Doctors have long taken for granted a devil’s bargain: Relieving intense pain, such as that caused by surgery and traumatic injury, risks inducing the sort of pleasure that could leave patients addicted. Opioids are among the most powerful, if not the most powerful, pain medications ever known, but for many years they have been a source of staggering morbidity and mortality. After the Civil War, thousands of veterans became addicted to morphine and opium, which were used to treat battle injuries and illnesses. In the 1990s, overprescribing by doctors, along with aggressive and deceptive drug marketing by pharmaceutical companies, led to a deadly and ongoing opioid epidemic that has killed more than 800,000 Americans.
The devil’s bargain has radically shaped the practice of medicine in 21st-century America. Since the opioid epidemic began, doctors have cut down severely on the amount of opioid medication they prescribe. Inevitably, this means some patients with real need for pain relief go undertreated or completely untreated. Though estimates vary, one 2018 analysis found that about 5 percent of people who are prescribed opioids for pain will develop a dependence; for many doctors, easing some patients’ suffering just isn’t worth the risk of saddling them with a potentially fatal drug dependence.
New research, published today in Science Advances, suggests that using opioids to relieve physical suffering without risking addiction is in fact possible. In the study, a team of researchers led by the neuroscientists Francis Lee at Weill Cornell Medicine and Anjali Rajadhyaksha at the Lewis Katz School of Medicine at Temple University blocked the rewarding properties of opioids in mice while preserving the drugs’ analgesic effects. (I’m a clinical psychiatrist at Weill Cornell and Lee is the chair of the psychiatry department, but we have never collaborated on research.) These findings, although preliminary, could fundamentally shift the paradigm of pain. They offer an opportunity for doctors and researchers to seriously consider a future in which pain and pleasure can be isolated and independently controlled.
The new study focuses on a type of drug called an MAGL inhibitor, which increases the level of an endocannabinoid, known as 2-AG, in the brain. Endocannabinoids are cannabis-like molecules that bind to the same receptors in the brain that the THC in marijuana does, but they produce a more powerful response. In one experiment, some mice received the MAGL inhibitor while others were designated as a control group. All of the mice were given opportunities to self-administer doses of a potent opioid. To the researchers’ surprise, the mice that received the MAGL inhibitor displayed less interest in the opioids while their counterparts more avidly self-administered. In a separate test, when heat was applied to the tails of mice (a mildly painful stimulus), those that had received the MAGL inhibitor did not flinch any more than those that received only opioids. In other words, the MAGL inhibitor seemed to diminish the rewarding effect of the opioids while preserving their painkilling benefit.
Psychiatrists have assumed for some time that opioids and endocannabinoids should, if anything, enhance each other’s pleasurable effects, because they both have receptors in the brain’s reward pathway. But Lee and Rajadhyaksha’s team determined that when 2-AG binds its receptor in the reward pathway, it inhibits the release of dopamine, thereby blunting the reward that an opioid would otherwise provide. Meanwhile, opioids’ analgesic effects are unimpeded in the body’s pain circuits, which have few receptors to which 2-AG can bind.
Neuroscientists I spoke with who were not involved in the study told me that the findings, if confirmed in future research, have the potential to meaningfully change pain medicine. Eric J. Nestler, a professor of neuroscience at the Icahn School of Medicine at Mount Sinai, called the study “a novel and exciting approach” to separating the addictive and painkilling properties of opioids. He also pointed out that, based on preliminary research, MAGL inhibitors seem to cause only minimal side effects in humans, such as slight sedation and lightheadedness. “The real proof will be in humans,” Nestler told me. Matthew Hill, a neuroscientist and cannabinoid expert at the University of Calgary, in Canada, was optimistic about the prospects for such proof. “The exciting aspect is that when it comes to the endocannabinoid system, a lot of what we learn from animal models translates to humans quite well,” he told me.
The flashiest implication of the new study is that, if it can indeed be replicated in humans, MAGL inhibitors could help curtail the opioid epidemic. Imagine that, after surgery or serious injury, you could leave the hospital with a bottle of pills that contain a compound of, say, Percocet and an MAGL inhibitor. Such a pill could feel as neutral as an Advil or Tylenol, though it would be a far stronger painkiller. MAGL inhibitors may even prove helpful in the treatment of people who are already addicted to opioids. Currently, the standard of care is managing patients’ withdrawal symptoms with drugs such as methadone and buprenorphine, which are themselves opioids and still retain some euphoric effects and potential for abuse. Adding an MAGL inhibitor to the mix could make methadone and buprenorphine safer to use.
The medical profession has struggled with a kind of pharmacologic Calvinism—the notion that if something feels good, it must be bad for you. That assumption has led some health-care providers to exaggerate the addictive risk of drugs such as Valium and Klonopin, which are used to treat anxiety, among other things. Similar myths abound in American culture, which frequently casts pain relief and pleasure as inseparable physical and psychological experiences—different sides of the same coin. For example, many advertisements for painkillers or muscle relaxants depict people experiencing not just relief from pain but a magical return to some pleasure, like playing sports or enjoying nature. Psychological adversity, including that caused by pain, is often thought to be conducive to personal growth. And as any trainer will tell you: No pain, no gain.
But the more scientists study pain and pleasure, the more their findings test existing assumptions about psychology and philosophy. Since the 1950s, researchers have understood that the neural circuits that give rise to pleasure and pain are largely distinct, though they are located near one another and interact. If you’ve ever been seriously injured in an accident, you might have experienced this separation for yourself: Your pain is kept temporarily in check by a surge of endorphins, the brain’s own painkiller, but chances are that you won’t feel euphoric. Other recent advances might also expand the boundaries of painkilling without causing addiction. Earlier this year, for example, the drugmaker Vertex Pharmaceuticals submitted an FDA application for a drug that blocks pain signals in peripheral nerves before they reach the brain. Because pleasure is an experience that arises in the central nervous system, the drug has little potential for abuse. If further research supports Vertex’s existing results, this will be a meaningful advance in the treatment of pain that arises from things like broken bones. But such a drug will likely leave deep internal pain untouched.
If Lee and Rajadhyaksha’s new study replicates in humans, it will have profound implications not just for how physicians treat pain but also for how all of us think about the very nature of pain. I would hope that doctors would be more generous about relieving pain if they can confidently impede or even block the risk of addiction. And understanding that pleasure and pain relief are not necessarily joined at the hip might help the rest of us be less moralistic about adversity in everyday life. Chronic pain is a major cause of disability, interferes with healthy habits such as exercise, and might even modestly shorten one’s lifespan. Why not keep it at bay?
For too long, doctors have feared pain relief while patients have suffered through intense discomfort—or risked addiction. Now researchers have the opportunity to reassess the risk-benefit calculus of pain. What a boon it would be for medicine to have a new generation of drugs that could take away our agony and leave the work of finding pleasure to us.