The understanding of chronic pain has evolved significantly, shifting from a focus on peripheral damage to recognizing the central mechanisms underlying pain perception. This perspective article explores the concept of nociplastic pain, a term introduced by the International Association for the Study of Pain (IASP) in 2017, which describes pain arising from altered pain modulation within the central nervous system, without clear evidence of tissue damage or inflammation.
The historical progression from fibrositis to fibromyalgia, and now to nociplastic pain, underscores the complexity of chronic pain syndromes and the need for a multidisciplinary approach to management. Nociplastic pain is characterized by central sensitization, leading to heightened pain sensitivity and often accompanied by comorbidities such as fatigue, sleep disturbances, and cognitive difficulties.
Advances in neuroimaging have revealed altered connectivity within key brain networks, such as the default mode and salience networks, in patients with nociplastic pain, providing insights into the neural underpinnings of this condition. The article also addresses controversies surrounding the role of small fiber neuropathy and autonomic dysfunction in nociplastic pain, highlighting the ongoing debates in the field.
The practical importance of recognizing nociplastic pain across various medical disciplines—including primary care, orthopedics, neurology, psychiatry, and rheumatology—is emphasized, with recommendations for integrating this knowledge into clinical practice. Emerging therapies, such as neurofeedback, hyperbaric oxygen therapy, and neuromodulation, offer new avenues for treatment, particularly for patients who do not respond to conventional approaches.
The article calls for continued research into the mechanisms of nociplastic pain, the development of reliable diagnostic tools, and the exploration of novel therapeutic strategies to improve patient outcomes. The recognition and management of nociplastic pain are crucial for advancing the care of patients with chronic pain, necessitating interdisciplinary collaboration and a patient-centered approach.
The Emergence of Nociplastic Pain
Rheumatologists and rheumatology have had a prominent role in the conceptualization of nociplastic pain since the prototypical nociplastic pain condition is fibromyalgia. Fibromyalgia had been previously known as fibrositis, until it became clear that this condition could be differentiated from autoimmune disorders because of a lack of systemic inflammation and tissue damage.
Nociplastic pain is now thought to be a third descriptor/mechanism of pain, in addition to nociceptive pain (pain due to peripheral damage or inflammation) and neuropathic pain. Nociplastic pain can occur in isolation, or as a comorbidity with other mechanisms of pain, as commonly occurs in individuals with autoimmune disorders.
We now know that the cardinal symptoms of nociplastic pain are widespread pain (or pain in areas not without evidence of inflammation/damage), accompanied by fatigue, sleep and memory issues. There is objective evidence of amplification/augmentation of pain, as well as of non-painful stimuli such as the brightness of lights and unpleasantness of sound or odors. Nociplastic pain states can be triggered by a variety of stressors such as trauma, infections and chronic stressors.
Together these features suggest that the central nervous system (CNS) is playing a major role in causing and maintaining nociplastic pain, but these CNS factors may in some be driven by ongoing peripheral nociceptive input. The most effective drug therapies for nociplastic pain are non-opioid centrally acting analgesics such as tricyclics, serotonin-norepinephrine reuptake inhibitors and gabapentinoids. However, the mainstay of therapy for nociplastic pain is the use of a variety of non-pharmacological integrative therapies, especially those which improve activity/exercise, sleep and address psychological comorbidities.
The Role of Rheumatology in Defining Nociplastic Pain
In 2017, the International Association for the Study of Pain formally acknowledged that there was a third descriptor/mechanism of pain, termed nociplastic pain. This move went largely unnoticed by non-pain researchers. But for those in the field of pain that had been studying these conditions, or individuals with these conditions, this was a watershed moment.
This represented formal acknowledgement that the science had evolved to show that in pain conditions such as fibromyalgia (FM), the pain and other symptoms that these individuals experience are very real and are likely coming from the central nervous system (CNS) rather than from ongoing peripheral nociceptive input. This notion that all pain had to have a peripheral cause was firmly held in both the field of pain and more broadly in clinical medicine.
In the pain field, nearly all preclinical pain researchers were of the belief (many still are) that in order to experience pain, there must be activation of a nociceptor in the periphery. Most animal models of pain intentionally ignore studying cortical or subcortical influences on pain. Not surprisingly then, massive amounts of preclinical animal pain research have taught us a tremendous amount about the mechanisms involved in nociception (i.e., the processes that involve activation of a peripheral nociceptor) but much less about pain, and very few drug targets identified by these peripherally focused animal models have been successfully translated into new analgesics.
In clinical medicine, there has been a parallel focus on peripheral drivers of pain. In subspecialty training, there is typically an intense focus on studying one region of the body. When individuals have pain in that region of the body or tissue, subspecialists carefully interrogate this region with both the history and physical exam and then have an increasingly complex set of imaging studies, biopsies, etc. that can be used to determine if there is peripheral damage or inflammation in that region of the body.
After these thorough clinical investigations—in nearly every clinical subspecialty—providers came up with one or more labels for individuals who had pain—but no demonstrable inflammation or damage that should be causing that pain. In rheumatology, our such syndrome was fibrositis. But gastroenterology had spastic colitis, urology had interstitial cystitis, dentistry had TMJ, gynecology had endometriosis and so on.
Nearly all of these conditions were formally renamed by subspecialty experts beginning in the 1970s, with the new names purposely connoting the fact that evidence suggested strongly that this condition was not characterized by peripheral damage or inflammation driving the pain. Often the suffix is replaced because of an absence of inflammation. Fibrositis became FM, spastic colitis became irritable bowel syndrome (IBS) and interstitial cystitis became bladder pain syndrome.
These foundational shifts in our understanding of each of these conditions took decades but one by one came to the same conclusions, that is, these common pain conditions were more driven by CNS than peripheral mechanisms, and that commonly used analgesics or anti-inflammatory drugs, for example, non-steroidal anti-inflammatory drugs (NSAIDs), opioids and corticosteroids appeared to be ineffective.
As such, treatment guidelines for all of these conditions now considered primarily nociplastic all have strongly recommended against the use of opioids for decades, well before there were neurobiological studies showing why opioids might be particularly ineffective in relieving (or even worsen) this type of pain.
Because the protean manifestations of autoimmune and rheumatological disorders involve the entire body and all tissues, rheumatologists are one of just a few specialties that carefully interrogate the entire individual. Not surprisingly then, rheumatologists that played a seminal role in moving fibrositis to FM emphasized the importance of systemic features of FM.
Wolfe led the development of all of the FM criteria, and his own work emphasized the importance of using a body map to assess widespreadness of pain, and that FM should be thought of as a continuum (degree of fibromyalgianess) rather than a discrete disorder. Wolfe also showed that comorbid FM (what had previously been called secondary FM) was very common in any autoimmune disorder.
Yunus emphasized the importance of polysensory sensitivity in FM, which we now understand to be important in nociplastic pain. Rheumatologists, Don Goldenberg, Buskila and Bennett, emphasized the overlap between FM and other common pain conditions, as well as the familial coaggregation of FM with other pain syndromes.
Hugh Smythe emphasized the finding of diffuse tenderness. Although not a rheumatologist, FM researcher Moldofsky showed the importance of sleep problems in both causing and treating FM. Thus, the original 1990 criteria for FM appreciated the presence of diffuse neurally mediated pain sensitivity (originally expressed by assessing the number of tender points) as well as the importance of widespreadness of pain. These are all key historical contributions to FM research that later became codified features of what we now call nociplastic pain.
Advancing the Understanding of Nociplastic Pain
Advances in a number of research techniques, especially functional, chemical and structural brain imaging, helped revolutionize the study of the CNS contributions to pain, and the legitimization of nociplastic pain. In the first functional MRI (fMRI) study of FM published in 2002, Gracely et al. were able to demonstrate that when these individuals were given a low-intensity stimulus that they felt as painful (but a control did not), this led to activation of multiple brain regions known to be involved in pain processing including both the primary and secondary somatosensory cortices.
This and other early functional imaging studies in conditions such as FM and IBS were beginning to show that these individuals were really experiencing pain, which was a revelation to some who felt that these were mainly neurotic middle-aged women who were feigning symptoms. In parallel, quantitative sensory testing (QST) studies showed that in conditions such as FM, individuals were not just tender in regions originally considered as tender points (for this and other reasons leading to the abandonment of tender points from subsequent FM criteria) and instead experiencing diffuse hyperalgesia/allodynia.
These findings strongly suggested a CNS cause of the pain. The term central sensitization began being used in a different way than the original preclinical studies (that focused on spinal mechanisms) to indicate that the entire CNS may be sensitized. One leap in inference came from early QST and functional neuroimaging studies in nociplastic pain states showing that groups of individuals with FM and other nociplastic pain states were just as sensitive (compared with controls) to the sensitivity of light or loudness of noise, as they were to painful stimuli.
This polysensory hyper-responsiveness can only be a CNS phenomenon—visual and auditory stimuli bypass the spinal cord and come directly into the brain via cranial nerves. These findings helped further solidify that nociplastic pain is primarily a CNS-driven disease. Corresponding early brain imaging findings in nociplastic states often identified hyperactivity of brain regions such as the insula, which also made sense in light of revelations by neuroscientists such as Craig and Tracey that were showing that the insula played a key sensory integration role and interoception.
In addition to these studies in primary/nociplastic pain conditions such as FM, similar methods were used to show that nociplastic pain is often present as a superimposed comorbidity in individuals where the primary mechanism of pain is nociceptive, that is, due to ongoing inflammation or damage from autoimmune disorders. For example, early studies showed high rates of FM in nearly every autoimmune disorder, a phenomenon originally termed secondary FM and later central sensitization or centralized pain.
In aggregate, studies in many conditions were showing that when central sensitization is present in a nociceptive or neuropathic pain state—that individuals had identifiable differences in pain processing on QST or functional imaging, and became less responsive to a number of peripherally directed therapies. For example, in osteoarthritis (OA), using the 2011 FM Survey criteria as a surrogate measure of central sensitization/nociplastic pain, the higher the FM score, the less likely individuals respond to lower extremity arthroplasty, as well as opioids used to treat the perioperative pain.
Nearly identical findings were noted in women receiving hysterectomy for chronic pelvic pain. Interestingly, the presence of central sensitization does not simply tell us that peripherally directed therapies will be less effective, this also implies that centrally directed therapies will be more effective. For example, in both OA and rheumatoid arthritis (RA), serotonin and norepinephrine reuptake inhibitors such as duloxetine and milnacipran are more likely to work in the subset of OA and RA patients with more widespread pain/nociplastic pain.
Key Insights into Nociplastic Pain
The best single determinant of pain mechanism is the spatial distribution (widespreadness) of pain. The more widespread pain is, and the more pain that occurs where there is no demonstrable inflammation, the more likely that there is a nociplastic component of pain. Symptoms such as fatigue, sleep, memory and mood problems, and sensitivity to non-painful sensory stimuli are also CNS-driven symptoms that are inherent to nociplastic pain.
These are not just symptoms that are due to pain—in longitudinal studies, the presence of these other non-pain symptoms predicts the subsequent development of nociplastic pain. A corollary is that these other symptoms should also be viewed as treatment targets, especially intervening to improve sleep.
The risk factors for developing nociplastic pain are becoming increasingly understood and include female sex, adverse childhood experiences, certain medical conditions, and various physical and psychological stressors. Functional brain imaging studies show abnormal brain connectivity between regions in the default mode, salience and sensorimotor networks in nociplastic pain conditions.
Individuals with nociplastic pain also have abnormal responses in the descending pain modulatory system, which modulates activity in the spinal dorsal horn and can have inhibitory or facilitatory influences on pain perception. This decrease in inhibitory CNS influences and increase in facilitatory influences leads to a net disinhibition that can be identified by a decreased threshold for nociceptive firing in the periphery.
There is also evidence of activation of the immune system in nociplastic pain conditions, but the inflammation seen is quite different than that seen in autoimmune disorders and can be best identified with assays that involve stimulating whole blood to bring out a primed immune system. Additionally, changes in peripheral nerve fibers, such as a decrease in intraepidermal nerve fiber density, may represent neuroplasticity rather than a primary pathological process.
Practical Recommendations for Recognizing and Managing Nociplastic Pain
The core treatments of nociplastic pain are non-pharmacological. Treatments must be individualized, but the first step is to validate these symptoms and to explain that there are often different underlying mechanisms of pain, that need to be treated in different ways. The diagnosis of nociplastic pain does not in any way imply that peripheral sources of pain do not exist in that individual and may not need treatment. To the contrary, it is important to identify and treat any potential peripheral pain generators.
The core tenets of treating nociplastic pain are to get individuals moving and sleeping. Poor sleep and physical inactivity can directly cause nociplastic pain, so focusing first on these comorbidities can be helpful. There are a multitude of ways to get individuals moving and physically active, and the methods that are most accessible to that individual (and if possible those that are patient-chosen) should be tried first.
Any slow, gradual improvement in physical activity can be beneficial, starting low and going slow. Walking, water-based exercise programs, and movement-based therapies like yoga and tai chi can all be effective. Similarly, methods to improve sleep range from simple sleep hygiene to cognitive-behavioral therapy for insomnia, and the use of low-dose tricyclic compounds or gabapentinoids before bedtime.
Analgesics for nociplastic pain are less responsive to non-steroidal anti-inflammatory drugs and opioids compared to nociceptive pain. However, NSAIDs may still be of benefit for individuals with comorbid nociceptive pain, such as osteoarthritis. Opioids should be used cautiously, if ever, in chronic nociplastic pain due to the potential for opioid-induced hyperalgesia. The classes of analgesics that have been shown to be efficacious include tricyclics, serotonin-norepinephrine reuptake inhibitors, and gabapentinoids.
Screening for and treating stress, trauma, and psychiatric comorbidities is also crucial, as there is a bidirectional relationship between these factors and nociplastic pain. Emotional awareness and expression therapy, as well as pain reprocessing approaches, may be particularly helpful for individuals where psychological stress is driving the pain.
Overall, the recognition and management of nociplastic pain require a multidisciplinary, patient-centered approach that integrates both pharmacological and non-pharmacological therapies. Continued research is needed to further elucidate the mechanisms underlying nociplastic pain and develop more effective diagnostic and treatment strategies to improve outcomes for patients suffering from this complex condition.
