No pain, no gain. It’s an old adage of gym culture that treats self-improvement as a product of triumph over discomfort. But we often view the opposite as true in society, too, viewing pain relief through a lens of skepticism, especially when it comes to pharmaceuticals.
Opioids are the poster child of this dichotomy. Doctors have been steadily prescribing fewer opioids for years, because of the damage wrought by these drugs’ euphoric effects and addictive properties. More than 80,000 Americans die each year from opioid-related overdoses. And after doctors first helped to fuel the crisis in Philadelphia and around the country by broadly overprescribing opioids, the reality today is that untold numbers of Americans live in pain as a result of a reluctance to take or prescribe them.
But what if doctors could uncouple the destructive aspects of opioids from the pain-relieving ones? What if a single pill had the power of OxyContin but the safety of Tylenol?
“If everything goes well, we will be able to help many more patients dealing with pain, without the possibility of becoming dependent on them.” — Dr. Anjali Rajadhyaksha, Temple University Health
That future could be stunningly close, according to a new preclinical study published in late November — and written up by The Atlantic and others — by two senior authors, including Temple University Health neuroscientist Dr. Anjali Rajadhyaksha.
“We’ve been working on this idea: Can we take the opioids and split them apart, taking the pain [relieving] parts away from the addictive [parts]? With this discovery, we could have an opioid that would not be addictive at all,” says Rajadhyaksha.
Rajadhyaksha resettled her lab (previously at Weill Cornell Medicine) in Philly last year after joining Temple Health as the school’s director of substance abuse research. The move was inspired by Dean Amy Goldberg — who, since being promoted to dean of the school in 2022, has made it a priority to drive impact in the areas of substance abuse and addiction treatment. Temple Health is currently working to formalize a new institute that would bring together Temple’s School of Public Health, the School of Science and Technology, and others to work collaboratively towards that goal, along with the surrounding community.
That vision is a big reason why Rajadhyaksha is now here: “To really think about substance-use disorders and addiction medicine with a 360-degree view, including the different schools and the community,” she says. Plus, there’s the fact that Philly is an epicenter of the crisis, with an estimated 75,000 city residents struggling with opioid dependency and abuse. “I was thinking about where I can really make a difference. And this is the place I can do it.”
Dr. Rajadhyaksha spoke to The Citizen about the status of her research and its far-reaching implications. This interview has been lightly edited for clarity and length.
Why’d you choose this area of research in the first place?
Probably 20 to 25 years ago, there was this shift in which neuroscience was becoming part of psychology and most of addiction research. In the field of substance-use disorders, as well as neuropsychiatric disorders, there was this move towards really trying to understand how drugs change the brain. Before that, most addiction research and substance use disorder research was really done at the behavioral level. The issue of addiction is not a personality disorder. It’s really the fact that these drugs change the brain.
I decided that I wanted to understand how misusing drugs affects the brain, how it affects behavior, and why some individuals actually get dependent on drugs whereas others don’t.
What’s the origin story of the research you and your colleagues published a few weeks ago in Science Advances?
About seven years ago, there was this big question as cannabis started getting legalized in states like Colorado, which was, does use of cannabis decrease use of opioids? There were anecdotal reports coming out from some of these states that it might be true, but nothing was evidence-based. We decided to test what THC — the main active ingredient of cannabis — does in mice, and we found no effect on reducing their opioid taking. So then we got very interested in what are called endocannabinoids. We started wondering about these endocannabinoids, and began testing them systematically in our animals.
What are endocannabinoids?
THC is a cannabinoid that is present in plants or synthesized. Then there are endocannabinoids, like 2-AG and anandamide, which we make in our brain endogenously. They act very similarly [to THC], but we don’t know a lot about them. Until last year, my lab was at Cornell. Dr. Francis Lee, who is the chair of psychiatry there, was studying certain genes that are responsible for the levels of endocannabinoids in our brain during its development — how, if they have mutations, they can affect anxiety and other mood related disorders. Right next door, my lab had been studying cocaine-use disorder for the longest time and we got interested in looking at those genes.
So what happened when you tested endocannabinoids?
Our hypothesis was either that it would not work at all, or it would make [the animals’ drug usage] worse, based on the THC research that we’d done. With anandamide, there was no effect. But with 2-AG, there was a blunting effect. My lead postdoc, Arlene Martinez Rivera, kept rigorously testing and kept getting really consistent data that elevating levels of 2-AG can really decrease drug taking in our animals. We were all blown away.
“I like to be a cautious scientist, and we do need to do many more studies, but we don’t see any negative effects so far, which is promising.” — Dr. Anjali Rajadhyaksha, Temple University Health
What we ended up finding is that 2-AG acts a certain way in brain regions that drive addiction or the rewarding properties of opioids, and it acts in a very different way in the parts of the brain that are important for the pain-relieving aspects of opioids. Increasing 2-AG, which is what our experiments were all about, affects only the addiction or reward related part of the brain, but not the pain relieving part of the brain.
The Atlantic this month wrote a story about your research, suggesting it could usher in a world where Oxycontin feels more like Tylenol on the body. Is that an apt description?
That was a nice title by Richard Friedman [of The Atlantic]. And that is the dream, to have opioids that are actually like Tylenol. A lot of scientists have been asking, how can we develop other lines of medications that are not opioids, which can relieve pain? There are some promising leads into non-opioid [pain relievers]; however, they’re not as effective as opioids are. I believe opioids are going to remain the mainstay treatment for pain for a long time, because they are so effective.
So we’ve been working on this idea: Can we take the opioids and split them apart, taking the pain [relieving] parts away from the addiction? With this discovery that we have made and this line of investigation, we could have an opioid — really, a combination drug — that would not be addictive at all.
The way you elevated 2-AG in your research was through an enzyme known as a MAG lipase inhibitor. What has been the research into MAG lipase inhibitors up until now?
Pharma has been developing MAG lipase inhibitors to relieve other conditions such as Tourette’s syndrome. And there’s some study on seizures and so on. But there’s something about the combination of 2-AG and opioids that led to our discovery from a clinical standpoint. So right now, the experiments we have done, and that we have published, are really to prevent people from developing a dependency. But we are also very interested in studying its use once an individual becomes dependent on opioids. Can it be used as a treatment for opioid-use disorder? We have started these experiments, and it’s looking very promising.
Did the animals show any side effects?
We have not seen any side effects. We have not seen anxiety. We have tested depressive-like behavior and we have not seen that. We have tested locomotion — does it affect the motor system? Does it make the animals lethargic? And we haven’t found that. I like to be a cautious scientist, and we do need to do many more studies, but we don’t see any negative effects so far, which is promising.
While testing this connection on mice, have you been testing a broad range of opioid drugs? Or just a small subset?
We have been studying morphine, oxycodone, and we’ve done some initial experiments of fentanyl. They all work in similar ways in the brain. 2-AG seems to be effective for all of these drugs, all of these opioids.
Down the road, how would the inhibitor be administered?
From a clinical perspective, the easiest would be one pill that has the opioid in combination with the inhibitor. From the perspective of a patient, it’s also easier. There’s more likelihood of patients taking one pill than if you have two or three pills that they have to take. So the dream is one pill. And so we are starting some of those experiments. When we do go to the clinical studies and clinical trials, that’s what we’d be working towards.
What’s a realistic timeline to begin testing the inhibitor in clinical trials with humans?
We want it to obviously happen fast. Pharma does have these inhibitors that they have been developing for other other conditions, as I mentioned. As you know, it takes years to develop drugs from the bench to the bedside. So we are trying to explore the possibility of acquiring some of these [research assets in the pipeline] that have gone through certain steps of development, like phase-one trials, and then we can directly go into phase-two trials for opioid-use disorder. So that route definitely will get us to at least the clinical trials phase much faster.
Fast forward 10 years. If your research progresses as you would like, what’s the impact it will make on the world of pain and addiction treatment?
What we are most excited about is the fact that, at the end of the day, opioids are going to remain the mainstay for management of pain. If everything goes well, we will be able to help many more patients dealing with pain, without the possibility of becoming dependent on them — after surgery, after going to the dentist, for patients with diabetic pain, and for those undergoing chemotherapy. My hope is that 10 years down the line, physicians won’t have to think so much about prescribing. There will be one pill — with morphine or oxycodone or even fentanyl, mixed with the inhibitor — that you can take and not have to worry at all about getting addicted.
