Patients living with fibromyalgia (FM) – a disease that predominantly affects women and is characterized by chronic pain, fatigue and brain fog – often find limited treatment options and a scarcity of explanations for their symptoms. Research led by Mass General Brigham investigators has found that cognitive behavioral therapy (CBT) can significantly reduce the burden of FM by, in part, reducing pain-catastrophizing, a negative cognitive and emotional response that can intensify pain through feelings of helplessness, rumination and intrusive thoughts. This finding is backed by neuroimaging data, evidencing reduced connectivity between regions of the brain associated with self-awareness, pain and emotional processing. Results are published on September 20 in Arthritis & Rheumatology.
“In this study, we looked at the interplay between psychological processes and the brain's connectivity patterns in response to pain,” said co-senior author Robert Edwards, PhD, a clinical psychologist in the Department of Anesthesiology, Perioperative & Pain Medicine at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system. “We wanted to explore how CBT, a talk therapy aimed at combatting maladaptive thoughts, can enhance individuals’ daily functioning and alter the brain’s processing of pain-related information.”
Edwards explains that CBT can reduce negative cognitive and emotional responses to pain. He says that while these responses are normal, they can amplify the disabling effects of chronic pain, and make conditions like FM more burdensome.
The research team for the study included researchers from three Mass General Brigham members: Spaulding Rehabilitation Hospital, Brigham and Women’s Hospital and Massachusetts General Hospital. Mass General Brigham brings together 16 member institutions, including academic medical centers, top-tier specialty hospitals, community hospitals and more. Research that spans more than one of these entities is more than the sum of its parts, helping to provide insights and unique perspectives from multiple settings and areas of expertise.
Researchers recruited 98 women, randomly assigning 64 to a treatment group receiving CBT and 34 to a control group that received education about FM and chronic pain but was not taught specific CBT techniques. All participants were between 18 and 75 years old and had a confirmed FM diagnosis for at least six months. To collect baseline data, all participants completed several validated pain and quality of life questionnaires.
Each group participated in eight intervention sessions, consisting of 60–75-minute visits with a licensed mental health provider. Participants were primarily assessed for their levels of pain interference, or a measure of how much their pain disrupted their daily activities, pain catastrophizing, pain severity and the overall impact FM had on patients’ quality of life.
Results demonstrated that those who underwent CBT experienced significantly greater reductions in pain interference. CBT participants also exhibited significantly less pain catastrophizing and reported that their FM symptoms had significantly less impact on their daily lives.
The team saw evidence that after undergoing CBT, patients experienced changes in the activities of all three networks that suggested a diminished focus on pain.
“Prior to participants undergoing CBT, we saw that certain parts of the brain linked to self-awareness and sensation were very connected, suggesting patients were pertinently aware of the pain sensation they were experiencing and internalized these symptoms,” said co-first author Jeungchan Lee, PhD, an instructor in the Department of Physical Medicine and Rehabilitation based at Spaulding Rehabilitation Hospital and the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital. “After CBT, these connections were significantly less strong, suggesting that patients were better at separating themselves from their pain after therapy.”
This study was limited to women, partly because of its high prevalence, and partly to eliminate confounding gender differences in brain activity. In the future, the researchers hope to collect data from men and non-binary patients with FM. Additionally, CBT includes several therapeutic components, and these results cannot be generalized to assess the impact across all forms of CBT on reducing FM chronic pain.
Both Lee and Edwards agree that these findings ultimately suggest that complex chronic pain conditions like fibromyalgia should be addressed with a multitude of pharmacological and cognitive therapies.
“I hope that these findings motivate healthcare providers to consider CBT as an effective treatment option to reduce the impact of pain patients experience,” explained Edwards. “Chronic pain conditions like fibromyalgia involve long-standing patterns of changes in the central nervous system, and CBT is one among many treatment options, such as medication and physical therapy, that we know can be beneficial for those living with FM.”
Authorship: Other Mass General Brigham authors of this study include co-first author Asimina Lazaridou (Brigham and Women’s Hospital), Myrella Paschali (Brigham and Women’s Hospital), Marco L. Loggia (Massachusetts General Hospital), Michael P. Berry (Massachusetts General Hospital), Kylie Isenburg (Massachusetts General Hospital), Alessandra Anzolin (Massachusetts General Hospital and Spaulding Rehabilitation Hospital), Arvina Grahl (Massachusetts General Hospital and Spaulding Rehabilitation Hospital), and co-senior author Vitaly Napadow (Massachusetts General Hospital and Spaulding Rehabilitation Hospital). Other authors include Dan-Mikael Ellingsen and Ajay D. Wasan.
Disclosures: The authors declared no potential conflicts of interest.
Funding: Supported by the National Institutes of Health: National Center for Complementary and Integrative Health (R01-AT007550, R33-AT009306, P01-AT009965), National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01-AR064367, R01- AR079110), and the National Center for Research Resources (P41RR14075, S10RR021110, S10RR023043).
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About Mass General Brigham
Mass General Brigham is an integrated academic health care system, uniting great minds to solve the hardest problems in medicine for our communities and the world. Mass General Brigham connects a full continuum of care across a system of academic medical centers, community and specialty hospitals, a health insurance plan, physician networks, community health centers, home care, and long-term care services. Mass General Brigham is a nonprofit organization committed to patient care, research, teaching, and service to the community. In addition, Mass General Brigham is one of the nation’s leading biomedical research organizations with several Harvard Medical School teaching hospitals. For more information, please visit massgeneralbrigham.org.
JOURNAL
Arthritis & Rheumatology
METHOD OF RESEARCH
Randomized controlled/clinical trial
SUBJECT OF RESEARCH
People
ARTICLE TITLE
A Randomized, Controlled Neuroimaging Trial of Cognitive-Behavioral Therapy for Fibromyalgia Pain
ARTICLE PUBLICATION DATE
20-Sep-2023
In a recent randomized clinical trial of patients with fibromyalgia, cognitive-behavioral therapy (CBT)—which uses structured techniques to alter distorted thoughts and negative moods—was superior to a matched education treatment in reducing the interfering effects of pain and other aspects of fibromyalgia on daily living.
Within the group that received CBT in the trial, which is published in Arthritis & Rheumatology, improvements were at least partly attributable to reductions in what’s known as catastrophizing, a state comprised of cognitive and emotional processes such as helplessness, rumination, and magnification of pain complaints.
Neuroimaging tests indicated that CBT exerts these effects by altering the connectivity of specific regions of the brain. Therefore, changes in the brain circuitry underlying pain catastrophizing may underpin CBT’s benefits for patients with fibromyalgia, a condition characterized by function-impairing symptoms such as widespread pain, fatigue, cognitive difficulties, and psychosocial distress.
“These findings contribute to a growing literature highlighting the benefits of non-pharmacologic treatments—including CBT—for chronic pain conditions such as fibromyalgia,” said corresponding author Jeungchan Lee, PhD, of Spaulding Rehabilitation Hospital and Harvard Medical School. “Identifying the multiple biopsychosocial mechanisms by which these treatments help to alleviate pain may help to facilitate the practice of precision pain medicine and improve treatment outcomes for the many patients suffering from chronic pain.”
URL upon publication: https://onlinelibrary.wiley.com/doi/10.1002/art.42672
Additional Information
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About the Journal
Arthritis & Rheumatology, an official journal of the American College of Rheumatology, is a peer-reviewed publication for scientists and clinicians interested in the natural history, pathophysiology, treatment, and outcome of the rheumatic diseases. The journal publishes the highest quality basic and clinical research related to the rheumatic diseases, encompassing a wide range of areas of investigative activity.
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JOURNAL
Arthritis & Rheumatology
ARTICLE TITLE
A Randomized, Controlled Neuroimaging Trial of Cognitive- Behavioral Therapy for Fibromyalgia Pain
ARTICLE PUBLICATION DATE
20-Sep-2023
Alternative pain control circuits in the brain produce relief similar to opioids without the downsides
Targeting a receptor for the neurotransmitter acetylcholine produces powerful analgesic effects in mice, even in animals with tolerance to opioids, suggesting a promising path to developing non-opioid painkillers.
Peer-Reviewed PublicationUNIVERSITY OF CHICAGO
The opioid epidemic in the United States has exacted an incalculable toll on individuals and communities, creating an urgent need for alternative painkillers. The search for non-opioid treatments is crucial, not only to mitigate the risks of addiction and overdose, but also to develop pain management tools that remain effective without inducing tolerance and other challenging side effects in patients.
New research from the University of Chicago identified an alternative signaling pathway in the brain of mice that relieves pain, even in animals that have developed tolerance to opioids. The study, published in Neuron in September, also showed that pain relief through this route did not induce tolerance, did not create withdrawals symptoms after treatment was stopped, and did not activate reward systems, limiting risk for addiction and making it a viable path to developing effective, non-opioid pain relief.
“There are multiple categories of non-opioid treatments, but the bad news is that nothing currently compares to opioids for the level of pain relief,” said Daniel McGehee, PhD, Professor of Anesthesia and Critical Care at UChicago and senior author of the new study. “Any alternative is a welcome option, and we have found pain control circuitry here that can produce relief similar to what we see with opioid activity, without the downsides.”
A different circuit for pain relief
The ventrolateral periaqueductal gray (vlPAG) is an area of the brain that serves as an important crossroads of systems that control pain. Previous research has shown that electrical stimulation and pharmacological treatments targeting this region can relieve pain, although the non-opioid circuits that alter pain through changes in activity in this part of the brain are less well-studied. One of these circuits involves the neurotransmitter acetylcholine, which affects activity in multiple parts of the brain. Targeting acetylcholine receptors can change pain responses, but the mechanisms by which naturally produced acetylcholine regulates pain control circuitry in the vIPAG had not been explored.
McGehee and Shivang Sullere, PhD, a previous graduate student in the Committee on Neurobiology at UChicago, now a postdoctoral scholar at the Harvard Medical School and the new study’s first author, investigated the dynamics of how acetylcholine is released in this area of the brain under various pain states, like inflammation, chronic neuropathy, or acute pain. McGehee’s lab published a paper in 2017 showing that targeting an acetylcholine receptor in the vIPAG called alpha-7 (⍺7) produced an analgesic effect. One might expect that the body would take advantage of this and release more acetylcholine in a painful scenario, but instead, the researchers saw the opposite effect—it was being suppressed. The team then set out to understand how and why this was happening.
The ⍺7 receptor is usually an excitatory receptor, meaning that it generates more activity in the nervous system. But when the researchers injected a drug that stimulates ⍺7 into the mice, the cells’ initial excited state quickly gave way to a prolonged quiet state, producing an analgesic effect that lasted for several hours.
“That was a huge and extremely unexpected outcome,” McGehee said. “Persistent inhibition was not on our radar at all. It was always a conundrum to me, but we saw that there is recruitment of another signaling pathway that is altering potassium channel function and causing these cells to shut down.”
When the team tested the effects of boosting acetylcholine in mice that had tolerance to opioids, they saw the same long-lasting analgesic effects. That's because the acetylcholine receptor is part of a different pathway than that used by opioids—the two operate independently, and if tolerance develops in the opioid circuits, acetylcholine’s effects are not altered. The animals also didn’t show signs of dependence or preference for environments where they received the drug that stimulated more acetylcholine in the absence of pain, which is a good sign that it doesn’t have addictive properties.
Separate imaging experiments also showed that higher levels of activity in cells that express ⍺7 correlated with higher levels of pain experienced by the animals: when those same cells were suppressed, pain was reduced as well.
“Not only do these cells relieve pain, they also accurately mirror the pain state of the organism. Through imaging methods, we can reproducibly monitor these neurons and acetylcholine in the vlPAG. This provides us a valuable biomarker for the pain state of an organism,” Sullere said. “This unexplored role of acetylcholine also points towards its potential involvement in the central sensitization processes that contribute to the development of chronic pain conditions. Modifying acetylcholine signaling provides an opportunity to relieve pain and prevent the establishment of the chronic pain state.”
Opportunities for new pain-relieving drugs
The results of this work point to multiple opportunities to develop new pain-relieving drugs, either by stimulating the release of acetylcholine or targeting ⍺7 receptors. McGehee said medications targeting these receptors have been tested for multiple diseases, but not yet as painkillers.
“This is a potentially valuable target for new development of analgesics,” he said. “We see that inhibiting these cells is important in terms of controlling pain, and it’s a very profound mechanism that works beautifully and to a similar degree to what we see with opioids.”
The study, “A Cholinergic Circuit That Relieves Pain, Despite Opioid Tolerance,” was supported by the National Institutes of Health (grants R21DA046184, R21NS120582, and R21NS110371). Alissa Kunczt, a former student at UChicago and now in the MD/PhD program at University of Wisconsin, Madison, was an additional author.
METHOD OF RESEARCH
Experimental study
SUBJECT OF RESEARCH
Animals
ARTICLE TITLE
A CHOLINERGIC CIRCUIT THAT RELIEVES PAIN, DESPITE OPIOID TOLERANCE
ARTICLE PUBLICATION DATE
20-Sep-2023
