Gabapentin as add-on to morphine for severe neuropathic or mixed pain in children from age 3 months to 18 years - Evaluation of the safety, pharmacokinetics, and efficacy of a new gabapentin liquid formulation: Study protocol for a randomized controlled trial

Background: Gabapentin has shown efficacy in the treatment of chronic neuropathic or mixed pain in adults. Although pediatric pain specialists have extensive experience with gabapentin for the treatment of neuropathic pain, its use is off-label. Its efficacy and safety in this context have never been shown. The aim of this trial is to compare gabapentin with placebo as add-on to morphine for the treatment of severe chronic mixed or neuropathic pain in children. This trial is part of the European Union Seventh Framework Programme project Gabapentin in Paediatric Pain (GAPP) to develop a pediatric use marketing authorization for a new gabapentin suspension. Methods/design: The GAPP-2 study is a randomized, double-blind, placebo-controlled, multicenter superiority phase II study in children with severe chronic neuropathic or mixed pain. Its primary objective is to evaluate the efficacy of a gabapentin liquid formulation as adjunctive therapy to morphine. Sixty-six eligible children 3 months to 18 years of age with severe pain (pain scores ≥ 7), stratified in three age groups, will be randomized to receive gabapentin (to an accumulating dose of 45 to 63 mg/kg/day, dependent on age) or placebo, both in addition to morphine, for 12 weeks. Randomization will be preceded by a short washout period, and treatment will be initiated by a titration period of 3 weeks. After the treatment period, medication will be tapered during 4 weeks. The primary endpoint is the average pain scores in the two treatment groups (average of two measures each day for 3 days before the end-of-study visit [V10] assessed by age-appropriate pain scales (Face, Legs, Activity, Cry, Consolability scale; Faces Pain Scale-Revised; Numeric Rating Scale). Secondary outcomes include percentage responders to treatment (subjects with 30% reduction in pain scale), number of episodes of breakthrough pain, number of rescue interventions, number of pain-free days, participant dropouts, quality of life (Pediatric Quality of Life Inventory), and acceptability of treatment. Outcomes will be measured at the end-of-study visit after 12 weeks of treatment at the optimal gabapentin dose. Groups will be compared on an intention-to-treat basis. Discussion: We hope to provide evidence that the combination of morphine and gabapentin will provide better analgesia than morphine alone and will be safe. We also aim to obtain confirmation of the recommended pediatric dose. Trial registration: EudractCT, 2014-004897-40. Registered on 7 September 2017. ClinicalTrials.gov, NCT03275012. Registered on 7 September 2017

Many Labs 2: Investigating Variation in Replicability Across Samples and Settings

We conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings. Each protocol was administered to approximately half of 125 samples that comprised 15,305 participants from 36 countries and territories. Using the conventional criterion of statistical significance (p < .05), we found that 15 (54%) of the replications provided evidence of a statistically significant effect in the same direction as the original finding. With a strict significance criterion (p < .0001), 14 (50%) of the replications still provided such evidence, a reflection of the extremely highpowered design. Seven (25%) of the replications yielded effect sizes larger than the original ones, and 21 (75%) yielded effect sizes smaller than the original ones. The median comparable Cohen’s ds were 0.60 for the original findings and 0.15 for the replications. The effect sizes were small (< 0.20) in 16 of the replications (57%), and 9 effects (32%) were in the direction opposite the direction of the original effect. Across settings, the Q statistic indicated significant heterogeneity in 11 (39%) of the replication effects, and most of those were among the findings with the largest overall effect sizes; only 1 effect that was near zero in the aggregate showed significant heterogeneity according to this measure. Only 1 effect had a tau value greater than .20, an indication of moderate heterogeneity. Eight others had tau values near or slightly above .10, an indication of slight heterogeneity. Moderation tests indicated that very little heterogeneity was attributable to the order in which the tasks were performed or whether the tasks were administered in lab versus online. Exploratory comparisons revealed little heterogeneity between Western, educated, industrialized, rich, and democratic (WEIRD) cultures and less WEIRD cultures (i.e., cultures with relatively high and low WEIRDness scores, respectively). Cumulatively, variability in the observed effect sizes was attributable more to the effect being studied than to the sample or setting in which it was studied.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Sociales::Instituto de Investigaciones Psicológicas (IIP

Autoradiograficzne badania tkanki mięśniowej myszy zarażonych Trtchtnella spiralts z zastosowaniem p32

Complex investigations into the metabolism of T. spiralis infected muscles showed, among others, an increase in the metabolism of high energy phosphorus compounds (Garbuliński et al., 1965). The results obtained with P32 held true for the whole muscular tissue containing both infected and non infected fibres. To conform these finding and reach more exact data about the localization of the occuring processes, autoradiographic method was recurred to. P32 was injected to normal and T. spiralis infected mice 11, 19 days or 8 weeks later; the animals were sacrificed 15 and 30 minutes, 1, 3, 6, and 24 hours since isotope injection, mean values of emulsion darkenings over the morphologic elements under examination being calculated from sections of diaphragmal muscles. A high larval metabolic rate was demonstrated in all periods examined. The isotope was also found to accumulate in the cuticle, less at 11 (greater permeability) than at 19 days or 8 weeks of infection. The penetration of high energy phosphorus compounds was mediated by the cyst formed round the parasite. The substance of the infected muscular fibre, contained, in the later period, between the cyst and the larval body, showed all the time an increased metabolic rate, higher than that of normal muscular fibres. Presumably, a significant role is played by the muscular fibre nuclei that not only persist but increase in size. In later phase of infection their P32 accumulation showed a higher percentage than that of normal fibres. The autoradiographic method has corroborated the data obtained with biochemical procedure and provided additional informations about localization of the occurring processes.W badaniach kompleksowych nad metabolizmem mięśni zarażonych T. spiralis wykazano m.in. wzrost metabolizmu wysokoenergetycznych związków fosforowych (Garbuliński et al., 1965). Wynik ten, uzyskany przy zastosowaniu P32, dotyczył całej tkanki mięśniowej, zawierającej włókna zarażone i nie zarażone. Dla sprawdzenia tych badań i bliższego zlokalizowania zachodzących zmian zastosowano metodę autoradiograficzną. Izotop P32 wstrzykiwano myszom zdrowym oraz zarażonym T. spiralis po 11 lub 19 dniach oraz po 8 tygodniach, zwierzęta zabijano po 15 i 30 min., 1, 3, 6 i 24 godz. od wprowadzenia izotopu i w preparatach z mięśni przepony obliczano średnie wartości zaczernień emulsji fotograficznej nad określonymi elementami morfologicznymi. Wykazano wysoki metabolizm larw we wszystkich badanych okresach. Izotop gromadził się też w oskórku - słabiej w 11 dniu p.z. (większa przepuszczalność) niż w 19 dniu lub po 8 tygodniach. W przenikaniu wysokoenergetycznych związków fosforowych bierze też udział wytworzona wokół pasożyta torebka. Substancja zarażonego włókna mięśniowego znajdująca się w późniejszym okresie między torebką a larwą wykazuje przez cały czas zwiększony metabolizm, większy niż w zdrowych włóknach mięśniowych . Wydaje się , że istotną rolę odgrywają w tym jądra włókna mięśniowego, które utrzymują się, a nawet powiększają swe wymiary. W późniejszej fazie inwazji akumulują one P32 w większym odsetku niż w normalnych włóknach. Metoda autoradiograficzna potwierdziła wynik uzyskany metodą biochemiczną i dostarczyła wielu szczegółów dotyczących lokalizacji zachodzących przemian

Non-inferiority double-blind randomised controlled trial comparing gabapentin versus tramadol for the treatment of chronic neuropathic or mixed pain in children and adolescents: The GABA-1 trial-a study protocol

Introduction Gabapentin is currently used â € off-label' in children and adolescents with chronic neuropathic pain, and reliable evidence of its effects and optimal dosing are lacking. Objectives The GABA-1 trial aims to compare the efficacy and safety of gabapentin liquid formulation relative to tramadol and to explore the pharmacokinetics of both drugs in the treatment of chronic, neuropathic or mixed pain in the paediatric population. Methods and analysis The trial is a multicentre, double-blind, double-dummy, randomised, active-controlled, non-inferiority trial. Participants aged from 3 months to &lt;18 years of age with moderate to severe (≥4/10 in age-appropriate pain scales) chronic neuropathic or mixed pain will be recruited in 14 clinical sites in eight European countries. A total of 94 subjects will be randomised to receive gabapentin and tramadol placebo or tramadol and gabapentin placebo throughout 16-19 weeks (including 3 weeks of titration [optimisation period], 12 weeks of treatment at a stable dose [maintenance period] and 1-4 weeks of tapering [discontinuation period]). The primary objective is to assess the efficacy of gabapentin relative to tramadol for the treatment of moderate to severe chronic neuropathic or mixed pain by comparing the difference in average pain scores (assessed by age-appropriate pain scales) between intervention arms after 15 weeks of treatment. Secondary objectives include the assessment of the safety, quality of life and global satisfaction with treatment and the description of the pharmacokinetic-pharmacodynamic relationship of gabapentin liquid formulation and tramadol oral drops to validate the recommended paediatric doses. Only rescue pain medication by paracetamol and/or ibuprofen is allowed during the trial. Ethics and dissemination Ethic approval was obtained in the eight participating countries. Results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences. Trial registration numbers 2014-004851-30 and NCT02722603. Trial status Ongoing research study, currently recruiting

Measuring the Semantic Priming Effect Across Many Languages

Semantic priming has been studied for nearly 50 years across various experimental manipulations and theoretical frameworks. These studies provide insight into the cognitive underpinnings of semantic representations in both healthy and clinical populations; however, they have suffered from several issues including generally low sample sizes and a lack of diversity in linguistic implementations. Here, we will test the size and the variability of the semantic priming effect across ten languages by creating a large database of semantic priming values, based on an adaptive sampling procedure. Differences in response latencies between related word-pair conditions and unrelated word-pair conditions (i.e., difference score confidence interval is greater than zero) will allow quantifying evidence for semantic priming, whereas improvements in model fit with the addition of a random intercept for language will provide support for variability in semantic priming across languages

Many Labs 2: Investigating Variation in Replicability Across Samples and Settings

We conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings. Each protocol was administered to approximately half of 125 samples that comprised 15,305 participants from 36 countries and territories. Using the conventional criterion of statistical significance (p &lt; .05), we found that 15 (54%) of the replications provided evidence of a statistically significant effect in the same direction as the original finding. With a strict significance criterion (p &lt; .0001), 14 (50%) of the replications still provided such evidence, a reflection of the extremely high-powered design. Seven (25%) of the replications yielded effect sizes larger than the original ones, and 21 (75%) yielded effect sizes smaller than the original ones. The median comparable Cohen’s ds were 0.60 for the original findings and 0.15 for the replications. The effect sizes were small (&lt; 0.20) in 16 of the replications (57%), and 9 effects (32%) were in the direction opposite the direction of the original effect. Across settings, the Q statistic indicated significant heterogeneity in 11 (39%) of the replication effects, and most of those were among the findings with the largest overall effect sizes; only 1 effect that was near zero in the aggregate showed significant heterogeneity according to this measure. Only 1 effect had a tau value greater than .20, an indication of moderate heterogeneity. Eight others had tau values near or slightly above .10, an indication of slight heterogeneity. Moderation tests indicated that very little heterogeneity was attributable to the order in which the tasks were performed or whether the tasks were administered in lab versus online. Exploratory comparisons revealed little heterogeneity between Western, educated, industrialized, rich, and democratic (WEIRD) cultures and less WEIRD cultures (i.e., cultures with relatively high and low WEIRDness scores, respectively). Cumulatively, variability in the observed effect sizes was attributable more to the effect being studied than to the sample or setting in which it was studied