These precautions work well. A 2009 study found that out of 26,000 patients worldwide who had received Xyrem in the prior nine years, there were only ten cases (0.04%) of patients abusing the drug (e.g., getting high, or driving soon after taking it) and two cases of sexual assault (0.008%).375 But GHB is a simple molecule that can be made from widely available ingredients, using fewer steps than it takes to make crystal meth, and recipes are available on the internet. So while Jazz’s REMS helped to keep patients and the public safe from Xyrem, it could do nothing to mitigate the harm of all the illicitly produced GHB available on the street. There are 1,000-2,000 GHB-related ER visits and hundreds of cases of GHB-related date rape in the US alone each year.376
As Jazz continued to study new uses for Xyrem, it turned out that the drug could also help patients suffering from fibromyalgia, a syndrome involving a combination of fatigue and pain that some researchers theorized was caused in part by patients sleeping so poorly that, in their exhausted state, they experienced normal stimuli, such a breeze across their skin, as pain. Jazz submitted extensive clinical trial data to the FDA seeking approval to expand Xyrem’s label to include the treatment of fibromyalgia, but in 2010 the FDA rejected the application out of concern for the public’s safety.
Very few patients suffer from narcolepsy, with maybe 50,000 diagnosed in the US and only 14,700 taking Xyrem as of the middle of 2019, while closer to ten million suffer from fibromyalgia.377 And even though Jazz promised it would take the same precautions when distributing Xyrem to patients with fibromyalgia, an expansion of the label might have increased the amount of Xyrem that Jazz shipped by over 100-fold. The FDA’s advisors feared that such a dramatic expansion of the supply would substantially increase the chances that the drug would be used inappropriately and that many more people might end up victimized with the help of an FDA-approved pharmaceutical.378
The agency’s caution with respect to Xyrem reflected an increased awareness of the harms the FDA knew it had helped unleash by authorizing the broad use of opioids years earlier.
With an understanding of benefit-risk tradeoffs, the levers that drug companies, physicians, and FDA have to control this balance, and concepts covered in earlier chapters like insurance design, we can look specifically at how these factors contributed to the opioid crisis.
Opioids: A Brief History
Opium has exacted a heavy toll throughout history. For millennia, humans have cultivated poppies and dried their milky, morphine-rich sap into opium, which has been smoked, swallowed, snorted, and, more recently, injected for recreational purposes, to alleviate pain, forget grief, or help children fall asleep.379 Ancient Sumerians called it “joy,” though the drug has a dark side and a bloody history.
In 1805, Friedrich Wilhelm Adam Serturner, an assistant pharmacist in Prussia, isolated crystals of a pure molecule from poppy juice and published a study claiming that it could induce sleep. Through self-experimentation, he discovered that, at low doses, the drug could relieve pain, at higher doses, it could induce euphoria, and at even higher doses, cause drowsiness and confusion. He named it Morphium after the Greek god of dreams; today, we call it morphine, and we call the class of drugs to which it belongs “opioids.”
These chemicals mimic natural endorphin molecules that our bodies release in response to physical discomfort or threat, which, in turn, suppress pain (e.g., why accident victims often don’t feel pain immediately after an accident, only after some time when endorphins have worn off) and even induces a state of euphoria (e.g., “runner’s high”). Chemicals of this class include morphine, heroin, fentanyl, and oxycodone, all of which interact with receptors on neurons in slightly different ways.
The isolation of morphine was a transformative advance. Physicians who had been hesitant to prescribe raw poppy juice or opium, for fear that the variation in potency from batch to batch could lead to overdose, could now administer a precise amount of pure morphine to patients. Serturner was widely recognized for his breakthrough and is counted among the founders of pharmaceutical science. But opium would not be tamed then. In an ending fit for a Greek tragedy, Serturner died addicted to the substance he’d discovered.380
Since the time of morphine’s discovery, we’ve continued to search for safer variants. When heroin was discovered towards the end of the 19th century, it was declared to be non-addictive, which of course turned out to be devastatingly inaccurate. Unfortunately, this has proven to be a recurring theme throughout the history of opioids.
As opioids became indispensable tools for managing severe post-surgical pain or the pain of patients suffering from terminal cancer, which torments patients as it eats away at their bones and other organs, the dangers of addiction and overdose weren’t always fully understood—even among the medical community. Opioids were known to be dangerous and addictive if not used properly, but following surgery, these drugs were thought to be safe because their administration was temporary. In the case of cancer, the side effects and risk of addiction didn’t seem as scary in the face of impending death, though as cancer treatments improved, patients could end up on opioids for years, blurring the line between treating patients who are living and those who are dying.
In 1980, a widely cited short letter in The New England Journal of Medicine reported that an analysis of nearly 40,000 hospitalized patients found that “despite widespread use of narcotic drugs in hospitals, the development of addiction is rare in medical patients with no history of addiction.”381 This, too, would turn out to be false, but physicians found the idea appealing that opioid drugs,382 when properly prescribed to patients in their care, would not lead to addiction. The medical community’s over-confidence that it had tamed opioids would contribute to their broader use to help patients suffering from chronic pain.
The Seeds of a Perfect Storm
The seeds of today’s opioid crisis were sown in 1995, due in large part to two key developments.
First, physician and President of the American Pain Society Dr. James Campbell gave an address declaring that, along with blood pressure, pulse rate, temperature, and rate of breathing, pain should be considered the 5th vital sign.383 This meant that, besides looking for objective measures of ill health, doctors should ask their patients if they are feeling pain and then try to treat it. This may seem surprisingly obvious today, but that’s the whole point: When a patient didn’t proactively complain, asking about pain hadn’t been standard practice, but now it would be.384 The VA, for example, took Dr. Campbell’s encouragement to heart, publishing a “Pain as the 5th Vital Sign Toolkit” in 2,000.385
Also in 1995, the FDA approved Purdue Pharma’s OxyContin, an extended-release formulation of the opioid oxycodone that was meant to be taken in pill form once every 12 hours to manage pain. It was designed to release oxycodone slowly, so that the patient would get a smooth, constant dose. Prior to this, nearly all opioids, with the exception of a long-acting morphine drug called MS Contin, were formulated as immediate-release (in that they released their contents all at once, not gradually) and had to be taken every 4-6 hours. The FDA thought OxyContin would be safer and less likely to lead to abuse, later explaining:
At the time of approval, FDA believed the controlled-release formulation of OxyContin would result in less abuse potential, since the drug would be absorbed slowly and there would not be an immediate “rush” or high that would promote abuse. In part, FDA based its judgment on the prior marketing history of a similar product, MS Contin, a controlled-release formulation of morphine approved by FDA and used in the medical community since 1987 without significant reports of abuse and misuse.386
The FDA went so far as to permit the following to appear on OxyContin’s prescription label:
Delayed absorption, as provided by OxyContin tablets, is believed to reduce the abuse liability of a drug.387
In an environment that was placing renewed emphasis on pain management and with the FDA indicating that OxyC
ontin was a preferred—if not the preferred—opioid, Purdue launched a vigorous promotional campaign and conducted additional clinical studies to show the utility of opioids to treat chronic non-cancer pain. Then, they got permission from the FDA to print on the label that their opioids could be used for all pain that couldn’t be adequately managed in other ways. Buying into the perception that OxyContin had the most favorable benefit-risk of any opioid in the long history of opioids, Purdue marketed its product as the weapon of choice in the war on pain with what court records now show to have been an indecent and illegal zeal, overstating OxyContin’s efficacy and lying about its risks.388
The company pushed non-specialist primary care doctors to prescribe the drug off-label for less severe pain indications, significantly outspending rivals like Johnson & Johnson, which marketed the competing medicine Duragesic. To spread the word, more than 5,000 doctors, nurses, and pharmacists attended all-expenses-paid resort-based speaker-training conferences during the first five years OxyContin was marketed.389 Some of these healthcare professionals were then paid by Purdue to extol the virtues of using OxyContin for various pain indications (nearly 2,500 physicians were on the company’s “speakers bureau” list by 2002). Purdue sponsored or directly financed more than 20,000 pain-related “educational programs” between 1996 and 2002 and spent nearly $5 million in advertising in medical journals in 2001 alone.390 Though the company avoided DTC advertising on television, it built or sponsored a variety of pain-focused consumer-facing websites. The company’s aggressive tactics quickly made OxyContin a blockbuster, generating over $1 billion in sales per year within five years of its launch.
And while all this would have been legal if Purdue had only made FDA-approved and true marketing claims and physicians disclosed all of these payments in gifts, as is now mandated by the Sunshine Act, Purdue crossed many lines. In 2007, Purdue Pharma and three of its senior executives were investigated and fined $634 million—still one of the largest financial penalties on record—for misleading doctors about the safety of its product.391 This included making fraudulent claims that OxyContin was less addictive, less subject to abuse, and less likely to cause withdrawal symptoms than other pain medicines.392 Still, cumulative OxyContin revenues have exceeded $35 billion, the majority of which were generated after that 2007 $634 million fine.393
A big problem was that OxyContin wasn’t nearly as hard to abuse as everyone seemed to think. In order to achieve an immediate release of its contents, all someone had to do was chew up a pill or crush it into a powder and snort it. Despite reports that MS Contin had been similarly abused, the FDA somehow didn’t see any of this coming.394 Referring to the approval of OxyContin in 1995, the FDA said recently:
There was no evidence to suggest at the time that crushing the controlled-release capsule followed by oral ingestion or snorting would become widespread and lead to a high level of abuse.395
Granted, at that time, MS Contin was not widely prescribed—nowhere near the level of OxyContin would be—so reports of abuse were infrequent and didn’t receive much attention. To be fair, the FDA did not anticipate OxyContin being prescribed so broadly for less-than-severe pain, as it would turn out to be. But in retrospect, the regulatory checks then in place failed to assess the risks of OxyContin and to put sufficient guardrails in place.396
Before long, the evidence of abuse became irrefutable. From 1999 to 2007, the number of opioid-related deaths in the US climbed from approximately 8,000 to over 18,000, with prescription opioids involved in most cases.397 The number of people addicted to opioids and seeking relief from the agony of withdrawal caused the street value of OxyContin to soar, to the extent that many pharmacies were forced to fortify their security. When they couldn’t get OxyContin, many even turned to heroin.
There were enough cases of patients reporting getting hooked on opioids following what seemed like legitimate medical use, such as a prescription to help manage post-surgical pain or chronic lower back pain, that it didn’t matter that most patients weren’t actually overdosing on their own prescriptions. The fact was that pharmaceuticals that had been developed in the US, approved by the FDA, aggressively marketed by a company, recommended by medical associations, and prescribed by physicians were contributing to a rising death toll, and there was plenty of blame to go around.
Each key stakeholder responded in a different way, with consequences that would tragically drive America’s opioid-related death toll far higher, to 47,600 in 2017, for reasons we’ll explore below.
The FDA’s Response
About five years after OxyContin came to market, the FDA removed the claim that delayed absorption might reduce abuse from its label. By 2003, they’d added to opioid labels stronger and more prominent language that cautioned users about the risk of addiction.398
OxyContin’s marketing materials now say:
Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed OxyContin. Addiction can occur at recommended doses and if the drug is misused or abused.
In 2007, the year Purdue was fined $634 million for misleading doctors about OxyContin, Congress granted to the FDA the power to regulate REMS programs. From then on, the FDA would only approve opioids in conjunction with REMS, and it retroactively imposed that requirement on opioids already on the market.
Physicians’ Response
For a long time, it was common for anyone released from the hospital after a surgery to get a prescription for generic Vicodin (hydrocodone plus acetaminophen),399 generic Percocet (oxycodone plus acetaminophen), or some other opioid—often enough for a whole month when only a few days’ worth would have been enough.400 With increased awareness of the opioid crisis, and in some cases in responses to new laws limiting prescription opioid use, physicians reduced the doses they prescribed, the number of pills per prescription, and the number of times they extended a patient’s prescription.401 Some stopped prescribing opioids entirely to avoid liability. Patients suffering from severe pain complained that they now had a harder time getting treated because other patients were abusing opioids.402
Overall, the number of opioid prescriptions has come down since its peak in 2010, but it is still much higher now than in the 1990s because physicians continue to operate with an imperative to treat patients’ pain and they have few alternatives. Try as they may to comply with medical guidelines to make the most of non-opioid drugs, physicians are constrained by those drugs’ benefit-risk profiles. Some of those non-opioid drugs are too weak to manage severe pain and/or cause serious side effects. For example, naproxen, ibuprofen, and aspirin can cause serious internal bleeding of the stomach and GI tract.403 At high doses, acetaminophen (Tylenol) causes liver failure. These purportedly safer options send hundreds of thousands of patients to the ER each year and kill several thousand.404 So when a physician is trying to help a patient already on non-opioid alternatives that is still suffering from severe pain, simply increasing the dose of these drugs is not as clear-cut a solution as it might seem.
In addition, a healthy physician-patient relationship is grounded in trust. To deny a patient in pain a prescription for an opioid because the physician worries that she might abuse it would undermine that trust. With a “not my patients” mindset, some physicians acknowledged that addiction was a problem but that it was happening to patients being treated by other, less responsible physicians.405
The Drug Industry’s Response
Realizing that the benefit-risk profile of prescription opioids still posed a significant problem, the biopharmaceutical industry responded by attempting to upgrade opioids to prevent abuse and reduce the likelihood of overdose with new ideas and technologies.406 Their goal was the same one chemists had long chased, to develop an abuse-resistant opioid, one that would neither lead to addiction nor overdose.
One idea involved mixing an opioid with niacin, a relatively safe drug that causes an unpleasant feeling o
f heat and flushing if someone were to crush or chew the pill, or take too many. But someone intent on abusing that opioid could counteract the effects of niacin with aspirin, so that one didn’t make it to market. Purdue itself upgraded OxyContin to be more abuse-deterrent by making its shell harder, which made it extremely difficult to chew. It also constructed a core that would cause the drug to turn to gel if mixed with a solvent, deterring its abuse via injection. Once the FDA approved the new OxyContin in 2010, Purdue pulled its older version off the market, and the FDA said it would not grant approval to any future generics without abuse-deterring features.407 Still, the new OxyContin’s abuse-deterrent features could be defeated and other companies attempted to develop more advanced versions. A drug named Xtampza ER featured new technology that caused the pill to release its painkiller only as slowly as intended—even when crushed or chewed—and also made it nearly impossible to snort or inject.408
Innovators and their investors had thought that if they created even more advanced types of opioid medications that would make it harder for patients to abuse, the FDA might reward these advances by both approving them and removing other, more-easily abused versions from the market. But that didn’t happen. Having already fallen for OxyContin’s false promise of being a much safer opioid, the FDA wasn’t about to again give physicians any excuse to underestimate the risks of any new opioids. The FDA set a high bar for any claims that a drug was harder to abuse and pointed to evidence that each new type of opioid drug, whatever its technological defenses, could technically still be manipulated by a determined abuser, maybe by using solvents to dissolve pills or a hammer to crack a hard, outer shell.
The Great American Drug Deal Page 29
