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“How much pain are you in?” It’s a harder question than you think. Tools for assessing patients’ pain—be they children or adults—rely on their perception: a subjective measure that eludes quantification and can change in response to any number of emotional, psychological or physiological factors.
Being able to objectively quantify pain could open the door to better pain management (especially for patients with chronic or neuropathic pain), better anesthetic dosing during surgical procedures, better understanding of addiction (and how to avoid it) and more.
To do so, we need measurable markers: physiologic parameters that reliably and quantitatively change during the experience of pain. But according to pain researcher David Borsook, MD, PhD—of Boston Children’s Hospital’s departments of Anesthesiology, Perioperative and Pain Medicine and Radiology—discovering such markers requires a better understanding of the larger context and of events that trigger pain, a perspective he refers to as “systems neuroscience.”
Along with colleague Lino Becerra, PhD, Borsook runs the PAIN Group—a first-of-its-kind multidisciplinary collaboration between Boston Children’s, Massachusetts General Hospital, McLean Hospital and Harvard Medical School aimed at evaluating long-term changes in brain function in children that can lead to chronic pain.
“In many pain-related conditions, the patient is normal and then something changes that alters their experience of pain,” Borsook says. “A twisted ankle could lead to complex regional pain syndrome [CPRS], surgery could lead to post-surgical neuropathy, a concussion can cause debilitating ongoing headaches, etc. The question is how do we integrate data from different research domains in such a way as to track the triggers?”
It’s a daunting task. To do it means imaging or otherwise measuring changes in brain activity, chemistry, etc. associated with different kinds of pain in different contexts, such as neuropathy, addiction, CPRS and migraine. Layered over that would be measurements in response to different stimuli, such as surgery, brain injury or hormones, and different kinds of treatment (e.g., psychological/physical/occupational therapy, various analgesics, anesthetics). And overlaying that is the myriad of neurologic circuits and networks involved in sensation, emotion, cognition, interoception (our perceptions of the body’s internal stimuli) and more.
Connecting the (pain) dots
Bit by bit, though, some pictures are starting to emerge. For instance, functional magnetic resonance imaging (fMRI) data are helping Borsook’s team understand and quantify how the activity between different parts of the brain changes during pain.
In a paper published this year inPain, they highlighted changes in CPRS patients in the functional connections between the amygdala—a brain structure involved in pain, reward, fear and anxiety—and other brain regions that regulate fear. The study also revealed how those connections change in response to treatment, suggesting that fMRI measures of amygdala connectivity could be a biomarker of CPRS treatment efficacy.
In other studies the group is starting to map differences in how the brain reacts to different combinations of pain and painkillers. For instance, in a separatePain paper this year, the team showed that in a post-surgical pain model, the nucleus accumbens (part of the brain’s reward circuit) releases dopamine (the pleasure transmitter) in response to treatment with NSAIDs (the painkiller family that includes ibuprofen) but not gabapentin (a common treatment for neuropathic pain). A neuropathic pain model, however, showed the opposite effect.
Stopping pain before it starts
As we untangle the complex pathways that fuel chronic pain, how do we take the next step: Stopping the pain it before it becomes chronic? “Protecting a child’s or adult’s brain from the changes that take place during chronic pain development could stop that development in the first place,” Borsook explains.
One context in which the PAIN team’s work could have major impact is surgery. “There are 29 million surgeries conducted in the U.S. every year,” Borsook notes. “About 30 percent of them result in chronic pain.” The team is investigating whether measurements of brain activity taken with near-infrared spectroscopy (NIRS, which measures blood flow and oxygen use) could help anesthesiologists titrate anesthetics more effectively.
“fMRI can measure responses, but NIRS is much more amenable to use in the operating room,” Borsook notes, pointing to a 2013 paper in the Annals of Surgery. “It could let us measure stress and anxiety related to the procedure, look at the effect of the anesthetic itself, and look for markers indicating the creation of pain triggers.”
Similarly, knowledge of how the brain and hormones interact may give insight into migraine, its relationship to puberty, how to measure it and how to stop it. “The prevalence of migraine shoots up around the time of puberty, especially in girls,” Borsook says. “Why? What are the triggers?”
He and his colleagues recently published a review inNeurobiology of Diseasediscussing the complex interplay of hormone effects, age- and sex-related physiologic changes, and brain function; how that interplay can lower the migraine threshold in girls’ brains; and how that migraine-prone state feeds on itself to make women more susceptible to future migraines.
“We suggest that there are a number of important routes of research that may help us better understand how hormones affect the migraine brain,” they wrote, such as studying brain function/hormonal relationships and the short- and long-term effects of “the pill” on migraine.
For their part the PAIN team has already documented connectivity changes in the hypothalamus (which regulates hormone balance) of migraine patients. As they reported in a PLoS ONE paper, these changes may help explain some autonomic symptoms of migraine (e.g., nausea, sweating, feeling of heat or cold).
In discussing a systems approach to pain, Borsook highlights the need to partner closely across disciplines to truly understand the biology underlying the pain experience. “Pain is part of many, many diseases,” he says. “Processes that alter the healthy brain in children and cause chronic pain produce changes that may affect individuals for life, and as such we have an urgent need to understand and prevent long-term changes. You have to collaborate with people from many biological and medical perspectives in order to draw a clear picture of what those changes are, and how to reverse or prevent them.”
