Nociplastic Pain: Clinical Features, Risk Factors, PDF

nature reviews neurology https://doi.org/10.1038/s41582-024-00966-8 Review article Check for updates Decipherin...

nature reviews neurology https://doi.org/10.1038/s41582-024-00966-8 Review article Check for updates Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms Chelsea M. Kaplan 1 , Eoin Kelleher 2 , Anushka Irani 3,4 , Andrew Schrepf1, Daniel J. Clauw 1 & Steven E. Harte 1 Abstract Sections Nociplastic pain is a mechanistic term used to describe pain that arises Introduction or is sustained by altered nociception, despite the absence of tissue Clinical presentation damage. Although nociplastic pain has distinct pathophysiology Risk factors from nociceptive and neuropathic pain, these pain mechanisms often Sensory abnormalities coincide within individuals, which contributes to the intractability of Brain abnormalities chronic pain. Key symptoms of nociplastic pain include pain in multiple body regions, fatigue, sleep disturbances, cognitive dysfunction, Immune function depression and anxiety. Individuals with nociplastic pain are often Peripheral mechanisms diffusely tender — indicative of hyperalgesia and/or allodynia — and are Subtypes of nociplastic pain: often more sensitive than others to non-painful sensory stimuli such top-down and bottom-up as lights, odours and noises. This Review summarizes the risk factors, Conclusion clinical presentation and treatment of nociplastic pain, and describes how alterations in brain function and structure, immune processing and peripheral factors might contribute to the nociplastic pain phenotype. This article concludes with a discussion of two proposed subtypes of nociplastic pain that reflect distinct neurobiological features and treatment responsivity. 1 Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan Medical School, Ann Arbor, MI, USA. 2Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK. 3 Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. 4Division of Rheumatology, Mayo Clinic Florida, Jacksonville, FL, USA. e-mail: [email protected] Nature Reviews Neurology Review article Key points early-life events, sociodemographic characteristics, lifestyle behav- iours and pain exposure, which all have roles in the onset of nociplastic pain. Brain, immune and peripheral contributions to nociplastic pain Nociplastic pain was recently endorsed as the third mechanistic are then described. Finally, we conclude with a discussion of two poten- descriptor of pain and is characterized by widespread body pain, often tial subtypes of nociplastic pain — top-down and bottom-up — that may co-occurring with fatigue and altered sleep, cognition and mood, as carry substantial treatment implications. well as multisensory hypersensitivity. Clinical presentation Nociplastic pain probably occurs on a continuum and can coexist Prevalence with nociceptive and/or neuropathic pain. No validated clinical diagnostic criteria currently exist specifically for nociplastic pain, so its true prevalence is difficult to estimate. Further- Although the exact cause (or causes) of nociplastic pain remain more, multiple mechanistic drivers might be present in any individual and unknown, female sex, early-life stressors, trauma, poor sleep, can evolve over time. However, data from COPCs provide useful insights. heightened somatic awareness and physical inactivity increase The prevalence of different COPCs varies from 2% to 6% for conditions the risk for nociplastic pain. such as fibromyalgia and IC/BPS, to approximately 10% each for cLBP, TMD and IBS4. These figures are consistent with estimates that at least Alterations in the central nervous system, particularly in brain 8–11% of the general population have chronic widespread pain5. Interest- regions situated within the default mode, salience and somatosensory ingly, compared with the general population, nociplastic pain symptoms networks, have been reported in many chronic pain conditions with have a much higher prevalence (10–48%) among people with an existing nociplastic features. diagnosis of an autoimmune rheumatic condition6 or other conditions such as sickle cell disease7, dry eye disease8 or osteoarthritis9 that have been historically considered as solely nociceptive. Introduction The identification of different pain mechanisms within individual In 2016, the term nociplastic pain was introduced to describe a third diseases is an active area of research that will result in more accurate pain mechanism1 that is distinct from both nociceptive and neuro- phenotyping in the future10–13. In addition, the updated classification pathic pain. Nociceptive pain is defined by the International Asso- system for chronic pain, implemented in ICD-11 in 2019, was developed ciation for the Study of Pain (IASP) as “pain that arises from actual or to improve the recording of chronic pain3. With this approach, chronic threatened damage to non-neural tissue and is due to the activation of primary pain comprises conditions such as fibromyalgia, IBS and many nociceptors”; neuropathic pain is defined as “pain caused by a lesion of the other COPCs, which are considered to be health conditions in or disease of the somatosensory nervous system.” The IASP defines their own right3. By contrast, chronic secondary pain describes cases nociplastic pain as “pain that arises from altered nociception despite in which the pain initially manifests owing to another condition such no clear evidence of actual or threatened tissue damage causing the as rheumatoid arthritis, and the term is used to identify the transition activation of peripheral nociceptors or evidence for disease or lesion in which pain requires treatment independent of the initiating disease of the somatosensory system causing the pain.” or pathology3. Nociplastic pain can manifest in any chronic pain condition. How- ever, this type of pain is best exemplified in conditions such as fibro- Symptoms myalgia, interstitial cystitis/bladder pain syndrome (IC/BPS), irritable People with nociplastic conditions typically experience pain that is bowel syndrome (IBS), chronic low back pain (cLBP), tension head- disproportionate to any peripheral pathology present4,14,15. The pain ache and migraine, and temporomandibular disorder (TMD), where itself is often constant and tends to follow a diffuse, widespread dis- nociplastic pain is thought to be the predominant pain mechanism2. tribution across the body11. Pain that is poorly localized, follows a non- These conditions have been collectively referred to as idiopathic pain anatomical distribution or is present in areas such as the upper arms or syndromes, centralized pain or central sensitivity syndromes, func- upper legs is suggestive of nociplastic pain6. The quality of the pain is tional pain syndromes and, most recently, chronic overlapping pain typically described as dull, deep and aching with variation in location conditions (COPCs)2. The 2019 International Statistical Classification and intensity over time, and is often accompanied by dysaesthesia and of Diseases (ICD-11) characterizes these conditions as ‘primary pain’, paraesthesias4,6,16. Furthermore, the pain is often unpredictable, wors- meaning that pain is the primary problem rather than a consequence ening or easing in response to multiple nonspecific factors11. Although of another disease3. As described in this Review, a majority of evidence this description is common for typical presentations, particularly for has suggested that this type of pain is driven primarily by aberrant pain conditions such as fibromyalgia, the exact pain characteristics can vary processing within the central nervous system (CNS), although periph- dramatically between individuals, in terms of location, severity and eral factors might also play an important part in pain manifestation in descriptors, and according to the dominating clinical syndrome pre- many individuals. sent. Therefore, considering nociplastic pain as a spectrum of different Our understanding of the phenotypic features as well as the under- pain features rather than a single, specific presentation is more helpful4. lying aetiology and pathophysiology of nociplastic pain is improving. Non-pain symptoms can often provide helpful diagnostic guid- This Review examines research findings from human participants pre- ance. Common non-pain symptoms include intrusive fatigue, poor sumed to have nociplastic pain, with an emphasis on clinical studies of refreshment from sleep, depressed mood, problems with concentra- COPCs. We delineate the key phenotypic features of nociplastic pain, tion and short-term memory, and hypersensitivity to visual, auditory including the spatial distribution of pain, as well as common comorbid and tactile stimuli4,11,12 (Fig. 1). Other factors suggestive of nociplastic symptoms including fatigue, sleep, memory, mood problems and pain include the presence of numerous comorbid illnesses and hyper- multisensory hypersensitivity. Next, we discuss risk factors spanning sensitivities that are often described as ‘allergies’, as well as a history of Nature Reviews Neurology Review article Widespread pain nociplastic severity, can predict surgery and opioid non-responsiveness following arthroplasty25 and hysterectomy26. The 2019 publication CNS symptoms of clinical criteria and a grading system specifically for nociplastic Brain fog Low mood pain in the musculoskeletal system13 is an improvement over previous Sleep disturbance measures and is useful for clinicians seeking an understanding of pain Fatigue mechanisms to help guide treatment decisions. Multisensory Head/facial pain Migraine Screening tools such as the Patient Health Questionnaire-9 hypersensitivity Pain Chronic tension-type (ref. 27), Generalized Anxiety Disorder-7 (ref. 28) and Insomnia Severity Light headache Temporomandibular Scale29,30, or short National Institutes of Health (NIH) Patient-Reported Odours Noises disorder Outcomes Measurement Information System (PROMIS) measures of Touch these same domains can also help to identify relevant non-pain features such as depression, anxiety and sleep disturbance, respectively. Work is underway to identify which tools or combination of features prove most useful for discerning different pain mechanisms10–13. Treatment options Musculoskeletal pain The core principles for treating nociplastic pain are summarized in Fibromyalgia Chronic low Box 1. A strong patient–clinician partnership, built on effective com- back pain munication, is essential for supporting the individual in taking an active Visceral pain IBS role in developing strategies to improve their quality of life31–33. Valida- Endometriosis tion of the experienced symptoms, offering an explanation of the pain Urological chronic pelvic pain process, highlighting the multifactorial nature of the pain, sharing a Vulvodynia specific diagnosis with the patient and setting realistic expectations can all help to encourage individuals to take an active role in their own treatment and to adopt self-management strategies31. Non-pharmacological options are the mainstay of evidence-based Fig. 1 | Central nervous system-mediated features of nociplastic pain. In options available to people with nociplastic pain4,6,32,34. Education is addition to widespread pain that can involve the viscera, head and face, and considered to be the foundation of developing a care plan and ena- musculoskeletal system, people with nociplastic pain often experience a cluster bles individuals to take a more active role overall4. Ideally, this educa- of central nervous system (CNS)-mediated symptoms, including cognitive tion would include a basic description of pain mechanisms including disturbances, mood problems such as depression and anxiety, unrefreshing sleep components of the biopsychosocial model, which acknowledges and fatigue, and multisensory hypersensitivity. Individuals with nociplastic pain that an individual’s experience of chronic pain involves a complex are commonly diagnosed with multiple chronic overlapping pain conditions. IBS, interaction between biological, psychological and social factors35,36. irritable bowel syndrome. Education could also include suggestions for healthy lifestyle habits such as strategies to increase physical activity, sleep better and man- age stress4. Various psychological treatment programmes incorporate unresponsiveness to conventional analgesics or procedures intended a number of these strategies, including classic pain-based cognitive to relieve pain4,6,13,17. In addition, a personal or family history of chronic behavioural therapy (CBT) given either in person or via the internet, pain not limited by any anatomical location should alert the clinician CBT for insomnia, or newer therapeutic approaches aimed at indi- to the possibility of nociplastic pain, as COPCs are often familial4,17. viduals with a history of trauma, for example, emotional awareness The combination of numerous symptoms affecting multiple systems exposure therapy or neural re-processing, as well as acceptance and and limited consultation time can be challenging for patients and clini- commitment therapy4,32,37. cians alike18. However, identifying and acknowledging this feeling of Increasing evidence has demonstrated the effectiveness of a num- overwhelm can be reframed as a useful indicator of nociplastic pain, ber of non-pharmacological therapies, including mindfulness, yoga, rather than a marker of failure17. Tai Chi, acupuncture or acupressure, and chiropractic manipulation37; however, more high-quality randomized controlled trials of these treat- Diagnostic tools ments are needed. In addition, several neurostimulatory approaches In addition to the clinical features described above, a range of question- have been shown to be of some benefit, including transcranial direct naires are available to assess the features of nociplastic pain. Although current stimulation, vagal nerve stimulation and transcutaneous questionnaire-based assessment should not replace clinical assess- electrical nerve stimulation38–41. ment, screening tools such as the Central Sensitization Inventory19,20 Although data that evaluate pharmacological options specific can be used to identify common characteristics of nociplastic pain11. for nociplastic pain are limited, the number of pharmacological treat- Abnormal scores on neuropathic pain questionnaires, such as PainDE- ments shown to be effective for chronic pain conditions overall is TECT21, can help to distinguish features of neuropathic pain from those diminishing4,32,34,42,43. Traditional so-called analgesic medications of nociplastic pain11,22,23. Furthermore, the severity of nociplastic pain including non-steroidal anti-inflammatory drugs and paracetamol can be measured using the Fibromyalgia Survey Criteria4,24. There is are typically ineffective, and opioids should be avoided by individu- increasing recognition that nociplastic pain should be considered as a als with nociplastic pain4,32,34. More effective medications include continuum rather than a binary diagnostic category. For example, the tricyclic compounds, such as low-dose cyclobenzaprine given at Fibromyalgia Survey Criteria, when used as a continuous measure of bedtime, serotonin–noradrenaline reuptake inhibitors (SNRIs) such Nature Reviews Neurology Review article Box 1 Core principles of treating nociplastic pain The core principles of treating nociplastic pain can be tailored to Treatment of comorbidities: each patient, and should begin with an acknowledgement that the Depression individual’s symptoms are real, in concert with a specific diagnosis4. Anxiety Non-pharmacological options, as listed below, are recommended as Post-traumatic stress disorder the first step for treatment. Insomnia Non-pharmacological therapies Non-pharmacological therapies: Patient education: Physical therapy Explain pain processes, treatment strategies and rationale using Acupuncture simple language Other integrative therapies, for example, yoga and Tai Chi Set realistic expectations and common goals Promote self-management Pharmacological therapies Centrally acting drugs Lifestyle: - Tricyclic antidepressants such as amitriptyline and Increase health-related physical activity cyclobenzaprine Diet and weight management - Serotonin–noradrenaline reuptake inhibitors such as duloxetine Address health behaviours, for example, substance use and milnacipran Proper sleep hygiene - Noradrenaline reuptake inhibitors such as esreboxetine Stress reduction - Gabapentinoids Continue life participation, such as work and social Simple analgesics and non-steroidal anti-inflammatory drugs have activities little effect Avoid opioids Psychological therapies: Cognitive behavioural therapies Potential future therapies Acceptance-based and mindfulness therapies Neuromodulation, such as transcranial stimulation and deep brain Others, including emotional exposure and awareness stimulation therapy Novel pharmacological therapies, such as cannabinoids as duloxetine and milnacipran, noradrenaline reuptake inhibitors This genetic predisposition probably interacts with environmental fac- such as esreboxetine, and gabapentinoids. Although the benefit of tors, perhaps through epigenetic influences, given the role of early-life these therapies is limited by marginal efficacy and side effects, these experiences on modulating genetic function49. classes of drugs can be considered as part of the multimodal strategy for improving quality of life in people with nociplastic pain4,32,43,44. Female sex All nociplastic pain conditions display a female sex preponderance and Risk factors are approximately 1.5–2 times more common in female than in male Given that the term nociplastic pain was first described in 2016 (ref. 1), individuals, particularly post-puberty50,51. In healthy people without few studies to date have focused solely on risk factors for this type of chronic pain, female individuals display greater sensitivity to painful pain. However, research in COPCs, and fibromyalgia in particular, can pressure and thermal stimuli, but not other modalities, than male indi- shed light on common precipitators. Factors spanning early-life events, viduals52,53. Although the underlying mechanisms off this difference are lifestyle behaviours and pain exposure influence nociplastic pain onset poorly understood, gonadal hormones, particularly oestrogen and (Fig. 2), as described in this section. testosterone, might have a role54–56. Evidence to support this hypothesis comes from the observation that sex differences in pain sensitivity Genetics appear around the time of puberty57, and that in female individuals, Nociplastic pain conditions, such as IBS and fibromyalgia, are complex pain responses vary with the menstrual cycle58. disorders that display heritability similar to other common chronic Sex hormones might modulate the pain experience through illnesses45. Genetic association studies have identified causal genetic actions on both the peripheral nervous system and the CNS. At high variants in serotonergic46 and adrenergic47 pathways, pointing to poten- concentrations, oestradiol displays anti-nociceptive effects and can tial underlying biological mechanisms. Findings from a large-scale modulate efficiency of descending pain inhibition in healthy women59; genome-wide association study of relevant chronic pain phenotypes, however, at low concentrations, oestradiol can enhance vulnerability such as multisite chronic pain, have suggested that genes associated to pain60. In a mouse study, orchiectomy of male mice produced longer with brain structure and function, as well as neurodegenerative, psy- lasting and more widespread sensitivity to pain than controls, whereas chiatric and autoimmune disease, might have a role in chronic pain48. testosterone administration to females or orchiectomized males had Nature Reviews Neurology Review article the opposite effect, suggesting that testosterone is protective against are more likely a risk factor than a primary pathophysiological driver widespread pain61. Testosterone also seems to exert anti-nociceptive of nociplastic pain. In line with this theory, population-based studies effects in humans. In a 2013 study of adult female individuals taking have suggested that approximately only 10% of cases of fibromyalgia oral contraceptives, reduced levels of endogenous testosterone were are attributable to ACEs76. associated with a reduced thermal pain threshold and reduced activity in the rostral ventromedial medulla (RVM), an important component Sociodemographic factors of the descending pain modulatory system (DPMS)60. Nociplastic pain is more common among socioeconomically deprived Painful menstrual cycles and higher prevalence of adverse child- individuals, those who are unemployed, those with lower education and hood experiences in female individuals might also contribute to the other vulnerable demographics77. The clustering of nociplastic pain elevated risk of nociplastic pain. For example, a 2021 study has shown within families suggests a mix of environmental, genetic and epigenetic that in a 10-year follow-up period, dysmenorrhoea increased the risk of influences78. This relationship is bidirectional: pain and related symp- developing chronic multisite pain (in non-pelvic anatomical locations) — toms can also lead to missed school, lower educational attainment, a cardinal feature of nociplastic pain62. Furthermore, another study unemployment or disability79. has shown that women with IBS were more likely to report a history of adverse childhood experiences (ACEs) than men63. Physical inactivity Physical inactivity is one of the most consistently identified risk fac- Age tors for nociplastic pain. One hypothesis is that physical activity alters Age displays a nonlinear relationship with pain. Most regional noci- descending pain modulation, having a protective role against the devel- plastic pain conditions increase in prevalence following puberty until opment of nociplastic pain. Preclinical work in mice has shown that mid-life64; however, conditions such as fibromyalgia peak later in life65, regular physical activity can decrease nociception through effects possibly owing to spreading regional pain. Differentiation between on the RVM80. In clinical studies, physical activity is associated with nociplastic pain and pain resulting from age-related degenerative diminished pain facilitation, whereas sedentary time is associated changes in which accruing nociceptive input can lead to peripheral with decreased pain inhibition81. Furthermore, cessation of regular and central sensitization is challenging66. exercise in healthy adults can lead to the development of nociplastic symptoms such as widespread pain and fatigue82. A cross-sectional Early-life factors analysis of middle-aged adults in the UK Biobank has found that levels Early-life stressors, such as intrauterine factors, maternal stress, low of objective physical activity are inversely associated with the number of birth weight67 and neonatal intensive care admission68 have been asso- painful body sites, a key marker of nociplastic pain83. ciated with heightened pain sensitivity69 and a higher prevalence of COPCs in later life70–72, suggesting that these factors predispose indi- Obesity viduals to nociplastic pain67,68. The landmark ACE Study identified a Obesity is associated with a greater prevalence of chronic pain disor- link between ACEs, such as physical and sexual abuse, with later-life ders, including fibromyalgia84. Weight loss can alleviate pain severity in morbidity73, which has been borne out for a range of health outcomes74. chronic pain and, notably, severe calorie restriction appears to reduce Although ACEs, and socioeconomic deprivation in childhood more gen- nociplastic pain even before major weight loss85,86. Mechanical changes erally, are associated with a range of COPCs, including fibromyalgia70, to joints and their associated muscles and tendons seen in obesity pelvic pain71, endometriosis75 and functional abdominal pain72, ACEs could contribute to ongoing nociceptive input and subsequent CNS Nociplastic pain risk factors In utero/infancy Childhood/adolescence Adulthood Old age Genetics and Adverse childhood experiences Poor socioeconomic position Painful conditions epigenetics Puberty/hormonal influences Physical inactivity Multimorbidity Sex Social and developmental Obesity Frailty Maternal stress context Sleep disturbance Low birth weight Depression and anxiety Trauma and stressors Physical injuries Fig. 2 | Risk factors for nociplastic pain across the lifespan. Nociplastic pain However, most individuals with these risk factors do not develop nociplastic is shaped by multiple factors, with childhood and adolescence representing a pain, and the exact mechanisms that promote versus prevent the development particularly vulnerable period of time. Risk factors might compound across the of nociplastic pain remain unclear. lifespan and increase overall risk for nociplastic pain (represented by the blue bar). Nature Reviews Neurology Review article sensitization87. A study by Singh et al. has demonstrated that adults studies has shown that physical trauma is associated with a greater with obesity experience significantly higher lumbar disc compression risk of developing widespread pain and fibromyalgia108. However, the forces while lifting than adults who do not have obesity or overweight88. majority of studies were rated low quality, and were limited by recall Obesity is also associated with a pro-inflammatory state, which might bias and confounding, for example, due to the psychological impact of also play a part in ongoing pain sensitivity89,90. Park et al. have shown traumatic events. A prospective study of US adults in road traffic colli- that serum concentrations of the pro-inflammatory cytokines CRP, sions has found that pain intensity in the emergency department was TNF and IL-6 were positively associated with measures of adiposity89. associated with widespread pain and non-pain symptoms suggestive In addition, obesity can effect physical activity91, mood85 and sleep92, of nociplastic pain, such as fatigue109. Nevertheless, although a higher which in turn can effect nociplastic pain. prevalence of nociplastic pain is apparent among people with certain painful comorbidities such as inflammatory arthritis and inflammatory Sleep disturbances bowel disease, the role of acute local injuries is uncertain. Sleep problems are consistently identified as an important risk factor for nociplastic pain, although uncertainty exists over which characteris- Trauma and stressors tics of sleep quality, such as total duration, phases of sleep and circadian Trauma and stressors during adulthood can initiate or exacerbate noci- rhythm, are most crucial. Foundational studies from Moldofsky93,94 have plastic syndromes. These factors include wartime deployment110, motor demonstrated that sleep deprivation can provoke fibromyalgia-like vehicle collisions111, terrorist events112 and severe infection113. A manifes- symptoms in healthy people, which has since been replicated several tation with prominent nociplastic characteristics is long COVID or post- times95. These experimental studies suggest that female individuals are COVID conditions, marked by fatigue, pain, cognitive complaints and more susceptible to the effects of sleep restriction, and that poor sleep sleep disturbances that develop after COVID-19 infection114. Although and physical inactivity act synergistically in the development of noci- some elements of long COVID appear pathogen-specific, such as the plastic symptoms. Epidemiological studies have also shown that self- persistent loss of smell and taste, the core features were accurately reported sleep problems are a strong risk factor for the development predicted early in the pandemic on the basis of other post-infectious of nociplastic pain96. syndromes seen following a wide variety of pathogens115. In summary, nociplastic pain is shaped by multiple factors, with Psychological factors childhood representing a particularly vulnerable period of time, but Nociplastic pain is closely intertwined with depression, anxiety and most individuals with the above exposures do not develop nociplas- catastrophizing97. In healthy adults, low mood amplifies pain percep- tic pain, and the exact mechanisms that promote versus prevent the tion via maladaptive thought processes and increased activity in brain development of this pain remain unclear. regions responsible for pain perception, suggesting that negative mood can predispose individuals to pain98. A 2023 longitudinal study of the Sensory abnormalities UK Biobank has highlighted that psychosocial factors, including low Abnormalities in sensory perception are common in people with noci- mood, feeling ‘fed up’ and stressful life events, contribute significantly plastic pain. Experimental measurement of perceptual responses to to the development of widespread pain over a 9-year follow-up period99. standardized and quantifiable physical stimuli using quantitative sen- However, for many people who experience chronic pain, factors such sory testing (QST) consistently shows that the majority of individuals as catastrophizing and depression arise owing to the pain itself and can with nociplastic pain display increased sensitivity to painful (referred improve dramatically after alleviation of pain100–102. Moreover, find- to as hyperalgesia) and normally non-painful (referred to as allodynia) ings in children indicate that although sleep disturbances, attention somatic stimulation when compared with individuals who are pain-free issues and somatic symptoms can predict multisite pain development, or have chronic pain without nociplastic features116–127. Pain hypersensi- anxiety and depressive symptoms do not103. Thus, a clear bidirectional tivity in nociplastic conditions is characteristically multisite and occurs relationship exists between mood and pain, but not all individuals with both in symptomatic body sites and in remote or asymptomatic body nociplastic pain have substantial mood issues76. sites; hypersensitivity outside the primary symptomatic area strongly suggests a process of CNS sensitization128. Many people with nociplastic Comorbidities and physical injuries pain also exhibit an imbalance in endogenous pain modulation, primar- The presence of ongoing pain is an important risk factor for the devel- ily observed as facilitated temporal summation of pain and impaired opment of nociplastic pain. A 2019 systematic review found that fibro- conditioned pain modulation on QST129–135, although work published myalgia is approximately four times more prevalent among adults in 2023 calls these findings into question136,137. with inflammatory arthritis than in the general population, with an Evoked pain functional MRI studies combine QST principles with estimated prevalence of 21% among adults with rheumatoid arthritis104. neuroimaging to investigate the link between pain sensations and Similar observations are made among adults with osteoarthritis105 or objective brain function. These studies have shown that increased pain other COPCs. In addition, IBS is present among one-third of people sensitivity in nociplastic pain is associated with augmented activation with inflammatory bowel disease106. of pain-promoting brain regions such as the insula, somatosensory The role of local physical injuries in the onset of nociplastic pain cortex and thalamus, and increased functional connectivity between is less certain. Evidence from a mouse model has suggested that nox- certain regions and brain networks, including the salience and default ious stimulation following an acute injury can predict nociplastic mode networks (DMNs)125,138–142. However, importantly, substantial pain53; however, evidence from human studies is relatively weak. inter-participant and intra-participant heterogeneity is observed in A prospective study of pain-free adults has found that occupational QST outcomes, and some individuals with nociplastic pain, although mechanical injuries were associated with an increased risk of develop- a minority, demonstrate normal to near-normal sensory process- ing chronic widespread pain, although this was smaller than the risk ing141,143–145. For these reasons, we advise against the use of QST for the conferred by psychosocial factors107. A 2018 systematic review of 20 clinical diagnosis or classification of nociplastic pain. Nature Reviews Neurology Review article People with nociplastic pain are frequently hypersensitive to non- themes in network abnormalities have emerged, which might represent somatosensory stimuli. For example, individuals with fibromyalgia the neural signatures of nociplastic pain, including default mode– self-report enhanced sensitivity to environmental auditory, visual salience–sensorimotor network enmeshment, deficits in descending and olfactory stimuli, such as loud noises, bright lights and strong pain modulation and altered reward processing. Much of the research in odours, respectively146,147. These observations have been confirmed this area has focused on people with fibromyalgia, as is reflected below; using experimental sensory tests in people with fibromyalgia148–153 or however, we also draw on neuroimaging studies from other COPCs. several other COPCs154–157. This hypersensitivity is also reflected in the function of the CNS during functional MRI tasks; for example, increased Brain network enmeshment insular and anterior lingual gyrus activation has been observed in peo- The brain is a complex network with systematic patterns of neural ple with fibromyalgia during non-painful tactile, auditory and/or visual activity that integrate information across disparate regions of the stimulation when compared with healthy individuals158–160. In addition, cortex. These patterns of neural activity form networks and can be a correlation exists between sensitivity to visual and auditory stimuli observed in the brain both at rest and while performing a task 171. Neu- and pressure pain thresholds at distant body locations in both healthy roimaging studies in people with nociplastic pain have found changes individuals and people with fibromyalgia151,158. across every large-scale canonical brain network; however, among Aberrant processing of sensory stimuli in nociplastic conditions is these findings, the most replicable are changes in the default mode, not limited to external and environmental stimuli but manifests also in salience and sensorimotor networks (Fig. 3). The DMN has major hubs increased interoceptive sensitivity, meaning a heightened awareness in the medial prefrontal cortex and posterior cingulate/precuneus, of somatic sensations arising from inside the body, such as heart palpa- and is involved in self-referential thought and is typically active at tions, dry eyes or bladder distention8,161–163. Interoceptive sensitivity, rest172. The salience network (SLN), consisting of hubs in the insular the spatial distribution of pain and environmental sensitivities together cortex and anterior cingulate cortex (ACC), directs attention and has are strongly correlated within individuals — a phenomena referred to as a key role in integrating sensory, emotional and cognitive informa- generalized sensory sensitivity164. This symptom cluster is associated tion173. In healthy individuals, these networks are anti-correlated: when with COPCs164. Furthermore, the presence of heightened interoceptive one network is active, the other is deactivated174. The sensorimotor sensitivity is associated with the development of new chronic pain syn- network (SMN), anchored by primary sensory and motor cortices, dromes in adults, as well as in children and adolescents164,165. Multisensory processes sensory input and initiates motor responses. Many stud- hypersensitivity can distinguish between people with pain conditions ies have now shown that in nociplastic pain conditions, these three and those without, as well as between individuals with localized, inter- brain networks are more connected, or enmeshed, with one another mediate and widespread, or nociplastic pain presentations147. Together, than in healthy individuals, in whom the networks are more distinct these data support the notion that CNS-mediated multisensory ampli- or even anti-correlated174. fication and altered sensory integration are crucial components of the Increased connectivity between regions of the DMN–SLN–SMN nociplastic pain phenotype. has been reported in people with fibromyalgia in resting-state stud- Individuals with nociplastic pain often report multisensory hyper- ies and during exposure to painful and non-painful sensory stim- sensitivity; however, studies have indicated that these individuals are uli141,160,175–178. This increased connectivity has also been identified across not able to better discriminate between different levels of sensory many other COPCs, including IC/BPS179,180, cLBP181,182, migraine183,184 input or detect sensations at a lower threshold than people without and cluster headache185, suggesting that brain network enmeshment nociplastic pain. This lack of heightened sensory detection and dis- is a general marker of nociplastic pain. The strength of connectivity is crimination has been demonstrated using tasks that consider tactile often related to increased clinical pain at the time of scanning175,182,186 discrimination and odour thresholds or discrimination157,166,167. Because and some evidence shows that connectivity decreases after success- individuals with nociplastic pain do not appear to be better at detecting ful treatment187,188. Furthermore, DMN–SLN–SMN enmeshment has or perceiving stimuli, it follows that the interpretation and salience also been observed in conditions traditionally thought of as driven of stimuli are the root of aversive perceptual experiences. Moreover, by peripheral damage or inflammation, including osteoarthritis186, although multisensory hypersensitivity is a normal feature of noci- rheumatoid arthritis189 and ankylosing spondylitis190,191. plastic pain at the group level, individuals do not necessarily show Several studies across different COPCs have shown that DMN– equal levels of hypersensitivity across all sensory modalities. Sensory SLN–SMN connectivity correlates with the spread of pain localiza- profiling has demonstrated that subgroups of individuals show dif- tion177,179,189. For example, in a study of people with chronic pelvic pain, ferent patterns of normal sensitivity with hypersensitivity and/or Kutch and colleagues found that both individuals with IC/BPS with hyposensitivity, which could represent unique endophenotypes to be widespread pain and those with fibromyalgia had similarly high SLN– explored in future research117. SMN connectivity, whereas individuals with pain localized only to the pelvic region were more neurobiologically similar to healthy controls179. Brain abnormalities Together, these findings suggest that nociplastic mechanisms are often The experience of pain is a product of neural activity across a complex present in subsets of individuals in any chronic pain condition and that network of brain regions, which is influenced even in healthy individuals DMN–SLN–SMN enmeshment is both a marker of nociplastic pain, as by a multitude of factors including nociceptive input, context, emo- well as pain intensity. tion and cognition168. Although the precise causes of nociplastic pain Altered connectivity in people with nociplastic pain could be a remain unknown, evidence has demonstrated that in some individuals, result of an increase in excitatory neurotransmitters and/or a decrease the CNS can drive, amplify and/or maintain a pain state in the absence in inhibitory neurotransmitters. People with fibromyalgia exhibit of ongoing tissue or nerve damage. Over two decades ago, neuroim- increased excitatory neurotransmission in the SLN192 and DMN193 as aging studies first demonstrated altered neural processing of pain in indicated by combined glutamate and glutamine levels measured by people with presumed nociplastic pain138,169,170. Since then, common magnetic resonance spectroscopy. Many studies have shown increased Nature Reviews Neurology Review article levels of glutamate and glutamine, particularly within the insula and elevated levels of glutamate and decreased levels of GABA in the insula posterior cingulate, are also frequently correlated with increased clini- of people with fibromyalgia are associated with increased pain sensitiv- cal pain severity in people with fibromyalgia193,194. A 2020 meta-analysis ity on QST192,196, mirroring preclinical findings in rats199. This finding fur- has found evidence of increased levels of glutamate and glutamine in ther suggests that altered excitatory and inhibitory balance contributes SLN and DMN regions across many nociplastic pain conditions, includ- to nociplastic pain. In support of this premise, we have more recently ing migraine, fibromyalgia, cLBP, TMD, pelvic pain and IBS, compared shown that higher excitatory than inhibitory tone in the anterior insula with controls195. However, no significant difference from controls is associated with large-scale connectivity patterns, hyperalgesia and was found when each pain condition was examined independently; clinical pain in individuals with fibromyalgia200. variations in study populations, methodology and regions of interest Despite increased connectivity from the SMN to the DMN and between studies make synthesis difficult. SLN regions, network connectivity within the SMN is decreased in Some evidence exists for altered γ-aminobutyric acid (GABA) levels people with nociplastic pain201. Primary somatosensory and motor in nociplastic pain, including reduced levels of GABA in SLN regions196,197 cortices have a somatotopic organization, meaning a continuous and increased levels of GABA in the DMN198. We demonstrated that representation of the body on the cortex, although an update to the ↓ Within-SMN functional connectivity DMN SMN mPFC S1 PCC M1 IPL ↑ DMN–SMN–SLN Neurochemical changes connectivity ↑ Endogenous opioids ↑ Glutamate and glutamine ↓ Noradrenaline and serotonin ↓ GABA ↑ Activation ↑ Facilitatory connectivity Immune mechanisms SLN during ↓ Inhibitory connectivity ↑ CSF inflammatory mediators ACC multisensory Insula stimulation ↑ Immunoreactivity of circulating cells Peripheral mechanisms ↓ Activity ↓ Intraepidermal nerve fibre ↓ Functional density connectivity Ongoing nociceptive input ↓ Inhibitory and peripheral sensitization connectivity DPMS ACC Amygdala Hypothalamus PAG ↑ Increased RVM ↓ Decreased Descending inhibitory Ascending and facilitatory effects nociceptive input Fig. 3 | The pathophysiology of nociplastic pain. Neuroimaging studies have influences on pain perception. Alterations in the immune system and peripheral shown abnormal brain connectivity in people with nociplastic pain. The spatial nervous system are also observed in people with nociplastic pain. Future work is distribution of pain across the body is associated with increased functional needed to understand how these systems interact in nociplastic pain states. ACC, connectivity between regions of the default mode network (DMN), salience anterior cingulate cortex; CSF, cerebrospinal fluid; GABA, γ-aminobutyric acid; network (SLN) and sensorimotor network (SMN) in pain conditions with IPL, inferior parietal cortex; M1, primary motor cortex; mPFC, medial prefrontal presumed nociplastic mechanisms. In addition, people with nociplastic pain have cortex; PAG, periaqueductal grey; PCC, posterior cingulate cortex; RVM, rostral altered activity within the descending pain modulatory system (DPMS), which ventromedial medulla; S1, primary somatosensory cortex. modulates activity in the spinal dorsal horn and can have inhibitory or facilitatory Nature Reviews Neurology Review article Box 2 Is the development of nociplastic pain associated with neural vulnerability? As most neuroimaging studies are performed in adults who have activity in SMN, SLN and DMN regions and reduced activity in a key often had chronic pain for years, studying the role of the central pain inhibitory region, the periaqueductal grey, in response to a nervous system in pain development or vulnerability is challenging295. painful stimulus at baseline when they were pain-free, compared To our knowledge, only two studies296,297 to date have examined brain with individuals who remained pain-free297. Interestingly, neither structure and function before the onset of pain, as described below. of these studies found brain structure to be predictive of future In a 2022 study of pain-free children enrolled in the longitudinal pain, suggesting that changes in brain structure result from Adolescent Brain Cognitive Development Study (ABCD Study), we neuroplasticity as a consequence of pain rather than the cause, as compared resting-state functional connectivity in children who previously thought298. These observations are in line with studies developed multisite pain 1 year after neuroimaging with children in adults with established nociplastic pain features, in which who remained pain-free. At baseline, children who developed heightened connectivity between the DMN, SLN and SMN is one multisite pain had increased functional connectivity between of the most consistent findings (as discussed in the section ‘Brain regions of the salience network (SLN), sensorimotor network (SMN) network enmeshment’)175,182,186,189,190. Together, the findings suggest and default mode network (DMN)296. Subsequently, a study in that these patterns of brain connectivity are trait-like and indicate an chemotherapy-naive adults has found similar results: people who underlying vulnerability in which brain function can predispose developed pain after chemotherapy treatment had increased brain an individual to developing pain. classic homunculus has been proposed within the past few years202,203. In addition to inhibitory effects, the DPMS can also be facilita- Accordingly, the SMN structural and functional alterations observed tory168,216. For example, in a functional connectivity study, we found in nociplastic pain might also be somatotopically specific and depend- that connectivity between the periaqueductal grey and RVM correlated ent on the region (or regions) of the body that are most affected, with pain facilitation in people with fibromyalgia217. By contrast, this for example: the S1 back region in cLBP181,204, the S1 pelvis region in connectivity correlated with pain inhibition in healthy controls, indi- chronic pelvic pain179 and the S1 hand region in carpal tunnel syn- cated by more efficient conditioned pain modulation on QST217. Simi- drome205. In line with this hypothesis, a 2023 study of adolescents with larly, another study in people with osteoarthritis has shown increased fibromyalgia has found decreased within-network SMN connectivity activity in the periaqueductal grey during painful stimulation that between somatotopically specific S1 regions that were reported as correlated with self-reported pain218. Together, these findings suggest painful on a bodymap178. Together, these findings indicate that in that the DPMS can also have a role in promoting pain. nociplastic pain, strong within-network connectivity between regions The key neurotransmitters involved in the DPMS include noradren- of the SMN shifts to increased connectivity between S1, SLN and DMN aline, serotonin and endogenous opioids168. People with nociplastic regions. More research is needed to determine the causal nature of pain have decreased levels of noradrenaline and serotonin in the cer- these connectivity changes, although some evidence has shown that ebrospinal fluid (CSF)219, whereas endogenous opioid levels in the CSF heightened SMN–SLN–DMN connectivity predates the development are elevated220. In addition, people with fibromyalgia have decreased of pain (Box 2). µ-opioid receptor number or availability in the brain221. One inter- pretation of these data is that individuals with nociplastic pain have Deficits in descending pain modulation increased levels of endogenous opioids, which in turn results in an The descending pain modulatory system (DPMS) modulates activity endogenous form of opioid-induced hyperalgesia221. The biochemical in the spinal dorsal horn and influences how nociceptive input from findings are aligned with clinical evidence that drugs that augment the periphery reaches the brain168. The DPMS includes the rostral ACC, noradrenaline, such as tricyclics or SNRIs, can be effective in treating amygdala, hypothalamus, periaqueductal grey and RVM. During evoked subsets of individuals with COPCs, whereas opioids are ineffective or pain, people with fibromyalgia have decreased activation in the ros- might make nociplastic pain worse222. Further supporting this hypoth- tral ACC, brainstem and dorsal horn206,207, and decreased connectivity esis, preliminary data show that low doses of the µ-opioid receptor between the ACC, amygdala, hippocampus and brainstem compared antagonist naltrexone reduce fibromyalgia pain223,224. with healthy controls208–210. Furthermore, decreased functional con- nectivity between regions of the DPMS is also present during the rest- Dysfunctional reward processing ing state in individuals with fibromyalgia211–213 and other COPCs214,215. Many studies have shown disrupted reward circuitry in chronic pain In people with migraine, functional connectivity between the periaq- states. People with fibromyalgia have decreased dopamine release ueductal grey and ACC increased after acupuncture treatment and in the striatum during experimental pain225. Similar findings were was associated with symptom improvement214. In summary, people reported in people with cLBP226. Some studies have found blunted with nociplastic pain have deficits in descending pain modulation, as neural activity in the nucleus accumbens during a reward task in people evidenced by reduced activity and functional connectivity in DPMS with cLBP or fibromyalgia compared with healthy controls227, although brain regions. other studies have found no differences in this activity228, perhaps Nature Reviews Neurology Review article owing to sex differences in reward processing229. Interestingly, reward and astrocytes could be potential therapeutic targets for inflammation- circuits have also been implicated in depression, and some evidence induced pain sensitivity257. Collectively, these studies show that the has shown that altered reward processing in people with chronic pain immune system, in concert with the CNS, is capable of producing a also correlates with depressive symptoms227,230. A growing body of similar set of symptoms as those associated with nociplastic pain, and research indicates that alterations in the function, structure and con- that some patterns of CNS reorganization — for example, increased nectivity of corticostriatal regions involved in reward processing can connectivity between elements of the DMN, SMN and SLN — that are successfully predict the transition from acute to chronic pain231–234. associated with nociplastic pain are also induced by immune–CNS One hypothesis for explaining these findings is that changes to reward crosstalk. processing render some individuals unable to experience pain relief Evidence from positron emission tomography (PET) studies has after treatment, as previous studies have indicated that the reward indicated microglial and astrocyte dysregulation in nociplastic pain system is key to experiencing analgesic effects235,236. conditions. One study using the PET ligand [11C]PBR28, a marker of microglia and astrocyte activation, found higher uptake values in Immune function people with fibromyalgia than in healthy controls across multiple Nociplastic pain conditions have been investigated for evidence of pain-processing regions of the cortex, including the somatosensory, dysregulated immune function for decades. Meta-analyses in people dorsolateral prefrontal and cingulate cortices, as well as the precu- with nociplastic pain have found some increased levels in blood markers neus258. Similarly, [18F]DPA-714, a marker of early microglial activation, of inflammation, including IL-8, compared with healthy controls237–240. showed increased binding in individuals with fibromyalgia in parallel However, the studies were limited by a high degree of heterogeneity brain regions compared with those shown with [11C]PBR28 (ref. 259). in findings between studies and issues with confounding influences Increased glial activity in nociplastic pain is one potential mechanism such as sedentary behaviour. Despite this evidence of inflammation by which TLR4 antagonists such as low-dose naltrexone reduce pain in nociplastic pain states, the classic nociplastic pain conditions such or fatigue in fibromyalgia, although modulation of endogenous opi- as fibromyalgia, IBS, tension headache and IC/BPS do not respond to oidergic tone is also a viable hypothesis, as discussed in the section anti-inflammatory or immunosuppressive therapies241. Conversely, ‘Deficits in descending pain modulation’260,261. However, many pain studies of CSF from people with fibromyalgia show that inflamma- conditions, including those with peripheral nociceptive input as a main tory molecules and signalling pathways are more active in the CNS in component, also show increased CNS uptake values for [11C]PBR28, nociplastic pain states than in healthy individuals242–244. These findings which suggests that this type of neuroinflammation is not specific to suggest that sensitization via inflammatory signalling molecules in nociplastic pain262. the CSF is a potential pathophysiological mechanism in nociplastic Definitive conclusions about the role of the immune system pain conditions. in nociplastic pain have been challenging for two reasons. First, Within chronic pelvic pain conditions, evidence indicates that nociplastic pain is rarely recognized until adulthood, which makes people with more nociplastic characteristics, such as increased wide- researching the developing immune system and its bidirectional spread pain, COPCs and increased experimental pain sensitivity, have communication with the CNS as pathophysiological drivers of pain heightened ex vivo immunoreactivity to agonists of Toll-like receptor 4 difficult to establish. Many studies show that people with nociplastic (TLR4), a highly conserved element of the innate immune system that is pain states disproportionately experience trauma and adversity in frequently found on sentinel immune cells as well as microglia and astro- childhood263–266; these experiences can affect the immune system, cytes in the brain and spinal cord245. Conversely, unstimulated immune which in turn might increase the proclivity to nociplastic pain. Second, profiles (measures of activity without any immune provocation) do animal models of nociplastic pain require induction of the widespread not distinguish between subtypes of disease246–248. This distinction is pain phenotype, which often involves using repeated mechanical or important because cell types rich in TLR4, such as monocytes, are criti- inflammatory insults that are rarely analogous to the natural history cal for communication between the immune system and the CNS and of nociplastic pain, in which psychosocial stressors are more common can even traffic into the CNS under conditions of stress249–251. than repeated injury or infection267. Future research should focus on Cytokines in the CNS promote conserved behavioural and physi- the interface between the developing immune system and the CNS ological changes, such as anorexia, fever, fatigue, social withdrawal and in humans, as well as reverse-translated models of nociplastic pain in sensitivity to pain, that are sometimes referred to as ‘sickness behav- the preclinical arena. iours’ and are associated with acute illnesses252. Work from the past few years has suggested that ex vivo immunoreactivity — the degree Peripheral mechanisms to which cells respond to a challenge by releasing pro-inflammatory In addition to central processes, peripheral mechanisms268 also probably cytokines — is associated with CNS adaptation and reorganization contribute to nociplastic pain; however, controversy exists around the across multiple brain networks in chronic pain as well, echoing findings specific role that these processes have in the pathogenesis of nociplastic from the sickness behaviour literature253–255. pain states. IgG from people with fibromyalgia produced hyperalgesia Inflammatory molecules originating in the periphery can influence when injected into mice and increased nociceptor responsiveness269, the CNS via multiple routes, including rapid transmission via interac- suggesting to these investigators that a potential antibody-dependent tion with receptors on primary afferent nerves, gradual transmission process of peripheral sensitization occurred, but this effect was not through volume diffusion across circumventricular organs outside the replicated by an independent research group270 and continues to be protection of the blood–brain barrier and direct transmigration of debated271. Instead, the latter study identified infiltration of sensory peripheral cells into the CNS parenchyma256. Evidence has suggested ganglia by neutrophils as essential to promoting pain hypersensitiv- that de novo synthesis of the IL-1 family in the CNS is a crucial step in ity and sensitization of dorsal horn cells to noxious stimulation, with initiating the central neuroinflammatory cascade, as summarized in the reversible effects when neutrophils were depleted270. This finding review by Mailhot et al.257. The authors suggest that reactive microglia supports a neutrophil-dependent mechanism of CNS sensitization. Nature Reviews Neurology Review article Fig. 4 | Subtypes of nociplastic pain: top-down Proposed subtypes of nociplastic pain and bottom-up. A summary of two potential subtypes of nociplastic pain, tentatively termed Top-down Bottom-up ‘top-down’ and ‘bottom-up’. Top-down nociplastic pain is unlikely to resolve after treatment directed at the periphery, which suggests that augmented pain Multisite pain and Yes Yes processing in the central nervous system can occur hyperalgesia and be maintained independent of nociceptive input. Individuals whose pain began early in life and Sex differences Female >> male Female > male have multiple chronic overlapping pain conditions (COPCs) and multisensory sensitivity are more likely to have top-down nociplastic pain. By contrast, Later in life Young bottom-up nociplastic pain stems from ongoing Age at pain onset (as nociceptive insults (often during puberty) accrue) peripheral nociceptive input and is likely to improve when that stimulus is removed. Individuals with the Family history of pain Yes No bottom-up form of nociplastic pain are less likely to have COPCs and other comorbidities, and often pain begins later in life. Figure adapted with permission Presence of multiple COPCs Yes Yes from ref. 286, Wiley. Psychological comorbidity High Moderate Increased sensitivity to High Low/moderate non-pain sensory stimuli Pain resolves when nociceptive input is No Yes removed Where these studies agree is that dorsal root ganglia are potentially mechanisms by the CNS, rather than a pathophysiological process of important but overlooked contributors of pain hypersensitivity in these the peripheral nerves themselves. nociplastic pain models. Follow-up studies have shown that IgG binds Collectively, the findings discussed here suggest that nociplastic to human anti-satellite glia cells in people with fibromyalgia with the pain and peripheral pain generators (whether nociceptive or neuro- degree of binding associated with disease severity272. pathic) mutually shape the experience of chronic pain. Continuous Small-fibre pathology is well documented in a substantial propor- nociceptive input from the periphery undeniably sensitizes the CNS tion of people with fibromyalgia273. Approximately 30–70% of people and, similarly, the CNS can generate the pain experience in the absence with the condition have reduced intraepidermal nerve fibre density of peripheral nociceptive input. Determination of the balance of (IENFD)274–279, which, in some cases, correlates with symptom sever- peripheral and central contributions in any given individual requires ity276. In addition, microneurography studies in people with fibromy- careful assessment of both peripheral drivers and aberrant CNS pro- algia have shown spontaneous activity in C-fibres280. Abnormalities cesses. In the following section, we discuss two potential subtypes of in the peripheral nerves of the skin of people with fibromyalgia was, nociplastic pain, and how the peripheral–central interaction differs to our knowledge, first observed decades ago by our group among between them. others281. The question is whether these findings have any role in the pathogenesis of nociplastic pain and its expression. Preclinical data Subtypes of nociplastic pain: top-down and suggest not282. We demonstrated that decreased IENFD, coupled with bottom-up increased nociceptive behaviours, can be induced in rodent models The pathophysiology of nociplastic pain includes amplification of simply by increasing glutamatergic tone in the insula282. Moreover, ascending pain information and/or loss of descending inhibitory pain decreased IENFD has been observed in nearly every chronic pain condi- controls, and these processes are believed to occur at the level of the tion and a substantial number of other human diseases (74 in a recent spinal cord, brainstem, subcortical structures and neocortex. This scoping review283), suggesting that this observation is nonspecific and complexity strongly suggests that the neural substrates of nociplas- is more likely to be an epiphenomenon rather than a causal factor of tic pain are heterogeneous and, thus, reflect underlying subtypes of nociplastic pain273,284. nociplastic pain. Within this framework, we posit that at least two broad We hypothesize that the observed reduction in IENFD is indicative subtypes of nociplastic pain exist — tentatively termed ‘bottom-up’ of adaptive neuroplasticity in structure and function within the periph- and ‘top-down’ — that reflect distinct neurobiological features and eral nervous system in response to persistent pain. This adaptation treatment responsivity286 (Fig. 4). is akin to alterations in brain structure identified in individuals with The concept of bottom-up nociplastic pain is most closely chronic pain285. Moreover, findings of C-fibre nociceptor hypersensi- related to the classic interpretation of activity-dependent central tivity in fibromyalgia might be the result of disinhibition of peripheral sensitization, first described by Woolf287, in which prolonged or Nature Reviews Neurology Review article repeated nociceptive stimulation leads to augmented pain process- degrees of central and peripheral mechanisms at play that contribute ing. Removal of the nociceptive stimulus results in the eventual nor- to their pain and related symptoms. malization of these processes. By contrast, top-down nociplastic pain suggests that augmented pain processing can occur and be Conclusion maintained independent of nociceptive input. Preclinical studies Nociplastic pain is part of a broader systemic, multisystem process that support this notion with evidence that animals can develop persis- leads to not only pain but also heightened sensitivity to a broad array tent nociceptive behaviours in absence of nociceptive input267. For of sensory stimuli. Fatigue, poor sleep, memory and mood issues are example, in rodent models of nociplastic pain, prolonged stress288, also common. Abnormal neural activity and altered immune function early-life trauma 289,290 and direct intracerebral neurochemical are key pathophysiological mechanisms of nociplastic pain. Numerous manipulation199,282 can produce widespread nociceptive behaviours peripheral abnormalities have also been identified in people with noci- and cellular and molecular indices of central sensitization. Nonethe- plastic pain. However, the precise role that each of these abnormalities less, establishing directionality in the sensitization process requires have in symptom expression is not fully understood. Although the careful longitudinal studies with measurement of both peripheral international pain research community works to develop and refine and central sensitization processes. formal definitions and diagnostic criteria of nociplastic pain, clinicians Emerging clinical evidence has suggested that similar top- can use the key phenotypic features of nociplastic pain, such as mul- down and bottom-up phenomena exist in humans. In a more nuanced tisite pain on a body map, to identify individuals who might have this interpretation of the IASP definition, we contend that, in some indi- underlying pain mechanism present. In some individuals, nociplastic viduals, nociplastic pain results from ongoing peripheral nocicep- pain or its antecedents might manifest early in the lifespan, which could tive input and is likely to improve when that stimulus is removed. be a window of opportunity for early intervention. For example, in a cohort of people with osteoarthritis and at least We can and should do better in preventing and treating nociplastic mild levels of nociplastic pain, we examined how total hip or knee pain. When this type of pain is identified, therapies that are directed arthroplasty influenced pain outside of the surgical site102. Approxi- preferentially towards CNS processes, including non-pharmacological mately two out of three individuals experienced dramatic reductions and whole-person integrative therapies, are much more likely to be in comorbid pain 1 year after the procedure, strongly suggesting effective than peripherally directed therapies or opioids. 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