Cost-Effectiveness Analysis to Inform Randomized Controlled Trial Design in Chronic Pain Research: Methods for Guiding Decisions on the Addition of a Run-In Period.

Introduction: Run-In (RI) periods can be used to improve the validity of randomized controlled trials (RCTs), but their utility in Chronic Pain (CP) RCTs is debated. Cost-effectiveness analysis (CEA) methods are commonly used in evaluating the results of RCTs, but they are seldom used for designing RCTs. We present a step-by-step overview to objectively design RCTs via CEA methods and specifically determine the cost effectiveness of a RI period in a CP RCT. Methods: We applied the CEA methodology to data obtained from several noninvasive brain stimulation CP RCTs, specifically focusing on (1) defining the CEA research question, (2) identifying RCT phases and cost ingredients, (3) discounting, (4) modeling the stochastic nature of the RCT, and (5) performing sensitivity analyses. We assessed the average cost-effectiveness ratios and incremental cost effectiveness ratios of varied RCT designs and the impact on cost-effectiveness by the inclusion of a RI period vs. No-Run-In (NRI) period. Results: We demonstrated the potential impact of varying the number of institutions, number of patients that could be accommodated per institution, cost and effectiveness discounts, RCT component costs, and patient adherence characteristics on varied RI and NRI RCT designs. In the specific CP RCT designs that we analyzed, we demonstrated that lower patient adherence, lower baseline assessment costs, and higher treatment costs all necessitated the inclusion of an RI period to be cost-effective compared to NRI RCT designs. Conclusions: Clinical trialists can optimize CP RCT study designs and make informed decisions regarding RI period inclusion/exclusion via CEA methods.

Transcranial direct current stimulation reduces ischemia-induced sensory disturbance in the hands of healthy subjects.

INTRODUCTION/AIMS: The treatment of entrapment neuropathies, such as carpal tunnel syndrome or cubital tunnel syndrome, has significant challenges that have yet to be solved. To a large extent, the success of the treatment of peripheral nerve damage is dependent on brain plasticity during the recovery process. Recently, noninvasive brain stimulation procedures, such as transcranial direct current stimulation (tDCS), to modulate brain activity have been developed. This study aimed to determine whether tDCS can improve artificially induced ischemic sensory disturbances in the finger. METHODS: Ten right-handed, healthy volunteers, with an average age of 25.5 years, participated in this study. A rubber bandage at the base of the right index finger was used to induce a regional sensory disturbance for 30 minutes. An anodal tDCS was applied over their left M1 area 15 minutes into the session. The current perception threshold (CPT) in the index and little finger pad was evaluated using the PainVision system and used as a measure of the sensory threshold. RESULTS: In the index finger, the CPT increased significantly with time, a finding that was absent after tDCS application. DISCUSSION: It has been reported that anodal tDCS over M1 primarily modulates the functional connectivity of sensory networks, and our findings demonstrate that it improved ischemia-induced sensory disturbances. Modulating the central nervous system using tDCS represents a potential avenue for treating entrapment neuropathies.

Pain perception in chronic knee osteoarthritis with varying levels of pain inhibitory control: an exploratory study.

Background and aims Pain is a disabling symptom in knee osteoarthritis (KOA) and its underlying mechanism remains poorly understood. Dysfunction of descending pain modulatory pathways and reduced pain inhibition enhance pain facilitation in many chronic pain syndromes but do not fully explain pain levels in chronic musculoskeletal conditions. The objective of this study is to explore the association of clinical variables with pain intensity perception in KOA individuals with varying levels of Conditioned Pain Modulation (CPM) response. Methods This is a cross-sectional, exploratory analysis using baseline data of a randomized clinical trial investigating the effects of a non-invasive brain stimulation treatment on the perception of pain and functional limitations due to KOA. Sixty-three subjects with KOA were included in this study. Data on pain perception, mood perception, self-reported depression, physical function, quality of life, and quantitative sensory testing was collected. Multiple linear regression analysis was performed to explore the association between the clinical variables with pain perception for individuals with different levels of CPM response. Results For KOA patients with limited CPM response, perception of limitations at work/other activities due to emotional problems and stress scores were statistically significantly associated with pain scores, F(2, 37) = 7.02, p < 0.01. R-squared = 0.275. For KOA patients with normal CPM response, general health perception scores were statistically significantly associated with pain scores, F(1, 21) = 5.60, p < 0.05. R-squared = 0.2104. Limitations of this study include methodology details, small sample size and study design characteristics. Conclusions Pain intensity perception is associated differently with clinical variables according to the individual CPM response. Mechanistic models to explain pain perception in these two subgroups of KOA subjects are discussed.

Fluid Administration in Emergency Room Limited by Lung Ultrasound in Patients with Sepsis: Protocol for a Prospective Phase II Multicenter Randomized Controlled Trial.

BACKGROUND: Sepsis remains a major health challenge with high mortality. Adequate volume administration is fundamental for a successful outcome. However, individual fluid needs differ between patients due to varying degrees of systemic vasodilation, circulatory flow maldistribution, and increased vascular permeability. The current fluid resuscitation practice has been questioned. Fluid overload is associated with higher mortality in sepsis. A sign of fluid overload is extravascular lung water, seen as B lines in lung ultrasound. B lines correlate inversely with oxygenation (measured by a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen ie, PaO2/FiO2). Thus, B lines seen by bedside ultrasound may have a role in guiding fluid therapy. OBJECTIVE: We aim to evaluate if fluid administration guided by lung ultrasound in patients with sepsis in emergency departments will lead to better oxygenation and patient outcomes than those in the standard therapy. METHODS: A phase II, multicenter, randomized, open-label, parallel-group, superiority trial will be performed. Patients will be recruited at emergency departments of the participating centers. A total of 340 patients will be randomly allocated to the intervention or standard-of-care group (30mL/kg). The intervention group will receive ultrasound-guided intravenous fluid until 3 B lines appear. The primary outcome will be oxygenation (measured as PaO2/FiO2 ratio) at 48 hours after starting intravenous fluid administration. Secondary outcomes will be patients' outcome parameters, including oxygenation after 15 mL/kg fluid at 6, 12, 24, and 48 hours; sepsis progress through Sequential Organ Failure Assessment (SOFA) scores; pulmonary edema evaluation; and 30-day mortality. RESULTS: The trial will be conducted in accordance with the Declaration of Helsinki. Institutional review board approval will be sought after the participating sites are selected. The protocol will be registered once the institutional review board approval is granted. The trial duration is expected to be 1.5-2.5 years. The study is planned to be performed from 2021 to 2022, with enrollment starting in 2021. First results are expected in 2022. Informed written consent will be obtained before the patient's enrollment in the study. An interim analysis and data monitoring will ensure the patient safety. The results will be published in a peer-reviewed journal and discussed at international conferences. CONCLUSIONS: This is a protocol for a randomized control trial that aims to evaluate the role of bedside ultrasound in guiding fluid therapy in patients with sepsis via B lines evaluation. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/15997.

Transcranial direct current stimulation effects on hand sensibility as measured by an objective quantitative analysis device: a randomized single-blind sham-control crossover clinical trial.

Studies show that transcranial direct current stimulation (tDCS) can modulate somatosensory processing, but optimum parameters for tDCS effects on hand sensibility remain in question. We aimed to test the effects of anodal tDCS (atDCS) and cathodal tDCS (ctDCS) compared with sham tDCS (stDCS) of primary motor (M1) and sensory (S1) cortices on healthy subjects' hand sensibility. In this single-blind clinical trial, 30 randomized healthy volunteers received six tDCS sessions over 6 weeks: one session each of atDCS, ctDCS and stDCS over M1, and one session each of atDCS, ctDCS and stDCS over S1. Current perception threshold (CPT) was assessed using an objective quantitative analysis device (PainVision) at baseline, immediately (T0) and 30 min (T30) after each intervention. Our results showed that both atDCS and ctDCS of S1 and M1 significantly increased CPT. M1 ctDCS at T30 had the greatest effect of all M1 and S1 stimulation conditions (mean difference: 32.94%, Z: 3.12, effect size: 1.82, P < 0.001 The largest effect at S1 was for atDCS at T30 (mean difference: 29.87%, Z: 2.53, effect size: 1.72, P < 0.001. Our results are consistent with tDCS' modulatory effects on hand sensation, especially M1 ctDCS and S1 atDCS.

Mirror imaging of finger mechanical stimulation affects secondary somatosensory response.

The aim of this study was to investigate the effect of finger-tip touch on the somatosensory cortex under mirror imaging conditions. Magnetoencephalographic recordings of somatosensory-evoked field responses to mechanical tactile stimulation of the index finger in both hands were obtained for the right-handed healthy participants as part of the following mirror or nonmirror tasks. Both hands were screened and mechanical stimuli were delivered to the right index finger pulp. A mirror was placed in front of the patient with the right hand facing the reflective surface, as if it were the left side (mirror task). Another task comprised the screening of right hands behind a partition, after which mechanical stimuli were delivered to the right index finger pulp without a mirror (nonmirror task). The same tasks for the left hand were also examined. The estimated current dipoles were identified and analyzed. In the measurements following all the tasks, the equivalent current dipoles (ECDs) were estimated in the corresponding contralateral primary somatosensory area (cSI). The other ECDs were estimated in the secondary somatosensory area both contralateral (cSII) and ipsilateral (iSII) to the stimulus side. The amplitudes of ECDs in the cSII area following the left index stimuli in the mirror task were significantly larger than those in the nonmirror task (P=0.043). The mirror effect on the somatosensory cortex in this study may be small, but a positive variation was shown in the form of a response to the actual stimulation in the hand opposite to the hand which was hidden behind the mirror.