The need to recognize and manage chronic nociplastic pain has become integral to rheumatology practice, as research over the past half-decade has affirmed that when central sensitization is present, patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (AxSpA), and other rheumatologic diseases are less responsive — or nonresponsive — to peripherally and axially focused anti-inflammatory and immunomodulatory therapies.
Central sensitization is a key feature of nociplastic pain, a third pain category, or mechanistic description, so named in 2017 by the International Association for the Study of Pain (IASP). The pain community’s new category — joining nociceptive and neuropathic pain — came after researchers in rheumatology led the way with decades of research showing that fibromyalgia (FM) is centrally mediated, often without ongoing peripheral nociceptive input.
Today, rheumatologists shoulder the weight of managing patients’ highly individualized needs, often despite a lack of training and comfort, and often within healthcare systems and care communities that themselves are not well equipped to treat chronic nociplastic pain.
“I assume that 20%-25% of our patients, with whatever disease they have…have pain that isn’t driven by inflammation. And if you ignore that, you do so at your peril and your patient’s peril,” said Eric M. Ruderman, MD, professor of medicine and associate chief of clinical affairs for the Division of Rheumatology at the Feinberg School of Medicine, Northwestern University, Chicago. “It’s a question we need to consider at all times when we’re assessing treatment response.”
Nociplastic pain is characterized by widespread pain and often co-occurs with fatigue and altered sleep, mood, and cognition — problems that characterize FM. But Ruderman and others emphasize that pain should be recognized and addressed by the rheumatologist regardless of whether a patient meets the formal definition of FM with its nonpain aspects.
“The biggest problem with the FM construct is it forces us to turn a continuum into a binary diagnosis,” wrote Daniel J. Clauw, MD, in a 2024 article in Annals of the Rheumatic Diseases entitled “From fibrositis to fibromyalgia to nociplastic pain: How rheumatology helped us get here and where do we go from here?”
“It is best to consider that some individuals with an autoimmune rheumatic disease will have a bit of superimposed nociplastic pain, and in some, this will be the primary driver of their pain and other symptoms,” wrote Clauw, professor of anesthesiology, medicine (rheumatology), and psychiatry at the University of Michigan, Ann Arbor, Michigan, and director of the Chronic Pain and Fatigue Research Center.
The recognition of FM and nociplastic pain is also important given recent and ongoing efforts to define “difficult-to-treat” rheumatic disease and better shape future research and new management approaches for patients who don’t respond to advanced therapies.
Teasing Apart Nociplastic Pain: Key Abnormalities and Risk Factors
The evidence that FM was likely driven more by central nervous system (CNS) mechanisms rather than peripheral damage and/or inflammation goes back more than 50 years. (Fibrositis was renamed FM in 1976, reflecting this understanding.) Starting in the 1990s and 2000s, advances in brain imaging, especially functional imaging (eg, fMRI), helped researchers document specific CNS contributions to pain. At the same time, quantitative sensory testing further demonstrated patients’ experience with diffuse allodynia.
Such research gradually helped legitimize FM in the field of rheumatology and lessen patient stigmatization. (Knowledge and views evolved similarly in other specialties with regards to pain conditions such as irritable bowel syndrome [once called spastic colitis] and painful bladder syndrome [also known as interstitial cystitis])
Today, as defined by the IASP, nociplastic pain is “pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain.”
It reflects sensitization of the CNS due to neural network dysregulation and multiple neurobiologic, psychosocial, and genetic factors. Functional brain imaging studies in patients who have chronic pain with nociplastic features have shown alterations in the CNS and abnormal brain connectivity between brain regions, notably increased functional connectivity between regions of the default mode, salience, and sensorimotor networks. (Enmeshment of these networks has been observed in patients with osteoarthritis, RA, and ankylosing spondylitis, according to Clauw.)
In addition to having excess ascending CNS nociceptive signaling, these patients also have decreased descending inhibitory signaling, according to recent reviews co-authored by Clauw, whose prolific research on centralized pain included the first fMRI evidence of augmented pain processing in FM in 2002. (A review he co-authored for Nature Reviews Neurology, published last year, provides extensive detail on potential mechanisms, clinical features, and risk factors.)
Clauw and other experts believe there is evidence for at least two types of nociplastic pain. “Top-down” nociplastic pain involves augmented pain processing as a sole pain mechanism, without nociceptive input; patients have a primary brain disorder early in life that manifests first with poor sleep or other problems and evolves into widespread pain. In the “bottom-up” subset, nociplastic pain is superimposed on a nociceptive or neuropathic pain state. (In rheumatology, this subset reflects what historically has been called “secondary FM.”)
While the exact causes of nociplastic pain remain unknown, certain factors, such as female sex, early-life stressors, trauma, poor sleep, physical inactivity, and genetics have been shown to increase risk.
Nociplastic Pain as a Barrier to Disease-Modifying Antirheumatic Drug (DMARD), Biologic Success
Numerous studies have documented the impact of FM/centralized pain on the assessment and treatment of rheumatic diseases. In a 2020 study of RA, for example, patients with high dysregulation of “conditioned pain modulation” — a measure associated with diminished inhibition of pain — were significantly less likely to achieve a European Alliance of Associations for Rheumatology (EULAR) response to DMARD therapy than those who had low dysregulation (22.5% vs 40.3%; P = .01).
Another study on PsA, for instance, found that widespread pain — the chief feature of nociplastic pain — was present in 35% of 69 patients starting DMARDs/biologics and that none of these patients were able to achieve a state of minimal disease activity at 4 months compared with 20% of the patients who did not have widespread pain.
For patients with concomitant FM or nociplastic pain, “we’ve learned that we often can’t get them into a state of low disease activity or remission as assessed by subjective responses on pain, fatigue measures, and patient global measures,” said Philip J. Mease, MD, director of Rheumatology Research at the Providence Swedish Medical Center and clinical professor at the University of Washington School of Medicine, both in Seattle, in an interview.
“Many rheumatologists have historically switched treatments, moving from one immunomodulatory medication to another…that’s a lot of visits, resource utilization, and potential adverse effects with each new medication,” said Mease, another leading researcher in the area of FM and central sensitization in rheumatic disease, and the author of a 2024 review of the complexity of pain, including nociplastic pain, in PsA and AxSpA.
“But rheumatologists are starting to step back and ask, is there objective evidence of inflammation?” he said in an interview. “And if not, let’s look to alternative explanations for the residual pain.”
Mease’s own research also speaks to the value of viewing FM on a continuum and against a broader backdrop of nociplastic pain. In a recent analysis from a multicenter registry of patients with PsA and AxSpA — the CorEvitas registry started in 2013 — Mease and his co-investigators reported that 11.1% of more than 1800 patients with PsA fulfilled the FM definition (scoring high on both the Widespread Pain Index [WPI] and the Symptom Severity Scale [SSS]), whereas almost twice as many — 20.6% — scored high on the WPI.
The analysis illustrates how, in a Venn diagram model, “the larger circle of patients has widespread pain…which is what I equate with having nociplastic pain,” and which needs attention regardless of whether FM criteria are met, he said.
What the Rheumatologist Can Do
Recent updates of practice guidelines for managing rheumatic diseases tend to encourage reassessment of the diagnosis when patients have not responded adequately to therapies. But “that’s as far as the guidelines go,” Mease said. “They’re saying, respect the possibility that residual pain may be due to something beyond the primary condition that the guidelines cover.”
Multiple reviews of nociplastic pain published in the rheumatology literature emphasize the importance of nonpharmacologic therapies and approaches — increasing physical activity, treating sleep problems, physical therapy, psychotherapy, cognitive behavioral therapy, mindfulness, and acupuncture, for instance — as core treatments.
Centrally acting drugs such as tricyclic antidepressants (eg, amitriptyline and cyclobenzaprine), serotonin-norepinephrine reuptake inhibitors (eg, duloxetine, milnacipran), and gabapentinoids also have a role for many patients, experts wrote. Opioids, as rheumatologists have generally known, should be avoided for this type of pain.
Clauw advocates using a body map to assess for widespread pain. “The more pain you see that is not explainable by the classic distribution of the arthritis or other disease, the more likely they have [nociplastic] pain superimposed and the more likely you’ll have to treat this with nonopioid, CNS-acting analgesics and aggressive use of nonpharmacologic therapies” with movement and sleep as a start, he said in the interview, noting that the presence of comorbid CNS symptoms (eg, altered sleep, cognition and mood, sensory hypersensitivity) makes nociplastic pain even more likely.
One problem is that many pain clinics are focused on specific injections and procedures that generally do not help nociplastic pain.
Pain medicine specialist Steven P. Stanos, Jr, DO, hopes this will change. “We knew there was a third, more ubiquitous bucket of pain classification, which we’d commonly call ‘mixed pain’… [but] work in rheumatology brought it all the way to the brain and helped the pain community step up our game to understand fibromyalgia and central sensitization and its impact on pain processing,” said Stanos, medical director of Pain Medicine Services at Swedish Medical System and past president of the American Association of Pain Medicine.
“That shift in understanding of central sensitization helped clinicians better conceptualize nociplastic pain,” he said.
With a better understanding of the range of signs and symptoms of nociplastic pain — and with greater understanding of the importance of a “biopsychosocial approach” to pain as highlighted by the federal government’s Interagency Task Force for Pain in 2019 — there’s “better buy-in [in the pain community] today for using a team-based multidisciplinary approach for treating nociplastic pain and other chronic pain conditions,” he said.
Also significant is increasing openness of patients to nonpharmacologic approaches, “especially to behavioral health and mind-body movement based on therapies like Tai Chi,” he said. In his pain clinic, patients with chronic pain conditions participate in “structured self-management boot camps” that integrate physical therapy, occupational therapy, pain psychology (including cognitive behavioral therapy and mindfulness training), Tai Chi and yoga, and relaxation training, along with medical management.
Nonpharmacologic interventions generally are provided empirically and are “not backed by carefully controlled trials,” Mease said. But a significant body of literature documents reductions in pain after interventions, and functional imaging studies have shown improvement in nociplastic pain-related brain abnormalities such as the continual activation of the default mode network.
Realistically, rheumatologists’ best course of action is often to build “virtual teams” of professionals who are knowledgeable and sensitive to the needs of patients with nociplastic pain, “so that we can tell a patient, based on where they live, ‘here’s the psychologist, here’s the PT [physical therapist] who we think would be good for you,’” Mease said.
PTs, Stanos noted, are increasingly learning how to work more effectively with patients suffering from chronic pain by pursuing training, for instance, in “pain neuroscience education,” which is a therapy approach that’s less about biomechanical and tissue causes of pain, and more about changes in pain processing. The approach is based on central sensitization and teaches patients “how they can modulate their ‘sensitized’ nervous system.” He advises asking if a physical therapist is “pain trained.”
Christopher T. Ritchlin, MD, MPH, professor of medicine at the University of Rochester Medical School, Rochester, New York, whose practice and research is focused on PsA, said he routinely — and early on — refers patients for sleep studies.
“Sleep is such an important [contributor] to nociplastic pain, and particularly in the PsA community where obesity is highly prevalent, there is a lot of obstructive sleep apnea,” he said. “If you’re not sleeping well and getting the restorative functions you need, one of the first things that emerges is nociplastic pain.”
Ritchlin said he often uses a low dose of amitriptyline to help normalize sleep patterns. In all patients, moreover, movement is critical, and Ritchlin tells patients to “move in a way that makes you happy, that you enjoy.” Guiding patients as needed toward treatment for anxiety and depression, stress, and a history of sexual trauma are also high on his list.
Ritchlin and Clauw both expressed the need for new care models — for instance, multidisciplinary clinics directed by specially trained advanced practice providers — to make integrative nonpharmacologic care and nonprocedural, nonopioid medication management directly available to patients. Right now, “we have no viable care models,” Clauw said.
In the meantime, patient education is invaluable. “I have people who I have on a disease-modifying or biologic therapy for their underlying disease, and also on duloxetine for the chronic pain piece, and they’ll come in and say, ‘I’m not doing well, and I think it’s my fibromyalgia’ or ‘I think it’s my underlying disease,’” said Ruderman. “Once you explain the issues, they get it. They can sense the difference. And that’s a step forward to addressing the problem better.”
What’s in Store for the Future?
Researchers have only begun to understand all the pathways and influences involved in nociplastic pain. “Twenty years ago, it was a graveyard for people to do research in this area,” Mease said. Increasingly, he said, understanding its pathophysiology has become “a legitimate area of research.”
In time, clinicians may see new tools for evaluation as well as practice guidelines that more specifically address the diagnosis and management of nociplastic pain. In one effort underway, the chronic pain work group of Outcome Measures in Rheumatology Clinical Trials is trying to develop simpler measures for distinguishing the three pain categories including measures that may be simpler but as sensitive and specific as the WPI/SSS. Such measures could potentially be used in practice, said Mease, who cochairs the working group.
In another effort, Clauw, whose past research has shown that multisensory hypersensitivity is a “really strong component” of nociplastic pain, is currently finding that a high score on a simple four-point rating scale that measures sensitivity to light, noises, and odors is itself highly predictive of nonresponsiveness to a new biologic in both RA and PsA. “As such studies get published and [clinicians] see that measures are getting simpler and simpler to use, I think they’ll do more,” he said.
Clauw wants to see the development of disease-specific measures of nociceptive pain that appreciate the differences between rheumatic diseases — not only with respect to their inflammatory components but also with respect to symptoms known to co-occur with nociplastic pain that also can be part of specific disease processes. “In patients with Sjögren’s or lupus, for instance, fatigue may not be as helpful a part of a nociplastic pain measure as it would for other conditions,” he said.
Ongoing projects to define “difficult-to-treat” disease for certain rheumatic diseases are taking FM/nociplastic pain and other comorbidities into account. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis’s difficult-to-treat PsA project, for instance, is attempting to delineate a subgroup of patients who are truly refractory — those “immunobiologically active patients who have objective signs of inflammation despite good treatment efforts” — from other patients who don’t reach treatment targets due to concomitant FM, depression, access issues, or other reasons, said Mease, a co-investigator of the project.
Such projects are important, he said, for the development of new medications, openness to clinical trials of dual biologic therapy, and for improved management overall. An Assessment of SpondyloArthritis International Society task force working on a definition of difficult-to-treat AxSpA recently published its findings, and a EULAR definition of difficult-to-treat RA was published in 2021.
Clauw, Mease, Ritchlin, and Ruderman reported that they have no relevant disclosures. Stanos reported consulting for Averitas, Collegium, and Vertex, and being on the speaker bureau of Averitas.