Doctors have long taken the devil’s bargain for granted. Relieving severe pain, such as that caused by surgery or trauma, risks inducing a type of pleasure that can make patients addicted. Opioids are one of, if not the most powerful of Although it is the most powerful painkiller ever known, it has been responsible for staggering morbidity and mortality for many years. After the Civil War, thousands of veterans addiction to morphine and opium used to treat combat injuries and illnesses. In the 1990s, overprescribing by doctors and aggressive and deceptive marketing of drugs by pharmaceutical companies led to a continuing and deadly opioid epidemic that killed more than 800,000 Americans.
The Devil’s Bargain fundamentally shaped American medical practice in the 21st century. Since the beginning of the opioid epidemic, doctors have cut off They are strict about the amount of opioid drugs they prescribe. This inevitably means that some patients who really need pain relief receive inadequate treatment or no treatment at all. Estimates vary, but in 2018 one analysis It was found that about 5 percent of people prescribed opioids for pain develop dependence. For many doctors, alleviating the suffering of some patients is not worth the risk of subjecting them to potentially deadly drug dependence.
New research published today scientific progresssuggests that it is indeed possible to use opioids to relieve physical pain without risking addiction. In this study, a research team led by neuroscientist Francis Lee of Weill Cornell Medical College and Anjali Rajadhyaksha of Temple University’s Lewis Katz School of Medicine maintained the analgesic effects of opioids in mice. blocked the beneficial properties of opioids. (I am a clinical psychiatrist at Weill Cornell University, and Lee is chair of the psychiatry department, but we have not collaborated on the research.) These findings, while preliminary, shift the pain paradigm. It can change radically. These offer physicians and researchers an opportunity to seriously consider a future in which pain and pleasure can be isolated and independently controlled.
The new research focuses on a class of drugs called MAGL inhibitors that increase levels of an endocannabinoid known as 2-AG in the brain. Endocannabinoids are cannabis-like molecules that bind to the same receptors in the brain as THC in marijuana, but cause a stronger response. In one experiment, some mice were given a MAGL inhibitor while others were designated as a control group. All mice were given the opportunity to self-administer strong opioids. To the researchers’ surprise, mice given the MAGL inhibitor showed no interest in opioids, while control mice were more eager to self-administer. In another test, when heat was applied to the mice’s tails (a mildly painful stimulus), mice given MAGL inhibitors flinched less than mice given only opioids. In other words, MAGL inhibitors appear to reduce the beneficial effects of opioids while preserving their analgesic effects.
Psychiatrists have thought for some time that opioids and endocannabinoids should somehow enhance each other’s pleasurable effects because they both have receptors in the brain’s reward pathways. But Lee and Rajadhyaksha’s team found that when 2-AG binds to receptors in the reward pathway, it blocks the release of dopamine, thereby blunting the reward that opioids are meant to provide. On the other hand, the analgesic effects of opioids are not blocked in the body. pain circuitthere are few receptors to which 2-AG can bind.
Neuroscientists I spoke to who weren’t involved in the study said the findings, if confirmed in future studies, could meaningfully change pain medications. Eric J. Nessler, 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 analgesic properties of opioids. He also noted that based on preliminary studies, MAGL inhibitors appear to cause minimal side effects. humanmild sedation and lightheadedness. “The real evidence will appear in humans,” Nessler told me. Matthew Hill, a neuroscientist and cannabinoid expert at the University of Calgary in Canada, was optimistic about the prospects for such evidence. “The exciting aspect is that when it comes to the endocannabinoid system, a lot of what we learn from animal models can be applied very well to humans,” he told me.
The splashiest implication of the new study is that MAGL inhibitors could help curb the opioid epidemic if they can actually be replicated in humans. Imagine being able to leave the hospital after surgery or serious injury with a bottle of pills containing, say, the compound Percocet and a MAGL inhibitor. Such tablets are feel It’s as neutral as Advil or Tylenol, but a much more powerful pain reliever. MAGL inhibitors may also be useful in treating people who are already addicted to opioids. Currently, the standard of care uses drugs such as methadone and buprenorphine to manage withdrawal symptoms in patients, but these drugs are themselves opioids and still have some euphoric effects and potential for abuse. Adding a MAGL inhibitor to the mix may make methadone and buprenorphine safer to use.
Medical professionals have struggled with a kind of pharmacological Calvinism, the concept that if something feels good, it must be bad for you. This assumption leads some health care providers to exaggerate Among other things, the risk of addiction for drugs such as Valium and Klonopin, which are used to treat anxiety disorders. Similar myths abound in American culture, where pain relief and pleasure are often viewed as inseparable physical and psychological experiences, different sides of the same coin. For example, many advertisements for painkillers and muscle relaxers show people experiencing not only relief from pain but also a magical return to some form of pleasure, such as playing sports or enjoying nature. is depicted. Psychological adversity, including that caused by pain, is thought to lead 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 results test existing assumptions about psychology and philosophy. Since the 1950s, researchers have understood that the neural circuits that cause pleasure and pain are largely separate, although they are located close to each other and interact. If you have ever been seriously injured in an accident, you may have experienced this breakup yourself. The pain will be temporarily suppressed by a rush of endorphins, the brain’s own painkillers, but you probably won’t feel any euphoria. Other recent advances may also expand the limits of painkillers without causing addiction. For example, earlier this year, drug company 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 occurs in the central nervous system, there is little potential for abuse of this drug. If further research confirms Vertex’s existing results, this could represent a meaningful advance in the treatment of pain resulting from fractures and other conditions. However, such drugs will likely leave deep internal pain untouched.
If Lee and Rajadhyaksha’s new research is replicated in humans, it will have profound implications not only for how doctors treat pain, but also for how we all think about the very nature of pain. That’s going to happen. I hope that doctors will be more generous about pain relief if they can confidently prevent or block the risk of addiction. And understanding that pleasure and pain relief are not necessarily tied together at the hip may prevent the rest of us from becoming moralistic about the adversities of everyday life. Chronic pain is a major cause of disability, can interfere with healthy habits such as exercise, and can even slightly shorten your lifespan. lifespan. Why not keep it at bay?
For too long, doctors have feared pain relief while patients suffered from intense discomfort. Or there was a risk of addiction. Researchers now have an opportunity to reevaluate pain risk-benefit calculations. What a boon to medicine it would be to have a new generation of medicines that could take away our pain and leave us to the task of finding joy.
