Giovanni Biasi

Reactivity to superficial and deep stimuli in patients with chronic musculoskeletal pain.

&NA; In this study, we evaluated pain sensitivity in patients with fibromyalgia or other types of chronic, diffuse musculoskeletal pain to establish whether fibromyalgia represents the end of a continuum of dysfunction in the nociceptive system. One hundred and forty five patients and 22 healthy subjects (HS) completed an epidemiological questionnaire to provide information about fatigue, stiffness, sleep, the intensity of pain (VAS 0–100) and its extent both at onset and at present. Algometry was performed at all American College of Rheumatology (ACR) tender points and at ten control points. Patients were divided into five main groups: fibromyalgia (FS) patients, secondary‐concomitant fibromyalgia (SCFS) patients, patients with widespread pain (WP) but not reaching the ACR criterion of 11 tender points, patients with diffuse multiregional pain (MP) not reaching the ACR criteria (widespread pain, tender point counts), and patients with multiregional pain associated with at least 11 tender points (MPTE). von Frey monofilaments were used to assess superficial punctate pressure pain thresholds. Heat and cold pain thresholds were determined with a thermal stimulator. Ischemic pain was assessed by the cold pressure test and the submaximal effort tourniquet test. The scores for stiffness and present pain intensity gradually increased concomitantly with the increase in tender point count and pain extent. The pressure pain thresholds for positive tender and positive control points were significantly lower in the SCFS, FS and MPTE groups than in HS, MP and WP groups, the latter three groups displaying similar values. In all groups, there were no differences in pain thresholds between positive tender and positive control points. The heat pain threshold and the pain threshold in the cold pressure test were lower in the FS and SCFS groups than in HS. The cold pressure tolerance was lower in patients with widespread pain than in HS. In the von Frey test, all patient groups except MP had similar values, which were significantly lower than in HS. Finally, all patient groups displayed lower tourniquet tolerance than HS. In each psychophysical test, patients with widespread pain and patients with multiregional pain showed similar thresholds; however, the thresholds in the MP or MPTE groups differed from those in the FS and SCFS groups. In the FS group, pain thresholds and pain tolerance did not differ according to the presence of ongoing pain at the stimulated site and were not correlated to ongoing pain. The results indicate that dysfunction in the nociceptive system is already present in patients with multiregional pain with a low tender point count; it becomes more and more severe as the positive tender point count and pain extent increase and it is maximal in fibromyalgia patients.

Predictors of psychological distress and well-being in women with chronic musculoskeletal pain : Two sides of the same coin?

OBJECTIVE To date, few results on well-being in chronic-pain patients have been published, while several studies in patients without pain have indicated that well-being may not be equivalent to absence of psychological distress. The aim of the present study was to investigate the relationship between psychological distress and well-being and to identify the predictors of each in patients with chronic nonmalignant pain. METHODS Sixty-nine women with chronic multiregional musculoskeletal pain, 41 of whom met American College of Rheumatology criteria for fibromyalgia, completed questionnaires on pain, fatigue, stiffness, physical disability (Fibromyalgia Impact Questionnaire), psychological distress [Multidimensional Affect and Pain Survey (MAPS), Symptom Check List-90 (SCL-90), State-Trait Anxiety Inventory Form Y2 (STAI-Y2)], and hedonic and eudaimonic well-being (MAPS). RESULTS Patients reported increased amounts of psychological distress (STAI-Y2 and SCL-90) compared to healthy people. Multiple regression analysis of patient data demonstrated that higher psychological distress was related to higher age, more intense pain, a higher positive tender point count, and more physical disability. Well-being (both hedonic and eudaimonic aspects) decreased with higher disability, but was independent of age, pain intensity, and number of positive tender points. Bivariate correlations showed that psychological distress was moderately related to eudaimonic well-being and strongly related to positive affect, an aspect of hedonic well-being. CONCLUSION In patients with chronic musculoskeletal pain, self-reports of well-being and low psychological distress only partially overlap with each other and are differently related to major patient symptoms, supporting the relevance of the concept of well-being to chronic-pain research and a need for further studies in this field.

Dimensions of “unidimensional” ratings of pain and emotions in patients with chronic musculoskeletal pain

Abstract The use of unidimensional scales to measure pain intensity has been criticised because of the multidimensional nature of pain. We conducted multiple linear regression analyses to determine which dimensions of pain – sensory versus affective – predicted scores on unidimensional scales measuring pain intensity and emotions in 109 Italian women suffering from chronic, non‐malignant musculoskeletal pain. We then compared the results with earlier findings in two groups of cancer patients suffering from acute post‐operative pain and chronic cancer‐related pain, respectively. Age, physical capacity and scores on the multidimensional affect and pain survey (MAPS) were used to predict patients’ ratings on one visual analogue scale (VAS) and three numerical rating scales (NRS) measuring pain intensity, anxiety and depressed mood. Unidimensional pain intensity ratings were predicted better from sensory than from affective pain predictors, and the affective predictors made no unique contribution (NRS), or only a very small one (VAS). Both sensory and emotional pain aspects were unique predictors of NRS anxiety and depression. Therefore, in contrast to earlier findings in two different types of cancer patients, in subjects affected by chronic non‐malignant musculoskeletal pain, the scores on unidimensional pain intensity scales mainly reflect sensory pain dimensions, supporting the discriminant validity of the NRS and VAS used. However, the patients had some difficulty in distinguishing between sensory and emotional information. For this reason, several unidimensional scales to rate pain intensity and emotions separately should be used to obtain a complete picture of the status and needs of any given patient.

Switch from infliximab to infliximab biosimilar: efficacy and safety in a cohort of patients with different rheumatic diseases

Dear Editor in Chief We read with great interest the manuscript by Nikiphorou et al. describing the effectiveness of infliximab-biosimilar CTP13 (INB) used as a switch from Remicade® (Janssen Biotech, Inc., Horsham, PA, USA) (infliximab (INX)) in patients with different established rheumatic diseases [1]. Thirty-nine patients on INX were switched to biosimilar after a mean time (SD) of 4.1 (2.3) years. The authors reported that INB clinical effectiveness, during the first year of switching, was comparable to INX in both the patient-reported outcomes and disease-activity measures, with no immediate safety signals. Eleven patients (28.2%) discontinued INB due to INX antibodies detected prior to INB infusion (3/11), latent tuberculosis (1/11), new-onset neurofibromatosis (1/11), and subjective reasons with no objective deterioration of disease (6/ 11). The authors suggested that subjective reasons, such as negative expectations, played a key role among INB discontinuations. In this regard, we report herein our experience in a cohort of 23 patients followed in our unit for different rheumatic diseases and switched, for local regulatory issues, to INB (Inflectra®) after amean time (SD) of 71.65 (44.40) months on INX (Remicade). More in detail, 11 out of 23 had psoriatic arthritis (7 with peripheral and 4 with axial involvement), 8/23 ankylosing spondylitis, 2/23 rheumatoid arthritis, 2/23 Crohn’s disease and associated axial spondyloarthritis, and 1/23 Behçet’s disease and associated axial spondyloarthritis. At the time of the switch, all of the patients were in complete disease remission on INX at a dose of 5 mg/kg every 8 weeks. After a mean time of 1.71 months (range 1–2) from the start of INB a disease relapse occurred in 7 out of 23 patients (30.43%). Their mean (SD) duration of previous INX treatment was 62.28 (49.95) months. Table 1 summarizes the clinical, demographic, and therapeutic data of the 7 subjects unresponsive to INB. INB was then suspended and IFX was readministered in all 7 patients at a dose of 5 mg/kg every 8 weeks, in association with a tapering dose of oral corticosteroids. In 5/7, the readministration of INX promptly led to a remarkable clinical improvement (4/5), or at least a partial one (1/5), with a significant decrement of the disease activity indexes. No amelioration was observed in 2/7 subjects. Among the 16 patients that were still on treatment with INB, 7 of them were under close observation and monitoring for uveitis relapse (1/7), recurrence of psoriatic lesions (1/7), arthralgia (4/7), and referredworsening of global quality of life (1/7). No changes in the response to treatment were observed in 9 out of 23 subjects (39.13%). INB was well tolerated and no adverse events were noted. In PLANETAS and PLANETRA studies, INB demonstrated equivalent efficacy to INX at 30-week follow-up, with a comparable pharmacokinetic profile and immunogenicity both in patients affected by ankylosing spondylitis (AS) and rheumatoid arthritis (RA) [2,3]. INB efficacy and safety have been confirmed also in the extension of the PLANETAS study in AS at 54-week follow-up [4]. Nevertheless, data on the effectiveness of the switch from INX to INB in patients in a stable disease remissionwhile on IFX are scarce, and future studies are needed. For the above reason, real-life data should be welcome, even though from uncontrolled series, until further trials are performed. In our cohort of patients, 30% of subjects switched from IFX to INB while in disease remission showed a rapid worsening of disease activity indexes. Moreover, 30% of patients still on treatment with INB were under evaluation for the potential reduction of the interval between INB administrations either the potential increase of INB dosage or a further switch from INB to IFX, due to a suspected lack of efficacy. Overall, it is unlikely that in our cohort of patients, only subjective reasons have played a role in the poor outcome observed in most subjects. Indeed, we did not observe any change in the response to treatment in only 40% of cases. Limitations of our study were the small number of patients, the absence of a control group, and the short-

A Meta-Analysis of the Tolerability of Amtolmetin Guacil, a Novel, Effective Nonsteroidal Anti-Inflammatory Drug, Compared with Established Agents

AbstractObjective: Gastrointestinal toxicity is the most important adverse effect of treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). The present metaanalysis was undertaken to systematically review available data from randomised clinical trials on the tolerability of amtolmetin guacil (amtolmetin guacyl), a novel, effective NSAID. Design: Eighteen studies comparing the clinical efficacy and tolerability of amtolmetin guacil versus other NSAIDs were identified. The predefined end-points of the meta-analysis were the incidence of adverse effects at the gastrointestinal level (either requiring or not requiring drug withdrawal) and discontinuing treatment because of adverse effects, together with the occurrence of mild/severe lesions (or of severe lesions only), evaluated in three studies by the use of endoscopy. Results: In all the studies, the frequency of adverse events and early cessation of treatment was lower in patients treated with amtolmetin guacil than with other NSAIDs. The overall odds ratio of adverse effects for amtolmetin guacil versus all the other drugs considered together was 0.2 [95% confidence interval (CI) 0.1 to 0.3]. The frequency and severity of gastric mucosal lesions at endoscopic evaluation was lower for amtolmetin guacil in comparison with other NSAIDs: the typical odds ratio for severe lesions was 0.3 (95% CI 0.1 to 0.7), and for mild and severe lesions was 0.1 (95% CI 0.1 to 0.4). Conclusion: This meta-analysis indicated that the gastric tolerability of amtolmetin guacil was higher than that of established NSAIDs. The clinical implications of these findings should be prospectively tested in large long-term treatment trials.

COMPARATIVE PHARMACOKINETIC STUDY OF A SINGLE DOSE OF TWO PROLONGED-RELEASE FORMULATIONS OF DICLOFENAC IN HEALTHY SUBJECTS

Abstract The pharmacokinetics of diclofenac sodium 150 mg in a new prolonged-release formulation (Dicloreum® CR [CR]) and a commercially available formulation (Dealgic® 75 [D]) were compared in 12 healthy volunteers. In this randomized, crossover study with a Latin-square design, diclofenac was administered as a single dose to subjects after eating. Blood samples were obtained before dosing and at 1, 2, 4, 6, 8, 14, 24, and 36 hours after dosing, and the plasma concentrations of diclofenac were determined by high-performance liquid chromatography. Possible adverse events were monitored during the study. After log-transformation of the comparable variables, no statistically significant differences were found between the two formulations with respect to the time between dosing and the appearance of the drug in serum, time to reach maximum concentration, elimination half-life, or mean residence time. The extent of absorption was assessed by estimating the area under the plasma concentration-time curve (AUC). AUC 0–24 was statistically significantly higher for CR than for D (2992.8 ± 280.2 and 2527.6 ± 109.9, respectively). No significant differences were found in AUC 0–36 , AUC 24–36 , or AUC 0–∞ . CR showed a statistically significantly higher maximum plasma concentration than D (516.9 ± 74.3 ng/mL and 382.9 ± 46.9 ng/mL for CR and D, respectively). The results of the present study suggest that CR is a useful, prolonged-release formulation for continuous, once-daily therapy.

Chronic pelvic pain: comorbidity between chronic musculoskeletal pain and vulvodynia.

Chronic pelvic pain (CPP) is a common condition that has a major impact on the quality of life of both men and women. Male CPP is usually attributable to well-defined urogenital conditions (most frequently infectious/non infectious prostatic diseases) or musculoskeletal or bowel diseases, whereas the features of female CPP are much more complex and are of particular clinical and epidemiological importance. It is a multifactorial syndrome that can be due to diseases of the urogenital, gastrointestinal, or musculoskeletal systems, or to neurological or neuropsychiatric disorders. It is not always easy to identify its predominant pathogenesis, although it often occurs as a central sensitization syndrome triggered by an initial stimulus which is no longer detectable and only manifests itself clinically through pain. In this respect, there are some very interesting relationships between vulvodynia and fibromyalgic syndrome, as identified in a preliminary study of women with chronic musculoskeletal pain in which it was demonstrated that vulvar pain plays an important role, although it is often overlooked and undiagnosed.

Pain Symptoms in Fibromyalgia Patients with and without Provoked Vulvodynia

Objective. The aim of the study was to compare the pain symptoms of fibromyalgia patients exhibiting (FMS+PVD) and not exhibiting (FMS) comorbidity with provoked vulvodynia. Study Design. The case control study was performed in 39 patients who had been diagnosed with FMS and accepted to undergo gynaecological examination and in 36 healthy women (C). All patients completed standardized questionnaires for pain intensity, pain area, and psychological functioning. The gynaecological examination included vulvar pain pressure reactivity (Q-tip), pelvic tone assessment (Kegel manoeuver), and a semistructured interview collecting detailed information about pelvic symptoms and sexual function. Results. FMS+PVD patients displayed a higher number of associated symptoms than FMS patients. The vulvar excitability was significantly higher in FMS+PVD than in FMS and in both groups than in Controls. Half of FMS+PVD patients were positive to Kegel manoeuver and displayed higher scores in widespread pain intensity, STAI-Y2, and CESD levels than Kegel negative patients. Conclusions. The study reveals that increased vulvar pain excitability may occur in FMS patients independently of the presence of coital pain. Results suggest that coital pain develops in patients with higher FMS symptoms severity due to the cooperative effects of peripheral and central sensitization mechanisms.

No enthesis should be overlooked when psoriatic arthritis is suspected: enthesitis of the extensor digitorum tendons.

A common and well-documented feature of spondyloarthropathies is inflammation of the peripheral enthesis1. Ultrasound (US) imaging is useful when assessing enthesitis, and many investigators have described its features2,3. A 50-year-old man with psoriasis developed morning stiffness, tenderness, and swelling of small joints in the hands asymmetrically during the last month. Clinical examination revealed tenderness and swelling of the proximal interphalangeal joints (PIP) of the second, third, and fourth fingers …

EFFICACY OF A PROLONGED-RELEASE DOSAGE FORM OF DICLOFENAC SODIUM IN SOME RHEUMATIC DISEASES

Twenty outpatients suffering from rheumatoid arthritis and 20 outpatients with scapulohumeral periarthritis were treated for 30 days with oral diclofenac sodium, either using one 150-mg prolonged-release capsule per day (10 patients with each diagnosis) or one 50-mg, enteric-coated tablet 3 times a day (10 patients per diagnosis). During treatment, visual analog scale scores for pain intensity, the severity of symptoms and signs, and results of laboratory tests (erythrocyte sedimentation rate, C-reactive protein, and rheumatoid factor) were monitored, as well as the local tolerability of the administered formulations. Systemic tolerability was also monitored by means of routine blood and urine laboratory tests. The single daily administration of 150 mg as a prolonged-release capsule dosage form yielded almost identical and very good anti-inflammatory and analgesic activity as the multiple daily administration of the 50-mg tablet: 16 cases of good activity and 4 of no efficacy with the prolonged-release formulation versus 15 cases of good efficacy and 5 cases of no efficacy with the enteric-coated tablet. As predictable, based on the different characteristics of the diseases, some patients with rheumatoid arthritis responded only partially to diclofenac treatment (60% had positive results), while in nearly all patients with scapulohumeral periarthritis, treatment with this nonsteroidal anti-inflammatory drug yielded the best clinical outcome (95% had positive results). Drug tolerability, both at the gastrointestinal and systemic levels, was excellent; no adverse events were reported. The prolonged-release formulation, which enables once-daily dosing, appears to be an optimal means to treat articular rheumatic diseases.