Story by Katie DuBoff
Photography by Ryan S. Brandenberg, CLA ’14
Illustration by Robert Frawley
When Marc Graver was in his mid-20s, a single opioid pill shaped how he looked at pain management for the rest of his life. Pain wasn’t the problem—opioids were. Recovering from hernia repair surgery, Graver followed his prescription instructions and took a pill for the pain. Minutes later, the room began to spin.
“I remember this like it was yesterday,” he says. “I fell out of bed and ended up on the floor, unable to move. Trying to get back up felt like I was climbing a mountain without any ropes.”
Graver lay there until the drug wore off.
“One pill had affected me so much that I vowed to never take opioids ever again,” Graver explains.
For nearly four decades, he has kept true to his word, relying instead on over-the-counter pain relievers through everything from dental bone grafts to gallbladder surgery.
Graver’s experience with opioids never led to addiction—but the paradox of powerful pain relief paired with unpredictable effects left a strong impression on him.
Anjali Rajadhyaksha works with others in her lab toward developing opioids that relieve pain without the addictive side effects.
Today, Graver works inside a research environment dedicated to unraveling this paradox: How can we separate the wonder from the woe? Since 2014, he has served as a senior administrator in the Center for Substance Abuse Research (CSAR) at Temple University’s Lewis Katz School of Medicine, where he supports scientists who are working to unlock how opioids interact with the brain—including neuroscientist Anjali Rajadhyaksha.
Rajadhyaksha’s lab is focused on how the brain works in addiction and mood disorders, and why some people may be more at risk for these conditions than others. Her work centers on a bold question: Could there one day be an opioid that delivers relief without creating dependency?
“Opioids are definitely the best pain management medications out there,” says Rajadhyaksha, director of CSAR and a professor in the Department of Neural Sciences at Katz. “I think that opioids are going to remain the mainstream medications for pain management. So, our idea is to remove the addictive properties of opioids while sparing their pain-relieving properties.”
How opioids work in the brain
Opioids are natural or synthetic chemicals that bind to receptors in the brain and block pain signals between the brain and body, making them highly effective at reducing pain. Doctors commonly prescribe them for pain management after surgery, injury, during cancer treatment and for some chronic conditions. At the same time, this powerful pain relief can come with significant risks, including the potential for addiction because opioids alter the brain’s reward circuits, making it difficult to stop taking them after repeated use.
Neurons, or nerve cells, are the basic units in the brain and nervous system that send signals throughout the body to control thinking, emotions and movement. Drugs interfere with how the brain sends, receives and transmits these signals. Opioid addiction, or opioid use disorder, is a complex and chronic brain disease marked by compulsive use of opioids despite their harmful consequences. Over time, continued opioid use alters the brain’s chemistry and can lead to physical dependence, meaning the body adapts to the drug, causing intense withdrawal symptoms if use is reduced or stopped—making it even harder to stop taking the drug.
Researchers at CSAR use multidisciplinary approaches including molecular biology, genetics, neuroscience and behavioral science to further the understanding of addiction and drug interactions. The center provides rich research opportunities for students such as PhD candidate Marco Ghilotti and undergraduate Emily Vu.
“Our idea is to remove the addictive properties of opioids while sparing their pain-relieving properties.”
—Anjali Rajadhyaksha
Director, Center for Substance Abuse Research
“Any disease is complex, but neurological diseases, especially addiction and neuropsychiatric disorders, are extremely complicated,” Rajadhyaksha says. “Understanding what’s going on in the brain to shed light on these disorders has been the driving force and motivation for me.”
The brain has a reward system that is wired to release small, healthy amounts of dopamine—a key neurotransmitter and hormone—during pleasurable activities like eating, socializing and sex. This reward circuit drives the brain’s motivation to repeat those behaviors. Addictive substances, including opioids, can cause the brain to release excessive amounts of dopamine, creating a powerful chemical signal to reinforce the link between consuming the drug and rewarding pleasure.
When it comes to easing patient suffering, Rajadhyaksha points out that currently the only choice for those seeking relief from severe pain without opioids’ habit-causing properties is to take pain medications that are not nearly as effective—or live with the pain, like Graver did.
“One of the challenges is to find an effective opioid replacement,” she says. “Researchers have been looking at nonopioid pain medications, and while some new options exist, they remain suboptimal treatments for pain compared to opioids.”
A hub for addiction research
Researchers at CSAR have been at the forefront of understanding the biological basis of addiction and substance use disorders since its founding in 1998.
“CSAR is very well known for the science and research and its work in substance use disorders and addiction, especially opioids,” says Rajadhyaksha. “Primarily, we are all neuroscientists interested in how opioids affect the brain and the pharmacology of opioids. Understanding the science behind addiction can help us create therapies to change lives, which would make a positive difference for so many given the huge opioid epidemic that has been inflicted.”
Rajadhyaksha envisions a world in which a patient can recover from surgery, serious illness or chronic pain without fear of getting addicted to opioids.She is working to make this dream a reality and garnering a lot of attention from peers and the media along the way. Her research has been published widely in scholarly journals and featured in The Atlantic, CBS News Philadelphia, The Philadelphia Citizen and more.
Since CSAR was established in 1998, its researchers have been at the forefront of understanding the biological basis of addiction and substance use disorders.
A new perspective
Before turning her attention to untangling opioids’ pain pathways in the brain, Rajadhyaksha’s interest began with cocaine addiction.
“When I started my lab 20 years ago, scientists were just starting to think about addiction as a brain disorder from the point of view of molecules and genes,” says Rajadhyaksha. “I got fascinated by how drugs change the brain and how are they doing it at a molecular level? And that, today, still fascinates me.”
Today, her research explores the brain’s endocannabinoid system—a complex network of neuromodulators that regulate a number of the body’s functions such as appetite, behavior, cognition, emotion and pain control.
“Our brain actually makes endocannabinoids, or chemicals, in the brain that play a variety of different roles,” she says.
CSAR’s state-of-the-art labs conduct preclinical research on drug interactions, receptor signaling and addiction-related neural pathways.
“Since most of addiction is behavior-related, we started wondering if we alter levels of these endocannabinoids, would it impact opioid-related behaviors?” To do so, Rajadhyaksha’s team uses behavioral assays that measure pain and addiction to examine whether there is a way to reduce an opioid’s dependency-inducing effects. Leveraging computational tools, she monitors how genetically manipulating molecules affect brain activity during pain and addiction-related behaviors.
“We identified that if we can inhibit a protein that occurs naturally in the brain called MAG lipase (MAGL) that results in higher levels of an endocannabinoid called 2AG, opioids still had their analgesic properties, or pain-relieving properties, but they were no longer rewarding or addictive,” she says.
Hope for the future
Rajadhyaksha’s studies have also seen no adverse effects. This preclinical breakthrough holds great promise for understanding how connections between the brain and opioids can be rewired. In time, she hopes to turn her bench-side discovery into patient-care applications.
“The next dream, of course, is can we develop a single pill that has an opioid along with a MAGL inhibitor that we can give for pain relief but has no addictive properties? So almost like the first nonaddictive opioid.”
While two pills are an option, Rajadhyaksha wants to make the process as simple for the patient as possible.
“In our preclinical work, we did the treatment of the inhibitor followed by the treatment of the opioid. A single pill— one combination drug—would be much simpler for patients to manage at home.”
Rajadhyaksha’s team uses behavioral assays measuring pain and addiction to determine whether there’s a way to reduce an opioid’s dependency-inducing effects.
To eventually translate this goal into therapies for patients living with pain, Rajadhyaksha is collaborating with departments across Temple on the next steps—a multidisciplinary approach that includes other scientists and physicians.
Chemists at the School of Pharmacy, for example, are helping her team screen for new compounds or modify their current inhibitors that would have more efficacy in patients.
Clinicians at Temple Health are also proving valuable to Rajadhyaksha’s work.
“Substance use disorders and addiction have a devastating impact on individuals, families and our communities. Understanding the science behind addiction is key to developing effective treatments. We want to take our basic science to patients. That’s the motivation for what we do.”
—Anjali Rajadhyaksha
Director, Center for Substance Abuse Research
“There’s nothing like having close ties with the hospital and the clinical departments,” she says. “Having conversations and building relationships with those on the frontlines of patient care is really, really educational. Being able to talk to my addiction medicine physician colleagues to understand what is actually happening when patients experience opioid cravings and withdrawal symptoms is really helpful for somebody like me doing the basic science.”
Now, with each gene and molecule that she analyzes, Rajadhyaksha’s dream to revolutionize pain management gets closer to reality.
“Substance use disorders and addiction have a devastating impact on individuals, families and our communities,” she says. “Understanding the science behind addiction is key to developing effective treatments. We want to take our basic science to patients. That’s the motivation for what we do.”
This is good news for Graver.
“I enjoy seeing the research play out and seeing how we can make a difference in people who get addicted to opioids,” he says. “It would be terrific to be able to treat pain without fear.”
Seeking Help
Recovery from addiction is possible. For help, please call the free and confidential treatment referral hotline (1-800-662-HELP) or visit findtreatment.gov.
In Philadelphia, Temple University Hospital provides evidence‑based addiction and behavioral healthcare through its Substance Use Disorder Clinic (215‑707‑1125) and integrated patient‑centered addiction treatment within primary care at the Temple TRUST Clinic (215‑707‑1122).