New progress in addressing cancer pain

Abstract

Although pain has long been recognized as a common feature of both cancer and cancer treatments, efforts to recognize and resolve it have faltered in part because of fragmented care, a lack of objective measurements, and limited options for mitigating moderate to severe pain. Recent studies have provided reason for optimism by reframing cancer pain as a dynamic, multifactorial phenomenon with diverse and potentially modifiable contributors; by clarifying some of its mechanistic causes; and by expanding the palette of possible interventions.

The traditional touch-a-hot-stove understanding of pain viewed the sensation as a warning: a protective mechanism to discourage pain-causing actions. Subsequent research, however, determined that this view of pain, called nociceptive, is fundamentally different from a second type, neuropathic, in which damage or disease results in malfunctioning nerves and a pain sensation often described as burning or tingling. Although opioid drugs are often effective in treating nociceptive pain, they are far less useful for treating neuropathic pain.

Recent studies have added further nuance with the recognition that biological, psychological, and social factors can influence pain perception; this observation has led to what is called the biopsychosocial model of pain. “I think we really started to recognize then that there are all of these different influences in the way that we experience pain, both in its intensity and also in its functional impairments, like how it affects our lives,” says Hailey Bulls, PhD, an assistant professor of anesthesiology and perioperative medicine at the University of Alabama at Birmingham.

Even so, she says that the multifactorial model does not always take into account the timing and ebb and flow of cancer pain–influencing factors. To help to fill the gaps, Dr Bulls and her collaborators created a new model for conceptualizing cancer pain through three interconnected phases: “predisposing factors that increase cancer pain risk, precipitating factors that trigger cancer pain onset, and perpetuating factors that sustain or exacerbate cancer pain over time.”¹ The new 3P-CP model, the researchers suggest, “has the potential to guide comprehensive assessment, risk mitigation, prevention, and intervention strategies—supporting efforts to deliver the right targeted and tailored treatments, to the right patients, at the right time.”

Newly diagnosed patients, for example, may have predisposing factors such as physical or mental health conditions that could increase their pain. Cancer is a major precipitating factor for pain, of course, but so are many cancer treatments—particularly ones with higher doses or longer durations. Physical inactivity, sleep disturbances, and medication dependencies, among other contributors, can all act as perpetuating factors that worsen the intensity of pain or prolong it.

The shift in how to think about cancer pain could offer a better across-the-board understanding that could serve as the foundation for more personalized, multidisciplinary treatment plans, Dr Bulls says. For instance, better up-front education might improve patients’ understanding of what to expect. As part of that education, focusing on modifiable behavioral factors such as physical activity, mood, and sleep could help to address symptoms regardless of the kind of cancer.

Timing the education to ensure that it sticks, however, can be tricky. Dr Bulls is collaborating with researchers at the Dana–Farber Cancer Institute in Boston, Massachusetts, on an intervention called Cancer Pain 101, and one lesson is that patients are not always in the right frame of mind to hear about pain immediately after their cancer diagnosis. “They might be overwhelmed,” Dr Bulls says. “I’ve heard people say, ‘It’s like I couldn’t take in anything else after that.’ So when we give people that information, I think, really matters.”

In one approach being tested by the researchers, patients taking opioids to help to manage their pain will receive information via several 10-min videos that they can access outside of clinical appointments. The patients will be encouraged to bring their questions to providers at their next appointment. “It gives people that space to say, ‘I’m in a place where I can hear this, and I can hear it at my own pace,’” Dr Bulls says. If the study suggests that the patients engage with the videos and find them helpful, the approach could be rolled out more broadly. Another important component of that education, she says, is discussing prescription opioids and both their benefits and risks in destigmatizing neutral language.

Layered onto the initial orientation could be a more personalized approach based on each individual’s circumstances. “We do want to know about limitations that may be specific to one group or another,” Dr Bulls says. Patients with painful chemotherapy-induced peripheral neuropathy who have lost sensation in their feet, for example, may benefit from physical therapy but not strenuous exercise. “It’s like we have a baseline approach that can be universally appropriate, but then we want to modify the pieces of it to meet those persons’ needs,” she says.

“We found that LRRC8A serves as an anchor to drag the receptor inside the cell so that the receptor will not sit on the cell surface or synapse to make trouble,” says study coauthor Hui-Lin Pan, MD, PhD, a professor of anesthesiology and perioperative medicine at the MD Anderson Cancer Center. The study suggests that triggering events such as tumors, surgery, and chemotherapy can injure nerves and reduce LRRC8A levels and thus free the pain receptor to reach the cell surface and ramp up its signaling. “It was really surprising when we found that this protein can actually regulate the pain transmission,” Dr Pan says of LRRC8A. “That was the most exciting part of the work.”

The discovery opens the door to a new pain-reduction strategy, especially for the significant number of patients with cancer who have a mix of both nociceptive and neuropathic pain, Dr Pan says. “This is why treating cancer pain is not straightforward,” he says. As a proof of concept, he and his colleagues used gene therapy in a rat model of nerve injury–induced chronic pain to reverse a reduction in LRRC8A levels; this approach eliminated the associated pain receptor’s “hyperactivity” and relieved the neuropathic sensation.

More encouraging news has come from other assessments of non-opioid alternatives. In 2025, the National Institutes of Health reported on a clinical trial that found a molecule called resiniferatoxin, derived from a cactus-like plant, to be safe and effective for controlling intractable pain in patients with terminal end-stage cancer.³ A single injection not only sharply reduced the patients’ need for opioids but also improved their quality of life. A separate clinical trial at Roswell Park Comprehensive Cancer Center in Buffalo, New York, is investigating the potential of the psychedelic drug psilocybin, which is found in “magic mushrooms,” to treat both physical and psychological pain. The trial is testing early evidence showing that psilocybin interacts with serotonin, which regulates mood and pain perception; that it reduces inflammation-related pain; and that it dampens pain contributors such as anxiety and stress.

For another collaboration aimed at improving cancer pain treatments, Dr Bulls is working to personalize intervention targets based on initial work in patients with chronic lower back pain. “We have all of these modifiable things that we know are associated with pain, and we don’t necessarily know which one to offer to which individual,” she says. One patient’s pain might be affected most by poor sleep, whereas another’s might be influenced by physical inactivity. Wearable devices, smartphone apps, electronic questionnaires, machine learning, and other technology could help to capture and interpret the data needed to reveal which factors are most relevant for each patient.

“I wonder, if we’re able to do that, if it will shake up how we think about these clusters of things that might relate to pain,” Dr Bulls says. Beyond known associations such as depression and pain, “maybe there are entirely different subgroups of people that we haven’t been able to recognize yet,” she says. “If we can understand who these subgroups are, then we can direct those treatments better and have much less variability in people’s responses to treatments.”