Pain and other symptoms of CRPS can be increased by ambiguous visual stimuli--an exploratory study.

BACKGROUND: Visual disturbance, visuo-spatial difficulties, and exacerbations of pain associated with these, have been reported by some patients with Complex Regional Pain Syndrome (CRPS). AIMS: We investigated the hypothesis that some visual stimuli (i.e. those which produce ambiguous perceptions) can induce pain and other somatic sensations in people with CRPS. METHODS: Thirty patients with CRPS, 33 with rheumatology conditions and 45 healthy controls viewed two images: a bistable spatial image and a control image. For each image participants recorded the frequency of percept change in 1 min and reported any changes in somatosensation. RESULTS: 73% of patients with CRPS reported increases in pain and/or sensory disturbances including changes in perception of the affected limb, temperature and weight changes and feelings of disorientation after viewing the bistable image. Additionally, 13% of the CRPS group responded with striking worsening of their symptoms which necessitated task cessation. Subjects in the control groups did not report pain increases or somatic sensations. CONCLUSIONS: It is possible to worsen the pain suffered in CRPS, and to produce other somatic sensations, by means of a visual stimulus alone. This is a newly described finding. As a clinical and research tool, the experimental method provides a means to generate and exacerbate somaesthetic disturbances, including pain, without moving the affected limb and causing nociceptive interference. This may be particularly useful for brain imaging studies.

Wherever is my arm? Impaired upper limb position accuracy in complex regional pain syndrome.

Knowledge of the position of one's limbs is an essential component of daily function and relies on complex interactions of sensorimotor body schema-related information. Those with Complex Regional Pain Syndrome (CRPS) express difficulty in knowing where their affected limb is positioned. The aim of this study was to determine the degree to which experimental data supported the reported difficulty in limb position sense. A controlled experimental design was used to measure upper limb position accuracy amongst those with CRPS of one arm. Position accuracy was individually measured in both arms and compared to a known target position. Video captured each of 36 trials (half with arm in full view and half with vision obscured). The error in degrees between actual and known targets was determined using video analysis software. The Brief Pain Inventory measured pain. A subjective mental image representation of both upper limbs was documented. The CRPS group had moderate pain intensity and were significantly less accurate in positioning both the affected and unaffected limbs compared to controls (p<0.001). Position accuracy of the CRPS affected limb significantly improved with vision (8.3 degrees in view, 10.7 degrees not in view). Subjective mental representations of the affected limb were visualised as distorted. Evidence of bilateral arm positioning impairments in unilateral arm CRPS suggests that central mechanisms are involved. Cortical reorganisation in regions associated with the body schema (i.e. primary somatosensory and parietal cortices) is proposed as an explanation. The exact relationship between pain and limb position deficits requires further exploration.

The molecular basis of pain and its clinical implications in rheumatology.

Nociceptive pain in response to peripheral noxious stimuli, and inflammatory pain resulting from tissue damage, serve as warnings that normal bodily function cannot resume until the stimulus abates or the tissue repairs. Stimuli cause numerous receptors, ion channels and other cellular machinery to respond, and propagate signals to the central nervous system, where this information is processed and perceived as pain. In healthy individuals, tissue damage results in physiologic--generally reparative--changes that lead to heightened sensory perception and, often, pain. In rheumatic diseases, the joint pain bears much in common with chronic inflammatory pain, but the underlying disease state is typically much more intricate and no reparative function is evident. Addressing the complex pains of rheumatic disease remains an ongoing challenge. Pain signaling pathways involve many molecular components that could potentially be targets for pharmacotherapeutic intervention, but the complexity of this system might also mean that multiple sites must be affected simultaneously to disrupt propagation of pain signals. In addition, to be therapeutically viable, pain drugs must be safe and not alter tactile sensory function, alertness or cognitive function. In this article we review the molecular functions in nociceptive, inflammatory and rheumatic pain pathways, and the therapeutic options they might offer.

The two homologous chaperonin 60 proteins of Mycobacterium tuberculosis have distinct effects on monocyte differentiation into osteoclasts.

Mycobacterium tuberculosis produces two homologous chaperonin (Cpn)60 proteins, Cpn60.1 and Cpn60.2 (Hsp65). Both proteins stimulate human and murine monocyte cytokine synthesis but, unlike Cpn60 proteins from other microbial species, fail to stimulate the breakdown of cultured murine bone. Here, we have examined the mechanism of action of these proteins on bone remodelling and osteoclastogenesis, induced in vitro in murine calvarial explants and the murine monocyte cell line RAW264.7. Additionally, we have determined their effect on bone remodelling in vivo in an animal model of arthritis. Recombinant Cpn60.1 but not Cpn60.2 inhibited bone breakdown both in vitro, in murine calvaria and in vivo, in experimental arthritis. Analysis of the mechanism of action of Cpn60.1 suggests that this protein works by directly blocking the synthesis of the key osteoclast transcription factor, nuclear factor of activated T cells c1. The detection of circulating immunoreactive intact Cpn60.1 in a small number of patients with tuberculosis but not in healthy controls further suggests that the skeleton may be affected in patients with tuberculosis. Taken together, these findings reveal that M. tuberculosis Cpn60.1 is a potent and novel inhibitor of osteoclastogenesis both in vitro and in vivo and a potential cure for bone-resorptive diseases like osteoporosis.

Mirror visual feedback for the treatment of complex regional pain syndrome (type 1).

Mirror visual feedback was originally devised as a therapeutic tool to relieve perceived involuntarily movements and paralysis in the phantom limb. Since this pioneering work was conducted in the mid-1990s, the technique has been applied to relieve pain and enhance movement in other chronic conditions such as stroke and complex regional pain syndrome (CRPS) type 1. This review describes how mirror visual feedback was first developed with amputees, its original application in CRPS, and how further research has demonstrated its potential benefit within graded motor imagery programs. We discuss the potential mechanisms behind this technique and consider the implications for clinical practice.

Body perception disturbance: a contribution to pain in complex regional pain syndrome (CRPS).

In spite of pain in the CRPS limb, clinical observations show patients pay little attention to, and fail to care for, their affected limb as if it were not part of their body. Literature describes this phenomenon in terms of neurological neglect-like symptoms. This qualitative study sought to explore the nature of the phenomenon with a view to providing insights into central mechanisms and the relationship with pain. Twenty-seven participants who met the IASP CRPS classification were interviewed using qualitative methods to explore feelings and perceptions about their affected body parts. These semi-structured interviews were analysed utilising principles of grounded theory. Participants revealed bizarre perceptions about a part of their body and expressed a desperate desire to amputate this part despite the prospect of further pain and functional loss. A mismatch was experienced between the sensation of the limb and how it looked. Anatomical parts of the CRPS limb were erased in mental representations of the affected area. Pain generated a raised consciousness of the limb yet there was a lack of awareness as to its position. These feelings were about the CRPS limb only as the remaining unaffected body was felt to be normal. Findings suggest that there is a complex interaction between pain, disturbances in body perception and central remapping. Clinically, findings support the use of treatments that target cortical areas, which may reduce body perception disturbance and pain. We propose that body perception disturbance is a more appropriate term than 'neglect-like' symptoms to describe this phenomenon.

Evidence for a mismatch between the brain's movement control system and sensory system as an explanation for some pain-related disorders.

The motor-control system usually operates below our conscious level, and we only become aware of the complex interaction between desired movements and actual movements when an irregularity in the system occurs. Recently, it has been proposed that such discordances in sensorimotor function may generate pain and other somaesthetic disturbances. This article describes this model of pain and determines how it may be applied to a range of chronic pain conditions in which there is a lack of obvious causal pathology, including complex regional pain syndrome. In addition, we discuss the clinical implications of such a theory and examine how enhancing sensory feedback may reduce chronic pain.

Measurement of S-nitrosothiols in extracellular fluids from healthy human volunteers and rheumatoid arthritis patients, using electron paramagnetic resonance spectrometry.

In human tissues, S-nitrosothiols (RSNOs) are generated by the nitric oxide (NO.)-dependent S-nitrosation of thiol-containing species. Here, a novel electron paramagnetic resonance spectrometry assay for RSNOs is described, together with its application to studies of human health and disease. The assay involves degrading RSNOs using N-methyl-d-glucamine dithiocarbamate (MGD) at high pH and spin trapping the NO. released using (MGD)2-Fe2+. Because dietary nitrate might contribute to tissue RSNOs, the assay was used to monitor the effect of Na15NO3 ingestion on plasma and gastric juice RSNOs in healthy human volunteers. Na15NO3 ingestion (2 mmol) increased gastric RS15NO concentrations (p<0.01), but there was no significant effect on plasma RS15NO concentrations. Having established that dietary nitrate was not a confounding factor, we applied the RSNO assay to matched plasma and knee-joint synovial fluid (SF) from rheumatoid arthritis (RA) patients, with healthy subjects as controls. Clinical markers of RA inflammatory disease activity were quantified, as were plasma and SF NO2- and NO3-. Median RSNO concentrations were 0 (interquartile range 68) nM, 109 (282) nM, and 309 (470) nM in normal plasma, RA plasma, and SF, respectively. The median RSNO concentration was significantly elevated in RA SF compared with RA plasma (p<0.05) and in RA plasma compared with normal plasma (p<0.05). SF RSNO concentrations correlated positively with SF neutrophil counts (rs=0.55, p<0.05) and inversely with blood hemoglobin concentrations (rs=-0.52, p<0.05), but not with NO2- or NO3-. Thus the raised levels of RSNOs in RA SF correlate with some established markers of inflammation, suggesting the described RSNO assay may have applications in rapid clinical monitoring of NO metabolism in human inflammatory conditions.

Xanthine oxidase mediates cytokine-induced, but not hormone-induced bone resorption.

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) have been implicated as mediators of osteoclastic bone resorption. Xanthine oxidase (XO) a ubiquitous enzyme is widely known for its production of these ROS. We therefore evaluated the potential of XO as a source of ROS in cytokine-and hormone-induced bone resorption. XO activity in rat calvarial osteoblasts was found to be significantly elevated upon stimulation by the cytokines, TNFalpha and IL-1beta. These cytokines also caused a dose related increase in bone resorption of mouse calvariae, which was significantly inhibited by catalase (10 IU/ml). Allopurinol, the competitive inhibitor of XO, also caused a dose related (1-50 microM) inhibition of TNFalpha (20 ng/ml) and (0.01-10 microM) IL-1beta (50 IU/ml)-induced bone resorption, respectively. PTH- and 1,25-(OH)2 Vitamin D3-induced bone resorption could also be inhibited by catalase (100 IU/ml) but was unaffected by allopurinol, indicating that another mediator, other than XO, is required for hormone-induced bone resorption. These results demonstrate, that modulation of the redox balance in the bone microenvironment, which contains XO, can affect the bone resorbing process. Therefore, XO may play a pivotal role in cytokine-induced bone resorption and, if manipulated appropriately, could show a therapeutic benefit in inflammatory bone disorders such as RA.