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A new Hulu series portrays the pharmaceutical industry’s role in the opioid crisis, but how much of it is real and how much is entertainment?

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Published On: 01/31/2022

Duration: 22 minutes, 24 seconds

Chris Aiken, MD, and Kellie Newsome, PMHNP, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.

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Transcript:

A new Hulu series portrays the pharmaceutical industry’s role in the opioid crisis, but how much of it is real and how much is entertainment?

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

KELLIE NEWSOME: On October 13, 2021 Hulu released a Dopesick, a series that traces the opioid crisis back to the release of Oxycontin by Purdue Pharma in 1996. The series, which is based on a journalistic account of the opioid crisis from Roanoke Virginia, centers around two story lines. One involves a primary care physician played by Michael Keaton. The other involves a team of US attorneys in Virginia who build a case against Purdue Pharma as they watch the opioid crisis unfold in their Appalachian town.

The show gets a lot of things right, and in this podcast we’re going to take a closer look at some of the medical concepts that take center stage in the plot. Warning: There are a few spoilers, but first, a spoiler of the CME questions for this podcast.

Which benzodiazepine has the lowest risk of accidental overdose?

A. Clonazepam

B. Diazepam

C. Oxazepam

D. Quazepam

History

CHRIS AIKEN: We’ll start with a brief history of Oxycontin and the opioid crisis. In 1996 Purdue Pharma launched Oxycontin, a controlled release version of the opioid pain medicine Oxycodone. Oxycodone had been used since World War I, but physicians reserved it for severe cases because of the drug’s addictive potential. Oxycodone is 1.5 times more potent than morphine. 

Despite this, Purdue argued that Oxycontin’s slow release mechanism reduced the drug’s abuse potential. Instant release Oxycodone had to be dosed every 4 to 6 hours, but Oxycontin could be dosed twice a day. Although they lacked clinical support for this wishful thinking, the FDA made an unusual decision to allow the company to state that Oxycontin’s abuse potential was lower than that of other opioids in its product labeling. No other opioid had this endorsement. 

Purdue pushed this message, and used it to gain approval of higher doses that brought the company more profit – since they charged by the milligram – and put patients at greater risk of respiratory depression. And since its release we’ve learned that long-acting opioids actually increase the risk of accidental overdose, since the drug lingers longer in the body. The same is true for benzodiazepines with a long-half life, so if you are prescribing a benzo to a patient taking an opioid, best to avoid the alprazolams, clonazepams, and diazepams – Xanax, Klonopin, and Valium, and stick with low doses of oxazepam– the risk of accidental overdose is lower with this one because it doesn’t accumulate metabolites or linger too long in the body. Lorazepam (Ativan) is a close second in its safety profile. But that risk is still high, even when these safer benzos are used with opioids. And here’s an uncomfortable fact. Benzodiazepines are involved in 80% of accidental opioid overdose deaths, and prescribing them with an opioid raises the risk of death 2-4 fold.

KELLIE NEWSOME: So the long half life didn’t turn out to be such a plus, and it didn’t turn out to be so long either. Purdue stretched the truth about the 12-hour coverage of their product. Many patients only got 8 hours of coverage with Oxycontin, sending them into daily withdrawal and a perceived need to take more and more.

That wasn’t the only exaggerated claim Purdue made to sell physicians on the safety of their product. They told physicians that the controlled release was less addictive because it delivered the drug at a steady rate, smoothing out the peaks and valleys of the instant release. They created a graph with a nearly straight line to demonstrate the stable blood levels, but there was a big problem with the graph – it used a logarithmic scale on the Y axis, effectively blurring the real peaks and troughs that the drug produced.

But those pharmacologic fibs were just a small fraction of the problem. The real reason Oxycontin was abusable was that it was easy to crush the controlled release, effectively turning it into a heavy loaded dose of Oxycodone. 

CHRIS AIKEN: It’s not clear why the FDA cleared all these false claims. Dr. David Kessler was the FDA director at the time, and he now admits it was a seriously flawed decision. But he does say the claim had support from other studies that showed drugs with slower release mechanisms had less addictive potential. One of those studies is from our own field – on alprazolam (Xanax). In 1995 researchers gave people with a history of benzo abuse either alprazolam instant release or extended release, and then asked them if they would pay money to get more of the drug on the street. Their answer was YES for the instant release, but NO for Xanax XR.

KELLIE NEWSOME: What does this say about the new extended release lorazepam, Loreev?

CHRIS AIKEN: Loreev is a new once-a-day lorazepam, and it peaks gradually – over 4 hours instead of 30 minutes like we see with instant release lorazepam. So it might have the same benefit as Xanax XR, but it has no clinical data to support that – it seems the drug was FDA approved on pharmacokinetic data alone. And even if these XRs are less addictive than instant release benzos, that doesn’t mean they have a lower overdose risk with opioids. Remember, it’s the long duration of action that raises that risk.

KELLIE NEWSOME: Back to the FDA’s generous approval of Oxycontin. Dopesick emphasizes a particular controversy around the approval – which is true. The FDA officer who green lighted Oxycontin’s claim of lower abuse potential was Curtis Wright. Before the approval, Mr. Wright met with Purdue executives in a hotel room and allowed the company to assist in drafting the labeling. Shortly after the drug’s release, Mr. Wright left the FDA and became an executive at Purdue Pharma with a $379,000 salary. 

Fortunately, truth has a way of catching up. In 2001 the FDA removed that language and added more warnings about addiction on the drug. Separately, the DEA began targeting Oxycontin as a source of diversion and abuse. The DEA director in Dopesick is a fictional character, but the attorneys in Virginia who take on Purdue Pharma are real. Another lawyer who shows up in the series is Rudy Giuliani, who was hired to represent Purdue shortly after leaving his office as mayor of New York. Strange, but true. Ironically, 10 years later Giuliani would occupy a key position in the 2016 Trump campaign, as opioid overdose deaths surged in battleground states key to the election, like New Hampshire, Ohio and Pennsylvania. Trump took a vocal stand against the spread of opioids, and his administration eventually settled with Purdue pharma – the same company that Giuliani represented – in a move that some praised and others criticized for letting the Sackler family that ran the company off the hook.

CHRIS AIKEN: Another improbable figure that shows up in Dopesick is James Comey. As director of the FBI, he meets with the Virginia attorneys and tries to shut down their investigation, but it turns out he had a big misunderstanding. He thought they were investigating Perdue Farms – the chicken company – not Purdue Pharma. We fact checked that scene, and it’s mostly true. In 2005, Purdue lawyers called James Comey to try to pressure him to call off the investigation. Comey got confused thinking it was the chicken company, but in the end he did the right thing. When he learned what the Virginia attorneys were up to, he gave them the green light to continue their case.

Two years later that investigation ended with a plea agreement, when Purdue Pharma plead guilty in 2007 to criminally misbranding the drug and misrepresenting its risks of addiction and paid a combined fine of over $600 million, which – to put it in perspective – hurts their bottom line about as much as the sales tax you have to pay when you go the grocery store. 

In 2010 Purdue developed a version of oxycontin that is harder to crush and abuse. This time the FDA required the drug company to follow up with clinical proof that the formulation deterred abuse, which it did in a 2016 paper that found a 30% reduction in abuse. The study probably overestimates that reduction, as it was carried out in a rarefied population. Either way, abuse deterrent formulations like these on the prescription side have not been entirely successful in the big picture, as people with opioid use disorders turned to heroin instead of pills to continue the opioid high.

And in the bigger picture, Purdue did not change their way of doing business. For example, they convinced an EMR company – Practice Fusion – to create a digital alert recommending strong opioids to physicians in return for a kickback from Purdue. Both companies were fined by the Justice department for that misbehavior in 2019, and other lawsuits from 45 states forced the company to file bankruptcy. Purdue Pharma is now effectively dissolved, and in September 2021 was restructured into a public benefit corporation that is focused on addressing the problems caused by the original Purdue pharma.

KELLIE NEWSOME: Oxycontin is still on the market. The Sackler family is no longer involved in the company, but they’ve maintained most of their multi-billion dollar wealth and avoided criminal liability. We don’t know much about the Sackler’s or their motivations, and the writers of Dopesick didn’t have any kind of direct access to them, so their portrayal is a best guess. It is true that Richard Sackler tried to shift the blame for the opioid crisis onto the people who became addicted to the drug, and it’s also true that he didn’t even read the report that the Virginia attorneys filed against him (he admitted to this), so unlikely that he learned from it.

The Sackler Family

CHRIS AIKEN: The Sackler family that ran Purdue Pharma was not always mired in controversy. The first generation of Sackler brothers were psychiatrists – all three of them – who were active in research on schizophrenia and bipolar disorder and together started Purdue pharma in 1952. They helped bring an end to the practice of lobotomies, employed people who were black-listed by the red scare, and were the first to fight for the racial integration of blood banks. Their father, Isaac Sackler, was a Jewish immigrant from Poland. As his sons were forging their careers nearly a century ago, Isaac Sackler gave them this prescient warning. “If you lose a fortune, you can always earn another. But if you lose your good name, you can never recover it.”

And now for the word of the day…. Glutavite

KELLIE NEWSOME: Wait a minute. Did we just say the first generation of Sackler’s were upstanding psychiatrists? Things are complex. Arthur Sackler was a died in the wool socialist, so much so that he spent much of the 1950’s dodging the red-baiting eyes of the FBI. But he was also the driving force in the family’s successful pharmaceutical businesses, and I say businesses because he established many shell corporations to hide his conflicts of interest. Most notably, he pioneered many of the direct-to-physician advertising techniques that the pharmaceutical industry uses today. If you’ve ever seen those disconcerting 60’s ads for Valium and Librium, that was Arthur Sackler.

Now, imagine if an advertising agency was conducting clinical trials, editing the medical journal that published those trials, all the while producing the pharmaceuticals that were advertised in those journals and featured in those clinical trials? Business schools might call that vertical integration, but in medicine we’d call it a conflict of interest. And that is what Arthur Sackler did with Glutavite and many other mid century pharmaceutical developments. 

CHRIS AIKEN: Sackler – along with his 3 brothers – owned and edited the Journal of Clinical and Experimental Psychobiology, which in 1958 published a seminal trial of L-Glutavite in schizophrenia. The patented vitamin was a remarkable success in this trial, allowing 70% of those who took it to live independently in what loo ked like a recovery from the illness. Glowing headlines went up…

Sackler owned the company that made L-Glutavate, and he listed it for sale on the New York Stock exchange the day the study went to press. He pocketed half a million, but whoever purchased L-Glutavite was not able to replicate Sackler’s success with the drug. Subsequent trials failed in schizophrenia and other populations, and when we unpack this vitamin you’ll see why.

L-Glutavite is a combination of vitamin B and monosodium glutamate – better known as MSG – the notorious flavoring agent in many Asian dishes. MSG is not a brain friendly ingredient, and is the cause of migraines for many people. Moreover, Sackler was supposedly treating schizophrenia by increasing glutamate, but today excessive glutamate is thought to be one of the leading causes of schizophrenia. So how did Sackler get such positive results in his L-Glutavite trial? We can only guess, but John Brennon, an associate of Sackler’s, told investigative journalist Gerald Posner that he thought someone had cooked the books.

Allen Frances, editor of DSM-IV, summed it up this way to the New York Times in 2017, “Most of the questionable practices that propelled the pharmaceutical industry into the scourge it is today can be attributed to Authur Sackler.” And Frances was not just referring to Glutavite. Author Sackler earned most of his vast fortune by inventing the business of medical advertising – all those ads you see in medical journals – they owe their cleverness to Author’s ingenuity. Sackler was convinced that a lifestyle drug for the everyday worries of modern life would become a blockbuster, and in 1960 he found it – in chlordiazepoxide (Librium), the first benzodiazepine. Sackler’s company was in charge of marketing for Librium and its successor diazepam (Valium), which by the way is a metabolite of Librium. He turned these into blockbuster drugs, and that status has continued. Today, 1 in 8 Americans take a benzodiazepine. 

It’s hard not to draw a connection between Author Sacker’s promotion of benzodiazepines and his nephew’s mission to do the same with opioids. Together, they are a dangerous mix, because both suppress breathing in different ways. Opioids slow respiratory rhythm in medulla, while benzodiazepines lower GABAergic activation of respiration. Alcohol takes this one step further by dampening the reflex response that makes you breathe when your carbon monoxide rises. The effect is like a stereo, and this analogy explains why benzodiazepine overdoses are rarely fatal on their own, but can easily turn deadly when taken with an opioid. If you unplug one speaker in a stereo, the music still plays. Unplug both, and it’s silence.

KELLIE NEWSOME: A lot of psychopharm books focus on the big picture, but when it comes time to write a prescription you need to know the nitty gritty. XR or regular release? Capsule or tablet? With or without food? The PDR says to take it twice a day, but what happens if I give it all at night? And hmmmm…. I see there’s a drug interaction, but how much should I lower the dose to adjust for that?  Drs. Aiken, Feder, and Carlat have the answers in the new textbook Prescribing Psychotropics: From Drug Interactions to Pharmacogenetics. Find out why Nassir Ghaemi called it “Not only useful, but engaging and entertaining.”  

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