Continuing Education Activity

Central pain syndrome (CPS) refers to chronic pain arising from injury or dysfunction within the central nervous system (CNS). Risk factors include genetic predisposition and environmental exposures such as trauma, stroke, or neuroinflammatory disease. The underlying mechanism involves central sensitization, in which the CNS amplifies pain signals despite minimal or absent peripheral input. Individuals with CPS may report burning, tingling, or stabbing pain, along with heightened responses to nonpainful stimuli (allodynia) and painful stimuli (hyperalgesia). Diagnosis of CPS is clinical and typically requires exclusion of peripheral or structural causes of pain. Management is multimodal and may include pharmacological therapy (eg, antidepressants and anticonvulsants), physical rehabilitation, and psychological support. Prognosis varies; many individuals experience persistent, functionally limiting symptoms that adversely affect quality of life.

This activity focuses on the evaluation and management of CPS, including a review of relevant neuroanatomy, risk factors, etiology, pathophysiology, and clinical presentation. This activity also presents current diagnostic and therapeutic recommendations to guide evidence-based practice. Additionally, this activity fosters effective collaboration within an interprofessional healthcare team, optimizing care for individuals with CPS and enhancing clinical outcomes.

Objectives:

• Identify key clinical features and mechanisms of central pain syndrome, including central sensitization.
• Implement evidence-based, multimodal management strategies, including both pharmacological and non-pharmacological therapies.
• Apply current diagnostic criteria and decision-making frameworks to avoid delays in recognition.
• Collaborate with the interprofessional healthcare team to educate, treat, and monitor patients with central pain syndrome to improve health outcomes.

Introduction

Central sensitization occurs when the nervous system remains in a state of hyperactivity, resulting in increased neuronal excitability and enhanced synaptic transmission.[1][2] Despite limited input from the peripheral nervous system (PNS), the central nervous system (CNS) persistently amplifies pain signals. This hyperexcitability heightens pain sensitivity through mechanisms such as ion channel upregulation, reduced inhibitory control, and maladaptive neural plasticity.[3] This state, which includes "wind-up" (temporal summation) as an acute precursor, causes ordinary touch to produce pain (allodynia) or a mild stimulus to feel more painful (hyperalgesia).[4]

Central pain syndrome (CPS), a subset of centralized pain disorders, results from CNS conditions such as stroke or spinal cord injury. CPS involves pathophysiological mechanisms distinct from those underlying nociplastic pain conditions, such as fibromyalgia. Although less prevalent than nociplastic pain, CPS frequently develops following neurological injury, making it crucial for healthcare providers to differentiate it from other centralized pain syndromes to guide appropriate interventions. Exposure to cold or emotional stress may exacerbate symptoms, but it is not essential for diagnosis.

CPS frequently coexists with memory impairment and anxiety, reflecting shared neurobiological pathways. Treatment involves targeted CNS therapies, including antidepressants such as serotonin-norepinephrine reuptake inhibitors (SNRIs) and anticonvulsants such as gabapentin. Conventional pain relievers, including nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, are typically ineffective for centrally mediated pain. Chronic pain affects up to 1 in 5 adults, with a substantial proportion exhibiting features of centralized pain symptoms.[5]

Etiology

Historically, CPS was regarded as a psychiatric diagnosis following traumatic brain injury or as a diagnosis of exclusion. Early theories proposed that CPS reflected a dysfunction of the nervous system, in contrast to the adaptive mechanisms underlying musculoskeletal (nociceptive) pain.[6] For example, withdrawing one's hand from an open flame is beneficial, as pain serves as a protective mechanism to limit harm. In contrast, CPS represents pain that lacks protective value—indeed, it is maladaptive.

Sensory amplification and pain intensify as multiple systemic syndromes overlap. An estimated 2% to 4% of the population experience fibromyalgia, 1% have chronic fatigue, and 4% are affected by somatoform disorders. Moreover, significant overlap exists between regional pain syndromes and psychiatric disorders.

CPS is a type of neuropathic pain that originates within the CNS. The condition can occur in patients with a history of multiple sclerosis or a recent stroke. Acute pain that becomes chronic may undergo centralization, putting patients at risk of developing centralized pain.

Although patients with CPS often perceive their pain as originating peripherally, it is predominantly centralized. Neural signals are amplified, leading to hyperalgesia and allodynia. Centralization of pain can occur when peripheral nociceptive input, such as that from rheumatoid arthritis, persists over time, creating a mixed pain state. Chronic back pain provides a common example of peripheral pain that centralizes over time.[7][8]

Risk factors for fibromyalgia mirror those for CPS and include trauma, infection, chronic stress, obesity, and depression. Centralized sensitization occurs with minimal or no nociceptive input. Functional neuroimaging can aid in diagnosing CPS.

In reality, centralized pain is not mutually exclusive from other types of pain. An overlap exists between pain states. Any central pain state may include a component of peripheral pain, such as peripheral neuropathy. Additionally, a significant family predisposition to CPS exists.[9][10] Psychological stressors can also trigger worsening symptoms. In many cases, environmental factors cause a triggering event in patients with genetic susceptibility, leading to the development of widespread, centralized pain.[11][12] Therefore, managing environmental stressors is crucial. Early-life trauma, infection, or emotional stress contributes to the development of centralized pain in approximately 5% to 10% of patients.[13][14]

Centralized pain is influenced approximately equally by environmental and genetic factors, each contributing around 50% to its development. First-degree relatives have an 8-fold higher risk of developing centralized pain compared with the general population. However, no significant difference exists based on the sex of the patient or family member. The genetic association is more prominent in families with a history of mood disorders.[15][16] Although a genetic component for centralized pain may exist, no single causative genetic polymorphism has been identified.[17]

Epidemiology

Chronic widespread pain, associated with centralized pain, occurs in 10% to 40% of patients with rheumatoid arthritis, psoriatic arthritis, osteoarthritis, spondyloarthritis, and systemic lupus erythematosus (SLE). Centralized pain occurs in 5% to 15% of the general population, most commonly in individuals with fibromyalgia. Diagnostic criteria for fibromyalgia substantially overlap with those for centralized pain, and patients reporting severe fatigue have a fivefold higher risk of developing widespread pain.[18] The prevalence of centralized pain in patients with knee osteoarthritis ranges from 10% to 15%, with higher rates observed in those with bilateral compared to unilateral knee pain.[19][20][21]

The reported centralized pain in patients with rheumatoid arthritis is estimated to be 13% to 40%. A key concern in this patient population is the risk of overtreating rheumatoid arthritis due to symptom amplification driven by centralized pain. Patients with comorbid fibromyalgia and rheumatoid arthritis typically have lower inflammatory markers but report a poorer quality of life compared with those who have rheumatoid arthritis alone.[22][23]

Centralized pain occurs in 10% to 30% of patients with spondyloarthritis. Among those with ankylosing spondylitis, 13% to 20% meet the criteria for fibromyalgia.[24][25][26] Patients with widespread pain are more likely to experience clinically significant fatigue and comorbid mood disorders, often with moderate-to-severe symptoms. In a study, centralized pain was identified in 53% of patients with psoriatic arthritis, compared with only 5% in the average population.[27] Patients with centralized pain were also more likely to be lost to follow-up after initiating treatment. Additionally, centralized pain affects 20% to 40% of patients with SLE or Sjögren syndrome, with prevalence increasing as chronic disease progresses and in those with comorbid depression.[28][29]

More than one-third of women with chronic back pain experience centralized pain. The daily impact of centralized pain is significant in patients with chronic back pain, often causing severe limitations in activity. Given the high prevalence of widespread, centralized pain in women with chronic low back pain, CPS should be considered in the differential diagnosis for this patient population.[30]

Pathophysiology

The pathogenesis of CPS remains unclear. The underlying mechanism may resemble those of neuropathic pain arising from other body regions or may involve overlapping lesions, features, and associated conditions.[31] Both central and peripheral mechanisms contribute to neuropathic pain, including alterations in the brain, spinal cord, and descending modulatory pathways.[32] Commonly affected regions include the lateral medulla, pontine base, and lateral or posterior thalamus.[33]

Toxicokinetics

No current peer-reviewed data demonstrate a direct link between any specific toxin and CPS. However, any etiology capable of inducing chronic pain, such as chemical agents, drugs (eg, disease-modifying antirheumatic drugs), or venom exposure, may plausibly contribute to centralized pain through chronic pain mechanisms.[34]

History and Physical

The diagnosis of CPS requires symptoms persisting for a minimum of 3 months, characterized by widespread allodynia or hyperalgesia in the absence of an identifiable nociceptive source. The International Association for the Study of Pain (IASP) defines CPS as pain resulting from a CNS lesion or disease. Central sensitization—characterized by heightened responsiveness of nociceptive neurons in the CNS to normal or subthreshold input—is a key mechanism underlying the condition. CPS may present as generalized pain or as pain affecting multiple discrete anatomical regions. Reproducible pain elicited by normal pressure during palpation typically indicates hyperalgesia or allodynia secondary to mechanical stimulation of joints or muscles.

Clinical features frequently associated with CPS include mood disturbances, fatigue, cognitive impairment, disordered sleep, pain catastrophizing, and symptoms suggestive of neuropathic pain, such as burning, numbness, tingling, and paresthesias. Affected individuals often report multifocal pain and memory difficulties and may meet diagnostic criteria for major depressive or generalized anxiety disorder. Noxious stimuli, such as extreme temperatures or loud auditory input, may exacerbate symptom intensity.[35] Using a standardized body diagram may assist in documenting pain distribution.

A comprehensive pain history should include the onset, description, location, radiation, quality, and severity of the pain. Additional elements include the mechanism of injury (if applicable), aggravating and relieving factors, frequency of symptoms, and presence of breakthrough pain. Associated features should also be assessed, such as muscle spasms or aches, temperature changes, restricted range of motion, morning stiffness, weakness, muscle strength, sensory changes, and alterations in hair, skin, or nail integrity.

Physical examination should include a detailed neurological assessment and a focused examination of the painful area. When evaluating for CPS, a complete musculoskeletal examination is recommended. Assessment for symmetrical tender points, characteristic of fibromyalgia, may also provide additional diagnostic insight. Any tenderness over soft tissues or joints should be documented.

To support a diagnosis of CPS, pain often appears in a widespread distribution, affecting the axial skeleton, both sides of the body, and regions above and below the diaphragm. Conversely, CPS becomes less likely when findings include swelling, structural abnormalities, focal neurological deficits, or signs of joint inflammation.

Evaluation

The diagnosis of CPS remains primarily clinical, as the results of standard laboratory tests, including complete blood count, erythrocyte sedimentation rate, C-reactive protein, thyroid-stimulating hormone, and creatine kinase, are typically unremarkable.[36] Laboratory testing should be reserved for cases when clinical suspicion warrants further evaluation. Genetic biomarkers for CPS are currently limited, and rheumatologic markers such as rheumatoid factor and antinuclear antibody are not indicated unless an autoimmune process is suspected.

Screening tools for CPS include the Central Sensitization Inventory (CSI) and painDETECT. These modalities assist in evaluating neuropathic pain and centralized pain syndromes such as fibromyalgia, respectively.[37] However, distinguishing between central and peripheral origins of pain can be challenging; for instance, painDETECT cannot localize the source of pain to either the CNS or the PNS with precision.[38]

Neuroimaging modalities, including magnetic resonance imaging (MRI) and functional MRI (fMRI), may aid in diagnosing CPS. FMRI studies have demonstrated structural and functional brain alterations in patients with chronic pain conditions. For instance, individuals with fibromyalgia often demonstrate distinct patterns of brain activation. FMRI may help identify patients at risk for developing centralized pain disorders and contribute to diagnosis and prognosis.[39] Notable fMRI findings include reduced brain volume, decreased cortical thickness, and elevated levels of excitatory neurotransmitters.[40]

Furthermore, fMRI provides insight into connectivity among multiple brain regions, with the degree of alteration often correlating with the extent of a patient's pain. In fibromyalgia, fMRI may offer an objective measure of symptom severity.[41] Patients with fibromyalgia demonstrate pain-related brain activity patterns that differ from those in the general population. As a diagnostic tool, fMRI shows promise for future application in evaluating various chronic pain disorders.[42] Positron emission tomography (PET) and electroencephalography (EEG) have also revealed heightened pain responses in individuals with CPS.[43][44]

Treatment / Management

Management of CPS often focuses on addressing the underlying chronic disease associated with centralized pain. Controlling comorbid conditions can significantly reduce pain severity.[45] For instance, in knee osteoarthritis, neuroimaging abnormalities related to centralized pain have been shown to improve following joint replacement. Central pain disorders generally respond better to neuromodulators, antiepileptics, or antidepressants than to pharmacologic agents targeting peripheral pain, such as NSAIDs or opioids. 

Nonpharmacological strategies, particularly cognitive-behavioral therapy, form the foundation of CPS management. A comprehensive, individualized approach is essential, as the underlying pathology may involve structural, immunological, or inflammatory mechanisms. Strong evidence supports the use of neuromodulation techniques in the management of chronic pain. These methods include deep brain stimulation (DBS), motor cortex stimulation (MCS), and peripheral nerve stimulation, as well as noninvasive modalities such as repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and transcutaneous electrical nerve stimulation (TENS).[46]

Self-directed or therapist-directed physical therapy techniques can include traction, massage, ultrasonographic therapy, hot or cold applications, positioning, meditation, active visualization, prayer, stretching exercises, and TENS. Female patients with chronic pelvic pain syndrome may benefit from myofascial physical therapy, which can alleviate hypertonicity, improve endogenous inhibitory system function, reduce sensitivity to experimental pain, and provide psychological benefits.[47]

TENS is commonly used to treat rheumatoid arthritis and osteoarthritis. Electrodes are placed over or near the pain site, with the dipole positioned parallel to major nerve trunks. However, TENS can cause hypersensitivity as an adverse effect and should be avoided in pregnant individuals, those with demand-type pacemakers, or when applied near the carotid sinus. MCS and DBS are effective treatment options for patients with refractory pain, central pain, and peripheral neuropathy.[48]

Occupational therapy proves beneficial for patients with chronic pain, particularly those with regional chronic pain syndrome, by promoting physical activity and helping manage physical symptoms.

Pharmacological treatments for CPS include tricyclic antidepressants, SNRIs, and anticonvulsants. Strong evidence supports the use of tricyclic antidepressants such as amitriptyline, SNRIs such as duloxetine and venlafaxine, and anticonvulsants such as pregabalin and gabapentin. Moderate evidence exists for tramadol and selective serotonin reuptake inhibitors, whereas weak evidence supports the use of S-adenosyl-L-methionine.

Differential Diagnosis

Central sensitization manifests in various chronic pain disorders, including fibromyalgia, interstitial cystitis, temporomandibular joint disease, and irritable bowel syndrome. The differential diagnosis for CPS is broad, encompassing autoimmune disorders such as rheumatoid arthritis and polymyalgia rheumatica, myopathies, painful peripheral neuropathies, somatization disorder, malingering, and withdrawal phenomena from physiological or psychological dependence on habit-forming substances.

Central sensitization frequently accompanies chronic back and neck pain and is also associated with conditions such as trauma, carpal tunnel syndrome, complex regional pain syndrome, lateral epicondylitis, osteoarthritis, and joint hypermobility syndrome. CPS develops following a stroke or as a sequela of neurological disorders such as multiple sclerosis.[49][50] Thalamic stroke, in particular, is linked to a specific form of CPS. Mood disorders, including major depressive disorder and generalized anxiety disorder, are also commonly comorbid with CPS.

Toxicity and Adverse Effect Management

Potential Complications of Central Pain Syndrome Management

Adverse events from pain management procedures are rare when performed by well-trained and experienced interventionalists. The most common complication is a vasovagal response.[51] However, serious complications can arise, such as spinal block with critical hypotension, central respiratory depression from high cervical block, cardiac rhythm disturbances due to inadvertent vascular uptake of injectate, acute contrast agent reactions, and pneumothorax. These complications require prompt management. Follow-up is essential not only for assessing the response and determining whether to repeat or alter the procedure, but also for monitoring delayed infectious complications such as infectious discitis, epidural abscess, meningitis, and cellulitis.

Opiates, particularly when combined with other sedating medications, can cause respiratory depression. A responsible caregiver should be trained to administer nasal naloxone. All sedating medications, including membrane stabilizers, whether used alone or in combination, increase the risk of falls and related injuries, such as fractures, subdural hematomas, and cognitive impairments that can hinder participation in cognitive behavioral therapies. The concurrent use of serotonergic drugs, either alone or in combination with tramadol (a Schedule IV controlled substance), poses a significant risk for drug interactions and the often-overlooked complication of serotonin syndrome.[52][53] Other medication classes, such as antineoplastics, also carry their own specific toxicities.

Most patients with CPS, or any other form of chronic neuropathic pain, typically exhibit some degree of sensory peripheral neuropathy, which increases the risk of falls. This risk should be considered during physical and occupational therapies. Gait belts with contact guard assistance are recommended for patients with even slight balance issues.

Treatment Caveats

Individuals with CPS, similar to those with other chronic illnesses, often explore alternative or experimental therapies. Some individuals resort to purchasing unregulated "magic pain pills" online or mortgage their homes to travel abroad for treatment from clinicians who promise to "easily cure all these cases." While medical tourism is expanding and certain patients may benefit from international treatment, these patients are often vulnerable to exploitation, warranting careful evaluation of such claims. Oral and topical alternatives, such as herbal treatments and methylene blue, are receiving more research attention.[54] However, drug-herb and drug-chemical interactions should be carefully considered.

Another important consideration is the lack of regulation. While certain herbs and chemical compounds are well-established for their beneficial effects, product labeling may not always accurately reflect the actual contents or confirm the absence of harmful substances, such as heavy metals.

Medical Oncology

A medical oncology consultation is warranted when malignancy is suspected, acute inflammatory markers are elevated without an identifiable cause, treatment of primary or metastatic lesions is indicated, or external beam radiation is being considered. Pain management in cancer survivors and patients undergoing cancer therapies involves special considerations, and referral to a physician authorized to recommend medical cannabis may be appropriate.[55] In the United States, relevant guidelines vary by state.

Prognosis

Prognosis improves when the underlying cause of pain can be cured, corrected, or effectively managed —for example, through shoulder replacement in patients with osteoarthritis. Individuals with osteoarthritis and centralized sensitization may experience pain relief with pharmacologic therapy targeting osteoarthritis; however, they often report poorer pain outcomes following joint replacement surgery.[56]

In patients with osteoarthritis comorbid with CPS, pain severity does not correlate with the radiographic severity of osteoarthritis. Additionally, patients with radiological evidence of osteoarthritis in a single joint are at increased risk of developing pain in multiple joints. This comorbid population also exhibits more synovitis and effusion in knee osteoarthritis.

Central sensitization contributes to inflammatory arthritis and affects a significant subset of the patient population. For example, individuals with rheumatoid arthritis and comorbid fibromyalgia report worse pain, poorer mental health, and greater reliance on pain medications, including prednisone, despite having lower levels of inflammatory markers.[57][58] Patients with inflammatory arthritis and centralized sensitization experience poorer overall outcomes.[59] Additionally, these patients also experience hyperalgesia at both articular and nonarticular sites.[60]

Complications

The impact of central sensitization extends across various conditions. In rheumatoid arthritis, central pain is associated with neuropathic symptoms, higher pain scores without changes in inflammatory markers, increased adverse outcomes, and reduced remission rates. Central sensitization also contributes to the increased use of opioids and higher pain severity in patients with osteoarthritis, leading to poorer patient outcomes.

Patients with bilateral knee pain are more likely to experience pain in additional joints within a year. In spondyloarthritis, central sensitization is associated with worse clinical outcomes, higher disease scores, and poorer treatment responses. In SLE, centralized pain is associated with greater sleep disturbances, mood changes, and worse overall outcomes. Patients with chronic back pain and central sensitization experience more intense pain and mood disturbances, as well as an increase in adverse outcomes. Joint hypermobility syndrome is linked to greater pain severity and poorer patient outcomes.

In carpal tunnel syndrome, central sensitization is associated with poorer surgical outcomes, while in lateral epicondylitis, it correlates with more severe pain, longer duration of pain, and a higher risk of failed treatments. For chronic whiplash injuries, centralized pain is associated with cognitive disturbances, more severe pain, and worse outcomes. Preoperative increases in fibromyalgia pain scores are associated with the use of more postoperative morphine equivalents and a reduced response to NSAIDs.[61]

Postoperative and Rehabilitation Care

Adequate pain control and early initiation of therapy following major surgeries are often believed to improve overall outcomes and reduce the incidence of chronic pain and disability. However, the literature on this topic is often indirect and nonspecific, focusing on specific disciplines or procedures that require extrapolation to broader contexts.[62][63] Nevertheless, the prevention of "sequelae of immobility," such as flexion contractures, deep vein thrombosis, muscle atrophy, compression neuropathies, and malnutrition, is universally accepted and does not require a peer-reviewed reference.

Consultations

The clinical scenario should guide specialist consultations. Rheumatology should be consulted for cases involving potential autoimmune disorders or elevated acute inflammatory markers. A neurology consultation is necessary when concerns arise for cerebrovascular accidents or other intracranial pathologies, such as demyelinating plaques.

Physical medicine and rehabilitation can assist with electrodiagnostic evaluations to differentiate between inflammatory and noninflammatory myopathies and to identify peripheral neuropathy, especially if conditions such as acute or chronic inflammatory demyelinating polyneuropathy are considered in the differential diagnosis.

Neurosurgery or orthopedic surgery should be involved if concerns arise about structurally relevant and potentially correctable spinal or peripheral joint pathologies. Neurosurgical intervention may also be indicated in certain cases for temporal lobe stimulation. Psychiatry or psychology is important for addressing potential somatization or hypochondriasis, as well as providing emotional support in the management of chronic, intractable pain.

Pain management consultations are essential for exploring both interventional and noninterventional treatment options, including medication management and the consideration of implantable technologies, such as subarachnoid pain pumps. Vascular surgery or interventional radiology should be consulted if a vascular etiology is suspected.

Deterrence and Patient Education

CPS arises from heightened sensitivity within the CNS, which lowers the threshold for pain perception. Educating patients and clinicians about the pathophysiology, prevalence, and management of this condition is essential for effective prevention and treatment, particularly in individuals with chronic diseases.

CPS manifests when the CNS becomes hyperresponsive, resulting in conditions such as allodynia, which is pain elicited by normally nonpainful stimuli—and hyperalgesia—exaggerated responses to painful stimuli. Up to 20% of individuals with chronic pain from any cause may exhibit features of CPS, highlighting its clinical importance. The risk increases in patients with rheumatologic or musculoskeletal conditions lasting longer than three months, with both environmental and genetic factors contributing to their development.

Importantly, CPS can coexist with peripheral pain, further complicating diagnosis and management. Over time, chronic disease itself may amplify central sensitization, increasing the prevalence of dual pain syndromes. fMRI has emerged as a valuable tool for identifying centralized pain patterns, thereby enhancing diagnostic accuracy and clinical precision.

CPS affects numerous chronic disease states, and is particularly associated with worse outcomes in osteoarthritis and rheumatoid arthritis. Managing both the primary condition and CPS simultaneously can lead to improved symptom control. Effective management often requires collaboration between a primary care physician (PCP) and a specialist in pain medicine. First-line pharmacological interventions include antidepressants and anticonvulsants, which help modulate abnormal CNS pain processing.

Early recognition and management of centralized pain in the course of chronic illness may help prevent progression to more debilitating states. A comprehensive, dual-focused treatment approach offers the best opportunity to enhance the quality of life for patients with CPS.

Pearls and Other Issues

Clinicians should remember that pain is a symptom, not an etiology or a diagnosis. Every symptom reflects an underlying process, whether identified, treatable, or yet to be recognized in the current scientific literature. Approximately 20% of individuals with chronic pain from known causes also experience CPS or widespread pain in other regions. Effective treatment requires addressing the primary cause of pain, acknowledging the limitations in treating certain conditions, and the distressing symptoms themselves, including pain.

Enhancing Healthcare Team Outcomes

Effective management of CPS requires a coordinated, interprofessional approach involving PCPs, pain medicine specialists, pharmacists, nurses, and subspecialists such as rheumatologists or neurologists. Early recognition of centralized pain is critical, as its treatment differs from that of peripheral or mechanical pain. Without appropriate diagnosis and management, CPS is associated with significant morbidity.

Initial evaluation typically includes laboratory tests such as complete blood count, erythrocyte sedimentation rate, C-reactive protein, creatine phosphokinase, and aldolase to help exclude underlying inflammatory or myopathic conditions. Clinicians should assess for hallmark features of central pain, including allodynia and hyperalgesia, particularly in patients with pain that persists for longer than 3 months. Both genetic and environmental factors may contribute to the development and persistence of CPS.

Pharmacological management often involves consultation with a pharmacist to guide the use of antidepressants, anticonvulsants, and other agents, including over-the-counter supplements or experimental therapies such as methylene blue. Pain medicine specialists may consider neuromodulation for refractory cases. When available, fMRI may provide supportive diagnostic information and should be discussed with a radiologist. Subspecialist input from rheumatology or neurology is often necessary to address underlying autoimmune or neurologic contributors to pain.

Management of CPS requires collaboration across multiple healthcare disciplines. However, coordination challenges frequently arise, as overlapping treatments, redundant testing, and polypharmacy increase the risk of harm. To ensure consistency and safety, a single lead clinician, often referred to as the “quarterback,” should oversee the overall care plan and track each clinical decision. This role is commonly filled by neurologists or physicians in physical medicine and rehabilitation who hold additional board certification in pain management. Nonetheless, a PCP can also serve in this capacity if they have the interest and expertise. However, many PCPs feel underprepared or lack the time to manage such complex cases comprehensively.

Preventing the progression to centralized sensitization is a critical goal due to the high burden of morbidity associated with this condition. Once established, symptoms of CPS are often persistent and do not fully resolve, and long-term outcomes remain guarded despite comprehensive care.

Nursing staff play a critical role in the care of individuals with centralized pain. These professionals act as liaisons among healthcare professionals, monitor patient progress, and often spend more time with patients than most other team members. This extended bedside presence increases the likelihood of detecting subtle physical or emotional changes that might otherwise go unrecognized. When consistently communicated with the healthcare team, nurses' observations can significantly influence management decisions. Additionally, nurses provide ongoing education and support, helping patients navigate their treatment plans and maintain realistic expectations.

Physical and occupational therapists contribute by addressing functional limitations and working to reduce long-term disability. Their hands-on involvement often allows them to detect early changes in limb temperature, color, or range of motion, as well as shifts in mood, affect, or motivation. These observations should be promptly communicated to the managing physician. In addition, therapy assistants and specialized professionals, such as music, art, play, or shop therapists, may offer valuable insights and therapeutic benefits. Together, each of these healthcare team members plays a crucial role in helping patients adapt, cope, and achieve an improved quality of life.

Effective management of CPS relies on providing meaningful patient education, fostering patient-centered communication, and a commitment to making incremental progress. Although complete pain elimination may not be achievable, an interprofessional team approach can consistently enhance functional outcomes and overall well-being.

Review Questions

• Access free multiple choice questions on this topic.
• Click here for a simplified version.
• Comment on this article.

References

1.

Latremoliere A, Woolf CJ. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009 Sep;10(9):895-926. [PMC free article: PMC2750819] [PubMed: 19712899]

2.

Cui CX, Liu HY, Yue N, Du YR, Che LM, Yu JS. Research progress on the mechanism of chronic neuropathic pain. IBRO Neurosci Rep. 2023 Jun;14:80-85. [PMC free article: PMC9827377] [PubMed: 36632243]

3.

Volcheck MM, Graham SM, Fleming KC, Mohabbat AB, Luedtke CA. Central sensitization, chronic pain, and other symptoms: Better understanding, better management. Cleve Clin J Med. 2023 Apr 03;90(4):245-254. [PubMed: 37011956]

4.

Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain. 2011 Mar;152(3 Suppl):S2-S15. [PMC free article: PMC3268359] [PubMed: 20961685]

5.

McBeth J, Jones K. Epidemiology of chronic musculoskeletal pain. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):403-25. [PubMed: 17602991]

6.

Clauw DJ, Hassett AL. The role of centralised pain in osteoarthritis. Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 107(5):79-84. [PubMed: 28967359]

7.

Mutso AA, Petre B, Huang L, Baliki MN, Torbey S, Herrmann KM, Schnitzer TJ, Apkarian AV. Reorganization of hippocampal functional connectivity with transition to chronic back pain. J Neurophysiol. 2014 Mar;111(5):1065-76. [PMC free article: PMC3949236] [PubMed: 24335219]

8.

Yu R, Gollub RL, Spaeth R, Napadow V, Wasan A, Kong J. Disrupted functional connectivity of the periaqueductal gray in chronic low back pain. Neuroimage Clin. 2014;6:100-8. [PMC free article: PMC4215524] [PubMed: 25379421]

9.

Buskila D. Genetics of chronic pain states. Best Pract Res Clin Rheumatol. 2007 Jun;21(3):535-47. [PubMed: 17602998]

10.

Arnold LM, Hudson JI, Hess EV, Ware AE, Fritz DA, Auchenbach MB, Starck LO, Keck PE. Family study of fibromyalgia. Arthritis Rheum. 2004 Mar;50(3):944-52. [PubMed: 15022338]

11.

Williams DA, Clauw DJ. Understanding fibromyalgia: lessons from the broader pain research community. J Pain. 2009 Aug;10(8):777-91. [PMC free article: PMC2741022] [PubMed: 19638325]

12.

Clauw DJ, Chrousos GP. Chronic pain and fatigue syndromes: overlapping clinical and neuroendocrine features and potential pathogenic mechanisms. Neuroimmunomodulation. 1997 May-Jun;4(3):134-53. [PubMed: 9500148]

13.

Clauw DJ, Schmidt M, Radulovic D, Singer A, Katz P, Bresette J. The relationship between fibromyalgia and interstitial cystitis. J Psychiatr Res. 1997 Jan-Feb;31(1):125-31. [PubMed: 9201654]

14.

McLean SA, Clauw DJ. Predicting chronic symptoms after an acute "stressor"--lessons learned from 3 medical conditions. Med Hypotheses. 2004;63(4):653-8. [PubMed: 15325010]

15.

Kato K, Sullivan PF, Evengård B, Pedersen NL. Importance of genetic influences on chronic widespread pain. Arthritis Rheum. 2006 May;54(5):1682-6. [PubMed: 16646040]

16.

Buskila D, Sarzi-Puttini P. Biology and therapy of fibromyalgia. Genetic aspects of fibromyalgia syndrome. Arthritis Res Ther. 2006;8(5):218. [PMC free article: PMC1779444] [PubMed: 16887010]

17.

Arnold LM, Fan J, Russell IJ, Yunus MB, Khan MA, Kushner I, Olson JM, Iyengar SK. The fibromyalgia family study: a genome-wide linkage scan study. Arthritis Rheum. 2013 Apr;65(4):1122-8. [PMC free article: PMC3618544] [PubMed: 23280346]

18.

Dean LE, Arnold L, Crofford L, Bennett R, Goldenberg D, Fitzcharles MA, Paiva ES, Staud R, Clauw D, Sarzi-Puttini P, Jones GT, Ayorinde A, Flüß E, Beasley M, Macfarlane GJ. Impact of Moving From a Widespread to Multisite Pain Definition on Other Fibromyalgia Symptoms. Arthritis Care Res (Hoboken). 2017 Dec;69(12):1878-1886. [PubMed: 28182834]

19.

Felson DT, Niu J, Quinn EK, Neogi T, Lewis CL, Lewis CE, Frey Law L, McCulloch C, Nevitt M, LaValley M. Multiple Nonspecific Sites of Joint Pain Outside the Knees Develop in Persons With Knee Pain. Arthritis Rheumatol. 2017 Feb;69(2):335-342. [PMC free article: PMC5292971] [PubMed: 27589036]

20.

Neogi T, Frey-Law L, Scholz J, Niu J, Arendt-Nielsen L, Woolf C, Nevitt M, Bradley L, Felson DT., Multicenter Osteoarthritis (MOST) Study. Sensitivity and sensitisation in relation to pain severity in knee osteoarthritis: trait or state? Ann Rheum Dis. 2015 Apr;74(4):682-8. [PMC free article: PMC4062615] [PubMed: 24351516]

21.

Neogi T, Guermazi A, Roemer F, Nevitt MC, Scholz J, Arendt-Nielsen L, Woolf C, Niu J, Bradley LA, Quinn E, Law LF. Association of Joint Inflammation With Pain Sensitization in Knee Osteoarthritis: The Multicenter Osteoarthritis Study. Arthritis Rheumatol. 2016 Mar;68(3):654-61. [PMC free article: PMC4827020] [PubMed: 26554395]

22.

Pollard LC, Kingsley GH, Choy EH, Scott DL. Fibromyalgic rheumatoid arthritis and disease assessment. Rheumatology (Oxford). 2010 May;49(5):924-8. [PubMed: 20100795]

23.

Andersson ML, Svensson B, Bergman S. Chronic widespread pain in patients with rheumatoid arthritis and the relation between pain and disease activity measures over the first 5 years. J Rheumatol. 2013 Dec;40(12):1977-85. [PubMed: 24187108]

24.

Baraliakos X, Regel A, Kiltz U, Menne HJ, Dybowski F, Igelmann M, Kalthoff L, Krause D, Saracbasi-Zender E, Schmitz-Bortz E, Braun J. Patients with fibromyalgia rarely fulfil classification criteria for axial spondyloarthritis. Rheumatology (Oxford). 2018 Sep 01;57(9):1541-1547. [PubMed: 28968885]

25.

Duffield SJ, Miller N, Zhao S, Goodson NJ. Concomitant fibromyalgia complicating chronic inflammatory arthritis: a systematic review and meta-analysis. Rheumatology (Oxford). 2018 Aug 01;57(8):1453-1460. [PMC free article: PMC6055651] [PubMed: 29788461]

26.

Bello N, Etcheto A, Béal C, Dougados M, Moltó A. Evaluation of the impact of fibromyalgia in disease activity and treatment effect in spondyloarthritis. Arthritis Res Ther. 2016 Feb 09;18:42. [PMC free article: PMC4748456] [PubMed: 26860612]

27.

Magrey MN, Antonelli M, James N, Khan MA. High frequency of fibromyalgia in patients with psoriatic arthritis: a pilot study. Arthritis. 2013;2013:762921. [PMC free article: PMC3586452] [PubMed: 23476767]

28.

Torrente-Segarra V, Salman-Monte TC, Rúa-Figueroa Í, Pérez-Vicente S, López-Longo FJ, Galindo-Izquierdo M, Calvo-Alén J, Olivé-Marqués A, Ibañez-Ruán J, Horcada L, Sánchez-Atrio A, Montilla C, Rodríguez-Gómez M, Díez-Álvarez E, Martinez-Taboada V, Andreu JL, Fernández-Berrizbeitia O, Hernández-Beriain JA, Gantes M, Hernández-Cruz B, Pecondón-Español Á, Marras C, Bonilla G, Pego-Reigosa JM., RELESSER Study Group of the Spanish Society of Rheumatology (SER). Study Group of Systemic Autoimmune Diseases of the SER (EAS-SER). Fibromyalgia prevalence and related factors in a large registry of patients with systemic lupus erythematosus. Clin Exp Rheumatol. 2016 Mar-Apr;34(2 Suppl 96):S40-7. [PubMed: 26575317]

29.

Wolfe F, Petri M, Alarcón GS, Goldman J, Chakravarty EF, Katz RS, Karlson EW. Fibromyalgia, systemic lupus erythematosus (SLE), and evaluation of SLE activity. J Rheumatol. 2009 Jan;36(1):82-8. [PMC free article: PMC2944223] [PubMed: 19004039]

30.

Nordeman L, Gunnarsson R, Mannerkorpi K. Prevalence and characteristics of widespread pain in female primary health care patients with chronic low back pain. Clin J Pain. 2012 Jan;28(1):65-72. [PubMed: 21677567]

31.

Klit H, Finnerup NB, Jensen TS. Central post-stroke pain: clinical characteristics, pathophysiology, and management. Lancet Neurol. 2009 Sep;8(9):857-68. [PubMed: 19679277]

32.

Cohen SP, Mao J. Neuropathic pain: mechanisms and their clinical implications. BMJ. 2014 Feb 05;348:f7656. [PubMed: 24500412]

33.

Misra UK, Kalita J, Kumar B. A study of clinical, magnetic resonance imaging, and somatosensory-evoked potential in central post-stroke pain. J Pain. 2008 Dec;9(12):1116-22. [PubMed: 18848810]

34.

Stretanski MF. Neuromodulation of neuropathic pain syndrome induced by elapidae (cobra) envenomation. Neuromodulation. 2009 Jan;12(1):44-8. [PubMed: 22151222]

35.

Staud R, Robinson ME, Price DD. Temporal summation of second pain and its maintenance are useful for characterizing widespread central sensitization of fibromyalgia patients. J Pain. 2007 Nov;8(11):893-901. [PMC free article: PMC2174917] [PubMed: 17681887]

36.

Lesuis N, van Vliet J, Boers N, den Broeder N, Cats H, Hulscher ME, Verrips A, den Broeder AA. The value of routine creatine kinase and thyroid stimulating hormone testing in patients with suspected fibromyalgia: a cross-sectional study. Rheumatology (Oxford). 2016 Jul;55(7):1273-6. [PubMed: 27032423]

37.

Neblett R, Cohen H, Choi Y, Hartzell MM, Williams M, Mayer TG, Gatchel RJ. The Central Sensitization Inventory (CSI): establishing clinically significant values for identifying central sensitivity syndromes in an outpatient chronic pain sample. J Pain. 2013 May;14(5):438-45. [PMC free article: PMC3644381] [PubMed: 23490634]

38.

Timmerman H, Wolff AP, Bronkhorst EM, Wilder-Smith OHG, Schenkels MJ, van Dasselaar NT, Huygen FJPM, Steegers MAH, Vissers KCP. Avoiding Catch-22: validating the PainDETECT in a in a population of patients with chronic pain. BMC Neurol. 2018 Jun 29;18(1):91. [PMC free article: PMC6026336] [PubMed: 29958535]

39.

Wager TD, Atlas LY, Lindquist MA, Roy M, Woo CW, Kross E. An fMRI-based neurologic signature of physical pain. N Engl J Med. 2013 Apr 11;368(15):1388-97. [PMC free article: PMC3691100] [PubMed: 23574118]

40.

Jensen KB, Srinivasan P, Spaeth R, Tan Y, Kosek E, Petzke F, Carville S, Fransson P, Marcus H, Williams SC, Choy E, Vitton O, Gracely R, Ingvar M, Kong J. Overlapping structural and functional brain changes in patients with long-term exposure to fibromyalgia pain. Arthritis Rheum. 2013 Dec;65(12):3293-303. [PMC free article: PMC3984030] [PubMed: 23982850]

41.

Napadow V, Kim J, Clauw DJ, Harris RE. Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia. Arthritis Rheum. 2012 Jul;64(7):2398-403. [PMC free article: PMC3349799] [PubMed: 22294427]

42.

López-Solà M, Woo CW, Pujol J, Deus J, Harrison BJ, Monfort J, Wager TD. Towards a neurophysiological signature for fibromyalgia. Pain. 2017 Jan;158(1):34-47. [PMC free article: PMC5161739] [PubMed: 27583567]

43.

Usui C, Soma T, Hatta K, Aratani S, Fujita H, Nishioka K, Machida Y, Kuroiwa Y, Nakajima T, Nishioka K. A study of brain metabolism in fibromyalgia by positron emission tomography. Prog Neuropsychopharmacol Biol Psychiatry. 2017 Apr 03;75:120-127. [PubMed: 28153806]

44.

Lee U, Kim M, Lee K, Kaplan CM, Clauw DJ, Kim S, Mashour GA, Harris RE. Functional Brain Network Mechanism of Hypersensitivity in Chronic Pain. Sci Rep. 2018 Jan 10;8(1):243. [PMC free article: PMC5762762] [PubMed: 29321621]

45.

Brummett CM, Urquhart AG, Hassett AL, Tsodikov A, Hallstrom BR, Wood NI, Williams DA, Clauw DJ. Characteristics of fibromyalgia independently predict poorer long-term analgesic outcomes following total knee and hip arthroplasty. Arthritis Rheumatol. 2015 May;67(5):1386-94. [PMC free article: PMC4414825] [PubMed: 25772388]

46.

Knotkova H, Hamani C, Sivanesan E, Le Beuffe MFE, Moon JY, Cohen SP, Huntoon MA. Neuromodulation for chronic pain. Lancet. 2021 May 29;397(10289):2111-2124. [PubMed: 34062145]

47.

Grinberg K, Weissman-Fogel I, Lowenstein L, Abramov L, Granot M. How Does Myofascial Physical Therapy Attenuate Pain in Chronic Pelvic Pain Syndrome? Pain Res Manag. 2019;2019:6091257. [PMC free article: PMC6930783] [PubMed: 31915499]

48.

Moore NZ, Lempka SF, Machado A. Central neuromodulation for refractory pain. Neurosurg Clin N Am. 2014 Jan;25(1):77-83. [PMC free article: PMC3867973] [PubMed: 24262901]

49.

American College of Rheumatology Pain Management Task Force. Report of the American College of Rheumatology Pain Management Task Force. Arthritis Care Res (Hoboken). 2010 May;62(5):590-9. [PubMed: 20461782]

50.

Borenstein DG, Hassett AL, Pisetsky D. Pain management in rheumatology research, training, and practice. Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 107(5):2-7. [PubMed: 28967362]

51.

Wang EJ. Interventional pain procedures and vasovagal reactions: Proceed with vigilance. Interv Pain Med. 2022 Sep;1(3):100107. [PMC free article: PMC11373079] [PubMed: 39238529]

52.

Bai AD, McKenna S, Wise H, Loeb M, Gill SS. Association of Linezolid With Risk of Serotonin Syndrome in Patients Receiving Antidepressants. JAMA Netw Open. 2022 Dec 01;5(12):e2247426. [PMC free article: PMC9856528] [PubMed: 36534400]

53.

Racz R, Soldatos TG, Jackson D, Burkhart K. Association Between Serotonin Syndrome and Second-Generation Antipsychotics via Pharmacological Target-Adverse Event Analysis. Clin Transl Sci. 2018 May;11(3):322-329. [PMC free article: PMC5944571] [PubMed: 29575568]

54.

Xue H, Thaivalappil A, Cao K. The Potentials of Methylene Blue as an Anti-Aging Drug. Cells. 2021 Dec 01;10(12) [PMC free article: PMC8699482] [PubMed: 34943887]

55.

Salz T, Chimonas S, Jinna S, Brens J, Kriplani A, Salner A, Rabinowits G, Currier B, Daly B, Korenstein D. Pain management for post-treatment survivors of complex cancers: a qualitative study of opioids and cannabis. Pain Manag. 2024 Feb;14(2):87-99. [PMC free article: PMC10918509] [PubMed: 38318666]

56.

Finan PH, Buenaver LF, Bounds SC, Hussain S, Park RJ, Haque UJ, Campbell CM, Haythornthwaite JA, Edwards RR, Smith MT. Discordance between pain and radiographic severity in knee osteoarthritis: findings from quantitative sensory testing of central sensitization. Arthritis Rheum. 2013 Feb;65(2):363-72. [PMC free article: PMC3863776] [PubMed: 22961435]

57.

Lee YC, Lu B, Boire G, Haraoui BP, Hitchon CA, Pope JE, Thorne JC, Keystone EC, Solomon DH, Bykerk VP. Incidence and predictors of secondary fibromyalgia in an early arthritis cohort. Ann Rheum Dis. 2013 Jun;72(6):949-54. [PMC free article: PMC3488361] [PubMed: 22791744]

58.

Chakr RMDS, Brenol C, Ranzolin A, Bernardes A, Dalosto AP, Ferrari G, Scalco S, Olszewski V, Kohem C, Monticielo O, Brenol JCT, Xavier RM. Rheumatoid arthritis seems to have DMARD treatment decision influenced by fibromyalgia. Rev Bras Reumatol Engl Ed. 2017 Sep-Oct;57(5):403-411. [PubMed: 29037312]

59.

Koop SM, ten Klooster PM, Vonkeman HE, Steunebrink LM, van de Laar MA. Neuropathic-like pain features and cross-sectional associations in rheumatoid arthritis. Arthritis Res Ther. 2015 Sep 03;17(1):237. [PMC free article: PMC4558794] [PubMed: 26335941]

60.

Meeus M, Vervisch S, De Clerck LS, Moorkens G, Hans G, Nijs J. Central sensitization in patients with rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum. 2012 Feb;41(4):556-67. [PubMed: 22035625]

61.

Edwards RR, Dolman AJ, Martel MO, Finan PH, Lazaridou A, Cornelius M, Wasan AD. Variability in conditioned pain modulation predicts response to NSAID treatment in patients with knee osteoarthritis. BMC Musculoskelet Disord. 2016 Jul 13;17:284. [PMC free article: PMC4944243] [PubMed: 27412526]

62.

Hirakawa K, Nakayama A, Arimitsu T, Kon K, Ueki H, Hori K, Ishimoto Y, Ogawa A, Higuchi R, Hosoya Y, Nanasato M, Isobe M. Feasibility and safety of upper limb extremity ergometer exercise in the cardiac intensive care unit in critically ill patients with cardiac disease: a prospective observational study. Front Physiol. 2025;16:1448647. [PMC free article: PMC11985777] [PubMed: 40224148]

63.

Szczotkowski D, Meyer-Moock S, Kohlmann T, Deppe K, Gärtner A, Hoffmann G, Isenberg T, Lindena G, Marschall U, Martin C, Metz-Oster B, Milch L, Möller A, Nagel B, Petzke F, Preissler A, Pritzke-Michael J, Schouten L, Schwenk K, Schumacher C, Waidner A, Kaiser U. Evaluating an early Interdisciplinary Multimodal Assessment for Patients at Risk of Developing Chronic Pain: Results of a Multicentre RCT in Germany. Pain Ther. 2025 Jun;14(3):1081-1102. [PMC free article: PMC12085446] [PubMed: 40232611]

Disclosure: Alexander Dydyk declares no relevant financial relationships with ineligible companies.

Disclosure: Emmanuel Chiebuka declares no relevant financial relationships with ineligible companies.

Disclosure: Michael Stretanski declares no relevant financial relationships with ineligible companies.

Disclosure: Amy Givler declares no relevant financial relationships with ineligible companies.