By George W. Sledge, Jr., MD
Of late, I have been considering pain. Or lack of pain. Jo Cameron is a 71-year-old woman living in Scotland who has led a fairly pain-free life. She considered childbirth "quite enjoyable really," and one time did not notice that her hand was being fried by a stove until she smelled burning flesh. She then had hand surgery of the sort guaranteed to hurt and barely noticed. She is essentially immune to pain, and this, in a "cherish your exceptions" sort of way, interested her doctors.
An article in the British Journal of Anaesthesia tells the science story. Jo has two linked mutations in the FAAH (fatty acid amide hydrolase) gene and in the related FAAH-OUT pseudogene (who says molecular biologists lack a sense of humor?). The end result of these mutations is a decreased ability to metabolize anandamide, an endocannabinoid compound that binds to a THC-like receptor. Anandamine, in elevated plasma concentrations, not only reduces pain sensitivity but increases happiness. There are genetically happy humans who have elevated anandamine levels in their blood, and mice genetically engineered to have increased anandamine levels are able to extinguish fear-based memories.
I suspect it is rare for articles in the British Journal of Anesthesia to go viral. I confess I had never read an article in the journal until now, and "Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity" is likely the last. But this article was written up in the popular press and read around the world. There's something about "feel no pain" that appeals to the public.
Nor is this the only pain-relief gene we know about. Ashlyn Blocker of Patterson, Georgia, has a mutation in the SCN9A gene. She grew up with a congenital insensitivity to pain, something totally dangerous for any young child. A November 15, 2012, New York Times Magazine story relates how the 6-month-old Ashlyn "rubbed big red splotches on her nose and almost chewed off part of her tongue with her emerging teeth." Once she "broke her ankle and ran around on it for two days before her parents realized something was wrong."
We think of pain as something bad, but Jo and Ashlyn's stories confirm something obvious: pain is an evolutionary necessity. It's not just some trivial "no pain, no gain" sports mantra. If an organism never feels pain, it never avoids those things that cause pain, and that does not, in simple Darwinian turns, support survival of the fittest, or—in my case—survival of the clumsy. Leaving your hand on a burning stove is not something likely to improve reproductive fitness, nor is biting off your tongue because it doesn't really hurt. One can easily understand why nature equips us with pain fibers, and why we should listen to them, other than not wanting to hurt.
Life is full of evolutionary double-edged swords, and oncologists are intimately familiar with the other edge of this particularly sharp weapon. A bone metastasis announces itself through constant unremitting pain in the back and pelvis, or a liver metastasis through the expansion of Glisson's capsule, or a parietal brain met through pounding headaches. From an evolutionary standpoint, pain doesn't accomplish too much when it trumpets an inevitably lethal event. It just hurts.
And this is where analgesia comes in. I need not bore you with an extensive review of the many ways in which cancer-related pain is eliminated, or at least controlled. Increasingly multidisciplinary approaches involving surgeons, anesthesiologists, radiation and medical oncologists, psychiatrists, and palliative care physicians, though still inadequate, have gone a long way to improving quality of life for patients with advanced cancer.
Despite the real advances made in pain management, I'm still impressed by how much of what we do for pain still involves the use of opioids. Whether short-acting or long-acting, natural or synthetic, they remain the mainstay of pain control in the majority of advanced cancers.
All of which brings us to the issue of addiction. In the United States, we are currently in the midst of an opioid addiction epidemic, an epidemic that is national in nature, devastating in impact for individuals and municipalities, tragic in its consequences, and—like everything in modern medicine—expensive. While the other epidemic, the viral pandemic, has largely pushed it out of the headlines, the opioid epidemic still tortures all too many of our fellow citizens.
All this, and something more: it is shameful. And we—the health care community writ large—are responsible for much of this shame.
Back in the day of ridiculous, over-the-top pharmaceutical parties at the ASCO Annual Meeting, the most egregious always involved the leading purveyor of pain medications, Purdue Pharma: its chocolate bar (a different addiction) was legendary. In my youthful naivete, I never thought much about these, other than their contribution to the cost of care. I believed, wrongly as it turned out, that addiction was not really a big problem for cancer patients. I used opiates almost entirely for metastatic disease, and I had been taught (and taught trainees and patients) that should a patient's cancer shrink on therapy, she would have diminished pain and therefore decreased need for pain medication. My patients were cancer patients, not drug addicts, after all. The addictive potential was low, unless you were one of those unfortunate, but fortunately rare, souls with a predilection for narcotics-seeking behavior.
We were also told that the newer generation of pain medications, like OxyContin and fentanyl patches, had lower addictive potential. Looking back, I don't have any memory of there being any supportive data for this claim, but the claim was part of the common conversation, and indeed was explicitly allowed by the FDA. Purdue trained its sales reps, who showed up in my clinic among others, to tell docs that oxy was less prone to abuse than morphine. We were taught that pain was the "fifth vital sign," and that the goal was drive the patient's pain away. Outside oncology, Purdue preached the virtues of oxy for chronic pain, where the data was incredibly mushy and a bit stinky as well. A veritable army of drug reps invited physicians on expensive boondoggles, usually vacations at five-star resorts in sunny climates. Key opinion leaders were enlisted in the crusade, for handsome fees.
And here the story gets ugly, fast. This new dogma, endorsed by government and spread by the profession and by company sales reps, was demonstrably wrong, and known to be so in a very short time. The first outbreaks of the current epidemic occurred in marginalized rural communities in states like West Virginia and Kentucky. Small pharmacies and doctor's offices, staffed by the greedy and corrupt, were suddenly prescribing huge amounts of OxyContin. That should have been a burning bush signal to all not willfully blind. When a Purdue sales rep discovered that one clinic he visited regularly was a drug mill for addicts, he notified his superiors at the company. His job, he was told, was to sell drugs, not to determine if a "doctor was a drug pusher," as a 2018 New York Times article subsequently reported.
We now know that Purdue Pharma was, for lack of a better word, evil. Purdue knew that OxyContin abuse was common by the mid-1990s and told no one: its drugs were crushed, snorted, sold by the corrupt to the emotionally frail. The company felt no responsibility to share this information with regulators or physicians, and when courageous physicians in the backwaters of Appalachia tried to get state health authorities to intervene, company doctors descended en masse to pooh-pooh the idea, treating the local doctors as country bumpkins, stupid hicks who did not understand the wonderful world of modern pain control. The story of Purdue's nauseating lack of conscience is told in Beth Macy's beautifully reported 2018 book Dopesick: Dealers, Doctors and The Drug Company That Addicted America.
And this was no low-level malfeasance in the company: the Sacklers, the family that owned the company, were well aware of this information, as were top company officials. Federal prosecutors recommended felony prosecutions for the company's executives but were overruled by the higher-ups in the Bush administration. Instead, they received a slap on the hand: a misdemeanor charge of "misbranding," accompanied by a (relatively large) fine. Rudolph Giuliani, still "America's Mayor," served as part of their defense team, in training for his later interactions with corrupt Ukrainian oligarchs and other related officials. He is said to have played an influential role in the decision to allow Purdue to keep manufacturing OxyContin, and in an agreement immunizing them against further lawsuits and keeping their officers out of jail.
I've often wondered why, if (as the Supreme Court affirms) companies have the rights of individuals under the Constitution, they can't also be convicted of mass murder and executed? The answer, in a roundabout way, appears to be that they can: Purdue Pharma has been the recipient of an avalanche of lawsuits, and filed for bankruptcy in September 2019, for its part in the epidemic. Through 2016 Purdue made $31 billion selling OxyContin; the proposed settlement would claw back $10-12 billion. While the Sacklers themselves have suffered the ignominy of art museums shedding their name from endowed wings, they have to date retained most of their ill-gotten gains, though the new settlement, if approved (and it may not be), would strip them of ~$3 billion.
One scion of the family complained, in a wonderfully droll June 19, 2019, article in Vanity Fair, of the unfairness of it all: "I really don't think there's much in the complaints, frankly, that's at issue that's not just, 'Oh, you shouldn't have marketed these things at all.' Right? And I guess that's a hindsight debate one can have." To paraphrase: We're sorry if anyone was harmed, but the opioid epidemic isn't out fault. We feel awful about all that. My entire family has been maligned, and for what? We were only doing what the then-current pain dogma suggested was appropriate. Well, no, but whatever allows you to sleep at night in your bed of riches.
Arthur Sackler, the founding member (along with his two brothers) of the Sackler empire, and paterfamilias of the Sackler clan, was one of those fascinating creatures you read about in a horror novel. He was a true polymath, conducting laboratory research of sufficient quality to be published in high-impact peer-reviewed journals. See, for instance, his "Effects of Thymectomy on the Resistance of Rats to Drowning and Histamine Stress", published in the November 4, 1961, issue of Nature. Certainly, few current articles in Nature include, for their material and methods section, phrases like "the remaining animals were subjected to drowning stress by immersion in water precooled and maintained at 6°C. Drowning time was determined by recording the time-interval up to the final submergence." A later (1963) Sackler article in Nature remains the definitive word on what happens to a rat's eosinophils when the rat is administered LSD. Answer: the eosinophils decrease. And the rats go crazy, man. To which I respond: it sure was easier to get a paper published in Nature in those days.
Sackler and his brothers took over Purdue, a failing pharmaceutical concern, and eventually turned it into the corporate powerhouse that created OxyContin. Along the way, he invented direct-to-consumer medical advertising, cordially despised by physicians but an inescapable aspect of evening news shows. An erudite man who prided himself on his culture and civility, Sackler and his descendants endowed museums and galleries around the world, including the Sackler wing at the Met, with its glorious Temple of Dendur. The Metropolitan Museum is now refusing to take any more Sackler money, as are sister institutions that happily held out their hands when the family were still considered legit philanthropists rather than sordid purveyors of addictive drugs.
The Oxy epidemic, followed by the related fentanyl and heroin epidemics, have had a devastating effect on communities around the United States. Deaths due to addiction have tripled in the last 30 years. The epidemic has also affected how physicians prescribe narcotics, and how those prescriptions are regulated by state and federal authorities. I've noticed a tendency by cancer doctors to outsource their pain medication prescribing to palliative care specialists, or to simply decrease the amount of pain medications they prescribe. This is a mixed bag, of course: reducing unnecessary or marginal uses of narcotics is a good thing, and palliative care specialists are a wonderful resource for my patients, but I worry that we might slip back to a time when cancer patients died in agony. That would be the Sackler's final, bitter bequest.
As if direct-to-consumer advertising wasn't bad enough. It's enough to want me to reach for some anandamide.