Individually tailored treatment targeting activity, motor behavior, and cognition reduces pain-related disability: a randomized controlled trial in patients with musculoskeletal pain. Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitus. Combined treatment of major depression in patients with borderline personality disorder: a comparison with pharmacotherapy. Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. A randomized controlled trial to evaluate the efficacy of community based physical therapy in the treatment of people with rheumatoid arthritis. Effects of intraoral appliance and biofeedback/stress management alone and in combination in treating pain and depression in patients with temporomandibular disorders. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses.
This study compares the outcomes of an individually tailored behavioral medicine intervention (experimental) with physical exercise therapy (control). The experimental intervention was systematically individualized according to each participant's behavioral treatment goals and functional behavioral analyses. One hundred twenty-two patients seeking care at 3 primary health care clinics because of musculoskeletal pain were randomized. Ninety-seven completed the trial. Data were collected at baseline, immediately after treatment, and at a 3-month follow-up. Analyses of data from completers, as well as intention-to-treat analyses, showed that the experimental group experienced lower levels of disability (P = .01), lower maximum pain intensity (P = .02), higher levels of pain control (P = .001), and lower fear of movement (P = .022) as a result of treatment condition. Self-efficacy (P = .0001) and physical performance (P = .0001) increased over time for both groups. Participants in the experimental group generally reported more positive effects after treatment. Treatment fidelity was maintained during the course of the study. Activity can be resumed and pain might be managed by the patients themselves if treatment incorporates the biopsychosocial explanatory model of pain and strategies are tailored according to individual's priorities of everyday life activities and empirically derived determinants of pain-related disability.
                This study shows that the biomedical and the psychosocial perspectives of the experiences and consequences of pain complement rather than contradict each other. Primary health care patients with persistent musculoskeletal pain benefit more from a systematic tailoring of treatments according to biopsychosocial factors than from a physically based exercise intervention. To compare the efficacy and safety of vildagliptin and metformin initial combination therapy with individual monotherapies in treatment-naive patients with type 2 diabetes mellitus (T2DM).
                This was a 24-week, randomized, double-blind, active-controlled study. Treatment-naive patients with T2DM who had a glycated haemoglobin (HbA(1c)) of 7.5-11% (N = 1179) were randomized equally to receive vildagliptin plus high-dose metformin combination therapy (50 mg + 1000 mg twice daily), vildagliptin plus low-dose metformin combination therapy (50 mg + 500 mg twice daily), vildagliptin monotherapy (50 mg twice daily) or high-dose metformin monotherapy (1000 mg twice daily). The primary objective was to demonstrate that HbA(1c) reduction from baseline with either combination therapy is superior to both monotherapies at the week 24 endpoint. Patients who failed glycaemic-screening criteria [HbA(1c )>11% or fasting plasma glucose (FPG) >15 mmol/l (270 mg/dl)] could enter a 24-week, single-arm substudy. These patients (N = 94) received open-label vildagliptin plus high-dose metformin combination therapy (100 mg + 1000 mg twice daily).
                From comparable baseline values (8.6-8.7%), HbA(1c) decreased in all four treatment groups, to the greatest extent with vildagliptin plus high-dose metformin combination therapy. Mean (SE) HbA(1c) change from baseline was -1.8% (0.06%), -1.6% (0.06%), -1.1% (0.06%) and -1.4% (0.06%) with vildagliptin plus high-dose metformin combination therapy, vildagliptin plus low-dose metformin combination therapy, and vildagliptin and metformin monotherapies respectively. The between-group difference was superior with vildagliptin plus high-dose metformin combination therapy (p < 0.001 vs. both monotherapies) and vildagliptin plus low-dose metformin combination therapy (p < 0.001 and p = 0.004, vs. vildagliptin and metformin monotherapies, respectively). Higher baseline HbA(1c) values were linked to greater HbA(1c) reductions, with changes of -3.2% (0.22%), -2.7% (0.22%), -1.5% (0.24%) and -2.6% (0.26%) respectively, occurring in patients with baseline HbA(1c)>or=10%. Reductions in FPG were superior with vildagliptin plus high-dose metformin combination therapy [change from baseline -2.63 (0.13) mmol/l] compared with both monotherapies [-1.26 (0.13) mmol/l and -1.92 (0.13) mmol/l, respectively; p < 0.001]. There was no incidence of hypoglycaemia or severe hypoglycaemia with either combination therapy, and neither was associated with weight gain. All treatments were well tolerated and displayed a comparable incidence of adverse events overall. Despite superior HbA(1c) lowering, the vildagliptin plus low-dose metformin combination therapy group demonstrated a favourable gastrointestinal (GI) tolerability profile compared with metformin monotherapy.
                In treatment-naive patients, combinations of vildagliptin and both high-dose and low-dose metformin provide superior efficacy to monotherapy treatments with a comparable overall tolerability profile and low risk of hypoglycaemia. The potential dose-sparing effect of adding vildagliptin to low-dose metformin in preference to the up-titration of metformin may allow patients to achieve equivalent or superior HbA(1c) lowering without the GI tolerability issues associated with higher doses of metformin. Combined treatment with psychotherapy and antidepressants is more effective than monotherapies. Recent data show that combined therapy has better results in patients with depression and Axis II codiagnosis. The aim of this study was to compare combined treatment using interpersonal psychotherapy (IPT) with pharmacotherapy alone in patients with depression and borderline personality disorder (BPD).
                There were 39 consecutive outpatients diagnosed with BPD who presented with a major depressive episode enrolled in this study. They were randomly assigned to 1 of 2 treatment groups: fluoxetine 20 mg to 40 mg daily or fluoxetine 20 mg to 40 mg daily plus IPT 1 session weekly. Owing to noncompliance, 7 patients dropped out. We assessed the 32 patients who completed the 24 weeks of treatment at baseline, Week 12, and Week 24, using a semistructured interview for clinical characteristics, the Clinical Global Impression Scale (CGI), the Hamilton Depression Rating Scale (HDRS), and the Hamilton Anxiety Rating Scale (HARS), and 2 self-report questionnaires, that is, the Satisfaction Profile (SAT-P) for quality of life and the 64-item Inventory for Interpersonal Problems (IIP-64). We performed statistical analysis, using univariate general linear models with 2 factors: duration and type of treatment.
                Changes in remission rates, CGI, and HARS score did not differ between treatments. According to changes in the HDRS scores; changes in psychological functioning and social functioning scores on the SAT-P; and changes in vindictive or self-centred, cold or distant, intrusive or needy, and socially inhibited scores on the IIP-64, combined therapy was superior to fluoxetine alone.
                Combined therapy with IPT is more effective than antidepressant therapy alone, both in treating symptoms of major depression and in improving dimensions of quality of life and interpersonal functioning. Optimal use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis is vital if progression of disease is to be reduced. Methotrexate (MTX) and sulfasalazine (SASP) are widely used inexpensive DMARDs, recently often combined despite no firm evidence of benefit from previous studies. Aim: To establish whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP.
                A randomised controlled study of step-up DMARD treatment in early rheumatoid arthritis. In phase I, 687 patients received SASP for 6 months. Those with a disease activity score (DAS) > or =2.4 were offered additional treatment in phase II (SASP alone, MTX alone or a combination of the two). The primary outcome measure was change in DAS.
                At 6 months, 191 (28%) patients had a DAS <2.4, 123 (18%) were eligible but did not wish to enter phase II, 130 (19%) stopped SASP because of reversible adverse events and 165 (24%) entered phase II. DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX: monotherapy arms did not differ. Improvement in European League Against Rheumatism and American College of Rheumatology 20, 50 and 70 scores favoured combination therapy.
                In this "true-to-life" study, an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP. There was no increase in toxicity. These results provide an evidence base for the use of this combination as a component of tight control strategies. The aim of this study was to compare efficacy and tolerability of initial combination therapy with vildagliptin/pioglitazone to component monotherapy.
                This 24-week, multicentre, randomized, double-blind, active-controlled study assessed the effects of the dipeptidyl peptidase-4 inhibitor vildagliptin (100 mg q.d.), pioglitazone (30 mg q.d.) and vildagliptin combined with pioglitazone (100/30 mg q.d. or 50/15 mg q.d.) in 607 drug-naive patients with type 2 diabetes (T2DM). The primary outcome measure was change from baseline in HbA(1c) in patients receiving initial combination therapy compared with pioglitazone monotherapy.
                After 24-week treatment, adjusted mean changes in HbA(1c) from baseline (approximately 8.7%) in patients receiving pioglitazone monotherapy, 50/15 mg combination, 100/30 mg combination and vildagliptin monotherapy were -1.4 +/- 0.1%, -1.7 +/- 0.1%, -1.9 +/- 0.1% and -1.1 +/- 0.1% respectively. Both low-dose and high-dose combinations were significantly more efficacious than pioglitazone alone (p = 0.039 and p < 0.001 respectively). Adjusted mean changes in fasting plasma glucose were -1.9 +/- 0.2, -2.4 +/- 0.2, -2.8 +/- 0.2 and -1.3 +/- 0.2 mmol/l respectively, and both combination groups were significantly more effective than pioglitazone monotherapy (p = 0.022 and p < 0.001 respectively). The overall incidence of adverse events ranged from 45.8% in the low-dose combination to 51.6% in the pioglitazone monotherapy group. The incidence of peripheral oedema was highest in patients receiving pioglitazone monotherapy (9.3%) and lowest in those receiving low-dose combination (3.5%). One mild hypoglycaemic event was reported by one patient receiving high-dose combination and one patient receiving vildagliptin monotherapy.
                First-line treatment with vildagliptin/pioglitazone combination in patients with T2DM provides better glycaemic control than either monotherapy component yet has minimal risk of hypoglycaemia and a tolerability profile comparable with component monotherapy. To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA.
                In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease-modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method.
                Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively.
                Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA. To evaluate the short term efficacy of a community based physical therapy (PT) program for people with rheumatoid arthritis (RA) through a single blind randomized controlled trial.
                Adults with active RA were referred by their physician for community based PT. Participants were randomized to either an immediate intervention group [experimental group (EG)] or a wait list control group (CG). The intervention was a standardized program of education and exercise consisting of at least 4 visits or 3 h of PT over 6 weeks. Baseline, 6, and 12 week assessments were by a blinded independent assessor. The primary outcome instrument was the Stanford Arthritis Self-Efficacy Scale (SES) and secondary outcome measures included the ACREU Rheumatoid Arthritis Knowledge Questionnaire (KQ) and visual analog scale for pain (VAS). Duration of morning stiffness, grip strength, and tender joint count were also collected at each assessment. Outcome analysis was conducted using analysis of variance.
                Of 150 eligible and randomized participants, 127 completed the study according to protocol. Baseline analysis showed no differences between the EG and CG for demographics, disease status, or other characteristics. At the 6 week assessment, primary outcome analysis for those who completed the protocol identified a mean change (improvement) of 13.5% in the EG and 5.8% in the CG, representing a 7.7% difference in change scores between the 2 groups [F(1,121) = 6.03; p = 0.015]. A statistically significant difference in change scores was also identified for the KQ [F(1,120) = 6.67; p = 0.011], but not for the VAS. Disease status measures did not change, except for duration of morning stiffness, which improved by 68.8 min in the EG and 8.3 min in the CG (F(1,121) = 4.50; p = 0.036].
                Four hours of a community based PT intervention delivered over 6 weeks significantly improved self-efficacy, disease management knowledge and morning stiffness in people with RA. To assess the differential efficacy of two commonly used treatments for temporomandibular disorders (TMD), intraoral appliances (IAs) and biofeedback (BF), separately and in combination, two studies were conducted. The first study directly compared IA treatment, a combination of biofeedback and stress management (BF/SM), and a waiting list control group in a sample of 80 TMD patients. Both treatments were determined to be equally credible to patients, ruling out this potential threat to the validity of the results obtained. The results demonstrated that the IA treatment was more effective than the BF/SM treatment in reducing pain after treatment, but at a 6-month follow-up the IA group significantly relapsed, especially in depression, whereas the BF/SM maintained improvements on both pain and depression and continued to improve. The second study examined the combination of IA and BF/SM in a sample of 30 TMD patients. The results of this study demonstrated that the combined treatment approach was more effective than either of the single treatments alone, particularly in pain reduction, at the 6-month follow-up. These results support the importance of using both dental and psychologic treatments to successfully treat TMD patients if treatment gains are to be maintained. To explore whether reported methodologic quality affects estimated intervention effects in randomized trials and contributes to discrepancies between the results of large randomized trials and small randomized trials in meta-analyses.
                Meta-analyses of randomized trials that included at least one large trial (>/=1000 participants) were included, regardless of the therapeutic area. Eligible meta-analyses were identified through electronic searches and bibliographies of relevant articles.
                Full-length randomized trials.
                Methodologic quality was assessed according to reported randomization, double blinding, and follow-up as separate components and by using the Jadad composite scale.
                Fourteen meta-analyses involving 190 randomized trials from eight therapeutic areas were included. Compared with large trials, intervention effects were exaggerated in small trials with inadequate allocation sequence generation (ratio of odds ratios, 0.46 [95% CI, 0.25 to 0.83]; P = 0.011), inadequate allocation concealment (ratio of odds ratios, 0.49 [CI, 0.27 to 0.86]; P = 0.014), and no double blinding (ratio of odds ratios, 0.52 [CI, 0.28 to 0.96]; P = 0.01). Large trials did not differ significantly from small trials with adequate generation of the allocation sequence, adequate allocation concealment, or adequate double blinding. No association was seen between reported follow-up and intervention effects. The Jadad scale provided no additional information because the scale and the quality components overlapped substantially.
                Inadequate generation of the allocation sequence, allocation concealment, and double blinding lead to exaggerated estimates of intervention benefit and may contribute to discrepancies between the results of large randomized trials and small randomized trials in meta-analyses.
Based on 23 trials, all at high risk of bias, there is insufficient evidence to establish the value of combination therapy over monotherapy for people with IA. Importantly, there are no studies addressing the value of combination therapy for patients with IA who have persistent pain despite optimal disease suppression. Well designed trials are needed to address this question.