Public Health estimated on a day-to-day basis, the U.S. is now seeing more overdose deaths than COVID-19 deaths.

In “Drug overdose deaths accelerating due to the pandemic,” the director of the CDC said the disruption of daily life from COVID-19 hit those with substance use disorder hard. “As we continue the fight to end this pandemic, it’s important to not lose sight of different groups being affected in other ways. We need to take care of people suffering from unintended consequences.” Again, we see the problems from fentanyl contamination. Opioids, primarily illegally manufactured fentanyl, were largely responsible for most of the overdose deaths. Synthetic opioid fatalities rose 38.4% from 2019 to 2020.

Recently, the American Medical Association noted a similar spike in overdose deaths driven by opioid deaths. The past president of the American Medical Association, Patrice Harris, warned of the necessity to continue to pay attention to health issues other than COVID. She said:

It is imperative that we continue to talk about other health issues that are impacting our nation . . . We are appropriately focused on COVID, it is still top of mind for most people, and it’s understandable that we can lose focus on other issues … but we still have to make sure we are focused on the overdose epidemic that we continue to experience in this country.

There was a study in in JAMA Network Open, “Trends in Drug Overdose Mortality in Ohio,” that looked at the overdose deaths in Ohio during the first seven months of the pandemic. Fatal overdoses rose sharply from the declaration of the pandemic on March 11^th 2020 to the week of May 31^st 2020, an increase of 70.6%. The initial spike in deaths was most pronounced for the youngest adults, those up to and including the age of 24. However, fatal overdoses followed a similar pattern in all age groups, including those 65 years and older. See the follow chart from the JAMA article.

Another study published in the Journal of Drug Issues assessed the relationships between COVID-19 stay-at-home orders and opioid overdoses in Pennsylvania. The authors said in an article for the Fix that Pennsylvania was one of the hardest hit states by the opioid epidemic. They found statistically significant increases in overdoses with heroin, fentanyl, fentanyl analogs or other synthetic opioids, pharmaceutical opioids and carfentanil. The researchers suggested in the Journal of Drug Issues that the observed increases were likely to be underestimates because of undercounts of monthly overdose incidents. They recommended these drug clsses be continuously monitored for changing patterns of use to help guide the most effective treatment interventions.

This analysis suggests that the onset of COVID-19 in the state of Pennsylvania, and resulting policy responses to mitigate infection, created unintended consequences for opioid overdose. These unforeseen outcomes obligate attention to how economic effects of the pandemic, coupled with mental health stress and other triggers for addiction, complicate and undermine patterns of opioid use and misuse, and emphasize the need for opioid use to be addressed alongside efforts to mitigate and manage COVID-19 infection.

It was pointed out how the economic recession associated with the pandemic undermined housing policy and access, “which will have lingering effects for social cohesion, access to medical care, and consistent routines critical for addiction management.” Percentages of fatal versus nonfatal overdoses remained relatively constant throughout the study at 16-17%. Heroin accounted for the largest percent (65%) of the total reported opioid-related overdose cases, followed by fentanyl (14%) and the unknown drug class (14%). “Increased mental health stress, social isolation, and economic uncertainty will likely continue to affect those most vulnerable to addiction and relapse.”

The double impact of COVID-19 and drug overdoses induced a drop in life expectancy for 2020. The CDC reported that life expectancy at birth for 2020 was 77.3 years, a decrease of 1.5 years from 78.8 in 2019. This was the lowest it has been since 2003. The decline in life expectancy was primarily due to COVID-19 (73.8% of the negative effect), unintentional injuries (11.2%), and homicide (3.1%). “Increases in unintentional injury deaths in 2020 were largely driven by drug overdose deaths.”

“The Leading Causes of Death in the US for 2020,” published in JAMA, found that COVID-19 was the third leading cause-of-death after heart disease and cancer. There were substantial increases from 2019 to 2020 for several leading causes. Heart disease deaths increased by 4.8%; unintentional injury by 11.1%; Alzheimer disease by 9.8%; and diabetes by 15.4%. Early estimates of life expectancy at birth for January 2020 to June 2020 showed declines not seen since World War II. See the following table taken from “The Leading Causes of Death in the US for 2020.”

The influence of the pandemic on the opioid epidemic has not gone unnoticed by the White House. In March of 2021, President Biden released a Statement of Drug Policy Priorities that said illicitly manufactured fentanyl and synthetic opioids other than methadone (SOOTM) have been the main influence behind the increase. However, overdose deaths from cocaine and other psychostimulants like methamphetamine have also risen. “New data suggest that COVID-19 has exacerbated the epidemic.” The American Rescue Plan, signed into law in March of 2021, set the following drug policy priorities for the administration:

Expanding access to evidence-based treatment;
Advancing racial equity issues in our approach to drug policy;
Enhancing evidence-based harm reduction efforts;
Supporting evidence-based prevention efforts to reduce youth substance use;
Reducing the supply of illicit substances; Advancing recovery-ready workplaces and expanding the addiction workforce; and
Expanding access to recovery support services.

Concern over the entwined consequences of the COVID-19 pandemic and the opioid epidemic exist beyond the US. In an opinion article for the BMJ, Ian Hamilton noted how the COVID-19 pandemic has amplified inequalities such as poverty, unemployment, poor housing and homelessness in the UK. He said these inequalities have been felt most acutely felt by those from the lowest socioeconomic groups. “Until effective ways of reducing social inequality are implemented, the best that we can hope for is timely specialist support for those developing drug related problems, such as dependency.” He concluded that problem drug use is an issue that will be with us for years and we need to build a workforce to meet the demand and ensure that these avoidable fatalities “are just that—avoided.”

07/10/18

Giving an Opioid Devil Its Due

thorny devil lizard; licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license

In December of 2002, Purdue Pharmaceutical executives received a subpoena from the office of the United States Attorney for the Western District of Virginia. Federal prosecutors were notifying Purdue that the Department of Justice had formally opened an investigation into how the company marketed OxyContin. Two assistant U.S. Attorneys had become aware of the false marketing claims made by Purdue sales reps for OxyContin “and they began to wonder if high-ups in the company had orchestrated that campaign.” The two men noticed that since Purdue had begun marketing OxyContin the cases they were getting had changed drastically. “By 2001, virtually all of them—robberies, fraud, assaults, and pill-mill cases—had a connection to Purdue’s drug.”

Over the next four years a team of federal prosecutors and investigators worked through thousands of Purdue emails, records and other documents. “They called former Purdue sales reps, marketing executives, researchers medical officers, and chemists to testify under oath before a federal grand jury.” While going through the subpoenaed documents, they discovered how Purdue misrepresented data in order to minimize OxyContin’s addictive potential. “The FDA has told Purdue that data was bogus, but the company trained its reps to use it anyway.”

They also discovered Purdue had concealed information that contradicted a claim made when OxyContin was first marketed, namely that patients on low doses (less than 60 mg daily) “could stop it abruptly without going through the anxiety and discomfort associated with opioid withdrawal.” This claim had been based on a Purdue-funded study that low dose patients exhibited “no overt withdrawal syndrome.” A Purdue researcher re-examined the study’s underlying data in 2001 and found that 25% of patients showed symptoms consistent with withdrawal. “But prosecutors found emails showing the company allowed sales reps to give the questionable study to doctors, apparently with the blessing of senior executives.”

Some Purdue medical officers wanted the company to notify the FDA about the withdrawal issue; to admit that tapering a dose was a “more prudent medical recommendation than stopping low dose OxyContin abruptly. “In grand-jury testimony, FDA officials said the agency never got that report.”

Prosecutors discovered that by 2000 Purdue has begun receiving calls from patients on low doses, who were experiencing significant withdrawal symptoms. Soon, Purdue officials were sending one another emails about the “risk management” implications if the study’s findings were inaccurate.

To this day, Purdue insists it first became aware of abuse problems with OxyContin in early 2000, “as a result of articles in Maine newspapers and when the U.S. Attorney there sent out an alert to doctors in the state.” But during their investigation prosecutors came across emails indicating that senior executives at Purdue “learned about wider abuse of OxyContin well before they said they did.” Prosecutors believed they had more than enough evidence to show that three senior company executives had misrepresented when they first learned of OxyContin’s abuse. They recommended the men be indicted on charges that included conspiracy to defraud the United States. In late September 2006 they sent a 120-page memo to their boss, the U.S. Attorney for the Western District of Virginia, with the recommended indictments. It was then forwarded to officials at the Justice Department headquarters for review and approval. The following excerpt is from the memo:

Had the conspirators provided Congress and their sales representatives with the truth, that is that PURDUE had been aware, at least as early as 1997-1998, that both MS Contin and OxyContin were subject to widespread abuse and diversion but continued to market OxyContin as less addictive, abusable and subject to diversion in the face of this knowledge, the sales representatives would have lost all credibility with health care providers, and PURDUE’s conduct would likely have been subject to much greater regulatory and Congressional scrutiny.

The above was gleaned from the expanded and updated edition of Barry Meier’s book, Pain Killer. Coinciding with the publication of the expanded edition of Pain Killer, two articles by Meir appeared in The New York Times, where he has been a reporter since 1989. Those articles are: “Origins of an Epidemic: Purdue Pharma Knew Its Opioids Were Widely Abused” and “Every Time I Thought the Purdue Pharma OxyContin Story Was Over, I Was Wrong.” In “Origins of an Epidemic,” Meir gave further details of how Purdue Pharma knew about serious abuse in the first years after OxyContin was put on the market. Even members of the Sackler family had been alerted about abuse problems with OxyContin and MS Contin.

Company officials had received reports that the pills were being crushed and snorted; stolen from pharmacies; and that some doctors were being charged with selling prescriptions, according to dozens of previously undisclosed documents that offer a detailed look inside Purdue Pharma. But the drug maker continued “in the face of this knowledge” to market OxyContin as less prone to abuse and addiction than other prescription opioids, prosecutors wrote in 2006.

But top Justice Department officials did not believe the felony charges against Purdue executives were justified. Instead, the case was settled through a plea bargain. “When the case was settled, the memo and the evidence within it were sealed and forgotten.”

In 2007, Purdue Pharma pleaded guilty to a felony charge of “misbranding” OxyContin while marketing the drug by misrepresenting, among other things, its risk of addiction and potential to be abused. Three executives — the company’s chief executive, Michael Friedman; its top medical officer, Dr. Paul D. Goldenheim; and Mr. Udell, who died in 2013 — each pleaded guilty to a misdemeanor “misbranding” charge that solely held them liable as Purdue Pharma’s “responsible” executives and did not accuse them of wrongdoing. The company and the executives paid a combined $634.5 million in fines and the men were required to perform community service.

In “Every Time I Thought the Purdue Pharma OxyContin Story Was Over, I Was Wrong,” Meier described how the complete Purdue OxyContin story told in Pain Killer came to him in spurts. He became interested in the back-story to Purdue Pharma and OxyContin after a 2001 interview he had with the Purdue CEO, Michael Friedman. This led to his 2003 edition of Pain Killer. Meir heard rumors of the Justice Department investigation, but when nothing happened, he assumed it just ran out of steam. Then he heard of the plea bargain, where “Purdue Pharma and the three executives I had interviewed were about to plead guilty to charges connected to the company’s deceptive marketing of OxyContin.” He received a tip about the sentencing from the U.S. Attorney for the Western District of Virginia because his writing on the issue for The New Times and in Pain Killer helped inform the original investigation documented in the 2006 memo.

Once again, Meier thought the OxyContin story was over. That is until he was given a copy of the 2006 Justice Department memo. After reading it, he realized just how much he hadn’t known back then. He even discovered that he was mentioned in the memo. Prosecutors found a tape recording of his 2001 interview with the Purdue CEO and planned to use it as an example of how the Purdue executives publically misrepresented the company’s knowledge of early OxyContin abuse. “Now, with the report in hand, I finally had the chance to bring the story of Purdue Pharma and OxyContin full circle, both in The Times and in an expanded edition of Pain Killer.”

Then on May 15, 2018 Reuters noted that six states, Nevada, Texas, Florida, North Carolina, North Dakota and Tennessee filed lawsuits against Purdue Pharma LP, accusing the company of “fueling a national opioid epidemic by deceptively marketing its prescription painkillers to generate billions of dollars in sales.” Sixteen other U.S. states and Puerto Rico have already filed lawsuits against Purdue, with New York and California preparing similar lawsuits. Fierce Pharma announced Massachusetts would be the first to not only file suit against Purdue, but also against its current and former executives and board members. This group includes members of the Sackler family that owns the stable of privately held Purdue Pharma companies.

On July 5^th Purdue Pharma dropped its effort to keep the Tennessee lawsuit sealed. The Tennessee Coalition for Open Government and the Knoxville News Sentinel were successful in their efforts to make public the details of the 274-page lawsuit against Purdue Pharma. The Tennessee Attorney General told the News Sentinel: “The state’s complaint contains specific examples of defendant’s unlawful conduct, its scale and impact on the state, the company’s knowledge of activities and financial gain.” He said there is proof the firm lied about the addictive properties of the drug OxyContin and actively marketed it to addicts.

The New York Daily News reported the unsealed lawsuit said Purdue called on two providers 48 times after the company had been told by law enforcement they were responsible for “significant interstates OxyContin diversion.” The lawsuit further states:

Purdue continued to make sales calls in spite of credible reports of patient overdoses, indictments, adverse licensure actions, a provider admitting he was addicted to heroin, a knife fight outside a provider’s office, muggings over controlled substances outside of a pharmacy linked to a specific provider, a clinic that had no examination tables or equipment, an admission by a provider that he was running a pill mill, a provider changing the name of his practice shortly after he was notified of a state investigation into his practice, a patient being coached in the waiting room about how to fill out intake forms, armed guards in provider waiting rooms, high numbers of patients who purchased OxyContin in cash, high numbers of out-of-state or out-of-county tags in providers’ parking lots, accusations of insurance fraud, choreographed urine screenings and pill counts, standing-room-only waiting rooms, and additional signs of problematic high volume practices.

It sounds like one of the devils in the opioid epidemic may just get its due.

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

03/16/18

Overdose No-Brainers

The governor of Pennsylvania, Tom Wolf, declared the heroin and opioid epidemic as a statewide disaster emergency. Among the enhancements of the declaration, there will be increased access to the Prescription Monitoring Program so that state officials can identify doctors who are overprescribing opioid medication, as well as patients who may be seeing more than one physician to multiply their access to prescription opioids. Several measures to expand, speed up, and improve access to treatment and will be instituted. These measures include: enabling EMS to leave naloxone behind after responding to an overdose and expanding access to medication for Narcotic Treatment Programs. Pharmacists will be permitted to partner with prisons and treatment programs to make naloxone available to individuals leaving those facilities.

The Fix reported there was bipartisan support for the governor’s action. U.S. Senators, Pat Toomey (R) and Bob Casey (D) publically praised the declaration. Senator Toomey said: “The opioid and heroin crisis has rightfully drawn bipartisan attention in Congress and all levels of government. Today’s opioid emergency declaration sends a clear message that more work remains to be done.” Senator Casey added: “This declaration will bring additional resources to bear on this horrific public health emergency that has ripped apart far too many families.”

Increased access to the Prescription Monitoring Program by state officials is not as Orwellian as it may sound. Limitations placed upon the DEA by the “Ensuring Patient Access and Effective Drug Enforcement Act of 2016” hobbled the DEA’s ability to go after drug companies suspected of enabling the widespread distribution of prescription pain medication. “Overall, the drug industry spent $102 million lobbying Congress on the bill and other legislation between 2014 and 2016, according to lobbying reports.” See “Head of a Snake” for more information on this issue.

Drug overdose data from the CDC indicated that in 2016, Pennsylvania had the fourth highest increase in drug overdose deaths with 37.9 per 100,000. West Virginia (52.0 per 100,00), Ohio (39.1 per 100,00), New Hampshire (39.0 per 100,00) and Kentucky (33.5 per 100,000) rounded out the top five states. This was a 44.1% increase from 2015 to 2016 for Pennsylvania, again placing them fourth behind the increases with the District of Columbia (108.6%), Maryland 58.9%) and Florida (46.3%). New Jersey (42.3%) rounded out the top five states with percentage increases of overdose deaths. See the following graphic from the CDC report on rates of drug overdose death by state for 2016.

Another CDC report indicated the death rate for drug overdoses for the twelve-month period ending with the 4^th quarter of 2016 was 19.8 per 100,000, an increase over the same time period for the 4^th quarter of 2015, 16.3 per 100,000. This was an increase of 21% from 2015. The New York Times said Dr. Andrew Kolodny, the director of opioid policy research at Brandeis University, was not surprised by the data. “We have roughly two groups of Americans that are getting addicted. . . . We have an older group that is overdosing on pain medicine, and we have a younger group that is overdosing on black market opioids.” See the following table from the CDC report.

Naloxone, as it was noted in the opening paragraph, is a crucial tool in the struggle against opioid overdoses. Yet it had a quiet, and rather unassuming life until the rise of the opioid epidemic. Jack Fishman originally synthesized naloxone for a private narcotics lab owned by Mozes Lewenstein in 1961. Harold Blumberg, a colleague of Lewenstein’s, had the idea of developing an opioid antagonist by making a small structural change to oxymorphone, a synthetic opioid. The FDA approved naloxone as an injection, Narcan, to reverse opioid intoxication in 1971. Generic versions of naloxone became available in 1985.

As the opioid crisis began to pick up steam in 2013, the FDA approved Evzio, a portable injection kit with a fixed dose of naloxone. In late 2015, they approved Narcan, now packaged as a nasally administered form of naloxone. A series of governmental initiatives were enacted to increase access to naloxone. From 2012 to 2016, the number of states with at least one law expanding access to naloxone increased from 8 to 46. A growing number of community organizations now provide naloxone kits and education programs to laypersons. But as Gupta et al. reported in The New England Medical Journal, between 2009 and 2015 the annual number of naloxone prescriptions only increased from 2.8 million to 3.2 million. While retail-prescription numbers were unchanged, the proportion attributed to clinics and EMS providers increased from 14% to 29%.

Although the slowed rate of using naloxone could be attributed to the stigma of opioid use and unfamiliarity with how to use naloxone, the rising cost and the limited number of manufacturers producing it, are more insidious reasons. While there are three manufacturers of naloxone approved by the FDA, there is only one supplier for all three formulations. Amphastar, the manufacturer of the 1-mg-per-millileter dose used off-label as a nasal spray, increased its price 95% to $39.60 in September of 2014. “Newer, easier-to-use formulations are even more expensive. Narcan costs $150 for two nasal-spray doses. A two-dose Evzio package was priced at $690 in 2014 but is $4,500 today, a price increase of more than 500% in just over 2 years.” See the following table of previous and current prices for naloxone.

The price increase for naloxone is related to the overall trend of rising prescription drugs prices across-the–board. See “Pharma’s Not Getting the Message” and “Pharma Companies Hunt in Packs” for more information on this. But unfortunately, none of the federal or state initiatives to expand the availability of naloxone address the drug’s high price. “Evzio’s price jumped significantly and without explanation the month before the CDC’s coprescription guidelines were released.” Several U.S. senators have sent letters to naloxone manufacturers asking them to explain their price increases, but this hasn’t resulted in any changes or public outrage, as happened with Mylan, the manufacturer of the EpiPen. Gupta et al. had some recommendations to address naloxone’s price increase.

First, naloxone could be purchased in bulk, which would create stable demand that might motivate additional companies to begin manufacturing the medication — a strategy that’s been used for vaccine manufacturing. Second, governments could invoke federal law 28 U.S.C. section 1498 to contract with a manufacturer to act on behalf of the United States and produce less costly versions of Evzio’s patented auto-injector in exchange for reasonable royalties — an approach that was considered for procuring ciprofloxacin during the anthrax threat in 2001. Third, in response to increases in generic drug prices, some observers have proposed allowing importation of generics from international manufacturers that have received approval from regulators with standards comparable to those of the FDA, a strategy that could be pursued for naloxone.

Gupta et al. also suggested the federal government could motivate additional companies to obtain approval to market generic versions of naloxone by prioritizing timely approval and waiving application fees. This would likely stimulate price competition. Resurrecting a discussion of the FDA switching naloxone to over-the-counter-status would benefit patient access. “The relative ease of receiving FDA authorization for over-the-counter medications would also probably attract additional manufacturers.”

Naloxone coprescribing and expanded availability represents only one of many potential strategies for reducing the number of prescription-opioid and heroin overdose deaths in the United States. But when governments promote naloxone use, they have a responsibility to ensure the drug’s affordability. Taking action now is essential to ensuring that this lifesaving drug is available to patients and communities.

As illustrated within the actions taken by Governor Tom Wolf of Pennsylvania, naloxone is a key factor in the fight against the opioid epidemic. Given the potential influence of state and federal officials and legislators, concerted efforts to force manufacturers to decrease the cost of naloxone products or to take steps to increase their competition should be a no-brainer strategy. Otherwise—and this itself is another no-brainer—the pharmaceutical companies will continue to siphon as much profit as they can from the opioid epidemic.

08/8/17

Kratom: Part of the Problem or a Solution?

In August of 2016 the DEA announced that it would temporarily classify kratom as a Schedule I substance. The public outcry against this plan influenced the DEA to reverse itself and delay scheduling kratom in October of 2016. The DEA announcement said before taking further action, it would solicit public comments and review the FDA’s “scientific and medical evaluation” of the proposed scheduling of kratom. Once the DEA has received and considered the information, it would decide how to proceed. But while we await the DEA’s decision, kratom is being sold in vending machines.

Advocates for kratom were overjoyed with the DEA’s decision. Chris Ingraham reported for The Washington Post that researchers welcomed the decision to delay scheduling kratom, but were concerned that the future of their research was still up in the air. After its October 2016 announcement, the DEA set a period for public comments on the potential scheduling of kratom until December 1^st of 2016. As of August 6^th, 2017, there has not been a public announcement about its decision or its review of the FDA report on kratom.

Since the DEA delayed a decision on kratom, it is still unregulated and will remain available for anyone to use without a prescription. And research into the risks and benefits of kratom can continue unhindered by a temporary Schedule I classification.

Andrew Kruegel of Columbia University is working to develop new painkillers from compounds contained in kratom. He commented: “I am encouraged that they will now be having more serious input on this important policy decision.” While the DEA announcement might be good news for now, studies with the methodology of rigorous, controlled trials typical of FDA evaluations don’t exist for kratom. So will the DEA wait for the months or years it could take to complete rigorous kratom studies before deciding whether or not to schedule it?

According to the American Kratom Association (here) and PinneyAssociates (here), Jack Henningfield did an “8-factor analysis” with kratom, which is the legal framework used by the FDA to assess the abuse potential of substances. Henningfield concluded that kratom had a low toxicity level; and that scheduling it as a controlled substance was not warranted.

It’s important to understand that although kratom has some mild effects similar to opioids, its chemical make-up is different, and it appears overall much safer, with apparently relatively small effects on respiration. In fact, kratom’s analgesic effects and impact on energy, combined with its favorable safety profile supports continued access by consumers to appropriately regulated kratom products while research on its uses continues.

STAT News identified another person doing research with kratom, Edward Boyer, who is currently at UMass Memorial Medical Center and Boston Children’s Hospital. Boyer has been interested in kratom since 2006. Even then there was a Catch-22 of sorts when trying to get government funding for kratom. “The National Institute on Drug Abuse didn’t want to fund kratom projects, saying it was a complementary and alternative medicine, while the National Center for Complementary and Integrative Medicine didn’t want to fund them because it was a drug of abuse.”

In 2008, Boyer and two colleagues filed a patent to use kratom or its chemical compounds as a new treatment method for opioid withdrawal, one of the ways it is currently used informally and non-medically. Two large freezer bags of kratom he obtained still sit in a cabinet of the UMass Memorial Medical Center’s toxicology office. Boyer said the bureaucratic nightmare of running the FDA gauntlet to do a clinical trial stopped them cold.

Andrew Kruegel’s research has had some promising initial results. His team was able to demonstrate that the main components of kratom primarily stimulated the painkilling response, while having minimal effects on the proteins that caused other side effects. But these findings need to be repeated in mice and then humans, “before they could claim that they have used kratom to create an opioid-like painkiller without as many risky side effects.” But there is a problem obtaining kratom of the quality needed for his research and the red tape involved in the process of obtaining it. “There is nowhere to buy the plant unless I am going to go to Indonesia and contact plantation owners.”

In the mean time, you can order kratom on the Internet from several vendors. And if you live near the East Coast Super Subs shop in Tucson Arizona, you can buy it out of a vending machine. Eric Boodman reported for STAT News that the vending machine there attracted five customers in an hour. The servers at the sub shop said it gets even busier around opening and closing time. Using cash or a credit card, a customer can buy as little as 10 grams for $5, or up to 120 grams for $50.

The almost-scheduling of kratom seems to have been good advertising for the herbal product. Drew Pickett, the owner of a second kratom vending machine company, Arizona Kratom, said many people discovered kratom because of the bad publicity. “People were like, ‘Wow, if the government doesn’t want me to have it, I want to try it.’” He estimated the aborted ban triggered a 400% boost in his sales.

One person said kratom helped him stop using heroin six years ago. Last year he relapsed, and was back using heroin for several months before he used kratom to wean himself off heroin for the second time. He found the Tucson Kratom vending machine when the kratom he used to get from head shops became too pricey. Now he wants to wean off of kratom as well. “I start with a lot of it initially … and then I taper down. I’ve been doing it very gradually and probably in the next two or three months, I’ll be done with it.”

But things aren’t all sunshine and happiness with the kratom vending machine. Dr. Mazda Shirazi, the medical director of the Arizona Poison and Drug information Center first heard about the machine when a patient of his began to show signs of liver toxicity from using kratom from the machine on a daily basis. He’s worried about the lack of regulation with kratom, meaning you can’t be sure of the purity of what you are buying. He’s also concerned that using kratom to wean off of opioids will give some addicts false hope. “I think it actually prolongs the addiction cycle and puts the patient in a dangerous situation, whereas by getting help they might be better off.”

Susan Ash, the founder of the American Kratom Association, saw the vending machine as a sign of how pervasive the opioid epidemic has become. “Maybe a person who is going to walk into that sandwich store and has never heard of kratom — maybe that will be their first day off of opiates.” She liked the idea of people not having to wait a day or longer for their kratom to arrive in the mail. But she worried the vending machine made kratom available to children under 18. “There’s not enough research to know how the substance affects developing brains.”

And there’s the rub: there simply isn’t enough reliable, replicated research with kratom to make an informed decision on how to use it or whether to schedule kratom. Henningfield’s study is suggestive of a good safety profile for kratom, but can’t be regarded as conclusive since it was funded by the American Kratom Association. In contrast to Henningfield’s safety assessment of kratom, others have said there is a real probability of becoming addicted with kratom.

The National Institute on Drug Abuse (NIDA) noted how two compounds in kratom, mitragynine and 7-hydroxymitragynine, interact with opioid receptors in the brain, and produce the same effects of sedation, pleasure and decreased pain as opioids. There are symptoms of withdrawal when an individual stops using kratom and some users have reported becoming addicted to kratom. Adverse health effects from kratom use include: sensitivity to sunburn, nausea, sweating, loss of appetite, and sometimes psychotic symptoms. Chronic use of kratom has been linked with liver problems, as noted above. Kratom by itself hasn’t been linked with deaths, but if mixed with other substances, it has been part of a fatal drug cocktail. See “Krypton Can Kill You” and “The Secret of Kratom” for more on this.

While it isn’t a federally controlled substance at this time, six U.S. states and three cities have listed kratom as a Schedule I substance. Globally, several countries have either regulated or banned kratom. In Europe, kratom is a controlled substance in Denmark, Latvia, Lithuania, Poland, Romania, Sweden and the UK. It is a controlled narcotic in Australia and New Zealand. Possession of kratom is illegal in Thailand and its use is prohibited in Malaysia. Canada has made it illegal to market it for human consumption.

What is clear is the need for reliable, replicated research with kratom. Edward Boyer said: “Is it an effective treatment for opioid withdrawal, or is it another pathway to addiction? I don’t think anybody has a defined concept of where it actually lies on that continuum.” Nevertheless, it seems there is growing anecdotal evidence of some level of dependence or addiction with kratom. If the DEA delays its decision to regulate kratom much longer, it might become part of the problem instead of a solution to the opioid epidemic.

07/18/17

Opana Cold Turkey

On June 8, 2017, the FDA did something it had never done before. It formally requested that a pharmaceutical company voluntary remove its opioid pain medication from the market. The company was Endo Pharmaceuticals and the opioid was Opana ER. “Should the company choose not to remove the product, the agency intends to take steps to formally require its removal by withdrawing approval.” Way to go FDA.

The FDA decision was based on a review of post marketing data, which showed a drastic shift in the route of Opana ER abuse after the drug was reformulated in 2012. This review demonstrated that instead of crushing and snorting Opanas, individuals abusing the drug were now dissolving and injecting it. The FDA’s decision follows a March 2017 FDA advisory committee meeting where a group of independent experts voted 18-8 that “the benefits of reformulated Opana ER no longer outweigh its risks.” The newly appointed FDA Commissioner, Scott Gottlieb said:

We are facing an opioid epidemic – a public health crisis, and we must take all necessary steps to reduce the scope of opioid misuse and abuse. . . . We will continue to take regulatory steps when we see situations where an opioid product’s risks outweigh its benefits, not only for its intended patient population but also in regard to its potential for misuse and abuse.

The NPR program, All Things Considered, interviewed Janet Woodcock, the director of the FDA’s Center for Drug Evaluation and Research about the decision on June 9^th. She said the decision was made due to the risks of abusing the product. An outbreak of HIV and hepatitis C, as well as cases of a serious blood disorder (thrombotic microangiopathy), were associated with individuals injecting the reformulated Opana ER. The request to remove Opana ER from the market is not an outright ban. When asked what the response from Endo Pharmaceutials has been, Dr. Woodcock said the company is evaluating the request.

Well, FDA does not have the authority for drugs to immediately remove them from the market. Generally we ask companies to voluntarily pull their drug off the market. If they are not willing to do that, we will issue a notice of a hearing, and we have to go through a judicial type of process.

Another NPR report on April 1, of 2016 said that the reformulation in 2012 effectively stopped people from snorting Opana, which had been the preferred method of abuse. “But the change also led a significant number of people to abuse the drug by injection.” Endo said the company’s decision to reformulate Opana was “a well-intentioned attempt to prevent abuse.” But there seems to have been an additional motivation for the action. According to NPR, “interviews with experts, court filings, documents from the FDA, as well as Endo’s own statements, suggest the company’s decision to reformulate Opana was also motivated in large part by financial interests.”

Soon after its release in 2006, there were reports of abuse and overdose deaths with Opana from around the country. But the painkiller was a major moneymaker for the company. It accounted for 14% of Endo’s total revenue; $384 million in net sales in 2011. In late 2011 the FDA approved Endo’s reformulated version of Opana and Endo began replacing the old version of Opana in pharmacies. That August, Endo filed a petition with the FDA (available in the NPR article), arguing that it removed the crushable version of Opana because it was a safety hazard. It also asked that the FDA refuse or withdraw the approval of generic versions of Opana because they were not crush-resistant.

In 2012 Endo filed a lawsuit to compel the FDA to speed up its review of their petition, predicting a spike of misuse and abuse if generic, crush-resistant versions of Opana went to market. It also estimated that if a generic version went to market, “annualized net sales will decrease by an amount up to $135 million.”

This was nothing new. In 2010 Purdue Pharmaceuticals reformulated OxyContin to make it crush resistant. And the FDA determined the reformulated version was much safer and that the benefits of the original no longer outweighed the risks. The agency blocked generic versions of OxyContin, which made Purdue billions. Dr. Anna Lembke, an assistant professor of psychiatry at Stanford University Medical Center said: “We see this again and again in the pharmaceutical industry. . . . They come up with some new fancy formulation of basically the same old drug … and then that way they have a new drug that they can charge a lot of money for.”

But on May 10, 2013, the FDA decided Endo’s tamper-resistant formula didn’t actually prevent drug abuse better than earlier versions of Opana without the abuse-deterrent feature. That day the price of Endo shares dropped more than 5 percent. The FDA said the reformulated version could be compromised when it was subjected to “cutting, grinding and chewing.” It could be “readily prepared for injection.” The agency also warned the preliminary data suggested the possibility “that a higher percentage of reformulated Opana ER abuse is via injection than was the case with the original formulation.”

The FDA said Endo could not refer to Opana ER as “abuse deterrent.” Writing for FiercePharma, Emily Wasserman quoted Douglas Throckmorton, a deputy director for the FDA’s Center for Drug Evaluation and Research, as saying: “We think the public health would not be served if a company can market itself as ‘abuse deterrent,’ if the scientific evidence did not support that claim.” The problems with Opana seemed to put the FDA on alert that abuse-deterrent technology may not be all that effective. An FDA spokesperson, Sarah Peddicord said: “The FDA is very concerned about potential unintended consequences of abuse-deterrent opioids (and purportedly abuse-deterrent opioids) and it is something we are actively looking at.”

FDA is requiring all sponsors of opioids with approved abuse-deterrent labeling to conduct long-term epidemiological studies to assess their effectiveness in reducing abuse in the real world. . . . Abuse-deterrent does not mean abuse-proof.

So while the June 8^th request by the FDA may be unprecedented, it seems to have been coming for a few years. Then a week after the FDA request, Scott Gottlieb ordered a review of all opioid pain relievers with abuse-deterrent formulas to see if they actually help prevent abuse and addiction. In a statement released on June 13^th, Gottlieb said there would be a public meeting to discuss whether they have the right information to determine if the abuse-deterrent products “are having their intended impact on limiting abuse and helping to curb the epidemic.”

The FDA, he said, recognizes there is a gap in their understanding of whether these products have a real-world, meaningful effect on opioid misuse and abuse. At the July 10-11 meeting, the FDA will engage external thought leaders to discuss how to better “evaluate the impact of these products in the real world.” There is a link in the statement to an issues paper that outlines some of the existing regulatory and public health challenges they face.

Opioid formulations with properties designed to deter abuse are not abuse-proof or addiction-proof. These drugs can still be abused, particularly orally, and their use can still lead to new addiction. Nonetheless, these new formulations may hold promise as one part of a broad effort to reduce the rates of misuse and abuse. One thing is clear: we need better scientific information to understand how to optimize our assessment of abuse deterrent formulations; and I look forward to a productive discussion on how to best tackle this challenge.

Sidney Wolfe, the founder of and senior advisor to Public Citizen’s Health Research Group supported the FDA request for Endo to remove Opana ER from the market. He also said the FDA had enough information before its approval in late 2011 to “reject the drug as possibly more dangerous than its older … version.” He was a member of the FDA’s Drug Safety and Risk Management Advisory Committee at the time, but for some reason, the approval decision was not presented to the Committee. Had the Committee advised rejecting the drug, and the FDA followed the Committee’s advice in 2011, the adverse effects leading the current request could have been avoided.

In addition to FDA’s serious mistake in approving the OPR version, Endo’s defiant response yesterday that they would not necessarily take this more dangerous form of the drug off the market is reckless. In proportion to how many people will use and, in many cases abuse the drug, causing deaths, hospitalizations and other preventable between yesterday’s FDA decision and the ultimate, but certain forced removal of the drug, Endo will be exposed to many product liability lawsuits from those damaged or their surviving families.

Endo suffered some significant financial withdrawal symptoms after the FDA request. The company’s shares were down more than 12% afterwards, according to Fortune. A financial analyst for RBS Capital Markets referred to Opana ER as a “declining asset” with sales expected to fall to $97 million in 2019 from an estimated $134 million in 2017. But Endo seems to have counted the potential future cost if it challenged the FDA recommendation and fought to keep Opana ER on the market. On July 6, 2017, Endo International announced it would voluntarily withdraw Opana ER from the market.

Ed Silverman reported for STAT News that Endo executives “blinked” by saying they were reconsidering their initial statement that they would review the FDA request and evaluate “the full range of potential options.” Silverman noted Opana ER hadn’t been a huge seller for Endo. And it seems the FDA request would impact sales even further. It only generated around $159 million in revenue in 2016. Through the first quarter of 2017, sales were $35.7 million, down from almost $44.7 million in the first quarter of 2016. Given the adverse impact on public health, and the potential for future product liability lawsuits, Endo did the right thing in deciding to go “cold turkey” with Opana.

05/16/17

Trouble with Tramadol

Regularly in the U.S. we hear news about the opioid epidemic. There is an ever-growing use of powerful opioids such as fentanyl, which is 50 to 100 times the strength of morphine; and carfentanyl (used as a sedative for large land animals) whose strength is 10,000 times that of morphine. CDC data released on December 30, 2016 indicated that 60.9% of the overdose deaths in 2014 involved an opioid. Between 2014 and 2015 drug overdose deaths increased by: 11.4%. The CDC suggested this increase was largely driven by synthetic opioids, most likely fentanyl, and heroin. While the opioid epidemic is not uniquely a US problem, it has a different face in other countries, such as Egypt, where the opioid of choice for abusers is tramadol. Yes tramadol, which is one-tenth the potency of morphine.

The Economist said tramadol use in Egypt was everywhere. Taxi drivers used them to stay awake. Wedding guests receive them as token gifts. Petty government officials even accept them as bribes. “Tramadol has become Egypt’s favourite recreational drug, supplanting heroin and cannabis.” Taha, a bank teller, said the drug helps him work. “It just makes you feel relaxed. Even if there are two men fighting to the death beside you, you wouldn’t care.”

There is no social stigma attached to tramadol use. It’s seemingly more religiously acceptable than alcohol or marijuana. Ibrahim began using half a tablet of tramadol because he felt socially awkward at the age of seven. “I found myself feeling unusually outgoing and positive.” Ten years later, he was using ten tablets daily.

Until recently, tramadol sold for the equivalent of 15 to 30 cents per pill. Tramadol use accelerated after the 2011 uprising in Egypt, partly because of the weakened state controls. Ehab El-Kharrat, an Egyptian doctor, said the tramadol came largely from India or China. Customs inspections began to tighten and the price rose sharply. At one point the price reached $1 to $3 a pill. “Since then we have seen a flood of people seeking help.” The head of a Cairo rehabilitation center said at least 40% of those attending his clinic are addicted to tramadol.

Yet enforcement is poor. Court cases are thrown out because of shoddy police work. Officers are often in cahoots with the drug dealers, or are themselves drug-users. And even if the government succeeds in restricting the supply of tramadol, there may be unintended consequences. If the pills become more expensive, users may switch to stronger heroin. Some worry that the worst of Egypt’s drug problem is yet to come.

The Daily Beast also reported on the tramadol problem in Egypt. A taxi driver threw up the first time he tried tramadol. But now he takes four or five doses daily. He justified his use by saying its one of the few ways to dull the pain of Egypt’s weak economy and trying political circumstances. “Food, gas, everything is so expensive. People are exhausted and take things like tramadol just to keep going.” Young cash strapped males form the core of its users.

A UNODC (United Nations Office on Drug and Crime) official estimated that 90% of the illicit tramadol in Egypt is produced in India, and then smuggled into the country. One supplier said it’s never been easier to keep stocked up on tramadol. Because of its ready availability, its use has begun to spread from younger working class males into the more affluent areas of Cairo, which doesn’t make drug dealers very happy. “It’s not good when [those] people buy tramadol, because it means they won’t buy more expensive things. . . But with the economy and everything, this seems to be what Egyptians want right now.”

The Expert Committee on Drug Dependence of the World Health Organization (WHO) gave an Updated Review Report on tramadol at its thirty-sixth meeting in June of 2014. The report noted how Egypt had up-scheduled tramadol in 2009 because of its increasing rate of abuse. There was also growing evidence of tramadol abuse in other African and West Asian countries, including: Egypt, Gaza, Jordan, Lebanon, Libya, Mauritius, Saudi Arabia and Togo. In most countries it is a prescription-only medicine.

Marketing authorizations for tramadol are held by dozens of companies. The WHO Report listed around thirty-five companies as examples. Corresponding to this, it also goes by dozens of trade names, literally from A (i.e., Acerna, Amanda, or Astradol) to Z (i.e., Zamadol, Zentra, or Zodol). The common formulas in the US are: ConZip, Ryzolt and Ultram.

Overall, tramadol has been seen as having a low potential for drug dependence. However, in the last few years, new data suggests that dependence may occur when it is used daily for more than a few weeks or months. The WHO finding here is consistent with the above reported abuse of Tramadol in Egypt. It is listed as a controlled or scheduled substance in several countries, including: Australia, Iran, Sweden, Venezuela, Ukraine, China, the United Kingdom, Jordan, Saudi Arabia, and Egypt. Since the WHO Report was published, tramadol has become a Schedule IV controlled substance in the U.S.

In summary, the data on the dependence potential of tramadol show that tramadol has a relatively low dependence potential and that dependence is associated with the use of tramadol over an extended period of time (more than a few weeks to months). The data also show a higher risk profile in former drug abusers and in medical staff personnel than in pain patients. Several studies indicate that the incidence of tramadol dependence may differ between countries and within different regions of countries, which may be associated with the availability and prescription practice for tramadol, and with the availability of alternative psychoactive substances for drug abusers.

DrugAbuse.com described tramadol as a fully synthetic opioid originally synthesized by a German company in 1962. It was finally brought to market as Tramal in 1977. It was not until 1995 that it became available in the U.S. as “Ultram.” Initially it was not a controlled substance. By 1996 the FDA revised the product label to require warnings about the potential for abuse. In 2009, the FDA again changed the product warning, now the alert of the possibility of a life-threatening condition, serotonin syndrome.

Between 2005 and 2011, emergency department visits related to non-medical tramadol use rose over 250%. Between 2008 and 2013, prescriptions for tramadol increased by 20 million. In 2014 another increase of 44 million prescriptions of tramadol occurred, possibly a reaction to the rescheduling of Vicodin from Schedule III to Schedule II. Also in 2014, tramadol was made a Schedule IV controlled substances by the DEA.

In 2009, Sansone and Sansone gave a good summary of some of the health risks with tramadol, including a description of serotonin syndrome (SS), and the risk of seizures if it was used concurrently with antidepressants, both tricyclics and SSRIs. There was a “Dear Healthcare Professional” letter distributed by the manufacturer warning of the potential adverse drug event of seizures when using tramadol and antidepressants. A follow up study noted a small and insignificant change in the prescribing habits after the release of the warning letter.

Serotonin syndrome was more common with excessive use/overdose of tramadol or coadministration with other medications, particularly antidepressants among the elderly. SS has been reported with combinations of tramadol and the following: fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), citalopram (Celexa), fluvoxamine (Luvox), venlafaxine (Effexor), and TCAs (tricyclics). Rimeron was implicated in one case study of tramadol use with elderly residents in a long-term care facility. They summarized their conclusions as follows:

In primary care settings, tramadol is a commonly prescribed synthetic analgesic. Two potential adverse reactions of tramadol are seizures and SS. Either of these reactions may occur with tramadol monotherapy, but both appear to be much more common with either abuse/overdose or in combination with other drugs, particularly antidepressants. These adverse reactions appear to be more common in the elderly. The majority of commonly prescribed antidepressants have been implicated in both of these adverse reactions. Clinicians are advised to be mindful of these potential adverse sequelae when prescribing antidepressants to patients on tramadol, particularly in the elderly and/or those who might be at a heightened risk (i.e., individuals with epilepsy, head injuries, neurological dysfunction). If coadministration is undertaken, we advise careful monitoring for these two particular hazards. Tramadol is a remarkable drug, but like all drugs, effective use entails balancing the benefits versus the risks.

Then on April 20, 2017, the FDA restricted the use of tramadol (and codeine) in children. They also recommended against the use of these medicines in breastfeeding mothers. Tramadol is contraindicated (the FDA’s strongest warning) to treat pain in children younger than 12 years old and for pain in children younger than 18 after surgery to remove tonsils and/or adenoids. “These medicines carry serious risks, including slowed or difficult breathing and death, which appear to be a greater risk in children younger than 12 years, and should not be used in these children.”

12/20/16

The Opioid Buzzard

The U.S. is in the midst of a health crisis from the use and abuse of opioids. Since 1999, the rate of overdose deaths from opioids—prescription pain relievers and heroin—nearly quadrupled. On an average day in the U.S. more than 650,000 opioid prescriptions are dispensed; 3,900 people begin nonmedical use of opioids; 580 people start using heroin; and 78 people die from an opioid-related overdose. Economically, there is a $20 billion cost in emergency department and inpatient care for opioid poisoning each year; and $55 billion spent on health and social costs related to prescription opioid abuse.

In order to address this opioid epidemic, the U.S. Department of Health and Human Services (HHS) launched an initiative in March of 2015 aimed at improving prescribing practices, expanding the access to and use of medication-assisted treatment and expanding the use of naloxone. So far, the Substance Abuse and Mental Health administration (SAMHSA) has awarded $10.7 million to 11 high-burden states for medication-assisted treatment (MAT). Applications were due in May of 2016 and awards were to be made to an additional 11 states. The above information and statistics were drawn from a Health and Human Services report, “The Opioid Epidemic: By the Numbers.”

Then in July of 2016, the HHS Secretary announced new rules that permit doctors licensed to dispense buprenorphine to see as many as 274 patients per year. The old limit was 100. HHS estimated that change permits as many as 70,000 more people to access buprenorphine. The former limit of 100 was seen by many as a barrier to individuals seeking to access MAT. “The rule aims to increase access to medication-assisted treatment and associated behavioral health supports for tens of thousands of people with opioid use disorders, while preventing diversion.” Clearly buprenorphine products like Suboxone are seen as a crucial element in our attempts to combat the opioid health crisis.

There are issues with this approach to treatment for the opioid crisis that I’ve addressed previously in articles such as: “The Seduction of Opioid Substitution” and “A Double-Edged Drug.” Here I want to look at how the company that brought buprenorphine treatment to market, Indivior/Reckitt Benckiser, tried to position itself as the primary service provider for buprenorphine-based MAT in the U.S. It’s kind of like a buzzard chasing off smaller scavengers from the carcass of an overdose victim. At one point, Reckitt Benckiser had 85% of the U.S. MAT market—almost all of it subsidized by taxpayers.

In 1994 Reckitt Benckiser established the Buprenorphine Business Group to develop buprenorphine as a treatment for opioid dependence. In 2000 legislation (DATA 2000) was passed in the U.S. permitting office-based treatment of opioid dependence. In 2002 the FDA approved Subutex (buprenorphine) and Suboxone (buprenorphine and naloxone) for the treatment of opioid dependence in the U.S. These products came to market in 2003. In 2007 the initial cap of 30 patients was raised to 100 for physicians with at least one year’s experience with buprenorphine. That same year Reckitt Benckiser acquired the rights for the sublingual film version of Suboxone from MonoSol Rx. Then in 2010 Suboxone sublingual film was launched in the U.S. Subutex tablets were discontinued in 2011; and Suboxone tablets met the same fate in 2012. In December of 2014, Reckitt Benckiser spun its specialty pharmaceutical company into a separate business and Indivior was born.

This history was taken directly from the Indivior website, where the company estimated they had treated 5 million individuals in the U.S. with Suboxone film and tablets and Subutex tablets. Here are some additional facts to add to the above timeline from a 2013 article, “Pharma Gamemanship.”

Reckitt Benckiser (RB) knew it only had patent exclusivity for their buprenorphine products until 2009. But they had a plan to circumvent the pending loss. As noted above, they acquired the rights for the sublingual film version of Suboxone in 2008. In October of 2008 they submitted a New Drug Application to the FDA for the film version of Suboxone; and it was approved in August of 2010. Reckitt Benckiser has patent exclusivity on the newer film version until 2023.

In their 2011 annual report (no longer retrievable from its website), RB indicated to their shareholders that competition from generics could take up to 80% of the revenue and profit from the U.S. Suboxone market. But they expected “that the Suboxone film will help to mitigate the impact.” In September of 2012 RB announced that they were voluntarily withdrawing Suboxone tablets from the market because of data they had received from the U.S. Poison Control Centers suggesting there were higher rates of pediatric overdose on the tablet formulation than the film version. They said they would take the tablet form off the market to “protect public health and safety.”

The very same day RB filed a “Citizen’s Petition” with the FDA calling for the agency to postpone the approval of generic version of Suboxone in the interests of public safety. Reporting for The Daily Beast, Christopher Moraff said the “data” they based their withdrawal of Suboxone tablets on was a single study RB had paid for itself. RB reportedly said the study demonstrated the risk factor for accidental ingestion was eight times higher in bottled tablets than for the individually packaged film. Yet its own data told a different story.

Compared to the more than 20,000 deaths in 2012 from prescription opiates and heroin, pediatric poisoning from Suboxone was far from a public health crisis. A preliminary study commissioned by Reckitt Benckiser found just 46 cases of serious injury or death out of more than 2,200 accidental pediatric exposures to Suboxone tablets between 2010 and 2012—which researchers described as not significantly different from poisonings from the film.

The FDA thought the RB study was inconclusive and did not demonstrate any difference in the safety profile or abuse potential of the two formulations. They said the study was poorly designed and conducted. “Reckitt’s own actions also undermine, to some extent, its claims with respect to the severity of this safety issue.” Despite the first report of pediatric death in June of 2010, RB continued marketing the tablets in multi-dose containers for two more years. And it continues to sell them throughout Europe, where Suboxone tablets are still under patent.

In June 2013 the FTC opened an investigation into whether Reckitt Benckiser abused public regulatory processes and fought for nearly two years to obtain more than 20,000 documents the company was fighting to withhold. That case is ongoing. In December of that year, federal agents raided Reckitt Benckiser’s West Virginia offices after the Department of Justice launched a criminal probe into the company’s Suboxone business. That investigation continues.

Public Citizen said that few, if any, companies went as far as RB to pre-emptively withdraw an off-patent drug from the market to make room for a newly patented successor. A year before the withdrawal of the tablets from the market, RB stated in its 2011 report that its goal was to convert as many tablet users as possible to the film version.

To this end, the company initiated a marketing campaign to persuade physicians to switch patients from the tablet to film form. It also employed more direct tactics to complement the marketing push, raising the price of the tablets to levels higher than the film versions. As a result of these efforts, tablet sales fell 19 percent between August 2011 and August 2012, while sales of Suboxone film doubled during the same period. By September 2012, the film version had captured 70 percent of the Suboxone market, clearing the way for the announcement of the withdrawal of the tablets that month.

So it should come as no surprise that a lawsuit has been filed by 35 states and the District of Columbia alleging that Indivior violated antitrust laws by trying to extend its monopoly over Suboxone. Reporting for CNN, Susan Scutti said the lawsuit charges that Indivior/RB and MonoSol Rx “conspired to block generic competitors for Suboxone by switching the drug from a tablet to a dissolving film.” A September 23, 2016 press release on the Indivior website said: “The Company intends to continue to vigorously defend its position.”

The International-Dictionary.com said there are two meanings for the word “buzzard.” The first one is zoological, referring to a bird of prey of the hawk family. The second meaning is “a blockhead; a dunce.” A quote attributed to Goldsmith reads: “It is common, to a proverb, to call one who can not be taught, or who continues obstinately ignorant, a buzzard.” It seems to me that either sense can be applied to Reckitt Benckiser and Indivior.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: opioid epidemic