Do analgesics improve functioning in patients with chronic low back pain? An explorative triple-blinded RCT.

PURPOSE: TREATMENT of patients with chronic low back pain (CLBP) aims to reduce disability, improve functional capacity, and participation. Time contingent prescription of analgesics is a treatment modality in CLBP. The impact of analgesics on functional capacity is unknown. Aim of the study was to explore the effect of analgesics on functioning measured by functional capacity evaluation, and self-reported disability in patients with CLBP. METHODS: Explorative Randomized Placebo-Controlled Clinical Trial was performed in an outpatient pain rehabilitation setting on patients waiting for rehabilitation. Included patients had low back pain lasting >3 months, visual analogue scale worst pain ≥4.0 cm, and age >18 years. Outcome measures before (T0) and after treatment (T1): functional capacity, pain intensity, Roland Morris Disability Questionnaire. T1: global perceived pain relief. Patient characteristics and psychological questionnaires were assessed. Fifty patients were included in this study and were randomly assigned to 2 weeks treatment or placebo. TREATMENT: acetaminophen/tramadol 325 mg/37.5 mg per capsule. Dose: maximum acetaminophen 1,950 mg and tramadol 225 mg per day; treatment and placebo titrated identically. Compliance and side-effects were monitored. TREATMENT effects between groups over time were compared. RESULTS: One patient (treatment group) was lost to follow-up. Forty-nine patients remained in the study. TREATMENT effects in primary outcomes did not differ significantly between groups. A subgroup of 10 (42%) patients (treatment group) reported global pain relief (responders) who reduced self-reported disability (p < 0.05). Responders had significantly lower catastrophizing scores. CONCLUSION: Overall treatment effects were small and non-significant. A subgroup, however, reported improved functioning as a result of treatment. Responders had lower catastrophizing scores.

Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial.

IMPORTANCE: Metformin treatment is associated with improved outcome after myocardial infarction in patients with diabetes. In animal experimental studies metformin preserves left ventricular function. OBJECTIVE: To evaluate the effect of metformin treatment on preservation of left ventricular function in patients without diabetes presenting with ST-segment elevation myocardial infarction (STEMI). DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled study conducted among 380 patients who underwent primary percutaneous coronary intervention (PCI) for STEMI at the University Medical Center Groningen, The Netherlands, between January 1, 2011, and May 26, 2013. INTERVENTIONS: Metformin hydrochloride (500 mg) (n = 191) or placebo (n = 189) twice daily for 4 months. MAIN OUTCOMES AND MEASURES: The primary efficacy measure was left ventricular ejection fraction (LVEF) after 4 months, assessed by magnetic resonance imaging. A secondary efficacy measure was the N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration after 4 months. The incidence of major adverse cardiac events (MACE; the combined end point of death, reinfarction, or target-lesion revascularization) was recorded until 4 months as a secondary efficacy measure. RESULTS: At 4 months, all patients were alive and none were lost to follow-up. LVEF was 53.1% (95% CI, 51.6%-54.6%) in the metformin group (n = 135), compared with 54.8% (95% CI, 53.5%-56.1%) (P = .10) in the placebo group (n = 136). NT-proBNP concentration was 167 ng/L in the metformin group (interquartile range [IQR], 65-393 ng/L) and 167 ng/L in the placebo group (IQR, 74-383 ng/L) (P = .66). MACE were observed in 6 patients (3.1%) in the metformin group and in 2 patients (1.1%) in the placebo group (P = .16). Creatinine concentration (79 µmol/L [IQR, 70-87 µmol/L] vs 79 µmol/L [IQR, 72-89 µmol/L], P = .61) and glycated hemoglobin (5.9% [IQR, 5.6%-6.1%] vs 5.9% [IQR, 5.7%-6.1%], P = .15) were not significantly different between both groups. No cases of lactic acidosis were observed. CONCLUSIONS AND RELEVANCE: Among patients without diabetes presenting with STEMI and undergoing primary PCI, the use of metformin compared with placebo did not result in improved LVEF after 4 months. The present findings do not support the use of metformin in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01217307.

Potentiation of a p53-SLP vaccine by cyclophosphamide in ovarian cancer: a single-arm phase II study.

The purpose of the current phase II single-arm clinical trial was to evaluate whether pretreatment with low-dose cyclophosphamide improves immunogenicity of a p53-synthetic long peptide (SLP) vaccine in patients with recurrent ovarian cancer. Patients with ovarian cancer with elevated serum levels of CA-125 after primary treatment were immunized four times with the p53-SLP vaccine. Each immunization was preceded by administration of 300 mg/m2 intravenous cyclophosphamide as a means to affect regulatory T cells (Tregs). Vaccine-induced p53-specific interferon-gamma (IFN-γ)-producing T cells evaluated by IFN-γ ELISPOT were observed in 90% (9/10) and 87.5% (7/8) of evaluable patients after two and four immunizations, respectively. Proliferative p53-specific T cells, observed in 80.0% (8/10) and 62.5% (5/8) of patients, produced both T-helper 1 and T-helper-2 cytokines. Cyclophosphamide induced neither a quantitative reduction of Tregs determined by CD4+ FoxP3+ T cell levels nor a demonstrable qualitative difference in Treg function tested in vitro. Nonetheless, the number of vaccine-induced p53-specific IFN-γ-producing T cells was higher in our study compared to a study in which a similar patient group was treated with p53-SLP monotherapy (p≤0.012). Furthermore, the strong reduction in the number of circulating p53-specific T cells observed previously after four immunizations was currently absent. Stable disease was observed in 20.0% (2/10) of patients, and the remainder of patients (80.0%) showed clinical, biochemical and/or radiographic evidence of progressive disease. The outcome of this phase II trial warrants new studies on the use of low-dose cyclophosphamide to potentiate the immunogenicity of the p53-SLP vaccine or other antitumor vaccines.

Immunization with a P53 synthetic long peptide vaccine induces P53-specific immune responses in ovarian cancer patients, a phase II trial.

The prognosis of ovarian cancer, the primary cause of death from gynecological malignancies, has only modestly improved over the last decades. Immunotherapy is one of the new treatment modalities explored for this disease. To investigate safety, tolerability, immunogenicity and obtain an impression of clinical activity of a p53 synthetic long peptide (p53-SLP) vaccine, twenty patients with recurrent elevation of CA-125 were included, eighteen of whom were immunized 4 times with 10 overlapping p53-SLP in Montanide ISA51. The first 5 patients were extensively monitored for toxicity, but showed no > or = grade 3 toxicity, thus accrual was continued. Overall, toxicity was limited to grade 1 and 2, mostly locoregional, inflammatory reactions. IFN-gamma producing p53-specific T-cell responses were induced in all patients who received all 4 immunizations as measured by IFN-gamma ELISPOT. An IFN-gamma secretion assay showed that vaccine-induced p53-specific T-cells were CD4(+), produced both Th1 and Th2 cytokines as analyzed by cytokine bead array. Notably, Th2 cytokines dominated the p53-specific response. P53-specific T-cells were present in a biopsy of the last immunization site of at least 9/17 (53%) patients, reflecting the migratory capacity of p53-specific T-cells. As best clinical response, stable disease evaluated by CA-125 levels and CT-scans, was observed in 2/20 (10%) patients, but no relationship was found with vaccine-induced immunity. This study shows that the p53-SLP vaccine is safe, well tolerated and induces p53-specific T-cell responses in ovarian cancer patients. Upcoming trials will focus on improving T helper-1 polarization and clinical efficacy.

Effects of alcohol (BAC 0.5‰) and ecstasy (MDMA 100 mg) on simulated driving performance and traffic safety.

RATIONAL: An increasing number of fatal road-accidents have been reported in which ecstasy was found in the blood of drivers. Although, ecstasy is frequently found to have been used in combination with alcohol, studies on the acute effects of ecstasy co-administered with alcohol on driving performance are relatively rare. OBJECTIVE: The present study was designed to establish the extent of driver impairment as a consequence of ecstasy or combined ecstasy and alcohol use as compared to driving under the influence of 0.3‰, 0.5‰ and 0.8‰ alcohol. Furthermore, subjective performance was also assessed. RESULTS: Alcohol and ecstasy mainly influenced automated driving performance such as lateral and speed control. However, small to no effects of the substances were found on more complex driving behaviour. Overall, variance within the different driving measures was high especially when participants were treated with 3.4-methylenedioxy-methamphetamine (MDMA) and alcohol. Furthermore, equivalence testing showed that combined use may lead to impaired driving for some, but not all, drivers. Participants rated their own performance to be slightly worse than normal in both studies. Since driving was actually seriously deteriorated, this was a falsely positive assessment of their condition. CONCLUSIONS: The dissociation between subjective perceptions and objective performance decrements are important notions for traffic safety since this may affect a driver's judgement of whether or not it is safe to drive. For example, an intoxicated individual might decide to drive because the feelings of alertness caused by MDMA cloud the impairing effects of other drugs such as alcohol, thereby creating a potentially serious risk for traffic safety.