Often in the drug industry, companies search for a discovery to treat a condition they believe can be treated by pharmaceuticals. Diabetes, high blood pressure, infectious diseases, and other illnesses and chronic ailments provided many profitable opportunities. However, there was one common complaint—chronic pain—that affected tens of millions of Americans and had stymied companies searching for an effective treatment.
That failure was not because of any lack of desire on the part of pharma. Instead, the plethora of remedies that started with patent drugs had demonstrated there were no good choices. Many drugs temporarily alleviated pain. Morphine, oxycodone, hydrocodone, and other opiates were effective pain relievers. They were listed, however, on the Controlled Substances Act because they had a notorious reputation for addiction.
A pharmacologist and a chemist at the National Institutes of Health had written in Science an overview about how years of academic and private company lab research had been devoted to finding a nonaddictive painkiller. Each ended in failure. The duo concluded it was unlikely such a medication was possible.
A few physicians, however, were intent on upending the traditional medical views about pain and how to treat it. Their reevaluation would encompass whether opioids had been unfairly judged and should be more widely dispensed. This movement inadvertently laid the groundwork for the Sacklers’ 1996 opioid-based blockbuster painkiller, OxyContin.
Until the early 1980s, medical schools taught physicians that pain was only a symptom of some underlying physical condition. Physicians invariably searched for the cause of the pain rather than treating it as a stand-alone ailment. The specialty of “pain management” did not exist.1 John Bonica, whom Time later dubbed “pain relief’s founding father,” was a leading voice challenging that conventional wisdom. Bonica was an Italian-born former professional wrestler, carnival strongman, and light heavyweight world boxing champion turned anesthesiologist. He suffered chronic shoulder and hip pain from his own sports career. His 1953 The Management of Pain, a 1,500-page monograph, was an unmatched resource.
Bonica believed doctors significantly underdiagnosed pain and, as a result, millions of patients suffered needlessly. In 1973, he organized a seven-day conference attended by 350 researchers from thirteen countries.2 The following year, Bonica cofounded the International Association for the Study of Pain (its journal, Pain, is the field’s leading publication).3 Three years later a multidisciplinary group of doctors and clinical researchers relied on Bonica’s research and created the American Pain Society (APS).4
The effort to prioritize pain was not long under way when a five-sentence “letter to the editor” in the January 10, 1980, New England Journal of Medicine sparked a parallel rethinking about conventional medical views on the risks of opioids. The authors were Dr. Hershel Jick and a graduate student, Jane Porter. They summarized their examination of 39,946 records of Boston University Hospital patients. Jick was a leading physician at the esteemed Boston Collaborative Drug Surveillance Program, financed in part by the NIH and the FDA. It was America’s largest independent effort to determine the risks of adverse reactions and potential abuse in hundreds of widely used medications.5 The duo reported that almost a third (11,882) of the patients had “received at least one narcotic preparation” but found only “four cases of reasonably well-documented addiction in patients who had no history of addiction.” Their conclusion was as unorthodox as it seemed decisive: “Despite widespread use of narcotic drugs in hospitals, the development of addiction is rare.”6
Jick and Porter’s letter cited two previous drug surveillance studies. Both involved only hospitalized patients, all of whom were given small doses of opioids in a controlled setting. Only a handful took opioids for more than five days. None were given painkillers when discharged from the hospital.7
The prestigious New England Journal of Medicine had a deserved reputation for publishing peer-reviewed, pioneering health studies. That ninety-nine-word letter drew attention precisely because it was published in the NEJM. Yet not even its most avid readers could have predicted the impact it would exert in the coming reassessment of using opioids to treat pain. What few knew was that the NEJM almost never had outside experts to review “letters to the editor.”8 If they had subjected the Jick and Porter letter to peer review, the editors would have had a more precise and accurate conclusion by making it clear that “the development of addiction is rare” in the controlled setting of a hospital. Instead, during the next two decades that letter was cited over six hundred times in textbooks, medical journals, and other publications.9 More than 80 percent of those who cited the Jick and Porter letter omitted any mention that it only studied hospitalized patients who took opioids for a few days. Instead it was mostly cited to buttress far broader conclusions about the safety profile of opioids.10 I 11
Whenever the consumer press mentioned the Jick and Porter study, it was invariably misdescribed to confer on it far more authority than it deserved. A Canadian psychologist writing in Scientific American called the 1980 letter “an extensive study” and altered its finding to be that “when patients take morphine to combat pain, it is rare to see addiction.”12 Time wrote that the “fear” of addiction “continues to hold sway over American medicine [and] is basically unwarranted.” It called the Jick-Porter letter “a landmark study” (it is unlikely the Time journalist read the study he cited; he listed its publication as 1982 [it was 1980], said that “it followed almost 12,000 Boston hospital patients [none were followed for observation],” and that the study “had eliminated those with a history of addiction [it had not].”13 A 1986 World Health Organization report, “Cancer Pain Relief,” cited the ninety-nine-word letter as a scientific cornerstone for challenging decades of medical dogma that “the risks of widely prescribing opioids far outweighed any benefits.”14
Six weeks after the WHO publication, the journal Pain published a startling report. The lead author of the “Chronic Use of Opioid Analgesics in Non-Malignant Pain” was Russell Portenoy, a thirty-one-year-old Memorial Sloan Kettering physician specializing in anesthesiology, neurology, pain control, and pharmacology. His coauthor was Kathleen Foley, a leading pain management specialist who was widely considered to be at the vanguard of palliative care.15
As had the WHO report, Portenoy and Foley cited the Jick-Porter letter. However, they did not rely on it. Instead, they presented the results of their own clinical study. It involved thirty-eight patients who had been administered narcotic analgesics—a third took oxycodone—for up to seven years. Sloan Kettering was one of the only American hospitals with a “formalized pain service… within the Department of Neurology.”16 Foley was its chief, and it was there that Portenoy had witnessed what Cicely Saunders had seen in London: opioids improved the quality of life for many terminally ill cancer patients. Two thirds of those studied had significant or total pain relief. There was “no toxicity,” the two doctors reported, and only two patients had a problem with addiction, both of whom had “a history of prior drug abuse.”17
“We conclude that opioid maintenance therapy can be a safe, salutary and more humane alternative to the options of surgery or no treatment in those patients with intractable non-malignant pain and no history of drug abuse.”18
When they had begun their study, Portenoy and Foley expected that they might find the opposite, a higher addiction correlation. The results led them to conclude that the National Cancer Institute and the federal government were not interested in educating doctors about opioids. Instead, as Foley later said, the pharmaceutical companies became “our colleagues in education.… It was the drug company that wanted to improve pain management.”19
The Portenoy-Foley paper helped kick off a contentious and at times acrimonious debate about whether opioids had been unfairly branded and therefore underutilized in pain management.20 While Foley focused on palliative and hospice care, the charismatic Portenoy emerged as the unofficial spokesman for the embryonic movement to reevaluate opioids.21
Portenoy was a smart physician who relished clinical research. He believed he was at the forefront of reassessing antiquated views about opioids, and that by doing so, millions of patients suffering from untreated chronic pain might be helped. Although Portenoy had noted in his 1986 study that opioids should be considered an “alternative therapy” until there was further clinical research, that caution often got lost in his zealous fervor. He at times called opioids a “gift from nature” while occasionally castigating doctors whose “opiophobia” prevented them from dispensing the medications.
An eclectic and informal network of physicians, from New York neurologists to California psychiatrists to North Carolina pain physicians, contributed to the nascent reevaluation effort. The American Academy of Pain Medicine became the first organization for physicians specializing in pain management. It was followed by the American Society of Addiction Medicine (its slogan is “Addiction is a chronic brain disease”). The physicians at the vanguard of the movement encouraged their patients suffering from chronic pain to form advocacy groups and petition the FDA and Congress to loosen the dispensing restrictions on opioids.
In 1990, Dr. Mitchell Max, the president of the American Pain Society, wrote a widely read editorial in the Annals of Internal Medicine in which he bemoaned the lack of medical progress in diagnosing and treating pain. “Unlike ‘vital signs,’ pain isn’t displayed in a prominent place on the chart or at the bedside or nursing station,” he wrote. Doctors were “rarely held accountable” for failing to treat pain. “Pain relief has been nobody’s job.”22
Part of the failure was because patients often did not tell their doctors about their pain. Max thought the easiest fix was to make certain that physicians asked patients on every visit about whether they were in pain. For decades, physicians had kept watch of four vital signs when examining patients: blood pressure, pulse, temperature, and breathing. Dr. James Campbell, the president of the American Pain Society, suggested “Pain as the 5th Vital Sign.”23
One reason doctors shied away from treating pain as a stand-alone condition was that there was no accepted diagnostic test, as there was for blood pressure or cholesterol. It was similar to evaluating psychiatric disorders, a somewhat subjective assessment based on the doctor’s observations and the patient’s descriptions of symptoms. In depression, anxiety, and other mental conditions, some patients were mildly affected in their daily lives whereas others had difficulty in functioning at all. The same was true with pain. What one patient described as moderate pain that restricted mobility might be excruciating to someone else.
As the Hamilton Rating Scales in the 1960s had become popular and simple tests by which to measure anxiety and depression, several “pain assessment” tools came into use in the mid-1980s. The McGill Pain Index had seventy-eight words related to pain divided into twenty sections. Patients picked the words that best described the state of their pain. The Memorial Pain Assessment Card had eight streamlined descriptions and included a single line on which patients marked the degree of pain intensity. A pediatric nurse and child life specialist in Oklahoma developed a chart with ten hand-drawn faces ranging from happy and laughing to angry and crying. The Wong-Baker Pain Rating Scale made it easy for children to pick the face closest to how their pain felt that day. Variations of that scale soon became a one to ten rating for adults, one being “very mild, barely noticeable,” and ten signifying “unspeakable pain.”
Although the pain tools were error prone since they relied on the patient’s subjective assessment, they were hailed as the first rudimentary measurements by which doctors could determine if their patient’s pain was getting better or worse. In that sense, it did not matter if a patient had a low or high pain threshold. What was important was whether their pain improved over time. The Joint Commission, an independent, not-for-profit organization responsible for accrediting 96 percent of all hospitals and clinics in the U.S, gave the first major endorsement for the concept that pain should be the fifth vital sign. When the Veterans Administration later embraced it, the practice did not take very long to move to the private sector.24
Portenoy’s 1986 article that concluded that “opioid maintenance therapy can be a safe, salutary and more humane alternative” was the first of a couple of dozen that physician pain advocates published in medical journals over the next few years. Based always on small trials or anecdotal reports, they bolstered the dual arguments that opioids did not deserve their fearsome reputation and that they were extremely “effective in treating long-term chronic pain.”25 Buried in their scientific footnotes was that “long-term” usually meant twelve to sixteen weeks and “effective in treating” meant “superior to placebo.”26
An anesthesiologist and dentist who specialized in pain management, J. David Haddox, pushed the boundaries of the reevaluation movement with a unique and controversial theory. He reported in Pain about the failure to treat the pain of a seventeen-year-old leukemia patient. According to Haddox, who went on to become the president of the American Academy of Pain Medicine and later worked for Purdue Pharma, the doctor’s botched treatment had “led to changes similar to those seen with idiopathic opioid psychologic dependence (addiction).” Pseudoaddiction was a syndrome, he posited, over which the patient had no control. It was caused inadvertently when doctors failed to prescribe sufficient painkillers. That caused “behavioral changes” in patients that most doctors misinterpreted as signs of addiction. Haddox contended that was only evidence that the patient was desperate to get enough medication for pain relief. The solution to pseudoaddiction was to dispense more narcotic painkillers.27
The nation’s three major pain associations embraced pseudoaddiction. In a joint statement they announced it “can be distinguished from true addiction in that the behaviors resolve when pain is effectively treated.”28 (It took twenty-five years before a comprehensive study revealed that in the 224 scientific articles in which the term was cited, only eighteen provided even the skimpiest anecdotal evidence to support the thesis. The study concluded that it was essentially a “fake addiction” and had “proliferated in the literature as a justification for opioid therapy for non-terminal pain.”)29
The same month that pseudoaddiction entered the vocabulary, a dozen prominent physicians published “The Physician’s Responsibility Toward Hopelessly Ill Patients” in The New England Journal of Medicine. Although it was about the treatment of terminally ill patients, their conclusion became a veritable slogan for the reevaluation movement: “The proper dose of pain medication is the dose that is sufficient to relieve pain and suffering.… To allow a patient to experience unbearable pain or suffering is unethical medical practice.”30
The movement’s progress could be measured by the number of states that adopted “intractable pain treatment” laws. Those statutes acknowledged patients had a right for treatment of their pain, and they shielded physicians from criminal or civil liability if the narcotics prescribed resulted in addiction. New Jersey was the first in 1984 to adopt such an act; eighteen others followed over a few years.31
Portenoy and colleagues contended that opioids should be the first treatment option “for patients with intractable nonmalignant pain and no history of drug abuse.”32 Instead of establishing a maximum dose, they posited that opioids should be dispensed until the patient’s pain was relieved.33
Liberally dispensing opioids was the perfect complement to the emerging field of proactive pain management. Opioids alleviate pain by blocking the brain’s receptors that send and receive pain signals. They do nothing to treat the underlying ailment that causes the pain. The twin themes—that not treating pain was negligent and that opioids were a reliable option for almost everyone—reinforced one another.34
The Sacklers would have been hard pressed to design a better lead-in to their release a decade later of OxyContin, their blockbuster opioid-based painkiller. When the pain reevaluation movement got under way in the mid-1980s, though, OxyContin was not yet on the drawing board. It was in the earliest stages of development by the time pain was on its way to becoming the fifth vital sign. Some suspect collaboration between Purdue and the leading physician advocates because they find it difficult to believe that they all were so utterly wrong about the diminution of the odds of addiction. That they were wrong, however, does not mean they were not sincere. The histories of medicine and the pharmaceutical industry are littered with practices and products that went from exalted pedestals to discarded dustbins.35
In the following decade, Purdue did what every other pharmaceutical company with an opioid-based product did: spent tens of millions in underwriting and subsidizing the physicians, advocacy groups, and pain societies at the forefront of the reevaluation movement.36 Many doctors who were pioneers in the movement reaped big fees as company lecturers. Purdue and other drug firms funded medical school courses, professional conferences and conventions, pain management junkets, and even pain-focused continuing education classes. And, as with every other major drug introduction, some government officials, even a few from the FDA, went through a revolving door to work eventually for Purdue and other firms selling their own branded opioids. Purdue and its rivals spent money on those advocates only because they were already promoting ideas about pain treatment that the firms embraced.37
Whether the flood of pharma money made the early advocates more resistant to admitting their mistake as reports emerged much later that Purdue’s opioid painkillers appeared far more addictive than any had forecast is a difficult assessment. They read the same news reports about the rising numbers of prescription opioid overdoses, illegal diversion, spiraling hospital admissions, and a surge in opioid-related crime. It was not just drug company money that kept them from admitting they had gotten it wrong. The leading pain management contrarians had built their reputations as physicians with the courage to challenge long-established medical dogma as archaic. Acknowledging that opioids were far more addictive than they had originally predicted would have shattered their careers.
At least publicly they clung to their old views even if privately they had second thoughts. The leading pain and opioid reevaluation proponent, Russell Portenoy, seemed never to waver from his early conclusions. By the time he appeared on Good Morning America in 2010, more than 300,000 Americans had died of opioid overdoses in the previous decade. Still, when asked about the risk of getting hooked, he assured ABC’s four million viewers that “Addiction, when treating pain, is distinctly uncommon. If a person does not have a history, a personal history, of substance abuse, and does not have a history in the family of substance abuse, and does not have a very major psychiatric disorder, most doctors can feel very assured that that person is not going to become addicted.”38 Yet, that same year, in a more reflective mood and what he thought was a private setting, Portenoy confided to another doctor, “I gave innumerable lectures in the late 1980s and ’90s about addiction that weren’t true.”39
I. In 2017, six researchers published in the NEJM the results of their review of all subsequent citations to the 1980 letter. “In conclusion, we found that a five-sentence letter published in the Journal in 1980 was heavily and uncritically cited as evidence that addiction was rare with long-term opioid therapy. We believe that this citation pattern contributed to the North American opioid crisis by helping to shape a narrative that allayed prescribers’ concerns about the risk of addiction associated with long-term opioid therapy.” The NEJM subsequently published a rare “Editor’s Note,” adding to its webpage with the original Jick-Porter letter: “For reasons of public health, readers should be aware that this letter has been ‘heavily and uncritically’ cited as evidence that addiction is rare with opioid therapy.” Dr. Jick told the Associated Press in 2017: “I’m essentially mortified that that letter to the editor was used as an excuse to do what these drug companies did.”