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Pain is an inconvenient reality. It is the most common reason people seek medical attention, affecting more people than diabetes, heart disease, and cancer combined. It exacts enormous costs in quality of life, not just for the pain sufferer, but for their families, caregivers, and communities. It is a symptom in hundreds of disorders, cutting across virtually every specialty in medicine. It is also intimately related to the ongoing opioid epidemic in America and beyond.
Patients are routinely prescribed opioids for acute pain after injury or surgery, and a substantial fraction of them will go on to become chronic opioid users. For some of these, the effects are devastating: In 2021, America saw over 100,000 drug overdose-related deaths, 75 percent of them caused by opioids, and the numbers have been climbing each year. For those who survive, opioid use takes a toll as well, causing changes in the brain that make it more difficult to work and to find enjoyment in daily life.
Pain and pleasure are two fundamental forces that motivate us. Our history with pain goes back to our most ancient ancestors: Protozoa, sponges, insects, crustaceans, and more possess the same families of ion channels that enable pain in humans. These channels sense harm-related signals in the environment, like noxious chemicals, and turn them into electrical signals in the nervous system, providing the basis for escape, avoidance, and learning. The dual teachers of pain and reward are at the core of our brain’s ability to rewire itself to avoid threats and pursue opportunities in changing environments.
Pain Falls Between the Cracks
In spite of its fundamental importance, pain has fallen between the cracks in our scientific disciplines and healthcare systems. Most medical schools provide only a handful of hours of pain education, distributed across four years. If a peripheral cause cannot be determined and eliminated, chronic pain patients are shuttled across departments, their pain “managed” but with little hope for a cure. They are often referred to psychiatrists, but few psychiatrists are equipped to deal with chronic pain. Pain barely appears in the Diagnostic and Statistical Manual of Mental Disorders and is absent from the Research Domain Criterion framework, although in real life it co-occurs substantially with depression and anxiety. In fact, there is evidence that links between pain and mental illness are causal and bidirectional.
Psychology also has a blind spot when it comes to pain. Pain researchers are uncommon in academic psychology departments and neuroscience programs. And though many forms of chronic pain are treatable with behavioral methods, clinical training programs equip newly minted psychologists to treat anxiety, depression, obsessive-compulsive disorder, panic disorder, personality disorders and more—but not pain. There is no National Institute of Pain.
Pain is a central part of being human: Many of our oldest philosophical and spiritual traditions address ways to manage, avoid, and sometimes accept it. The Bhagavad Gita, for instance, instructs us to be at peace “in cold and heat, in pleasure and pain, in honor and dishonor.” The Roman stoic Marcus Aurelius wrote in the book Meditations, “Pain is neither intolerable nor everlasting, if thou bearest in mind that it has its limits, and if thou addest nothing to it in imagination…” These traditions teach us how to think about suffering and how to tap into our brains’ innate capacity to self-regulate. Although our ancestors knew nothing of the brain pathways that create pain, the central principles they taught and lived by have been rediscovered and adapted by modern approaches to pain treatment.
The Oldest Cure in the Book
Morphine–derived from the opium poppy–is the oldest drug in modern medicine’s pharmacopeia. Its medicinal use dates to ancient Egypt. It also has long been known that morphine and other opioids are addictive. One of the earliest synthetic drug formulations—developed by Bayer in the 1890s—was designed to make morphine less addictive and marketed as a “soothing syrup” to help children sleep. That drug is heroin, which is illegal in the US because of its high risk for abuse.
The evidence from randomized clinical trials of opioid treatment shows that its benefits are surprisingly modest. In the most recent meta-analysis, pain control was less than one point on a ten-point scale, and its efficacy declined with prolonged treatment. Meanwhile, basic research indicates that opioids can sensitize nociceptive neurons in the spinal cord, increase neuroinflammation, and increase pain in the long-term. The dose required to maintain the same degree of pain control rises dramatically (there is a 40-fold difference between the lowest and highest doses offered by some manufacturers), because the nervous system desensitizes to opioids when they are used continuously.
Desensitization to opioids is a powerful example of an opponent process, in which short-term effects (pain relief and possibly a “high”) are counteracted by long-term adaptations (desensitization). The net result with opioids is short-term pain relief but long-term anhedonia—reduced joy and motivation, also called hyperkatifeia—along with uncontrolled pain. The longer one takes the drug, the lower the benefits and greater the costs. After taking opioids even for a short period of time in some studies, individuals experience increases in both pain sensitivity and negative emotion unless the drugs are actively “on board.”
Other popular “painkillers” don’t work as well as it might seem, either. How about an ibuprofen or acetaminophen for low back pain? Their effects are barely better than taking a placebo pill. With regard to neuropathic pain, which is caused by a lesion or disease in the central nervous system (e.g., diabetes, stroke, or nerve injury), antidepressants, gabapentinoids, and even opioids are prescribed. But whichever drug is used, the effects are modest on average. How about cannabinoids? It’s taken as established truth that they are good for pain. But in a recent meta-analysis, they provided only a three-to-four percent improvement over placebo.
The pharmaceutical industry has spent billions of dollars developing pain treatments, with (at least so far) unimpressive results. Every drug has side effects; many are ineffective. Many drug companies have simply stopped trying to advance new therapeutics for managing pain. Clinical trials are expensive, so most pain treatments will never be vetted as extensively as drugs or reported in major medical journals, particularly if the treatments are principles and practices that are freely available. All this work has given us some good ideas about what doesn’t work very well.
Clues from the Brain
Research across sensory modalities has found that our perceptions are constructions: The brain interprets sensory input through a lens of memory, logic, and emotion. Our perception is not a veridical reflection of the world, but rather a guess, an inference, about what is really there based on multiple context clues. That’s why we see faces, effortlessly and automatically, in particular configurations of clouds. And it is why people with some pain conditions feel pain when they look at emotionally distressing pictures. These “biases” help us act not just on what is immediately presented to our senses, but what is likely to be there, and they help us predict and respond to situational demands in advance: They alter our pain sensitivity to prepare for action in a dangerous situation.
Because pain is a construction based only partly on input from the body, the brain has the capacity to alter pain and the feelings and motivations surrounding it in multiple ways. Descending modulatory systems can enhance or inhibit pain-related signals in the spinal cord before they even reach the brain. The brain maintains a balance between promoting and inhibiting pain, and nerve injuries can shift the balance towards a pain facilitation state. Essentially, the brain has “decided” that when an injury is perceived, it should feel pain, which can promote recovery. Pain also drives decision-making at several levels: what we escape now, what we avoid in the future, for which threats we should be vigilant, and what cues signal danger. Pain is the experience that drives fear-conditioning and other forms of threat-learning. The activity in these systems is also subject to construction, as the brain “decides” which sensations are truly threats to the body and what defensive adaptations are necessary to prevent future harm.
These principles suggest why pain-related brain activity is sensitive to context, past experiences, and suggestion. Giving a placebo treatment—e.g., a sugar pill or inert ointment—can reduce activity in brain areas involved in constructing the pain experience and induce the release of endogenous opioids and dopamine. In some studies, placebo treatments coupled with suggestions about increases and decreases in pain can affect pain-related activity in the human spinal cord. These neurobiological effects play out in real life: Clinically, placebo treatments can reduce pain related to migraines and other headaches, osteoarthritis, gastrointestinal pain, and more.
Placebo treatments and interventions based on manipulation of the social and environmental context don’t all affect pain by the same neurological pathways. For example, suggestions about social context (how other people perceive pain) and classical conditioning can both exert substantial effects on the experience of pain and even autonomic responses to painful events. But their effects on pain are mediated by different brain systems; prefrontal cortical systems are involved in social cognition, and hindbrain systems in associative learning. There appears to be no “final common pathway.” But behind all these interventions is the brain’s mental model of the painful event and whether it is conceived of as damaging or dangerous, now or in the future.
Emerging research on underlying brain systems supports the idea that chronic pain, even more strongly than pain evoked acutely by somatic stimuli, is an integrative construction that extends beyond the detection of painful stimuli. Neuroimaging of pain sensations in hypersensitive patients has found enhanced activity in brain regions that also encode pain in healthy people. Moreover, new studies have found that chronic pain induces changes in affective and motivational circuits that don’t respond to noxious input—that is, their activity doesn’t increase as one turns up the level of painful heat or pressure applied to the body. These circuits include the ventromedial prefrontal cortex (vmPFC), posterior cingulate, nucleus accumbens, and hippocampus.
Whether back pain progresses from acute to chronic, for example, appears to be related to the strength of functional connectivity between the vmPFC and the nucleus accumbens, as measured with fMRI. Stronger correlations between activity in the vmPFC and pain encoding regions have been found in chronic back pain, fibromyalgia, failed back surgery, and more. Other studies suggest that pain is not localized to any one brain network but is instead an altered global brain state that is defined by a pattern of interconnections across many regions spanning the brain.
Some of the key brain areas for chronic pain intersect with what has come to be known as the “default mode network” (DMN), so named because it is primarily active when a person is simply resting without any external stimulation (i.e., daydreaming, mind-wandering, etc.). This network seems to encode, in various ways, our conception of situations—mental conceptions of the environment and our capacity to act in it—particularly as they relate to the self and future well-being. The vmPFC is a key “node” in the DMN. Patterns of activity in the vmPFC encode our personal memories, the value we place on rewards, imagined futures, the hidden causes to which we attribute rewarding or punishing outcomes, and the meaning we ascribe to events. But the vmPFC is also a primary driver of autonomic activity and hormone release; its response during stress determines heart rate increases and the brainstem activity that controls autonomic output. It is also among the brain areas most strongly associated with immune responses.
My colleagues and I have proposed that the DMN plays a central role in constructing situational meaning, linking conceptual thought with the mobilization of physiological resources to meet the demands that bear on one’s personal well-being. This hypothesis gives vmPFC and the DMN a critical role in avoidance learning, linking actions and other cues (sensations, places) to danger, and guiding actions to avoid threats. This inherently requires inference or guesswork because no two situations are the same. If you injure your back alpine skiing, should you be afraid of skiing again?
More broadly, the vmPFC helps determine how we generalize our experiences, which, in turn, depends on what we think was the underlying cause and whether it will recur in new scenarios. For example, in the case of back surgery for chronic pain, our brain contains a mental model of this situation—local injury and inflammation, with the expectation that the pain will last for a few months and decrease gradually as the injury heals. When you feel local back pain, you are not surprised because you attribute it to the model. You take a walk and feel some pain, but this is normal—it fits within the model. But what happens if the pain starts to get worse again or spreads to other parts of the body? This might prompt a more sinister interpretation: that the body is and will remain dysregulated in ways unexplainable by medicine.
This view might be reinforced by physicians who are unable to identify a physiological cause for the pain. As one patient described it, “I’ve always been told that I’m broken.” Once pain has persisted for a long time, clinicians might say that until a cause is found, the patient will always be in pain. Others might say that pain is a sign of bodily injury, so he or she should avoid doing something if it hurts. While these statements may be reasonable guesses, they have powerful nocebo (the opposite of placebo) effects: The suggestion of ongoing harm can enhance threat signaling in brain and body. More perniciously, they reinforce maladaptive beliefs about the meaning of pain, as a sign of bodily harm or dysfunction and an indicator of future dysfunction. My colleagues and I think that such mental constructs are maintained in the DMN, forging the link between this system and chronic pain.
A family friend recently wrote me about her experience with Complex Regional Pain Syndrome, a form of neuropathic pain that she developed after a cycling accident. She tried over 20 unsuccessful treatments, including three stellate ganglion blocks, 200 hours of physical therapy, yoga, direct current microstimulation, and pulsed electromagnetic field therapy. At the end of this odyssey, she has been able to substantially reduce her pain, return to work, and eliminate all of the invasive interventions. What worked? It’s not clear that any single treatment was a magic bullet. In this journey, she established a “new brain-based belief system,” thinking of her pain and its peripheral signs—including inflammation and other visible signs—as the result of an unconscious threat response in her brain. She framed recovery as an “argument with the body,” an attempt to convince her brain that the injury is healed and there is no longer a need to mount a threat response. And “when the argument was won, acceptance. Relief.”
What works may be different for each individual, but a common principle may be changing those systems in the brain that maintain the belief that the body is under threat. But what is convincing to one person (or one person’s unconscious brain) may not be to another. I’ve heard many stories of people who have been in chronic pain for years, finding substantial relief in a single session of therapy, or after reading a book whose ideas resonate. Others need more support and personalized guidance.
My laboratory has recently completed a study of a treatment called Pain Reprocessing Therapy (PRT), a combined psychological and behavioral treatment that is designed to do two things. The first step is to help patients realize that pain does not reflect tissue damage or harm. It is a “false alarm” created by the brain, unpleasant but not dangerous. The second step is to put that realization into practice by performing the movements and exposing oneself to the situations that created pain and fear in the past. In a randomized clinical trial, patients who received PRT achieved remarkable reductions in pain. Though the participants had been in pain for ten years on average, two thirds were pain-free or nearly so after four weeks of treatment (eight sessions). Patients randomized to placebo or usual care showed much more modest gains.
Like other psychological treatments, PRT gives people principles to practice in their daily lives, so benefits didn’t end after the eight sessions were finished. They were nearly as large a year later. Using fMRI after treatment, we found reductions in pain-encoding parts of the anterior insula and anterior cingulate, the two areas most strongly associated with sensing pain and regulation of the autonomic nervous system. And while there were many auxiliary benefits (improved mood, sleep, and function), the strongest predictor of pain reduction was change in beliefs about the causes and meaning of pain.
Recent studies have also found substantial improvements with other psychological and behavioral treatments. Some methods, such as Emotional Awareness and Expression Therapy, focus on associations between emotional trauma and pain. Others, like Mindfulness-Oriented Recovery Enhancement (MORE), aim to change the meaning of pain and stressors. In one recent study, MORE substantially reduced both pain and opioid use. The effects were larger the longer the follow-up; at nine months, MORE cut opioid use in half.
These approaches, which combine methods used in cognitive behavioral therapy (CBT) in a novel way, are not yet standard practice in the psychological treatment of pain. But they appear to work substantially better: While standard psychological modalities yield only modest effects (comparable to or weaker than the drug effects mentioned above), these new treatments have shown substantial and durable benefits, at least in initial studies. Many questions remain about the types of chronic pain for which each of the new treatments is helpful, who will benefit most, how extensive the treatment must be, and how easily people can be trained to deliver it.
As for CBT and other standard psychological approaches to pain, the lack of compelling data does not mean they cannot be important treatment avenues for many people. Such treatments are not standardized the way that drug treatment is: They are tailored to the individual patient, and many individual practitioners have converged on principles similar to those in PRT or MORE. This suggests that the optimal ingredients of CBT for pain remain to be discovered.
Several principles underlying psychological treatments like PRT depart from standard pain psychology. First, they provide an explanation for chronic pain that acknowledges its reality while affirming that it is not a sign of damage to the body but the result of sensitization in neural circuits, drawing on findings in neuroscience. The belief that “pain does not equal damage” helps patients see that pain, while unpleasant, can be safe. Second, it encourages them to turn their attention back to the body by practicing mindful attention to the physical sensations of emotion and of pain, and even engage in painful movements deliberately.
These clinical effects dovetail with findings from my laboratory that focusing on the non-affective aspects of pain (i.e., treating it as an “interesting sensory experience”) can produce more pain relief than turning attention away from the body (e.g., distraction). By the same token, we’ve found that mindful acceptance of pain is one of the most potent interventions for reducing pain-related brain activity. If pain is viewed as fundamentally safe, it’s okay to perform painful movements; this pain exposure may be a key to re-training the brain towards a less sensitive state.
Exposure has two other advantages: Putting nascent beliefs into practice, it amplifies commitment to the idea that pain is safe. And it provides somatosensory input to help the brain recognize pain signals as part of the normal sensory landscape. Beyond overcoming negative beliefs, some emerging treatments focus on re-engaging positive experiences—like the practice of “savoring” positive experiences (cultivating enjoyment) in MOST or exploring pain sensations with a curious or even playful attitude in PRT (“wow, look at my brain tricking me!”)— ideas antithetical to regarding pain as a threat.
We have a long way to go in understanding how to help those who suffer from chronic pain find their individual paths to recovery. But advances in that direction have been significant, demonstrating that such pain is real but that its root causes are in the brain rather than in local tissue—i.e., “where it hurts.” Innovations in pain psychology have shown that even with acute pain-inducing pathology after an injury, cognitive approaches can re-shape neural circuits to minimize suffering and promote recovery.
At the same time, researchers into the biology of chronic pain are developing biomarkers to sharpen diagnosis and prognosis, and track treatment response on a larger scale than ever before. Toward that end, the UK Biobank has gathered genetic, clinical, neuroimaging, and other measures on approximately 500,000 individuals, including those with dozens of pain disorders. The Acute to Chronic Pain Signatures program is taking a comprehensive approach to understanding vulnerability to post-surgical chronic pain, using neuroimaging, metabolomics, transcriptomics, lipidomics, and systemic inflammation data in more than 2,000 patients followed over time. All in all, the future of pain treatment is looking brighter than it ever has—and there is not a moment to lose in moving forward.
This article first appeared in the Spring 2022 issue of our Cerebrum magazine. Click the cover for the full e-magazine.