Impact of neonatal pain and opiate administration in animal models: A meta-analysis concerning pain threshold.

BACKGROUND AND AIM: Neonatal intensive care treatment, including frequently performed painful procedures and administration of analgesic drugs, can have different effects on the neurodevelopment. This systematic review and meta-analysis aimed to investigate the influence of pain, opiate administration, and pre-emptive opiate administration on pain threshold in animal studies in rodents, which had a brain development corresponding to preterm and term infants. METHODS: A systematic literature search of electronic data bases including CENTRAL (OVID), CINAHL (EBSCO), Embase.com, Medline (OVID), Web of Science, and PsycInfo (OVID) was conducted. A total of 42 studies examining the effect of pain (n = 38), opiate administration (n = 9), and opiate administration prior to a painful event (n = 5) in rodents were included in this analysis. RESULTS: The results revealed that pain (g = 0.42, 95%CI 0.16-0.67, p = 0.001) increased pain threshold leading to hypoalgesia. Pre-emptive opiate administration had the opposite effect, lowering pain threshold, when compared to pain without prior treatment (g = -1.79, 95%CI -2.71-0.86, p = 0.0001). Differences were found in the meta regression for type of stimulus (thermal: g = 0.66, 95%CI 0.26-1.07, p = 0.001; vs. mechanical: g = 0.13, 95%CI -0.98-1.25, p = 0.81) and gestational age (b = -1.85, SE = 0.82, p = 0.027). In addition, meta regression indicated an association between higher pain thresholds and the amount of cumulative pain events (b = 0.06, SE = 0.03, p = 0.05) as well as severity of pain events (b = 0.94, SE = 0.28, p = 0.001). CONCLUSION: Neonatal exposure to pain results in higher pain thresholds. However, caution is warranted in extrapolating these findings directly to premature infants. Further research is warranted to validate similar effects in clinical contexts and inform evidence-based practices in neonatal care.

Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis.

OBJECTIVES: To investigate whether treatment effects of pharmaceutical compounds compared with placebo controls are systematically different to the effects of the same compounds compared with active treatment controls in rheumatoid arthritis (RA) clinical trials. METHODS: We systematically identified randomised controlled trials (RCTs) in RA, and matched active treatment arms with comparable regimens, populations, background therapy, and outcome reporting, by the nature of their control group (active comparator or placebo). Medline, EMBASE and CENTRAL were used to identify RCTs investigating disease modifying anti-rheumatic drug therapies until December 2021. Using mixed-model logistic regression we estimated OddsRatios (OR) for achieving an American College of Rheumatology (ACR) 20/50/70% response at weeks 12 and 24. Risk of bias was assessed using the Cochrane Tool. RESULTS: We screened 8328 studies and included 40 for analysis after detailed review of 590 manuscripts; unique compounds had significantly higher responses in active comparator trials compared with their effects observed in placebo controlled trials, with ORs of 1.67 (95% CI 1.46 to 1.91; p<0.001) for ACR20, 1.50 (95% CI 1.29 to 1.75; p<0.001) for ACR50 and 1.65 (95% CI 1.30 to 2.10; p<0.001) for ACR70 (week 12); corresponding ORs for ACR 20, 50, and 70 (week 24) were 1.93 (95% CI 1.50 to 2.48; p<0.001), 1.75 (95% CI 1.32 to 2.33; p<0.001) and 1.68 (95% CI 1.21 to 2.34; p<0.001), respectively. Sensitivity analyses showed consistent results. CONCLUSION: Placebo controlled trials lead to smaller effect sizes of active compounds in RCTs compared with the same compound in head-to-head trials. This difference may be explained by potential nocebo effects in placebo-controlled settings and needs to be considered when interpreting head-to-head and placebo-controlled trials, by patients, investigators, sponsors and regulatory agencies.

A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases.

OBJECTIVES: Informing an international task force updating the consensus statement on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) selectively targeting interleukin-6 (IL-6) pathway in the context of immune-mediated inflammatory diseases. METHODS: A systematic literature research of all publications on IL-6 axis inhibition with bDMARDs published between January 2012 and December 2020 was performed using MEDLINE, EMBASE and Cochrane CENTRAL databases. Efficacy and safety outcomes were assessed in clinical trials including their long-term extensions and observational studies. Meeting abstracts from ACR, EULAR conferences and results on clinicaltrials.gov were taken into consideration. RESULTS: 187 articles fulfilled the inclusion criteria. Evidence for positive effect of IL-6 inhibition was available in various inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, cytokine release syndrome due to chimeric antigen receptor T cell therapy and systemic sclerosis-associated interstitial lung disease. Newcomers like satralizumab and anti-IL-6 ligand antibody siltuximab have expanded therapeutic approaches for Castleman's disease and neuromyelitis optica, respectively. IL-6 inhibition did not provide therapeutic benefits in psoriatic arthritis, ankylosing spondylitis and certain connective tissue diseases. In COVID-19, tocilizumab (TCZ) has proven to be therapeutic in advanced disease. Safety outcomes did not differ from other bDMARDs, except higher risks of diverticulitis and lower gastrointestinal perforations. Inconsistent results were observed in several studies investigating the risk for infections when comparing TCZ to TNF-inhibitors. CONCLUSION: IL-6 inhibition is effective for treatment of several inflammatory diseases with a safety profile that is widely comparable to other bDMARDs.

Risk of Clinically Relevant Venous Thromboembolism in Critically Ill Patients With COVID-19: A Systematic Review and Meta-Analysis.

Background: Early during the course of the ongoing COVID-19 pandemic, reports suggested alarmingly high incidences for thromboembolic events in critically ill patients with COVID-19. However, the clinical relevance of these events was not reported in several studies. Additionally, more recent research showed contradictory results and suggested substantially lower rates of venous thromboembolism. Thus, the aim of the present study was to summarize evidence on the incidence of clinically relevant venous thromboembolism (VTE)-defined as VTE excluding isolated subsegmental pulmonary embolism (PE) and distal deep vein thrombosis (DVT)-in adult critically ill patients with COVID-19. Methods: We performed a systematic review of studies reporting the incidence of clinically relevant PE and/or DVT in critically ill patients with COVID-19. Scientific reports published in the English language between January and October 2020 were included. We conducted a random-effects model meta-analysis to calculate incidence estimates of clinically relevant VTE and bleeding events. We also performed exploratory meta-regression and subgroup analyses of different diagnostic approaches and additional factors that possibly influenced the incidence of these outcomes. Results: Fifty-four articles (5,400 patients) fulfilled the predefined inclusion criteria, of which 41 had a high risk of bias. The majority of included patients were male, > 60 years, and overweight. Twenty-one studies reported the use of prophylactic doses of heparin. Pooled incidences for clinically relevant PE were estimated at 8% (95% CI, 4-11%), for proximal DVT at 14% (95% CI, 9-20%), and-after exclusion of studies with a high risk of bias-for the composite outcome of VTE at 18% (95% CI, 13-24%). Clinically relevant bleeding occurred at a rate of 6% (95% CI, 2-9%). Conclusions: We summarized currently available data on the rate of clinically relevant VTE in critically ill patients with COVID-19. Pooled incidence estimates were lower than those reported by previous review articles. In the absence of evidence-based anticoagulation guidelines for critically ill patients with COVID-19, the results of our study provide clinically important information for an individual risk-benefit assessment in this context. Registration: The study protocol was prospectively registered in PROSPERO on June 22, 2020 (CRD42020193353; https://www.crd.york.ac.uk/prospero).

Methodological aspects of economic evaluations conducted in the palliative or end of life care settings: a systematic review protocol.

INTRODUCTION: In light of this growing palliative care and end of life care patient population, as well as new (expensive) drugs and treatments, quality research providing evidence for decision-making is required. However, common research guidance is lacking in this field, especially in respect to the methods applied in economic evaluations. Therefore, the aim of the planned systematic review is to identify and summarise relevant information on methodological challenges, potential solutions and recommendations for conducting economic evaluations of interventions in adult patients, irrespective of their underlying disease and gender in the palliative or end of life care settings, with no restrictions in regards to countries/geographical regions. The results of this systematic review may help to clarify the current methodological questions and form the basis of new, setting specific methods guidelines and support ongoing applied economic evaluations in the field. METHODS AND ANALYSIS: A systematic review will be conducted using Medline, Embase, Health Technology Assessment Database and NHS Economic Evaluation Database to identify the studies published from 1999 onwards with relevant information on methodological challenges, potential solutions and recommendations for conducting economic evaluations in the palliative or end of life care settings. Articles in English, German, Spanish, French or Dutch language will be considered. Two independent reviewers will conduct the screening of articles; any discrepancies will be resolved by discussion and involvement of a third reviewer. Predesigned data extraction forms will be applied, consequently narratively synthesised and categorised. Studies' methodological quality will be critically appraised. Besides existing economic guidelines and checklists for specific information on the palliative and end of life care sector will be searched. ETHICS AND DISSEMINATION: Ethical approval is not required, as this is a planned systematic review of published literature. An article will be disseminated in a related peer-reviewed journal, as well as presented at leading palliative care and health economic conferences. PROSPERO REGISTRATION NUMBER: CRD42020148160.

Efficacy outcomes in phase 2 and phase 3 randomized controlled trials in rheumatology.

Phase 3 trials are the mainstay of drug development across medicine but have often not met expectations set by preceding phase 2 studies. A systematic meta-analysis evaluated all randomized controlled, double-blind trials investigating targeted disease-modifying anti-rheumatic drugs in rheumatoid and psoriatic arthritis. Primary outcomes of American College of Rheumatology (ACR) 20 responses were compared by mixed-model logistic regression, including exploration of potential determinants of efficacy overestimation. In rheumatoid arthritis, phase 2 trial outcomes systematically overestimated subsequent phase 3 results (odds ratio comparing ACR20 in phase 2 versus phase 3: 1.39, 95% confidence interval: 1.25-1.57, P < 0.001). Data for psoriatic arthritis trials were similar, but not statistically significant (odds ratio comparing ACR20 in phase 2 versus phase 3: 1.35, 95% confidence interval: 0.94-1.94, P = 0.09). Differences in inclusion criteria largely explained the observed differences in efficacy findings. Our findings have implications for all stakeholders in new therapeutic development and testing, as well as potential ethical implications.