Neuropathic pain clinical trials:factors associated with decreases in estimated drug efficacy

Multiple recent pharmacological clinical trials in neuropathic pain have failed to show beneficial effect of drugs with previously demonstrated efficacy, and estimates of drug efficacy seems to have decreased with accumulation of newer trials. However, this has not been systematically assessed. Here, we analyze time-dependent changes in estimated treatment effect size in pharmacological trials together with factors that may contribute to decreases in estimated effect size. This study is a secondary analysis of data from a previous published NeuPSIG systematic review and meta-analysis, updated to include studies published up till March 2017. We included double-blind, randomized, placebo-controlled trials examining the effect of drugs for which we had made strong or weak recommendations for use in neuropathic pain in the previously published review. As the primary outcome, we used an aggregated number needed to treat for 50% pain reduction (alternatively 30% pain reduction or moderate pain relief). Analyses involved 128 trials. Number needed to treat values increased from around 2 to 4 in trials published between 1982 and 1999 to much higher (less effective) values in studies published from 2010 onwards. Several factors that changed over time, such as larger study size, longer study duration, and more studies reporting 50% or 30% pain reduction, correlated with the decrease in estimated drug effect sizes. This suggests that issues related to the design, outcomes, and reporting have contributed to changes in the estimation of treatment effects. These factors are important to consider in design and interpretation of individual study data and in systematic reviews and meta-analyses.</p

Scientific Opportunities with an X-ray Free-Electron Laser Oscillator

An X-ray free-electron laser oscillator (XFELO) is a new type of hard X-ray source that would produce fully coherent pulses with meV bandwidth and stable intensity. The XFELO complements existing sources based on self-amplified spontaneous emission (SASE) from high-gain X-ray free-electron lasers (XFEL) that produce ultra-short pulses with broad-band chaotic spectra. This report is based on discussions of scientific opportunities enabled by an XFELO during a workshop held at SLAC on June 29 - July 1, 2016Comment: 21 pages, 12 figure

The impact of and subsequent chronic pain on patients' daily lives

Aim: The aim of our study was to carry out a literature review and develop a model illustrating the domains of patients' lives that are impacted by herpes zoster (HZ) and subsequent chronic pain. Subjects and methods: Biomedical databases and online congress archives were searched using keywords related to HZ or post-herpetic neuralgia (PHN) and social, psychological or physical impact. A total of 733 abstracts were reviewed, and 29 publications containing concepts reported by patients were retained for the model. Wilson and Cleary’s model was used to organise the findings. Links between concepts were documented on three levels: hypothesis, observation and evidence. The final model illustrates the concepts impacted by HZ and PHN, relationships between these concepts and the level of evidence identified. Results: The concepts identified from the articles were grouped into the following categories: biological/ physiological, symptom status, functional status, health perceptions, characteristics of the individual, health-related quality of life (HRQOL), treatment and characteristics of the environment. Evidence exists showing that HZ-related pain directly impacts functional status, health perceptions and HRQOL. Conclusion: Patients report that all major domains of life are impaired by HZ or subsequent chronic pain. HZ and its painful and debilitating complications can have a substantial impact on physical, psychological, social and role functioning, HRQOL and activities of daily living. The impact on elderly patients needs to be further assessed with appropriately designed and validated instruments, with specific attention paid to dependence

The relevance of real-world data for the evaluation of neuropathic pain treatments

Treatment of neuropathic pain (NP) is challenging. Interest in real-world evidence (RWE) for benefit-risk assessments of NP treatments increases given the paucity of drugs showing efficacy in randomized controlled trials and restricted labels of available medicines. To provide further context, a literature review regarding regulatory use of RWE and a clinical trial registry search for randomized controlled trials over the last 10 years was carried out. Taken together, and especially for available NP treatments, there is increasing support to consider RWE when evaluating their benefit-risk profile. Examples are provided in which RWE could be used effectively for updating the product label and informing treatment recommendations. Collected and analyzed according to state-of-the-art standards, RWE can inform treatment recommendations and product label decisions

On the effectiveness of private transnational governance regimes - evaluating corporate sustainability reporting according to the Global Reporting Initiative

The increasing involvement of multinational enterprises (MNEs) in global governance has been both applauded for its potential to make governance more effective and criticized for lacking democratic legitimization. Hence we investigate the effectiveness of one transnational governance regime, corporate sustainability reporting according to the Global Reporting Initiative (GRI). We found that the GRI has been successful in terms of output effectiveness by promoting the dissemination of sustainability reporting, in particular among Asian and South American companies. However, the outcome effectiveness of the GRI is limited as reporting showed a rather uniform content across countries and sectors which does not reflect materiality considerations. As GRI reporting does not seem to have facilitated greater company–stakeholder interaction, its impact effectiveness is likely to be limited too

Consumer Response to Drug Risk Information:The Role of Positive Affect

Risk disclosure is an essential element of the marketing of prescription drugs and other medical products. This study examines how consumers respond to verbal information about the frequency and severity of medical-product risks and how media-induced affect can moderate such responses. The study finds that consumers tend to overestimate the actual likelihood of adverse events described with words such as “common” or “rare” (compared with the probabilities such terms are typically intended to convey) and that consumers tend to give little weight to such probability language when forming product use intentions. However, consumers in positive media-induced moods seem to engage in more nuanced evaluation of product risk information, weighing both frequency and severity information and using such information to make inferences about other product attributes (e.g., product efficacy). These findings suggest that medical marketers and regulators need to devise more effective means of communicating risk probability to consumers and that positive mood induction (e.g., by placing advertisements in upbeat media environments) can enhance consumers' ability to process product risk information

The 5% Lidocaine-medicated Plaster: Its Inclusion In International Treatment Guidelines For Treating Localized Neuropathic Pain, and Clinical Evidence Supporting Its Use

When peripheral neuropathic pain affects a specific, clearly demarcated area of the body, it may be described as localized neuropathic pain (LNP). Examples include postherpetic neuralgia and painful diabetic neuropathy, as well as post-surgical and post-traumatic pain. These conditions may respond to topical treatment, i.e., pharmaceutical agents acting locally on the peripheral nervous system, and the topical route offers advantages over systemic administration. Notably, only a small fraction of the dose reaches the systemic circulation, thereby reducing the risk of systemic adverse effects, drug-drug interactions and overdose. From the patient's perspective, the analgesic agent is easily applied to the most painful area(s). The 5% lidocaine-medicated plaster has been used for several years to treat LNP and is registered in approximately 50 countries. Many clinical guidelines recommend this treatment modality as a first-line option for treating LNP, particularly in frail and/or elderly patients and those receiving multiple medications, because the benefit-to-risk ratios are far better than those of systemic analgesics. However, some guidelines make only a weak recommendation for its use. This paper considers the positioning of the 5% lidocaine-medicated plaster in international treatment guidelines and how they may be influenced by the specific criteria used in developing them, such as the methodology employed by randomized, placebo-controlled trials. It then examines the body of evidence supporting use of the plaster in some prevalent LNP conditions. Common themes that emerge from clinical studies are: (1) the excellent tolerability and safety of the plaster, which can increase patients' adherence to treatment, (2) continued efficacy over long-term treatment, and (3) significant reduction in the size of the painful area. On this basis, it is felt that the 5% lidocaine-medicated plaster should be more strongly recommended for treating LNP, either as one component of a multimodal approach or as monotherapy

The solitary nucleus connectivity to key autonomic regions in humans

The nucleus tractus solitarius (NTS) is a key brainstem structure relaying interoceptive peripheral information to the interrelated brain centres for eliciting rapid autonomic responses and for shaping longer-term neuroendocrine and motor patterns. Structural and functional NTS' connectivity has been extensively investigated in laboratory animals. But there is limited information about NTS' connectome in humans. Using MRI, we examined diffusion and resting state data from 20 healthy participants in the Human Connectome Project. The regions within the brainstem (n = 8), subcortical (n = 6), cerebellar (n = 2) and cortical (n = 5) parts of the brain were selected via a systematic review of the literature and their white matter NTS connections were evaluated via probabilistic tractography along with functional and directional (i.e. Granger causality) analyses. The underlying study confirms previous results from animal models and provides novel aspects on NTS integration in humans. Two key findings can be summarized: (1) the NTS predominantly processes afferent input and (2) a lateralization towards a predominantly left-sided NTS processing. Our results lay the foundations for future investigations into the NTS' tripartite role composed of interoreceptors' input integration, the resultant neurochemical outflow and cognitive/affective processing. The implications of these data add to the understanding of NTS' role in specific aspects of autonomic functions

Narrative review of the efficacy and safety of the high-concentration (179mg) capsaicin patch in peripheral neuropathic pain with recommendations for clinical practice and future research

High-concentration capsaicin patch (HC capsaicin patch) is a locally acting treatment option for adults with peripheral neuropathic pain (pNeP) of various etiologies. Numerous clinical trials, post hoc analyses, and meta-analyses have investigated the efficacy and tolerability of the HC capsaicin patch. Despite this extensive body of research, a comprehensive narrative review covering publications on different pNeP conditions is lacking. This narrative review aims to fill the gap by analyzing 52 studies, including randomized controlled trials and real-world evidence. The results show that the HC capsaicin patch consistently provides pain relief and improves quality of life for several pNeP conditions, with increasing benefits seen with repeated treatments. It was found to be superior to placebo and comparable to standard care, regardless of the origin of the pain. Early initiation of therapy appears to improve efficacy, although patients with more prolonged pain also benefit. While the exact mechanisms of action are still unclear, there is evidence to suggest a potential benefit from nerve regeneration in some conditions. However, limited information exists regarding the alteration of treatment intervals and the variation in the size of the painful area upon re-treatment. The review also identifies variability in response rates for different types of pNeP and a lack of reliable predictors of treatment success, indicating a need for further research. In conclusion, the HC capsaicin patch is effective and well tolerated across a range of pNeP conditions, with increasing efficacy upon retreatment. It is a valuable treatment option, although more research is needed to refine its clinical use and explore its full therapeutic potential