When a 60-year-old runner fell, broke his hip, and injured his knee in a bad spill during a 2019 marathon, he had no idea that his painful injuries would produce a research landmark in the effort to alleviate one of the nation’s most pressing problems: the opioid addiction crisis affecting millions of Americans.
In July 2021, researchers described his novel recovery in what they call a “first case report” to show their seemingly unlikely experimental results. Identified in the report only by his pseudonym, Dineen, the injured runner successfully self-administered a “pharmaco-behavioral intervention,” which combined prescribed drugs with a psychological treatment. Specifically, in this case, it was an “open” placebo—a pill with no active ingredients that nonetheless allowed him to reduce his opioid drug dosage and ultimately wean himself off the painkillers sooner, just a short time after leaving the hospital.
The promise of the results are profound because the need for new pain treatments is dire. “Anyone taking prescription opioids is at risk for unintentional overdose or death and can become addicted,” reads a warning on a web page of the U.S. Centers for Disease Control and Prevention. “Up to 1 out of 4 people receiving long-term opioid therapy in a primary care setting struggles with opioid use disorder.”
Though the case of the injured marathoner is only a single data point needing confirmation from further research, Dineen’s experience demonstrates the feasibility of reducing and even ending the use of addictive painkillers and thus “initiates a discussion of new approaches for opioid management,” writes Spaulding Rehabilitation Hospital’s Maria Anayali Estudillo-Guerra, Leon Morales-Quezada, and their co-authors.
A bold step
The treatment Dineen received is technically known as a conditioned open-label placebo (COLP). “Open-label” means that the person prescribed a placebo knows they are getting an inert substance with no active pharmacological ingredients that can actually affect their symptoms. As proto.life has reported, a growing body of research documents open-label placebos’ ability to affect pain and a number of other symptoms. “Conditioned” indicates that researchers use traditional Pavlovian techniques to train experimental subjects to associate the placebo with effects of active drugs that they receive at the same time.
He volunteered for a small trial testing whether a conditioned open-label placebo could cut the amount of opioids that patients use.
Dineen needed surgery, followed by a stay for rehab at Spaulding. He could have been like so many others, in the words of Michael Bernstein of the Brown University School of Public Health, who was not involved. Every day, all across America, people with injuries “show up at the hospital and walk away with opioids.” Even if the pharmaceutical marketing scandals that gave perverse incentives to doctors to overprescribe opioids are in the past, opioid addiction remains a real risk of taking such drugs. Like many opioid users, Dineen was facing an indeterminate period taking these potentially dangerous drugs. “It would be very interesting and very important,” Bernstein reflects, “if we could find a way to reduce how many opioids a patient is going to end up taking after they leave the hospital.”
That was exactly the aim of a pilot study going on at Spaulding Hospital while Dineen was there. He volunteered for a small trial testing whether a conditioned open-label placebo could cut the amount of opioids that patients use. The people in the experimental group underwent six days of conditioning that combined opioids and placebos. For the first three days, “you are free to ask for your opioid any time that you need it,” Morales-Quezada, the study leader, told proto.life in an interview. “But every time [experimental subjects] get your opioid, you will get this capsule,” he continued, referring to the placebo. On the fourth day, however, experimental subjects got only the inert pill, which “triggers the placebo effect.” On the fifth day, to strengthen their conditioning, the protocol called for them again to receive opioids in conjunction with the placebo. And then on the sixth day, only the placebo. A control group, meanwhile, received six straight days of standard treatment with opioids.
The experiment proved to be a success. Members of the group that received the placebo pills along with the opioids did in fact turn out to need less of the actual drug to achieve pain control similar to what the control group experienced. For Dineen, however, it was a failure: To his disappointment, he learned that he had been a control.
Worried about the addictive drugs he would need to continue taking after discharge, but eager to benefit from the results of the study he had participated in, he asked the researchers if he could try the experimental treatment when he went home. The researchers were intrigued by this offer. Since the placebo is safe and cheap and requires no government approvals, there was very low risk, so they agreed.
Under their daily supervision, he followed the same regimen used by the experimental group in the just-completed study, Morales-Quezada says. But then something remarkable happened. Not only did Dineen, like the experimental group, reduce his opioid consumption—he weaned himself off. On the seventh day, acting on his own initiative, “He was able to get rid of the opioids altogether,” says Morales-Quezada, who is now leading a full-scale clinical trial of a conditioned open-label placebo to reduce opioids. Should pain flare up, Dineen told the researchers, he used the placebos along with over-the-counter medications, or even on their own.
Other studies are also exploring the potential use of placebos as “dose-extenders” for opioid drugs, which means using them to enhance the effect of the actual drugs in hopes of allowing pain sufferers like Dineen to take smaller quantities to achieve the same relief. Doing so would reduce the risk of addiction and ease the mind of the prescribing physician. “The sense I get is that doctors are nervous about overprescribing opioids to their patients, so this is a real potential synergy between public health and medicine,” says Bernstein, who is working on his own clinical trial of placebo and opioids in patients with pain from surgery and other acute conditions.
Children treated with stimulants to ameliorate ADHD could be “effectively treated on 50% of their optimal stimulant dose” when they also received open-label placebos.
Research on placebos as opioid extenders is relatively new, but the idea that placebos can replace problematic drugs is not. In 2010, a team led by pediatrician Adrian Sandler of the Olson Huff Center in Asheville, North Carolina, published results showing that children treated with stimulants to ameliorate attention deficit hyperactivity disorder (ADHD) could be “effectively treated on 50 percent of their optimal stimulant dose” when they also received open-label placebos.
Other researchers are exploring whether the conditioned open-label placebo approach can help people who are already addicted to opioids recover, specifically by using it as a dose-extender for methadone, “the gold standard of medication-based treatment” for opioid addiction, wrote Annabelle Belcher of the University of Maryland School of Medicine in a 2019 article. Side effects of methadone, including heart and lung problems, make the prospect of lowering doses of methadone an attractive therapeutic goal, she and her co-authors wrote. A clinical trial to test this approach just wrapped up this year, but its results are not yet available.
Bernstein of Brown University also notes a further issue: Will doctors be willing to use open-label placebos in their clinical practices in the first place? In a study of orthopedic surgeons published this month, he and co-authors found evidence of widespread hesitancy to forgo full doses of opioids.
“Roughly half of physicians thought that open placebos would probably or definitively be effective for reducing Vicodin, [and] roughly half also thought it would be effective for reducing pain,” he says. “What’s interesting is that only around 20 percent said that they would personally be willing to consider using open placebos.” Bernstein could only speculate on their reasons, so he favors continued “digging down to see what that barrier is for doctors.”
Perhaps more research can persuade more of them to try this approach? “We’ll just have to see where this field takes us over the coming years,” Bernstein says.