Pain is hurting us. One in five Americans — more than 50 million adults — suffers from chronic, unrelieved pain, making it one of the most pervasive medical problems of our time. According to the National Institutes of Health, this condition costs society up to $635 billion a year in health care expenses and lost productivity, exceeding the costs of heart disease and cancer combined.

But that’s not the only problem. In recent decades, physicians have increasingly prescribed opioids to alleviate both acute and chronic suffering. This has led to a major rise in addiction. Data from the U.S. Centers for Disease Control and Prevention reveals that during a 12-month period ending in 2023, more than 111,000 people in the United States died from drug overdoses. Fentanyl and other synthetic opioids are involved in nearly 70% of overdose deaths, the CDC data shows.

USC Dornsife researchers are taking a two-pronged approach to overcoming this tragic situation by developing effective, nonaddictive pain medications and pinpointing ways to curb opioid misuse and addiction.

Transcendence’s Twin

“No pain, no gain” goes the saying made popular by 1980s exercise videos. Today, some may scoff at the simplistic sentiment, but our ancestors would probably give it the nod of approval.

Discomfort has long been thought to be transcendence’s twin. For millennia, painful maturation rites, such as facial scarring, marked passage into adulthood. The agony of childbirth brings the joy of new life. And, of course, Christians believe that Christ’s suffering led to humanity’s salvation from its sins.

“Some concepts of well-being actually involve pain, not the elimination of it,” says Peter Redfield, Robert F. Erburu Chair in Ethics, Globalization and Development and professor of anthropology. “Being able to bear pain can be seen as a mark of exceptional heroism, religious devotion or simply the necessary maturity to make it through life.”

Yet, even our most stoic forebears occasionally sought relief, turning to their era’s version of a medicine cabinet: the herb chest.

Plant Power

More than 40,000 years ago, evidence suggests a Neanderthal ingested poplar for relief from an aching jaw abscess. Researchers came to that conclusion after analyzing the dental plaque still present on his teeth when explorers discovered the remains of his jaw in a Spanish cave in 1994. His natural remedy mirrors modern practices, as the tree’s bark contains salicylic acid — the active ingredient central to aspirin’s pain-relieving effect.

David McKemy, professor of biological sciences, says we have plants to thank for many of our modern sources of pain relief.  “If you look at what’s pharmaceutically available to treat pain, almost every remedy is derived from a plant at some level. They virtually all started with somebody, many centuries ago, chewing on a leaf and experiencing relief.”

Plants have also been instrumental in helping us gain a broader understanding of our perception of pain and sensation. Nobel Prize-winning research that included work by McKemy, which used capsaicin from chili peppers and menthol from mint, led to the discovery of the protein receptors responsible for our sensations of heat and cold.

McKemy identified the TRPM8 protein as crucial to cold sensation, a finding that may significantly impact headache treatments. His recent study revealed that when this gene was blocked in mice, they didn’t exhibit migraine symptoms. He hopes this discovery will one day bring migraine relief to the one in 10 people globally affected by this condition.

Other labs at USC Dornsife are exploring promising treatments derived from the cannabis plant to treat neuropathy, or nerve pain, a condition often resistant to conventional medications such as opioids and notoriously difficult to manage.

Our bodies have two receptors that interact with compounds from the cannabis plant to reduce pain. One of these receptors, known as CB2, is active primarily at sites of inflammation and thus shows promise in relieving inflammatory and neuropathic pain. Unfortunately, its close homologue, CB1, is located in the brain and its activation can lead to well-known psychoactive effects. This makes it difficult to test on patients.

Vsevolod “Seva” Katritch, professor of quantitative and computational biology and chemistry, is researching how to design cannabinoids that selectively target CB2. Two of his recent studies, including one conducted in collaboration with Valery Fokin, professor of chemistry, discovered several new compounds that target CB2. Their goal is to offer powerful relief for those suffering from neuropathy and other pain conditions — without affecting cognitive function.

Holistic Remedies

Historically, the quest for pain relief has encompassed more than just herbal remedies. “Alternative treatments,” as they’re known today, likely share a timeline as ancient as the use of medicinal herbs. In 1991, the discovery in the Italian Alps of a 5,000-year-old mummy with tattoo marks around diseased and worn joints suggests an early form of acupuncture for pain relief. While acupuncture is still widely practiced and has many enthusiastic adherents, its efficacy is a topic of debate in the scientific community where there is some indication that its benefits may be influenced by the placebo effect.

Doerte Junghaenel, senior research scientist at the USC Dornsife Center for Economic and Social Research, studies the management of chronic pain. She acknowledges the benefits of nonmedicinal alternatives, such as acupuncture, but emphasizes the individuality of pain treatment — there is no one-size-fits-all solution.

She also points out a significant, often overlooked path for pain management: psychological methods. Doctors are increasingly making referrals to pain psychologists a standard part of treatment plans. These psychologists employ therapies such as cognitive behavioral therapy, mindfulness, and acceptance and awareness therapy to combat chronic pain. However, not all patients have easy access to these types of additional treatment.

Junghaenel, associate professor (research) of psychology and gerontology, notes that many people benefit from this holistic approach that encompasses a joint focus on physiology as well as psychology.

“Our mind and our body are powerfully interconnected,” she says. “How people respond psychologically and emotionally has a tremendous impact on their experience of pain.”

Always On My Mind

In our quest to relieve pain with drugs, we have tragically unleashed a different kind of suffering. Some 2.5 million adults in the U.S. now struggle with the abuse of prescription painkillers. Since 1999, nearly a million people have died due to drug overdoses, largely from opioids.

The number of fatalities due to drug overdoses has been climbing rapidly in recent years due to the powerful synthetic opioid fentanyl, which has flooded the illicit drug market. Just a few, minuscule grains of fentanyl can be lethal. Alarmingly, nearly one in two American adults know someone who has died from an overdose.

Finding new pain medications that aren’t addictive and ways to better treat addiction are vital to saving lives.

Getting (un)Hooked

Opioids are manufactured from a plant that humans have relied upon for millennia for pain relief: poppies. Evidence of sap from poppy flower pods has been found in Neolithic human encampments dating from the sixth millennium B.C.E.

Opium targets the mu-opioid receptor (µOR), a small protein that dots the surface of nerve cells in our spinal cord and brain. When opioids activate these receptors, it inhibits the release of neurotransmitters that normally help us perceive pain.

Beginning in the early 1800s, scientists harnessed opium to develop a range of painkillers known as opioids, from morphine to the more recently developed fentanyl. These drugs revolutionized health care, significantly reducing the agony of severe injuries, surgery and cancer. However, they also come with serious drawbacks.

Beyond pain relief, µOR activation by opioids releases a flood of “feel-good” chemicals in the brain, triggering euphoria. This pleasurable side effect can unfortunately lead to addiction, with devastating consequences.

Katritch has made promising strides in the development of revolutionary substitutes for opioids. In their most recent breakthrough, published in Nature last year, Katritch and his cross-institutional research partners found that by modifying fentanyl to bind in the sodium pocket on µOR, the drug activated only the receptor’s analgesic properties, eliminating euphoria — and the risk of triggering addiction.

This discovery, as well as Katritch’s research on cannabinoid receptors, was facilitated by research conducted by Vadim Cherezov, Ester Dornsife Chair in Biological Sciences and professor of chemistry. Cherezov’s lab is improving our understanding of the structure and function of proteins such as µOR, helping scientists like Katritch develop better drug treatments.

Their research is underway at USC Dornsife’s Center for New Technologies in Drug Discovery and Development (CNT3D), co-directed by Katritch. CNT3D is focused on cutting-edge drug development, leveraging machine learning, artificial intelligence and the latest advancements in chemistry and biology. The center’s researchers are working on innovative therapeutic solutions for a wide range of conditions, including pain and addiction.

The Will to Succeed

The development of pain medication without euphoric effects would be a significant advancement, but better tools for understanding and managing addiction are equally important.

John Monterosso, associate professor of psychology, specializes in addiction and self-control. He notes a fundamental issue in treating addiction: its propensity to hijack our inbuilt urge to seek pleasure. Our body naturally encourages behaviors that benefit us by releasing pleasurable chemicals such as serotonin and dopamine. From enjoying a nourishing meal to the comfort of a warm hug, we’re biologically wired to seek experiences that evoke pleasure and joy.

Unfortunately, the intense euphoria brought on by opioids, despite the considerable damage it metes out over time, doesn’t register with our pleasure-reward system as problematic. Essentially the body just follows standard operating procedure by continuously seeking pleasure. This can make abstaining from opioids particularly challenging, especially as they cause the brain to rewire, resulting in an escalation of craving.

Resisting the siren call of instant gratification often hinges on willpower, a distinctly human trait, says Monterosso.

“You won’t get this from a rat pressing a lever in a lab for cocaine, but a person will sometimes say, ‘This cocaine use is really not making my life better. Even though I have the urge to do it, and it provides immediate reward, I would be better off if I stopped,’” Monterosso says. Of course, choosing to stop is much easier said than done.

Research by Antoine Bechara, chair and professor of psychology, found that the self-control necessary for sobriety may not be uniformly inherent in everyone. He discovered that those with a weaker prefrontal cortex — the brain region associated with decision-making and impulse control — have a higher propensity for substance abuse disorders (SUDs). “Addiction is a disease of decision-making,” he says.

Screening patients for prefrontal cortex dysfunction could be one way to prevent addiction. By proactively identifying patients with a greater risk of addiction, doctors could either prescribe an opioid alternative or track patients more closely for signs of dependency if they are taking an opiate.

The brain’s extensive capacity to modify and adapt itself, an attribute scientists call “neural plasticity,” could also be used to treat SUDs, Bechara notes. Cognitive training can make use of this ability by strengthening a patient’s prefrontal cortex, improving impulse control and helping avoid a relapse.

Mental Exercises

More transcendental experiences can also spark this neurological restructuring. Psychedelics, a class of drugs that spark hallucinations, have a long history of spiritual and recreational use.

But these experiences also have therapeutic potential, says Katritch. Psychedelic treatment, usually performed in combination with psychotherapy, is also showing increasing promise as a conduit for neural plasticity, positively rewiring addicts’ brains to potentially vault them out of self-destructive habits.

More than 150 recent clinical studies suggest that psilocybin, a hallucinogenic derived from certain mushrooms, can help patients battling a variety of SUDs, as well as other enduring psychological challenges such as PTSD and depression.

“Psychedelics activate the same receptors in our brain as serotonin, the ‘happiness hormone.’ Moreover, recent research shows that it allows the brain to form new neural connections across its different brain regions,” Katritch says.

In laboratory settings, the neural rewiring can be observed within just an hour of administering psilocybin, and persists well beyond the immediate effects. This capacity for creating new brain circuitry remains for months following a dose.

Katritch notes that this neurological reconfiguration is believed to help the brain ‘relearn’ more efficiently, offering a promising angle for treating persistently negative states such as anxiety, PTSD and addiction.

However, the intense hallucinations that accompany psychedelics pose significant clinical challenges. Psychedelics should be used very carefully and under therapist supervision. The experiences they trigger can be unsettling for some or even harmful to the mental health of certain patients predisposed to psychosis. They also make studying the efficacy of psychedelics tricky.  Because patients will unmistakably know if they’ve taken a hallucinogen, researchers cannot use placebos for comparative studies.

To address this, Katritch is investigating synthetic substances that mimic the mind and mood-adjusting qualities of psychedelics without the hallucinogenic side effects, hoping that they also spark neural rewiring. “Mild, nondissociating psychedelics would be a much safer alternative with a huge potential impact on the treatment of mood disorders and addiction,” he says.

Innovative new drug therapies could be a game-changer in alleviating SUDs, but treatment for sobriety will likely always require a comprehensive approach.

Over time, those with addiction may lose many of the most rewarding aspects of their lives — jobs, friends, hobbies — as substances become their sole source of pleasure. Monterosso notes support groups like Narcotics Anonymous can be highly effective in helping to combat the downward motivational spiral that occurs with addiction. Engagement with such groups help those with addictions rebuild social connections and rediscover a sense of purpose.

Emphasizing holistic recovery, Monterosso advises, “It’s vital to build sources of value that outweigh the allure of addiction. That’s why treating the entirety of a person’s life experience is often the most effective way to overcome addiction.”