Microheterogeneity of acute phase proteins in patients with clinically active and clinically nonactive osteoarthritis.

Microheterogeneity of two acute phase glycoproteins, alpha-1-acid glycoprotein (AGP) and alpha-1-antichymotrypsin (ACT), concentrations of AGP, ACT, and C-reactive protein (CRP), and levels of three cytokines: interleukin 1 beta (IL-1-beta), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were determined in 61 serum samples and 7 synovial fluids (SFs) obtained from patients (n = 61) with osteoarthritis. Using affinity immunoelectrophoresis with concanavalin A (conA), a significant decrease in the reactivity of AGP and ACT with this lectin was found in patients with clinically active osteoarthritis when compared to those with clinically nonactive disease (p < 0.001 and p < 0.05, respectively). There was no increase in the concentration of AGP, ACT, and C-reactive protein (CRP) in the sera examined. In particular, no increase in the serum level of these proteins was found in the patients with clinically active disease. Low concentrations of IL-6 and TNF-alpha were found in most sera and SFs examined. In 6 out of 7 SFs available, IL-6 concentrations were higher than in the respective serum samples but for TNF-alpha the same could be shown in one case only. Low concentrations of IL-1-beta were found in 4 serum samples obtained from patients with clinically active osteoarthritis and in no SF specimen studied. In the entire group, serum level of TNF-alpha correlated weakly with the AGP and ACT reactivity coefficients with conA (r = 0.3634, p < 0.005 and r = 0.3324, p < 0.02, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Do cytochrome enzymes influence the therapeutic effect of tropisetron in fibromyalgia?

It is well known that the 5-HT3 receptor tropisetron shows a bell-shaped dose-response curve in the treatment of pain associated with fibromyalgia. The best results are achieved with a daily oral dose of 5 mg for 10 days. Dosages of 10 and 15 mg per day have a much weaker effect. If tropisetron is administered by intravenous injection, a regimen of 5 mg per day over 5 days will suffice to reduce pain substantially. An open study of selected cases revealed that 2 mg of tropisetron daily for 5 days also yielded satisfactory pain reduction, whereas this was not observed in a placebo-controlled double-blind study. We therefore investigated which factors might be responsible for the different effects of the drug. Judging from the above-mentioned studies, the effect of a minimum dosage of tropisetron could be assumed to be partly attributable to the different half-life periods. This is supported by the markedly different rates of constipation, a characteristic side effect of the drug, reported by the two studies.

Fibromyalgia treatment with intravenous tropisetron administration.

A prospective, randomized, placebo-controlled, multicenter, double-blind trial in fibromyalgia patients demonstrated that peroral daily treatment with 5 mg tropisetron for 10 days produced a significant reduction in pain and other symptoms. The aim of the present study was to determine whether intravenous administration of 2 mg tropisetron daily for a limited period of time would produce quicker and more favorable results. In the first cohort 18 fibromyalgia patients received a single intravenous injection of 2 mg tropisetron. In the second cohort 24 fibromyalgia patients were treated with 2 mg intravenous tropisetron daily for 5 days. Pain intensity was measured with the visual analog scale and the pain score. Pain at tender and control points (dolorimeter) as well as 17 ancillary symptoms before and after treatment were evaluated. Pain intensity was followed-up by means of a patient diary until recurrence. Dolorimetry revealed that a single intravenous injection of 2 mg tropisetron significantly reduced pain and enhanced pain threshold. These effects, however, lasted for only a few days. Of 18 patients in the first cohort, only three showed no response to therapy. Of the 24 patients in the second cohort, 23 showed pain reduction when 2 mg tropisetron was administered daily for 5 days. Pain relief lasted for 2 weeks to 2 months in 20 of these patients. Two patients stopped filling in the pain diary. Twelve ancillary symptoms such as sleep disturbances, fatigue, morning stiffness were also significantly improved by the latter treatment. In the global assessment 16 out of 24 patients showed significant improvement and seven showed slight improvement. Only one patient experienced no improvement. Tolerability was good. In conclusion, intravenous injection of 2 mg of the 5-hydroxytryptamine3 receptor antagonist tropisetron once daily for 5 days produced a longer-lasting therapeutic effect on fibromyalgia symptoms than did peroral daily treatment with 5 mg of this drug. The results achieved are currently being evaluated in a randomized, placebo-controlled, double-blind trial.

Short-term treatment of primary fibromyalgia with the 5-HT3-receptor antagonist tropisetron. Results of a randomized, double-blind, placebo-controlled multicenter trial in 418 patients.

We investigated the efficacy and tolerability of short-term treatment with tropisetron, a selective, competitive 5-HT3-receptor antagonist in fibromyalgia. The trial was designed as a prospective, multicenter, double-blind, parallel-group, dose-finding study. We randomly assigned 418 patients suffering from primary fibromyalgia to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily for 10 days. Clinical response was measured by changes in pain score, visual analog scale, tender point count and ancillary symptoms. Responders were prospectively defined as patients showing a 35% or higher reduction in pain score. Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) than placebo (26.2%) (p < 0.05). In the visual analog scale, the group administered 5 mg tropisetron showed a significant improvement (p < 0.05) and the group administered 10 mg tropisetron showed a nonsignificant clinical benefit. The number of painful tender points was significantly reduced (p = 0.002) in the 5 mg tropisetron group. Regarding ancillary symptoms, the 5 mg tropisetron group showed a significant improvement (p < 0.05) in sleep and dizziness. The patients' overall assessment of efficacy was significantly higher for 5 mg (p = 0.016) and 10 mg (p = 0.002) tropisetron than for placebo. The safety and tolerability of tropisetron was good; gastrointestinal tract symptoms were the most frequently reported adverse events. Short-term treatment of fibromyalgia patients with 5 mg tropisetron for 10 days proved to be efficacious and well tolerated. In this study a bell-shaped dose-response curve was seen.

[Serotonin concentration in serum of patients with generalized tendomyopathy (fibromyalgia) and chronic polyarthritis]. / Die Serotoninkonzentration im Serum bei Patienten mit generalisierter Tendomyopathie (Fibromyalgie) und chronischer Polyarthritis.

The serum concentration of serotonin (S-5-HT) was measured in 31 patients with primary fibromyalgia, 21 patients with rheumatoid arthritis (RA) (15 of them with secondary fibromyalgia) and 20 healthy volunteers. Both patients with primary fibromyalgia and rheumatoid arthritis had significantly lower S-5-HT levels when compared to healthy controls, and S-5-HT concentrations in patients with secondary fibromyalgia were even significantly lower than those of RA-patients. Unlike the patients with rheumatoid arthritis, a significant correlation between S-5-HT level and the number of "tender points" as well as mean pressure tenderness at 24 different points was found in patients with primary fibromyalgia. Conversely, in patients with rheumatoid arthritis the S-5-HT level correlated significantly with erythrocyte sedimentation rate. These results suggest different pathological mechanisms of S-5-HT decrease in patients with primary fibromyalgia and rheumatoid arthritis. On the other hand, they raise the question whether secondary fibromyalgia may be a pathogenetically different syndrome mimicking symptomatically primary fibromyalgia.

The classification of fibromyalgia syndrome.

As has been shown by a number of working groups, primary fibromyalgia syndrome does not represent a single clinical entity. It is possible to distinguish between a subgroup with high pain sensitivity and no associated psychiatric condition, a second and a third subgroup characterized by depression associated with fibromyalgia syndrome, and a fourth group with somatoform pain disorder of the fibromyalgia type. Mild inflammatory processes must be considered as the cause in the first group, while depression is combined with fibromyalgia in the second and the third group. In the fourth group, serious previous or still existing psychological problems or also insufficient coping with illness symptoms must be regarded as the reason for pain chronification. Group 1 benefits from a blocking of the 5-HT3 receptors by means of tropisetron, for example. This does not only affect pain chronification but also the inflammatory process itself. Group 2 and 3 needs antidepressant treatment, whereas the focus should be on psychotherapy in group 4. Groups 1, 2 and 3 will also profit from multimodal physical treatment programs, to a certain extent this applies to group 4 as well. So-called mixed types require a combination of therapeutic measures.

[Subgroups of fibromyalgia]. / Ein Modell zur Einteilung des Fibromyalgiesyndroms.

As has been shown by a number of working groups, primary fibromyalgia syndrome does not represent a single clinical entity. It is possible to distinguish between a subgroup with high pain sensitivity and no associated psychiatric condition, a second subgroup characterized by depression and concomitant pain symptoms associated with fibromyalgia syndrome, and a third group with somatoform pain disorder of the fibromyalgia type. Bland inflammatory processes must be considered as the cause in the first group, while depression is the underlying reason for the development of pain in the second group. In the third group, serious previous or still existing psychological problems or also insufficient coping with illness symptoms must be regarded as the reason for pain chronification. Group 1 benefits from a blocking of the 5-HT3 receptors by means of tropisetron, for example. This not only affects pain chronification but also the inflammatory process itself. Group 2 needs antidepressant treatment, whereas the focus should be on psychotherapy is group 3. Groups 1 and 2 will also profit from multimodal physical treatment programs; to a certain extent this applies to group 3 as well. So-called mixed types require a combination of therapeutic measures.

[5-HT3 receptor antagonist als analgetics in rheumatic diseases]. / 5-HT3-Rezeptor-Antagonisten als Analgetika bei rheumatischen Erkrankungen.

Various rheumatic diseases like fibromyalgia, systemic inflammatory rheumatic disorders and localized diseases, such as arthritides and activated arthroses, tendinopathies and periarthropathies, as well as trigger points can be improved considerably by treatment with the 5-HT3 receptor antagonist tropisetron. Particularly in the latter group of diseases, local injections have done surprisingly rapid analgesic action. This effect matches that of local anesthetics, but lasts considerably longer and is comparable to local injections of local anesthetics combined with corticosteroids. The action of the 5-HT3 receptor antagonists can be attributed to an antinociceptive effect that occurs at the same time as an antiphlogistic and probably also an immunosuppressive effect. Whereas an inhibited release of substance P from the nociceptors, and possibly some other neurokins as well, seems to be the most likely explanation for the antinociceptive action, the antiphlogistic effect is primarily due to an inhibited formation of various different phlogistic substances; in some conditions, like systemic inflammatory rheumatic diseases, for example, the 5-HT3 receptor antagonists may exert an immunosuppressive effect in addition to this.

[Intramuscular etofenamate in the treatment of acute lumbago. Effectiveness and tolerance in comparison with intramuscular diclofenac-Na]. / Etofenamat i.m. zur Behandlung der akuten Lumbago. Wirksamkeit und Verträglichkeit im Vergleich zu Diclofenac-Na i.m.

In a controlled multi-center single-blind study, the relative efficacy and tolerance of i.m. injectable preparations of etofenamat(e) and diclofenac sodium were investigated in 96 patients with acute lumbago. Treatment resulted in obvious improvement in function and reduction in pain, no statistical difference being found between the two drugs. In 43% of the patients treated with etofenamat(e) and 27% of those receiving diclofenac, the final medical report indicated very good therapeutic results. Under etofenamat(e) i.m. therapy, no side effects occurred, and in no case did treatment have to be discontinued. Under diclofenac, two patients experienced adverse reactions, one allergic exanthema, and the other itching and a sensation of heat. A further patient experienced no improvement after the first injection and discontinued treatment.

Local treatment of tendinopathies and myofascial pain syndromes with the 5-HT3 receptor antagonist tropisetron.

UNLABELLED: The use of local tropisetron injections improved the treatment of tendinopathies considerably, with the effect being comparable to the topical application of local anaesthetics combined with depot corticosteroids. On the other hand, local injection of prilocaine alone exerted a shorter and weaker effect on the condition. OBJECTIVES: After it had been proven that systemic application of the 5-HT3 receptor antagonist tropisetron exerts an analgesic effect on musculoskeletal pain in fibromyalgia, we investigated the efficacy of the substance in tendinopathies and myofascial pain syndromes. RESULTS: Local injections of tropisetron as a treatment for trigger points in myofascial pain syndrome also brought about rapid and prolonged relief in the majority of cases. The analgesic effect was far superior to the action of local anaesthetics. CONCLUSION: The present findings indicate that the analgesic action of the 5-HT3 receptor antagonist tropisetron sets in rapidly and lasts for a long time. Various mechanisms are under discussion to explain the long duration of the effect. Tropisetron not only has an analgesic but probably also an antiphlogistic effect which can be attributed to the inhibited release of substance P and other neuropeptides from the nociceptors and the blocked release of phlogistic substances from macrophages, monocytes etc.

Treatment of systemic sclerosis with the 5-HT3 receptor antagonist tropisetron.

BACKGROUND: There is no known disease-modifying therapy for progressive systemic sclerosis. OBJECTIVES: It was shown that a patient with secondary fibromyalgia syndrome for whom the development of systemic sclerosis was suspected because of a Raynaud's phenomenon and the presence of SCL-70 antibodies in the serum had experienced a clear pain reduction under treatment with tropisteron, which is the reason why this drug was also used with established systemic sclerosis. METHOD: Two patients with progressive systemic sclerosis and positive SCL-70 antibodies were treated for 6 weeks with 5 mg tropisetron daily. Both patients had clear skin symptoms, functional impairments of the locomotor system, and a secondary fibromyalgia syndrome. The skin score and joint motion were checked before, during, and after treatment. In addition, the patients filled in the visual analog scale for pain at these times. At the end of the 6 weeks, the patients showed a clear improvement of the skin score and the movability of various joints as well as a clear reduction of pain. The medication was well-tolerated. Constipation developed in the patients; it could be controlled with laxatives. Follow-up questioning of the patients after 3 months showed that their condition had remained stable. CONCLUSION: Two patients with progressive systemic sclerosis showed an improvement of various symptoms under a blockade of the 5-HT3 receptors via tropisetron. The long-lasting effect pointed to immunomodulation. The two cases give cause for clarifying this by means of clinical studies, which should also investigate the question of dosage (possibly 5 mg tropisetron twice daily).

Treatment of chronic low back pain with tropisetron.

BACKGROUND: Various pathophysiological processes can lead to chronic back pain, which necessitates a differentiated therapeutic approach. In addition, psychic and psychosocial processes may influence the clinical picture. METHOD: Twenty-five patients with chronic back pain were enrolled in the study. Patients suffering from psychosocial stresses and depressions were excluded from the study. The patients with painful tendinopathies and myofascial pain syndromes were treated with local injections of 5-10 mg tropisetron, and patients with degenerative processes were treated for 5 days with an intravenous (i.v.) bolus injection of 5 mg tropisetron (Navoban). Before treatment and 7 and 14 days later, the visual analog pain scale was filled in. The long-term drug therapy could be continued. RESULTS: There was a highly significant pain reduction with a very potent effect both in the locally treated group and in the intravenously treated group. Most of the patients could discontinue or reduce their long-term therapy with non-steroidal anti-inflammatory drugs or analgesics. CONCLUSION: A marked improvement in pain could be achieved in an open study by treating back pain of a primarily somatic nature with the 5-HT3 receptor antagonist tropisetron. A reduction in pain of > or =50% was reported by 76% of the patients. These results should be substantiated by the corresponding randomized, placebo-controlled, double blind studies that are needed to investigate the true benefit of treating back pain with 5-HT3 receptor antagonists.

Results of the intravenous administration of tropisetron in fibromyalgia patients.

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.

Do predictors exist for the therapeutic effect of 5-HT3 receptor antagonists in fibromyalgia?

From the findings outlined below, there are no reliable predictors of the therapeutic effect of the 5-HT3-receptor antagonists in fibromyalgia. Neither clinical change in pain and vegetative symptoms, nor alterations in biochemical parameters are appropriate predictors of response. The accompanying psychological changes in the form of depressive disorders appear to be somewhat predictive of decreased therapeutic effect, if such definitive statements can be applied to individual cases. If, following new trials, it becomes possible to judge the response of patients to therapy after 3-5 days treatment with 2 mg intravenous tropisetron then predictors will be unnecessary in practice.

The use of 5-HT3 receptor antagonists in various rheumatic diseases--a clue to the mechanism of action of these agents in fibromyalgia?

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.

[The influence of depression on the effect of Tropisetron in the therapy of fibromyalgia]. / Beeinflusst die Depressivität den Behandlungseffekt von Tropisetron bei Fibromyalgiepatienten?

As described elsewhere the oral administration of 5 mg of the 5-HT3-receptor-antagonist Tropisetron in fibromyalgia exhibited less amelioration of pain in patients with a depression in comparison to patients without depression. Since an intravenous treatment seems to increase the effect of Tropisetron, the question arises whether patients with depression profit from the intravenous therapy. Methods 68 out patients with fibromyalgia according to ACR-criteria were enrolled in the study. The patients filled in a VAS pain and the Beck Depression Inventory (BDI) before and after a bolus i.v. injection of 5 mg Tropisetron for 5 days [Beck AT, Steer Ra. Beck-Depression-Inventory (BDI) In: Hautzinger M (Hrsg der dt. Ausg.). Testhandbuch. 1. Auflage Bern: Verlag Hans Huber, 1994]. In the beginning the patients had to have > or = 40 mm in the VAS pain from 0-100 mm. The patients were divided into three groups: group 1 = patients with a BDI<19 without experience with antidepressive drugs (n=26); group 2=patients with a BDI > or = 19 (n=22) and negative experience with antidepressive substances, and group 3=patients with a BDI > or = 19 and an accompanying antidepressant drug therapy and some benefit under this therapy (n=20). Results Before the therapy there was no significant difference in VAS pain in the groups, but in BDI there was a significant difference between group 1 (BDI mean value 11.5) in comparison to group 2 (BDI mean value 26.1) and group 3 (BDI mean value 24.8). After therapy all three groups had a significant amelioration of pain: group 1: p=0.000023; group 2: p=0.00073; group 3: p=0.0145. There was a significant difference between the group with BDI<19 and the group with antidepressant drug in amelioration of pain (p=0.044). A significant correlation was found in group 2 with Beck > or = 19 between amelioration of pain and BDI after therapy (p=0.008, r=0.666). In this group a pain-reactive depression and in group 3 an endogenous depression must be discussed.

Spinal factors in the generation of fibromyalgia syndrome.

In fibromyalgia as well as in low back pain we frequently find disturbances of the posture of vertebral column clinically and radiologically. Also, reduction in the mobility of whole spine and localized movement impairments in both conditions was present. It is likely that the disturbances are responsible for the first manifestations of fibromyalgia in a single localization, especially in lumbar and cervical regions.

[Local treatment of periarthropathies with the 5-HT3-receptor-antagonist tropisetron]. / Die Lokalbehandlung von Periarthropathien mit dem 5-HT3-Rezeptor-Antagonisten Tropisetron.

All substances used in the local treatment for periarthropathies, such as local anesthetics, corticosteroids or botulinum toxin A, possess certain disadvantages. Finding alternatives to these agents in the local treatment of the disease therefore seems desirable. Comparative studies proved a local injection of the 5-HT3 receptor antagonist, tropisetron (Navoban(R)), to be more effective than an injection of the local anesthetic prilocaine in treating periarthropathies of different localizations. A comparison between the local injection of 10 mg of depot dexamethasone combined with 60 mg of lidocaine and 5 mg of tropisetron showed that the two regimens had the same effect. These findings demonstrate that a local injection of 5 mg tropisetron does represent an alternative to the local treatment with corticosteriods plus local anesthetics. However, these results should be corroborated by additional studies.

Local treatment of tendinopathies: a comparison between tropisetron and depot corticosteroids combined with local anesthetics.

OBJECTIVE: To determine whether local injection of the 5-HT3-receptor antagonist, tropisetron. reduces pain in tendinopathies to the same degree as a local injection of corticosteroids in combination with local anesthetic. METHODS: Forty patients with tendinopathies were enrolled in this randomized, observer-blind study. An injection of either 5 mg tropisetron. or 10 mg dexamethasone combined with 60 mg lidocaine was administered around the affected tendon. The effect was measured with a visual analog pain scale before the injection, after 3 hours and on each of the following 7 days, in patients with good effects also 3 months after the injection. RESULTS: There were no significant differences between the tropisetron and the corticosteroid/anesthetic group in terms of pain at rest or on movement during the study. Both treatments were well tolerated. CONCLUSION: Local injection of tropisetron seems to be as safe and as effective as the combination of corticosteroids and local anesthetics in the treatment of painful tendinopathies.