Patients with certain genetic variations have a higher risk for respiratory depression when they take opioids to relieve pain after surgery. The heat map shows high-risk patients to the right of the dotted line. 

One of the most common surgical procedures for children—a tonsillectomy—can be among the most painful. And in the urgency to free children from agony after the operation, doctors often turn to opioids.

Early in his career as a pediatric anesthesiologist at Cincinnati Children’s Hospital Medical Center, Senthil Sadhasivam, an MD, MPH, was horrified to see a devastating result of this practice: A child at another hospital died from respiratory depression brought on by the prescribed opioids.

The disturbing outcome—and dozens of others throughout the country where children died or suffered brain damage—inspired a direction for his research. “My interest was, in and around surgery, why opioids kill some patients and cause adverse outcomes in others, while many survive and do well,” he says. The disparate responses from child to child, he and his then-colleagues suspected, could have to do with differences in their genes. One genetic variation linked to the rapid metabolization of certain opioids had already been identified in children who died after taking codeine for tonsillectomy pain.

After recruiting 2,000 children undergoing tonsillectomies, Sadhasivam and his collaborators found answers. In a 2014 paper published in the journal Pharmacogenomics, they identified three genetic variations that, when found together, were associated with and highly predictive of morphine-induced respiratory depression. The variations influenced receptors, enzymes and other proteins that play a role in how the body metabolizes, transports and responds to opioids. Certain patients, the findings indicated, were genetically more susceptible to dire and even fatal outcomes from a routine opioid prescription.

Sadhasivam, who went on to Indiana University before joining the University of Pittsburgh in 2021, would build on this research, identifying genetic variations associated with a range of other responses to opioids—from adverse side effects like nausea and vomiting to a dependence on the medication.

Such findings open new possibilities for care providers who manage pain around surgery. Using preoperative genotyping, they can identify a predisposition before a child undergoes surgery and, armed with this info, proactively plan for alternative pain management methods or lower doses. The approach is an example of pharmacogenetics, in which providers tailor medications to genetic variations in individual patients, rather than waiting to react to how a patient responds. Sadhasivam and his colleagues put in place such guided pain management at Cincinnati Children’s, and he is now working with others to expand the practice at UPMC hospitals.

The need for a more targeted approach to opioids has become urgent. As Sadhasivam was conducting his early research, concern about the overuse of opioids was mounting throughout the country on multiple levels.

In 2013, the FDA issued a warning about the safety risks of using codeine after tonsillectomies for children; in 2017, the agency went further by restricting the use of it and another opioid, tramadol (though Sadhasivam says that doctors continue to prescribe other opioids, like oxycodone and hydrocodone, that carry similar risks).

At the same time, opioid use disorder, addiction and overdose deaths were skyrocketing across the United States.

“Everyone—nurses, physicians, surgeons—wanted to make sure the patient would not have pain,” says Pitt’s Jacques Chelly, an MD, PhD, director of acute pain clinical research and a professor of anesthesiology and perioperative medicine and of orthopaedic surgery. “And opioids were prescribed like candies.”

In October 2017, the federal government declared the opioid epidemic a public health emergency. Many doctors had long turned to opioids as a blunt instrument to knock out pain, without a full appreciation of how its risks varied from patient to patient; now they had to consider how prescribing opioids after surgery contributed to the crisis.

One large study cited in a 2019 U.S. Department of Health and Human Services report showed that among a group of patients who were given a course of opioids to treat pain following surgery and had not used opioids before, about 6% became chronic users. For certain operations, such as lumbar spine fusions, Sadhasivam says, the rates are higher. While the percentage may seem small, 50 million surgical procedures happen each year in this country.

But the risk is not the same for everyone. Just as Sadhasivam’s work had highlighted how drastically a patient’s genome could affect their response to opioids, a litany of factors determine how susceptible they are to opioid misuse. The Health and Human Services report, for example, notes that patients were more likely to become chronic opioid users after surgery if they had a history of tobacco use, alcohol and substance use disorders, anxiety, depression, other pain disorders or comorbid conditions.

Doctors and health agencies began to appreciate that more individualized treatment for pain was necessary. Across the field, researchers are trying to figure out how to alleviate suffering while taking into account a patient’s risk of adverse side effects, dependency, misuse and addiction. Truly personalized care calls not only for a better understanding of the patient, but more evidence-backed alternatives rather than a one-size-fits-all approach.

When Sadhasivam joined Pitt two years ago as a professor in the Department of Anesthesiology and Perioperative Medicine, executive vice chair for clinical quality, patient safety and clinical research, and director of Perioperative Research and the Perioperative Genomics Program, strides toward identifying alternatives to opioids, as well as a more personalized approach to treat pain, were already well underway in his new departmental home.

'It might work for you'

Ruthann Smyth (not her real last name) is no stranger to pain. She has undergone several operations on her neck, knees and spine over the last 30 years. Along with the acute pain she suffered from those procedures, Smyth was diagnosed in 2000 with rheumatoid arthritis, leaving her with chronic pain. Nonetheless, she avoids opioids.

“I don’t want to be addicted,” she says. “It could be really easy when you’re hurting all the time.”

She also had a bad experience in the past: Morphine she received for a neck surgery in 1993 left her nauseated and hallucinating. “I didn’t like that feeling,” she says, and has since sought to manage her pain through other means.

In 2017, though, Smyth fell and tore the labrum in her hip. The torment was bad enough that she desperately needed a new solution. “I couldn’t get any relief. The pain was just crippling,” she says. “I couldn’t move my left leg at all.” Since 2004, she had been seeing Chelly for relief.

Chelly recommended that Smyth try a device called the NSS2-Bridge that stimulates nerves of the ear.

“Dr. Chelly told me, ‘I have this device, and I think it might work for you,’” she says. The device, battery-powered and disposable, uses electrodes to stimulate the nerves in a patient’s ear to help relieve pain with what’s known as auriculotherapy. It was already FDA-approved to treat opioid withdrawal symptoms such as abdominal pain. When Chelly learned about the device, he reached out to the company, proposing to test it on other kinds of pain.

Smyth, who is also a UPMC employee, was willing to try anything that didn’t involve an opioid prescription. Instructed to use the device when she felt the pain, she tried it for four days—and says it made a big difference. Her leg soon felt good enough that she was able to start physical therapy. As she continues to manage her pain, she appreciates Chelly’s willingness to explore different options that match her preferences and history. “He has really helped me immensely,” she says.

Chelly and Sadhasivam are now collaborating on a four-year National Institute on Drug Abuse grant to study whether using the NSS2-Bridge can reduce the opioid requirement for patients after open surgery. They’ll also study whether it reduces psychological symptoms that can increase a patient’s experience of pain, like anxiety and depression, and lead to more opioid use. In a small study, Chelly found evidence that use of the device was associated with reductions in pain and less opioid use after kidney donor surgery.

Exploring the effects of the Bridge device is just one example of the Department of Anesthesiology and Perioperative Medicine’s commitment to finding new options for patients. Chelly and Ajay Wasan are the directors of the Center for Innovation in Pain Care, focusing on acute pain and chronic pain, respectively. The center, begun under department chair Aman Mahajan, aims to enhance outpatient care with multiprong, interdisciplinary treatments and digital health tools that reduce reliance on opioids. Their work considers genetics and mood disorders that contribute to pain syndromes and opioid use disorder—looking at the “whole patient.”

The drive to reduce opioid reliance has long been an area of emphasis among the department’s faculty. When Chelly joined Pitt and UPMC in the early 2000s, he says, the department “started a regional anesthesia program to focus on reducing the amount of opioid at that time, even when the crisis was not really recognized.”

Their push for more alternative approaches to opioids, in collaboration with others across UPMC departments, has led to changes at system hospitals. Wasan, an MD, MSc who joined Pitt in 2013, and other administrators in their department led a pain steering committee that helped coordinate better pain care and opioid prescribing through education efforts and outreach.

“When we look at the amount of opioid that we use [at UPMC] today, it is a fraction—and when I say a fraction, I mean 80 or 90% less—of what it was when Dr. Wasan and myself joined,” Chelly says. “And we are not stopping.”

Supported by a Shadyside Hospital Foundation grant, Chelly is working with colleagues to develop an opioid-free surgery pathway at UPMC Shadyside Hospital, making use of nonopioid medications, regional anesthesia and even complementary and alternative techniques like mindful breathing, aromatherapy and hypnosis. His team will also develop tools to identify patients who are a good fit for the pathway. (Meanwhile, Pitt’s School of Dental Medicine has established opioid-free prescribing guidelines for the vast majority of procedures performed at its clinics.)

Research funding has been catching up with the opioid crisis. Five years ago, the National Institutes of Health (NIH) established the Helping to End Addiction Long-term (HEAL) Initiative, which has awarded tens of millions of dollars to Pitt researchers, including Sadhasivam and Wasan, to study prevention and treatment strategies to address opioid misuse and addiction. About a quarter of the initiative’s funding is going toward improving pain management, especially approaches beyond opioids.

“The receptiveness has warmed up over the years,” says Wasan. “Unfortunately, it took an opioid crisis and an epidemic to actually create a lot more funding for pain [management] that maximizes nonopioid approaches.”

Wasan is not only a pain management specialist, but also a psychiatrist. “Appreciation that psychological factors have a major impact on pain, pain experience and disability has been around for literally 50 years now,” Wasan says. Tending to those conditions can bring down the need for opioids.

But even though that understanding has long existed for chronic pain, Chelly says it is only much more recently—in the last decade—that psychological and psychosocial factors have been taken seriously in relation to acute and postsurgical pain. Findings are promising: A 2018 study in the Journal of Pain by researchers in Iowa tested a one-day therapy workshop on veterans who had high levels of pain and psychological distress before they underwent orthopaedic surgery. The 44 patients who took part in the workshop—which involved acceptance, mindfulness and behavioral training—saw quicker pain relief and stopped using opioids sooner than those who didn’t in the three months after their procedures.

Chelly and others at Pitt are investigating other means of providing relief to surgical patients who want to avoid opioids through methods that aim to reduce anxiety. In trials at UPMC Shadyside, Chelly saw that aromatherapy reduced opioid use by more than 30% after hip replacement. And Shiv Goel, an MD clinical associate professor of anesthesiology and perioperative medicine and chief anesthesiologist at Shadyside, has been studying whether music therapy helps to reduce anxiety and pain among the hospital’s surgical patients.

The NIH and other funding organizations have started to offer more support to researchers like Chelly to study methods that have long been in use as alternative medicine or for other purposes but currently lack strong evidence to treat surgical pain.

In another study, published in November in the Journal of Clinical Medicine, Chelly and Sadhasivam shared findings from a pilot study of a device called the NeuroCuple; it’s a patch that contains billions of “nanocapacitors,” minuscule structures that store electrical charges, and reduces pain by using the charges to bring down inflammation. They found that patients using the patch reported less pain in the first three days after total knee and hip arthroplasty and were less likely to request an opioid prescription after they were discharged. More evidence is still needed to establish either the NeuroCuple or the NSS2-Bridge as an effective pain management tool, but each may become a future routine option for a patient looking to avoid opioids or take less of them.

Proactive precision

Sadhasivam remains frustrated with how reactive much of current pain management is. Doctors prescribe opioids based on simple factors like weight, he says, then respond to reactions or continued severe pain. About a decade ago, he and colleagues implemented preoperative genotype-based risk assessment at Cincinnati Children’s based on their research, which showed its potential. But later, he says, the hospital stopped the practice after insurers rejected reimbursements for it.

The practice remains rare, even in many of the best academic medical settings. “Even if they do it, they may do one or two genes, and the average anesthesiologist or surgeon doesn’t know what to do with it,” Sadhasivam says.

In response, he started a company, OpalGenix, supported by multiple NIH Small Business Programs grants, to develop a platform backed by his research to assess the risks of opioids for a patient before a procedure. (Its name is a mashup of opioid, algesia and genetics.) He hopes to help physicians more easily conduct genotype-based risk prediction and build up evidence of its benefits.

Along with the predisposition for severe side effects of opioids that Sadhasivam has studied, researchers have also identified a genetic variation, carried by at least 2% of people, associated with addiction. Opioids don’t bind as well with certain opioid receptors in these patients, so they need a higher dose to experience the analgesic effect—but don’t suffer bad side effects. The combination—higher dose, few adverse effects—leaves them more susceptible to addiction. In December 2023, the FDA approved the first genetic test for identifying genetic risk for opioid addiction. Sadhasivam, Chelly and Wasan are now working on implementing it in some high-risk UPMC surgical patients.

The OpalGenix platform, though, will go beyond genetics to produce a risk assessment grounded in other considerations such as medical history, demographic factors and psychological conditions.

Taking all this into account, the algorithm will then offer a personalized recommendation for the patient’s pain care that could include lower dosing, nonopioid medications and alternative therapies. “With our approach, it’s all proactive,” Sadhasivam says.

As OpalGenix moves toward bringing a product to fruition, he is championing the expansion of preoperative genotyping at UPMC hospitals, in collaboration with the UPMC Genome Center.

With support from another NIH grant, Sadhasivam is implementing a screening for genes that influence opioid metabolism and responses among pregnant women undergoing cesarean sections at UPMC Magee-Womens Hospital. At UPMC Children’s Hospital of Pittsburgh, Sadhasivam and his collaborators are genotyping teenagers undergoing spine fusion surgery so that doctors can minimize adverse outcomes from methadone prescriptions. With Phil Empey, a PharmD and PhD at the School of Pharmacy and the Institute for Precision Medicine, Sadhasivam is working toward incorporating preoperative genotyping for pain management into UPMC patients’ electronic health records.

Although getting genotyping into the clinic has its hurdles, he says, a proactive approach will make the initial care more effective, reducing the length of hospital stays and bringing down costs for patients, insurers and hospitals. The commercial route, he says, can get these new approaches to the clinic more quickly, where they can help patients.

“If you can make even a small difference,” he says, “that would save a lot of suffering.”

Read more from the Winter 2024 issue.