Evidence Of Central Sensitization Research Articles

Visceral and somatic sensory function in functional dyspepsia

Visceral hypersensitivity is one of the proposed underlying mechanisms in functional dyspepsia (FD). It is not clear whether visceral hypersensitivity in FD is a manifestation of a central sensitization also encompassing somatic sensitization. Transient receptor potential vanilloid-1 (TRPV(1)) pathways are involved in gastric mechanosensory physiology and the TRPV(1) receptor agonist, capsaicin, has been used as a chemical stimulant. In this double-blind, randomized study we evaluated both visceral and somatic sensory function in 34 FD patients and 42 healthy controls using quantitative sensory testing. Visceral pain sensitivity was assessed using a validated gastric pain model with oral capsaicin capsule titration and somatic pain sensitivity was determined by foot heat and hand electric stimulation. The median capsaicin dose required to attain moderate pain was 0.5mg in FD and 1mg in controls (P = 0.03). At these doses, mean pain intensities on a 0-100 visual analog scale were greater for FD than controls [56.9 (95% confidence intervals, 52.2-61.5) vs 45.1 (41.6-48.6), resp.] (P = 0.005). Overall, mean somatic sensory and pain thresholds were similar in FD and control groups, but in a subgroup of FD pain hypersensitivity was seen on the hand and on the foot at different stimulation thresholds. A majority of patients with FD have visceral chemo-hypersensitivity involving TRPV(1) pathways. A substantial subgroup also has somatic hypersensitivity as evidence of central sensitization.

Evidence for central sensitization in chronic whiplash: A systematic literature review

It has been suggested that sensitization of the central nervous system plays an important role in the development and maintenance of chronic (pain) complaints experienced by whiplash patients. According to the PRISMA guidelines, a systematic review was performed to screen and evaluate the existing clinical evidence for the presence of central sensitization in chronic whiplash. DATABASES AND DATA TREATMENT: Predefined keywords regarding central sensitization and chronic whiplash were combined in electronic search engines PubMed and Web of Science. Full text clinical reports addressing studies of central sensitization in human adults with chronic complaints due to a whiplash trauma were included and reviewed on methodological quality by two independent reviewers. From the 99 articles that were identified, 24 met the inclusion criteria, and 22 articles achieved sufficient scores on methodological quality and were discussed. These studies evaluated the sensitivity to different types of stimuli (mechanical, thermal, electrical). Findings suggest that although different central mechanisms seem to be involved in sustaining the pain complaints in whiplash patients, hypersensitivity of the central nervous system plays a significant role. Persistent pain complaints, local and widespread hyperalgesia, referred pain and (thoracic) allodynia, decreased spinal reflex thresholds, inefficient diffuse noxious inhibitory controls activation and enhanced temporal summation of pain were established in chronic whiplash patients. Although the majority of the literature provides evidence for the presence of central sensitization in chronic whiplash, underlying mechanisms are still unclear and future studies with good methodological quality are necessary. In addition, international guidelines for the definition, clinical recognition, assessment and treatment of central sensitization are warranted.

Sensory function after cavernous haemangioma: a case report of thermal hypersensitivity at and below an incomplete spinal cord injury

Case report of a 42-year-old woman with non-evoked pain diagnosed with a cavernous C7-Th6 spinal haemangioma. To assess the effect of intramedullary haemorrhage (IH) on nociception and neuropathic pain (NP) at and below an incomplete spinal cord injury (SCI). Sensorimotor Function Group, Hospital Nacional de Parapléjicos de Toledo (HNPT). T2*-susceptibility weighted image (SWI) magnetic resonance imaging (MRI) of spinal haemosiderin and a complete pain history were performed 8 months following initial dysaesthesia complaint. Thermal pain thresholds were assessed with short 1 s stimuli, while evidence for central sensitization was obtained with psychophysical electronic Visual Analogue Scale rating of tonic 10 s 3 °C and 48 °C stimuli, applied at and below the IH. Control data were obtained from 10 healthy volunteers recruited from the HNPT. Non-evoked pain was present within the Th6 dermatome and lower legs. T2*-SWI MRI imaging detected extensive haemosiderin-rich IH (C7-Th5/6 spinal level). Cold allodynia was detected below the IH (left L5 dermatome) with short thermal stimuli. Tonic thermal stimuli applied to the Th6, Th10 and C7 dermatomes revealed widespread heat and cold allodynia. NP was diagnosed following IH, corroborated by an increase in below-level cold pain threshold with at- and below-level cold and heat allodynia. Psychophysical evidence for at- and below-level SCI central sensitization was obtained with tonic thermal stimuli. Early detection of IH could lead to better management of specific NP symptoms, an appreciation of the role of haemorrhage as an aggravating SCI physical factor, and the identification of specific spinal pathophysiological pain mechanisms.

The potential use of brain imaging as a tool to predict chronic pain after surgery

Brain imaging is a powerful tool in the investigation of mechanisms underlying pain perception, both acute and chronic. To date, brain imaging has not been applied to the specific model of predicting postoperative pain or investigating its maintenance once established. However, each of the features associated with postoperative pain (psychological phenotypes, peripheral evidence of central sensitization, neuropathic-like symptoms) has been investigated using these modalities with some success. The aim of brain imaging modalities is to explain, from a neurophysiological standpoint, some of the bedside observations seen to be associated with the development of chronic postoperative pain. This understanding serves 3 main purposes. First, from an academic point of view, it offers insights into pain mechanisms in general. Second, it identifies potential targets for pharmacologic and psychological interventions to reduce the risk of conversion to chronic postoperative pain. Third, it offers the potential to monitor the effects of proposed treatments with a quantifiable, objective measure, thus ensuring treatments are doing what they are hypothesized to do.

Above-level mechanical hyperalgesia in rats develops after incomplete spinal cord injury but not after cord transection, and is reversed by amitriptyline, morphine and gabapentin

Spinal cord injury (SCI) is a major cause of persistent neuropathic pain of central origin. Recent evidence suggests neuropathic pain in clinically complete SCI patients correlates with limited sensory function below the lesion (sensory discomplete). On this basis we examined if the onset of mechanical hyperalgesia was different in rodents after a severe incomplete clip-compression SCI versus a complete spinal cord transection at thoracic segment T13. Above-level withdrawal behaviors evoked by forepaw stimulation provided evidence of mechanical hyperalgesia after incomplete but not complete SCI, whereas below-level responses evoked by hindpaw stimulation revealed hypersensitivity after both injuries. The latency of the above-level response was 4–5 wks but was longer after a moderate clip-compression injury. Mechanical hyperalgesia was fully reversed by three analgesic drugs used in treating neuropathic SCI pain, but their duration of action differed significantly, showing a rank order of amitriptyline (24–48 h) ≫ morphine (6 h) > gabapentin (2 h). Evidence of central sensitization in cervical spinal cord segments that receive sensory projections from the forelimbs was provided by immunohistochemistry for Zif268, a functional marker of neuroplasticity. Zif268-immunoreactive neurons in laminae I/II increased in response to repetitive noxious forepaw stimulation in the incomplete SCI group, and this response was reduced in the complete transection and sham-operated groups. These data are consistent with the hypothesis that neuropathic pain of cord origin is more likely to develop after SCI when there is an incomplete loss of axons traversing the lesion.

Descending Inhibitory Pain Modulation Is Impaired in Patients With Chronic Pancreatitis

Pain is a prominent symptom in chronic pancreatitis (CP), but the underlying mechanisms are incompletely understood. We investigated the role of descending pain modulation from supraspinal structures as well as central nervous system sensitization in patients with pain from CP. Twenty-five patients with CP and 15 healthy volunteers were included. Descending pain modulation was investigated by diffuse noxious inhibitory control (a descending inhibitory response after conditioning stimulation). Central pain processing was investigated as the perceptual responses to multimodal (electrical, thermal, and mechanical) stimulations of the rectosigmoid and evoked brain potentials after electrical stimulation of the rectosigmoid. Compared with healthy volunteers, the efficacy of diffuse noxious inhibitory control was reduced in patients with CP (13% +/- 21% vs 39% +/- 22%, respectively; F = 3.8; P = .01); central sensitization was indicated by remote hyperalgesia in the rectosigmoid to electrical stimulation (21 +/- 15 mA vs 27 +/- 15 mA; F = 6.2; P = .02) and heat stimulation (51 degrees C +/- 5 degrees C vs 53 degrees C +/- 4 degrees C; F = 5.9; P = .02). Compared with controls, patients with CP had increased latency of the early P1 peak to rectosigmoid stimulation (85 +/- 21 ms vs 108 +/- 28 ms, respectively; P = .02), possibly reflecting reorganization of central pain pathways. Patients with CP have impairments in inhibitory pain modulation and evidence of central sensitization. Treatment of their pain therefore should focus not only on the pancreas, but also on descending pain modulation from supraspinal structures and central nervous system sensitization.

Central Sensitivity Syndromes: An Overview

ABSTRACT.Objective: To discuss the concept of central sensitivity syndromes [CSS] and its significance. An overview of the current literature was incorporated with the author's insight and views.Findings: A good number of disorders that show clinical overlap with fibromyalgia syndrome also meet the Yunus criteria for CSS. These criteria are based essentially on two components: mutual associations and evidence for central sensitization [CS] among them. While CS is likely to be the common binding glue for the CSS diseases, other pathophysiological mechanisms may also be involved. CSS is based on a biopsychosocial model.Conclusions: The CSS seems to be an important concept for future research and medical education, as well as patient care.

O367 Evidence for central sensitization in women with endometriosis

O367 Evidence for central sensitization in women with endometriosis

Duloxetine, a centrally acting analgesic, in the treatment of patients with osteoarthritis knee pain: A 13-week, randomized, placebo-controlled trial

Pain is a common cause of disability in osteoarthritis. Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), has demonstrated analgesic effects in diabetic peripheral neuropathy and fibromyalgia. Considering its central mechanism of action, duloxetine may be effective in other pain states with evidence of central sensitization. Herein, we report the results of a 13-week, randomized, double-blind, placebo-controlled trial of duloxetine (60–120 mg/day) versus placebo in the treatment of knee pain in 231 patients meeting clinical and radiographic criteria for osteoarthritis of the knee. Duloxetine was superior to placebo on the primary efficacy measure (weekly mean 24-h pain scores) beginning at Week 1 and continuing through the treatment period ( P ⩽ .05). There was also a significant improvement in the WOMAC physical functioning subscale and several other secondary outcomes. Adverse-event rates did not differ significantly between treatment groups (49.5% for duloxetine 60–120 mg/day, and 40.8% for placebo).

T1462 Central Sensitization - Induction of Both Rectal Hypersensitivity and Activation of the Diffuse Noxious Ihibitory Control (DNIC) Following Acid and Capsaicin Infusion in the Human Esophagus

INTRODUCTION: As visceral afferents from different regions of the gastrointestinal tract converge at the level of the spinal cord, we hypothesized that strong sensitization of oesophagus could induce widespread visceral hypersensitivity and DNIC activation at the same time. METHODS: Fifteen healthy volunteers (11 males, mean age 33, range 24-52 years) underwent randomized investigation two different days. Moderate pain assessment was measured at baseline and 30, 60 and 90 minutes after an experimental esophageal perfusion with either placebo or 180 ml 0.1M HCl + 2 mg capsaicin. An esophageal catheter was designed for electrical stimulation and perfusion. A multimodal rectal probe including electrical, mechanical and heat stimulation was developed to evaluate remote viscero-visceral hyperalgesia to the esophageal sensitization. Referred pain areas were drawn to all modalities. RESULTS: An increased sensitivity to mechanical (P=0.01) and heat stimulation (P<0.01) was demonstrated in the rectum. Simultaneously a decreased sensitivity to electrical stimulation was found both in the esophagus (P<0.03) lasting all 90 minutes and in the sigmoid colon (P<0.001) at 60 minutes after sensitization. Referred pain areas during heat and mechanical stimulation were unchanged. Referred pain areas to electrical stimulation were reduced in esophagus in the treated group (P=0.01) and increased in sigmoid colon in the treated group (P=0.03). CONCLUSION: This study provides new evidence of central sensitization. The model mimics clinical pain such as patients suffering from IBS or other functional gastrointestinal diseases. The activation of DNIC (either modality specific or through spinal or supraspinal pathways) could make this model suitable for future pharmacological studies of drug intervention.

Role of central sensitization in symptoms beyond muscle pain, and the evaluation of a patient with widespread pain

Patients with widespread pain or fibromyalgia syndrome have many symptoms besides musculoskeletal pain: e.g. fatigue, sleep difficulties, a swollen feeling in tissues, paresthesia, cognitive dysfunction, dizziness, and symptoms of overlapping conditions such as irritable bowel syndrome, headaches and restless legs syndrome. There is evidence for central sensitization in these conditions, but further studies are needed. Anxiety, stress and depression are also present in 30-45% of patients. Other factors that may contribute to symptoms include endocrine dysfunction, psychosocial distress, trauma, and disrupted sleep. Evaluation of a patient presenting with widespread pain includes history and physical examination to diagnose both fibromyalgia and associated or concomitant conditions. Fibromyalgia should be diagnosed by its own characteristic features. Some patients with otherwise typical symptoms of fibromyalgia may have as few as four to six tender points in clinical practice. Patients with rheumatoid arthritis and systemic lupus erythematosus should be evaluated for fibromyalgia, since 20-30% of them have associated fibromyalgia, requiring a different treatment approach.

Exploring the neurophysiological basis of chest wall allodynia induced by experimental oesophageal acidification – evidence of central sensitization1

In somatic models of central sensitisation (CS) allodynia develops following changes to somatic A-beta fibres, allowing these afferents which normally only process innocuous sensations to encode pain. The aim of this study was to determine whether somatic allodynia induced by visceral sensitisation occurs via N-Methyl-D-Aspartate (NMDA) receptor mediated changes to the neurophysiological characteristics of somatic A-beta fibres. Twelve healthy subjects had oesophageal, chest wall and foot pain thresholds (PT) to electrical stimulation measured, and chest wall evoked potentials (CEP) recorded before and 30 minutes after distal oesophageal acidification on 2 separate visits. Intravenous ketamine (an NMDA receptor antagonist) or saline was given 30 minutes post acid with repeated oesophageal and chest wall PT measurements and CEP recordings. Distal oesophageal acidification reduced PT to electrical stimulation on the anterior chest wall (37 +/- 10 mA v 29 +/- 7 mA p = 0.01) and proximal oesophagus (46 +/- 10 mA v 33 +/- 11 mA p = 0.001) but not the foot (37 +/- 25 mA v 39 +/- 23 mA p = 0.12). The induction of chest wall somatic allodynia was accompanied by a reduction in the latency of the P1 (36 +/- 3 ms to 30 +/- 4 ms p = 0.016) and P2 (87 +/- 7 ms to v 76 +/- 7 ms p = 0.049) components of the CEP. NMDA receptor antagonism reversed both visceral and somatic pain hypersensitivity but did not affect CEP latencies. These data provide objective neurophysiological evidence that CS contributes to the development of somatic allodynia following visceral sensitisation.

Fibromyalgia and Overlapping Disorders: The Unifying Concept of Central Sensitivity Syndromes

To discuss fibromyalgia syndrome (FMS) and overlapping conditions, eg, irritable bowel syndrome, headaches, and chronic fatigue syndrome, within the concept of central sensitivity syndromes (CSS). A critical overview of the literature and incorporation of the author's own views. The concept of CSS seems viable. It is based on mutual associations among the CSS conditions as well as the evidence for central sensitization (CS) among several CSS members. However, such evidence is weak or not available in other members at this time, requiring further studies. The biology of CSS is based on neuroendocrine aberrations, including CS, that interact with psychosocial factors to cause a number of symptoms. CSS is an important new concept that embraces the biopsychosocial model of disease. Further critical studies are warranted to fully test this concept. However, it seems to have important significance for new directions for research and patient care involving physician and patient education. Each patient, irrespective of diagnosis, should be treated as an individual considering both the biological and psychosocial contributions to his or her symptoms and suffering.

Abnormal endogenous pain modulation and somatic and visceral hypersensitivity in female patients with irritable bowel syndrome

To investigate the role of endogenous pain modulatory mechanisms in the central sensitization implicated by the visceral hypersensitivity demonstrated in patients with irritable bowel syndrome (IBS). Dysfunction of modulatory mechanisms would be expected to also result in changes of somatic sensory function. Endogenous pain modulatory mechanisms were assessed using heterotopic stimulation and somatic and visceral sensory testing in IBS. Pain intensities (visual analogue scale, VAS 0-100) during suprathreshold rectal distension with a barostat, cold pressor stimulation of the foot and during both stimuli simultaneously (heterotopic stimulation) were recorded in 40 female patients with IBS and 20 female healthy controls. Rectal hypersensitivity (defined by 95% CI of controls) was seen in 21 (53%), somatic hypersensitivity in 22 (55%) and both rectal and somatic hypersensitivity in 14 of these IBS patients. Heterotopic stimulation decreased rectal pain intensity by 6 (-11 to -1) in controls, but increased rectal pain by 2 (-3 to +6) in all IBS patients (P < 0.05) and by 8 (-2 to +19) in IBS patients with somatic and visceral hypersensitivity (P < 0.02). A majority of IBS patients had abnormal endogenous pain modulation and somatic hypersensitivity as evidence of central sensitization.

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.

New evidence for central sensitization of fibromyalgia patients: Windup maintenance is abnormal

New evidence for central sensitization of fibromyalgia patients: Windup maintenance is abnormal

Differential behavioral outcomes in the sciatic cryoneurolysis model of neuropathic pain in rats

We have previously introduced a novel animal model of neuropathic pain in rats following a peripheral mononeuropathy produced by freezing the common sciatic nerve, a technique termed sciatic cryoneurolysis (SCN). In this study, we have further characterized the temporal pattern of behavioral changes following SCN, including thermal hyperalgesia and mechanical allodynia. These behaviors were assessed using noxious thermal (radiant heat) and non-noxious tactile (von Frey filament) stimuli, respectively. Following unilateral SCN, animals exhibited significant ( P < 0.001) bilateral tactile hypersensitivity (allodynia) that persisted at least 10 weeks. However, this lesion did not result in thermal hypersensitivity (hyperalgesia). In fact, thermal sensitivity in the operated limb remained significantly suppressed throughout the 10 weeks ( P < 0.001). Furthermore, we observed autotomy in 76% of SCN-lesioned animals as well as transient weight loss and pale eye syndrome (PES), a phenomenon previously unreported in other neuropathic pain models. PES is a sustained, visibly distinct pallor of the normally pink eye color of the albino rat. We believe PES is a putative marker of heightened sympathetic efferent activity. The severity of autotomy following SCN correlated significantly with both weight loss ( P < 0.001) and the expression of PES ( P < 0.001). Autotomy behavior preceded the onset of allodynia; however, there was no correlation between the severity of expression of these behaviors. These behavioral sequelae are comparable to those seen in other animal models of neuropathic pain, but differ in respect to the increased frequency of autotomy and the lack of thermal hyperalgesia. Our findings support the hypothesis of a sensory basis for autotomy and provide further evidence of central sensitization or disinhibition as the basis for allodynia following peripheral nerve injury. However, the results also indicate independence between the genesis of autotomy and allodynia in animal pain models. The manifestation of sustained allodynia following SCN indicates that this model yields behavioral sequelae similar to those seen in neuropathic pain syndromes in humans.