Scandinavian journal of rheumatology. Supplement最新文献

Background: Since the good effect of intra-articular injections of the 5-HT3 receptor antagonist tropisetron in patients with arthritides and activated osteoarthritis has already been demonstrated in pilot studies, the effect of tropisetron is compared with that of methylprednisolone here.

Objectives: In a double-blind study, 34 patients with gonarthritides or activated osteoarthritis (18 patients with rheumatoid arthritis, 16 patients with osteoarthritis) were treated with a single intra-articular injection of 10 mg tropisetron (18 patients) or 40 mg methylprednisolone (16 patients). Before treatment as well as one and three weeks later, the intensity of rest pain and pain following exercise was measured with the visual analog scale (VAS) for pain and the clinical findings in the knee joint were recorded.

Results: By means of the intra-articular tropisetron treatment, the inflammatory joint process with arthritides and activated arthroses could be influenced in a similar way as with corticosteroid treatment. No significant differences were detected.

Conclusion: According to the results presented here, the intra-articular treatment with the 5-HT3 receptor antagonist tropisetron in patients with gonarthritides and activated arthroses was about equally effective as those for treatment with corticosteroids. Therefore, it can be used as an alternative in patients for whom concomitant diseases like diabetes and hypertension make it difficult to use corticosteroids. Whether increasing the tropisetron dose may further improve the results remains to be determined in future studies.

Vegetative and functional symptoms are, besides pain and tenderness of tender points, considered as additional information for the diagnosis of fibromyalgia (FM). In clinical trials, vegetative and functional symptoms have been included for selection of patients (e.g. sleep disturbances) and as secondary outcome parameters. Despite the relevance of these symptoms, no validated method is currently available but symptom lists are ad hoc developed by investigators. In this manuscript, data from a published double blind, randomised study are reanalysed which compared oral therapy over 10 days with 5 mg, 10 mg, and 15 mg to placebo in FM patients. This study applied a list of 17 vegetative and functional symptoms, which had to be scored by the patients by use of a 4-point severity scale (0 = none to 3 = severe). Factor analysis of the baseline data from 195 patients suggested to separate 6 sub-scales: Cardiovascular, gastrointestinal, psychiatric (sleep disturbance), nervous, autonomic system, and general disorders. Sleep disturbances, general symptoms (morning stiffness, fatigue) and autonomic symptoms (cold extremities, hyperhidrosis) were most severe in intensity. Analysis of sensitivity for treatment effects made use of differences between placebo and 5 mg tropisetron in changes between baseline and final assessment of the tropisetron trial. While, on the item level, differences in favour of tropisetron could only be demonstrated for sleep disorders, on the sub-scale level, also favourable effects of tropisetron could be shown for cardiovascular and nervous system complaints and, as a tendency, for general symptoms. On the other side, the sub-scale score of gastrointestinal symptoms worsened under tropisetron whilst it improved under placebo which effect was due to side effects of the active treatment. It is concluded that symptom clusters like sub-scales of a list of vegetative and functional symptoms will be more suitable for diagnostic purposes and evaluation of treatment outcome of clinical trials. Further research is urgently required which addresses the development of a FM-specific scale to assess vegetative and functional symptoms.

Objective: Central pain processing is altered in patients with fibromyalgia syndrome (FMS). The serotonin metabolism, especially the 5-HT3 receptor, seems to play an important role.

Methods: We investigated the effect of the local injection of the 5-HT3 receptor antagonist tropisetron on the perception and central processing of pain in FMS patients using painful mechanical stimulation and functional magnetic resonance imaging (fMRI) within the framework of a pre-/posttreatment double-blind design.

Results: In the contralateral primary somatosensory cortex, contralateral posterior insula, and anterior cingulate cortex, we found that the activation was significantly reduced after treatment. On average, patients rated the stimulation-induced pain intensity as stronger in the session after treatment compared to before treatment, although the individual data revealed a heterogeneous pattern. All patients showed sensitisation during the painful stimulation, which was not influenced by the treatment.

Conclusions: Both the sensory-discriminative and motivational-affective components of pain as measured by fMRI were altered by tropisetron.

Objective: To characterize the immune modulatory effects of 5-HT3 receptor antagonist treatment in patients with fibromyalgia, autoimmune disorders, and chronic pain.

Methods: Multiplex-assisted cytokine measurements were performed before and during treatment. Whole blood stimulation with TNF-alpha was carried out to determine the proinflammatory response induced by exogenous TNF-alpha.

Results: Five of nine patients clinically responded to treatment, and two had a moderate response. All patients had significantly elevated levels of T-H1 cytokines more prominent than TNF-alpha, IL-1beta, and IL-6. Treatment resulted in transient effects on peripheral monocyte counts in all but one patient, a plasma IL-1beta increase in two responder patients, and decreased T-H1 cytokines in two responder patients. Ex vivo TNF-alpha stimulation was transiently reconstituted in three responder patients to a significant level. Three patients showed a marginal reconstitutive response.

Conclusion: 5-HT3 receptor blockade transiently affects monocyte tissue infiltration, modulates T-H1 cytokines in clinical responders as well as MIP-1beta in moderate responders, and transiently affects the ex vivo response to exogenous TNF-alpha.

Objective: The aim of the study was to assess the influence of the 5HT3-receptor antagonist tropisetron on circulating catecholamines as biochemical markers of the activity of the sympathoadrenal system in fibromyalgia. Moreover, serum concentrations of serotonin, somatomedin C, oxytocin, calcitonin-gene-related-peptide, calcitonin and cholecystokinin were assayed as putative markers in pain-related disorders like primary fibromyalgia.

Methods: In 96 patients, who met the ACR classification criteria for fibromyalgia, and in 20 sex and age matched controls concentrations of dopamine, noradrenaline, adrenaline, serotonin and tropisetron were assayed in serum by HPLC with electrochemical detection. All other transmitters were determined by ELISA.

Results: There was with the exception of tropisetron, calcitonin and dopamine, no correlation between doses of tropisetron 5, 10, 15 mg respectively and significant changes in circulating transmitters or other transmitters as putative biochemicals markers in primary fibromyalgia. Regarding the prediction of pain reduction to tropisetron, patients with elevated dopamine and/or reduced plasma 5-HT concentrations tended to show a higher response rate.

Conclusion: Despite these partly disappointing results another prospective pilot study with selected patients vs. age and sex matched controls, double blind and with comparison of other 5HT3-receptor antagonists e.g. dolasetron and granisetron e.g. after i.v. bolus injection is suggested. Still the data obtained in this preliminary paper provide some evidence regarding the present discussion on subgroups of patients with primary fibromyalgia.

The observed effects on the symptoms of fibromyalgia of daily oral administration of 5 mg of the 5-HT3 receptor antagonist, tropisetron, for 10 days, could be maintained or exceeded with intravenous administration of only 2 mg of the formulation. Following a single i.v. injection of 2 mg tropisetron, a more rapid and profound reduction in pain was achieved than with 5 mg oral tropisetron per day. In individual cases, patients who had previously experienced no reduction in pain from 10 days of 5 mg oral tropisetron daily responded to i.v. therapy. A more favourable and persistent effect on pain, combined with a simultaneous significant improvement in various vegetative and functional symptoms was achieved with five days treatment with 2 mg tropisetron i.v. per day. The results outlined and the possibility for rapid improvements with drug treatment of fibromyalgia should be confirmed in randomised, placebo controlled trials.

According to the American College of Rheumatology the diagnosis of fibromyalgia is based on criteria for the classification of fibromyalgia consisting entirely of clinical signs and symptoms. For diagnostic reasons autonomic disturbances and mental features have to be considered. The distinction between fibromyalgia (tender points) and myofascial pain syndrome (trigger points) is essential. Internal and neurological disorders as a primary cause of fibromyalgia have to be excluded. The etiology and pathogenesis of fibromyalgia still remain uncertain. The myopathological patterns in fibromyalgia are non-specific: type II fiber atrophy, an increase of lipid droplets, a slight proliferation of mitochondria, and a slightly elevated incidence of ragged red fibers. Initial reports on some allelic abnormalities in the serotonin system seem to highlight the important role of serotonin already presumed earlier. Significantly high levels of substance P in the cerebrospinal fluid of FM patients additionally support the impact of these neurotransmitters on both nociceptive and antinociceptive mechanisms.

Repetitive synaptic excitation or the application of L-glutamate into the vicinity of multireceptive neurons in the dorsal horn of the spinal cord and corresponding structures of the trigeminal nucleus increases neuronal excitability, which is then reflected by an expansion of the receptive field (Fig. 1). Similar alterations of the receptive field of neurons have been observed in various other brain regions. The receptive fields of multireceptive neurons also expand their size following mechanical, chemical, inflammatory or nerve injuries. Since these multireceptive neurons are activated by converging non-nociceptive and nociceptive afferents an increased excitability of these neurons may also be the mechanism by which pain refers to distant somatic and visceral structures (Fig. 2). The increase in neuronal excitability is mediated to a great extent by the co-activation of glutamate receptors and receptors for substance P, a neuropeptide long thought to have a role in pain perception. There is evidence from recent research that this facilitatory effect on glutamatergic synaptic transmission involves membrane receptor phosphorylation, and enhances activity-dependent gene expression (Fig. 3). In order to investigate the time-dependent processing of ongoing afferent noxious stimulation in the central nervous system we recently employed the quantitative autoradiographic 14C-2-deoxyglucose technique in a model of chronic monoarthritic pain in the rat. A synopsis of these most recent experimental data and results from previous electrophysiological in vivo and in vitro studies suggests that dorsal horn neurons and probably also other neurons in pain-related structures become spontaneously active and can maintain their activity without further noxious peripheral input.

In a pilot study, the action of the 5-HT3 receptor antagonist, tropisetron, on different types of local rheumatic pain and inflammatory effects was studied. With intra-articular injection of tropisetron, an improvement in inflammation and pain was obtained in inflammatory rheumatic diseases and activated osteoarthrosis. Also, the majority of patients with localized soft-tissue rheumatic diseases (periarthritis) demonstrated an obvious decrease in their pain following local infiltration of tropisetron. Chronic low back pain and cervical pain responded somewhat to i.v. treatment with tropisetron. The effect of the 5-HT3 receptor antagonists is probable primarily to limit the release of substance P, which acts as a pain and inflammatory mediator, and is itself released by the neurogenic inflammation that occurs after the binding of serotonin to its corresponding receptor. These results should be backed up with placebo controlled studies, which if confirmed, might imply that 5-HT3 receptor antagonists could supplement or replace the local administration of corticosteroids.