Peripheral and central sensitization in musculoskeletal pain disorders: an experimental approach

This report provides a brief introduction to the manifestations of peripheral and central sensitization involved in musculoskeletal pain disorders. It has become increasingly evident that muscle hyperalgesia, referred pain, referred hyperalgesia, and widespread hyperalgesia play an important role in chronic musculoskeletal pain. A better understanding of the involved basic mechanisms and better methods to assess muscle pain in the clinic may provide new possibilities for designing rational therapies and for targeting the pharmacologic intervention optimally. Peripheral sensitization plays an important role for increased sensitivity of deep tissue. However, central sensitization may be equally important but less addressed. Quantitative sensory testing provides the possibility to evaluate these manifestations in a standardized way in patients with musculoskeletal pain or in healthy volunteers (eg, experimentally induced referred pain can be used to assess the potential involvement of central sensitization in musculoskeletal pain conditions). Central sensitization may play a role in the persistence, amplification, and spread of pain. Interventions should take this aspect into consideration.     

Pain mechanisms in osteoarthritis: understanding the role of central pain and current approaches to its treatment

In this literature review, the mechanisms underlying pain associated with osteoarthritis (OA) are discussed, along with evidence for the efficacy of medications thought to act centrally to relieve OA pain. We survey the cascade of events from inflammation to activation of nociceptive and neuropathic pathways, to the development and maintenance of central and peripheral sensitization. Preclinical and clinical evidence for the sensitization hypothesis is discussed, along with recently identified genetic variations that may increase sensitivity to pain in patients with OA. Evidence is presented for the efficacy of centrally acting analgesics for OA pain (opioids, antiepileptics, tricyclic antidepressants, and serotonin/norepinephrine receptor inhibitors).     

The neuropharmacology of centrally-acting analgesic medications in fibromyalgia

As demonstrated above, the anatomy and neuropharmacology of the pain pathways within the CNS, even to the level of the midbrain, are extraordinarily complex. Indeed, discussions of the effects of these agents on the neuropharmacology of the thalamus, hypothalamus, and cortex were excluded from this review owing to their adding further to this complexity. Also, the dearth of data regarding FMS pain pathophysiology necessitated a relatively generic analysis of the pain pathways. As mentioned in the introduction, the current thought is that central sensitization plays an important role in FMS. However, we see in this chapter that the behavioral state of central sensitization may be a result of alterations in either the ascending systems or in one or more descending systems. Studies to assess the presence or relative importance of such changes in FMS are difficult to perform in humans, and to date there are no animal models of FMS. Accepting these limitations, it is apparent that many drugs considered to date for the treatment of FMS do target a number of appropriate sites within both the ascending and descending pain pathways. The data regarding clinical efficacy on some good candidate agents, however, is extremely preliminary. For example, it is evident from the present analysis that SNRIs, alpha 2 agonists, and NK1 antagonists may be particularly well suited to FMS, although current data supporting their use is either anecdotal or from open-label trials [114,149]. Other sites within the pain pathways have not yet been targeted. Examples of these include the use of CCKB antagonists to block on-cell activation or of nitric oxide synthetase antagonists to block the downstream mediators of NMDA activation. Efficacy of such agents may give considerable insight into the pathophysiology of FMS. Finally, as indicated previously, FMS consists of more than just chronic pain, and the question of how sleep abnormalities, depression, fatigues, and so forth tie into disordered pain processing is being researched actively. Future research focusing on how the various manifestations of FMS relate to one another undoubtedly will lead to a more rational targeting of drugs in this complex disorder.     

Chronic widespread pain in the spectrum of rheumatological diseases

Chronic pain is very common in all European countries, with musculoskeletal problems predominating. About 1% of the adult population develops a syndrome of chronic muscle pain, fibromyalgia (FMS), characterized by multiple tender points, back or neck pain, and a number of associated problems from other organs, including a high frequency of fatigue. Evidence points to central sensitization as an important neurophysiological aberration in the development of FMS. Importantly, these neurological changes may result from inadequately treated chronic focal pain problems such as osteoarthritis or myofascial pain. It is important for health professionals to be aware of this syndrome and to diagnose the patients to avoid a steady increase in diagnostic tests. On the other hand, patients with chronic widespread pain have an increased risk of developing malignancies, and new or changed symptoms should be diagnosed even in FMS. In rheumatology practice it is especially important to be aware of the existence of FMS in association with immune inflammatory diseases, most commonly lupus and rheumatoid arthritis. Differential diagnoses are other causes of chronic pain, e.g. thyroid disease. The costs of this syndrome are substantial due to loss of working capability and direct expenses of medication and health-system usage. Fibromyalgia patients need recognition of their pain syndrome if they are to comply with treatment. Lack of empathy and understanding by healthcare professionals often leads to patient frustration and inappropriate illness behavior, often associated with some exaggeration of symptoms in an effort to gain some legitimacy for their problem. FMS is multifaceted, and treatment consists of both medical interventions, with emphasis on agents acting on the central nervous system, and physical exercises.     

Evidence of involvement of central neural mechanisms in generating fibromyalgia pain

Fibromyalgia syndrome (FMS) is characterized by widespread pain, fatigue, sleep abnormalities, and distress. Because FMS lacks consistent evidence of tissue abnormalities, recent investigations have focused on central nervous system mechanisms of pain. Abnormal temporal summation of second pain (wind-up) and central sensitization have been described recently in patients with FMS. Windup and central sensitization, which rely on central pain mechanisms, occur after prolonged C-nociceptor input and depend on activation of nociceptor-specific neurons and wide dynamic range neurons in the dorsal horn of the spinal cord. Other abnormal central pain mechanisms recently detected in patients with FMS include diffuse noxious inhibitory controls. These pain inhibitory mechanisms rely on spinal cord and supraspinal systems involving pain facilitatory and pain inhibitory pathways. Brain-imaging techniques that can detect neuronal activation after nociceptive stimuli have provided additional evidence for abnormal central pain mechanisms in FMS. Brain images have corroborated the augmented reported pain experience of patients with fibromyalgia during experimental pain stimuli. In addition, thalamic activity, which contributes significantly to pain processing, was decreased in fibromyalgia. However, central pain mechanisms of fibromyalgia may not depend exclusively on neuronal activation. Neuroglial activation has been found to play an important role in the induction and maintenance of chronic pain. These findings may have important implications for future research and the treatment of fibromyalgia pain.     

The rational management of fibromyalgia patients

The exponential increase in pain research over the last 10 years has established fibromyalgia (FM) as a common chronic pain syndrome with similar neurophysiologic aberrations to other chronic pain states. As such, the pathogenesis is considered to involve an interaction of augmented sensory processing (central sensitization) and peripheral pain generators. The notion, that FM symptomatology results from an amplification of incoming sensory impulses, has revolutionized the contemporary understanding of this enigmatic problem and provided a more rational approach to treatment. To date, the management of FM has been mainly palliative, with the aims of reducing pain, improving sleep, maintaining function, treating psychologic distress and diminishing the impact of associated syndromes. The rapidly evolving neurophysiologic, psychophysiologic and molecular biologic basis for chronic pain states has already opened up new avenues for management which should be applicable to this difficult group of patients. Indeed, it is now possible to think about a "rational" approach to managing FM patients that was unthinkable just a few years ago.     

Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome

In addition to the debilitating fatigue, the majority of patients with chronic fatigue syndrome (CFS) experience chronic widespread pain. These pain complaints show the greatest overlap between CFS and fibromyalgia (FM). Although the literature provides evidence for central sensitization as cause for the musculoskeletal pain in FM, in CFS this evidence is currently lacking, despite the observed similarities in both diseases. The knowledge concerning the physiological mechanism of central sensitization, the pathophysiology and the pain processing in FM, and the knowledge on the pathophysiology of CFS lead to the hypothesis that central sensitization is also responsible for the sustaining pain complaints in CFS. This hypothesis is based on the hyperalgesia and allodynia reported in CFS, on the elevated concentrations of nitric oxide presented in the blood of CFS patients, on the typical personality styles seen in CFS and on the brain abnormalities shown on brain images. To examine the present hypothesis more research is required. Further investigations could use similar protocols to those already used in studies on pain in FM like, for example, studies on temporal summation, spatial summation, the role of psychosocial aspects in chronic pain, etc. Mira Meeus is financially supported by a Ph.D. grant (“Chronic pain in chronic fatigue syndrome: a biopsychosocial approach”) supplied by the Higher Institute of Physiotherapy, Department of Health Sciences, Hogeschool Antwerpen, Antwerp, Belgium and co-financed by Faculty of Physical Education and Physiotherapy, Vrije Universiteit Brussel (VUB), Brussels, Belgium (OZR project OZ.R. 1234/MFYS Wer2).     

Cough, pain and dyspnoea: similarities and differences

The three common symptoms, pain, dyspnoea and cough, share some important features. We felt that the analogies to be made among them could be instructive, possibly suggesting new avenues of research. Each of these symptoms can be profoundly uncomfortable, and can profoundly degrade quality of life. The sign, cough, is often given more prominence than the symptom, urge to cough, but both are important to the patient (the former may be of more concern to nearby people). Advances in pain research over the last several decades have pointed the way to new studies of dyspnoea; they may serve as a model for the psychophysical study of the perception of urge to cough, as well as providing models for understanding both central and peripheral sensitization of the afferent pathway. We briefly review here the afferent and central pathways and psychophysics of pain, dyspnoea and urge to cough.     

Evidence for Shared Pain Mechanisms in Osteoarthritis,Low Back Pain,and Fibromyalgia

Osteoarthritis (OA), low back pain (LBP), and fibromyalgia (FM) are common chronic pain disorders that occur frequently in the general population. They are a significant cause of dysfunction and disability. Why some of these chronic pain disorders remain localized to few body areas (OA and LBP), whereas others become widespread (FM) is unclear at this time. Genetic, environmental, and psychosocial factors likely play an important role. Although patients with OA, LBP, and FM frequently demonstrate abnormalities of muscles, ligaments, or joints, the severity of such changes is only poorly correlated with clinical pain. Importantly, many patients with these chronic pain disorders show signs of central sensitization and abnormal endogenous pain modulation. Nociceptive signaling is actively regulated by the central nervous system to allow adaptive responses after tissue injuries. Thus, abnormal processing of tonic peripheral tissue impulse input likely plays an important role in the pathogenesis of OA, LBP, or FM. Tonic and/or intense afferent nociceptive barrage can result in central sensitization that depends on facilitatory input from brainstem centers via descending pain pathways to the spinal cord. Abnormal endogenous control of these descending pathways can lead to excessive excitability of dorsal horn neurons of the spinal cord and pain. Ineffective endogenous pain control and central sensitization are important features of OA, LBP, and FM patients.     

Pharmacological modulation of pain-related brain activity during normal and central sensitization states in humans

Abnormal processing of somatosensory inputs in the central nervous system (central sensitization) is the mechanism accounting for the enhanced pain sensitivity in the skin surrounding tissue injury (secondary hyperalgesia). Secondary hyperalgesia shares clinical characteristics with neurogenic hyperalgesia in patients with neuropathic pain. Abnormal brain responses to somatosensory stimuli have been found in patients with hyperalgesia as well as in normal subjects during experimental central sensitization. The aim of this study was to assess the effects of gabapentin, a drug effective in neuropathic pain patients, on brain processing of nociceptive information in normal and central sensitization states. Using functional magnetic resonance imaging (fMRI) in normal volunteers, we studied the gabapentin-induced modulation of brain activity in response to nociceptive mechanical stimulation of normal skin and capsaicin-induced secondary hyperalgesia. The dose of gabapentin was 1,800 mg per os, in a single administration. We found that (i) gabapentin reduced the activations in the bilateral operculoinsular cortex, independently of the presence of central sensitization; (ii) gabapentin reduced the activation in the brainstem, only during central sensitization; (iii) gabapentin suppressed stimulus-induced deactivations, only during central sensitization; this effect was more robust than the effect on brain activation. The observed drug-induced effects were not due to changes in the baseline fMRI signal. These findings indicate that gabapentin has a measurable antinociceptive effect and a stronger antihyperalgesic effect most evident in the brain areas undergoing deactivation, thus supporting the concept that gabapentin is more effective in modulating nociceptive transmission when central sensitization is present.     

Comparing the association of widespread pain,multi-joint pain and low back pain with measures of pain sensitization and function in people with knee osteoarthritis

Clinical Rheumatology - To compare 1. measures of pain sensitization (PS) in people with widespread pain (WSP), multi-joint pain, low back pain (LBP) and knee osteoarthritis (KOA) only, in people...     

The role of central sensitization in shoulder pain: A systematic literature review

IntroductionHyperexcitability of the central nervous system has been suggested to play an important role in pain experienced by patients with unilateral shoulder pain. A systematic literature review following the PRISMA guidelines was performed to evaluate the existing evidence related to the presence of central sensitization in patients with unilateral shoulder pain of different etiologies including those with chronic subacromial impingement syndrome. Studies addressing neuropathic pain (e.g., post-stroke shoulder pain) were not considered.MethodsElectronic databases PubMed, EBSCO, and Web of Science were searched to identify relevant articles using predefined keywords regarding central sensitization and shoulder pain. Articles were included till September 2013. Full-text clinical reports addressing studies of central sensitization in human adults with unilateral shoulder complaints including those diagnosed with subacromial impingement syndrome were included and screened for methodological quality by two independent reviewers.ResultsA total of 10 articles were retrieved for quality assessment and data extraction. All studies were cross-sectional (case–control) or longitudinal in nature. Different subjective and objective parameters, considered manifestations of central sensitization, were established in subjects with unilateral shoulder pain of different etiologies, including those receiving a diagnosis of subacromial impingement syndrome. Overall results suggest that, although peripheral mechanisms are involved, hypersensitivity of the central nervous system plays a role in a subgroup within the shoulder pain population.ConclusionsAlthough the majority of the literature reviewed provides emerging evidence for the presence of central sensitization in unilateral shoulder pain (including those diagnosed with subacromial impingement syndrome), our understanding of the role central sensitization plays in the shoulder pain population is still in its infancy. Future studies with high methodical quality are therefore required to investigate this further.     

Impact of nervous system hyperalgesia on pain, disability, and quality of life in patients with knee osteoarthritis: a controlled analysis

OBJECTIVE: Refractory, disabling pain associated with knee osteoarthritis (OA) is usually treated with total knee replacement. However, pain in these patients might be associated with central nervous sensitization rather than peripheral inflammation and injury. We evaluated the presence of hyperalgesia in patients scheduled for a total knee replacement due to knee osteoarthritis with refractory pain, and we assessed the impact of pressure pain threshold measurements (PPT) on pain, disability, and quality of life of these patients. METHODS: Sixty-two female patients were compared with 22 age-matched healthy controls without reported pain for the last year. PPT was measured at the lower extremities subcutaneous dermatomes, over the vastus medialis, adductor longus, rectus femoris, vastus lateralis, tibialis anterior, peroneus longus, iliacus, quadratus lumborum and popliteus muscles and at the supraspinous ligaments from L1-L5, over the L5-S1 and S1-S2 sacral areas and at the pes anserinus bursae and patellar tendon. RESULTS: Patients with knee OA had significantly lower PPT over all evaluated structures versus healthy control subjects (P<0.001). Lower PPT values were correlated with higher pain intensity, higher disability scores, and with poorer quality of life, except for the role-emotional and general health status. Combined PPT values over the patellar tendon, at the S2 subcutaneous dermatome and at the adductor longus muscle were the best predictors for visual analog scale and Western Ontario and McMaster Universities Osteoarthritis Index pain scores. CONCLUSION: Patients with pain due to osteoarthritis who were scheduled for total knee replacement showed hyperalgesia of nervous system origin that negatively impacted pain, knee functional capacity, and most aspects of quality of life.     

Management of peripheral pain generators in fibromyalgia

Fibromyalgia is a widespread chronic pain disorder that is characterized in part by central sensitization and increased pain response to peripheral nociceptive and non-nociceptive stimuli. Part of the comprehensive pain management of patients with fibromyalgia should include a thoughtful evaluation and search for peripheral pain generators that either are associated with fibromyalgia or are coincidentally present. The identification and treatment of these pain generators lessens the total pain burden, facilitates rehabilitation and decreases the stimuli for ongoing central sensitization.     

Validity of the Central Sensitization Inventory (CSI) through Rasch analysis in patients with knee osteoarthritis

Clinical Rheumatology - Central sensitization (CS) is a known contributor to chronic pain in people with knee osteoarthritis (KOA) and is commonly measured by psychophysical testing or...     

Associations between insomnia and central sensitization in cancer survivors undergoing opioid therapy for chronic cancer pain: A STROBE-compliant prospective cohort study

Several risk factors for insomnia in cancer patients have been recognized, including chronic pain and treatment with opioid. Although associations between insomnia and central sensitization were previously reported in patients with chronic non-cancer pain, those have not been elucidated among cancer survivors undergoing opioid therapy for chronic cancer pain. To investigate the associations between insomnia and central sensitization among cancer survivors undergoing opioid therapy for chronic cancer pain, consecutive patients undergoing chemotherapy with chronic cancer pain under opioid therapy on an outpatient basis were enrolled from September 2019 to August 2020 and answered questions from the Athens Insomnia Scale (AIS) for assessing insomnia. Pain characteristics, including pain intensity, neuropathic pain, central sensitization assessed using the central sensitization inventory (CSI), opioid use disorder, and pain-related psychological symptoms were also examined. Uni- and multivariate regression analyses were performed to elucidate correlations between the AIS score and these pain characteristics. Of 44 enrolled patients, 20 patients completed to answer all questions. Insomnia was identified in 9 patients (45%). Although AIS scores showed no significant associations with pain intensity, neuropathic pain, opioid use disorder, or psychological symptoms, multivariate regression analysis revealed that CSI scores showed a positive relationship with AIS scores (P = .004). Discrimination was assessed using linear regression analysis which confirmed a significant association between the AIS and CSI scores (P = .002). Insomnia appears to be associated with central sensitization in cancer survivors with chronic cancer pain under opioid therapy.     

Role of Functional Brain Imaging in Understanding Rheumatic Pain

Rheumatic pain and, in particular, rheumatoid arthritis, osteoarthritis and fibromyalgia, are common and debilitating chronic pain syndromes. Recently, human functional neuroimaging, for example EEG, fMRI, and PET has begun to reveal some of the crucial central nervous system mechanisms underlying these diseases. The purpose of this review is to summarise current knowledge on the brain mechanisms of rheumatic pain revealed by functional neuroimaging techniques. The evidence suggests that two mechanisms may be largely responsible for the clinical pain associated with these rheumatic diseases: abnormalities in the medial pain system and/or central nervous system sensitisation and inhibition. If we can understand how functioning of the central nociceptive system becomes altered, even in the absence of peripheral nociceptive input, by using functional neuroimaging techniques, in the future we may be able to develop improved, more effective treatments for patients with chronic rheumatic pain.     

Pathophysiological mechanisms in chronic musculoskeletal pain (fibromyalgia): the role of central and peripheral sensitization and pain disinhibition

Chronic musculoskeletal pain has biological, psychological and social components. This review deals with the biological factors, with emphasis on the fibromyalgia syndrome (FMS). Studies on central sensitization of pain-transmitting neurons, changes in endogenous pain modulation that give rise to pain disinhibition, referred pain, pain-related decrease in muscle strength and endurance, and pain generators in deep tissues are reviewed. In FMS there is strong scientific support for the statement that the biological part of the syndrome is a longstanding or permanent change in the function of the nociceptive nervous system that can be equated with a disease. Further research is necessary in order to determine which methods are best for diagnosis of the pain hypersensitivity in clinical practice. FMS may be the far end of a continuum that starts with chronic localized/regional musculoskeletal pain and ends with widespread chronic disabling pain.