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.

Measuring Contralateral Silent Period Induced by Single-Pulse Transcranial Magnetic Stimulation to Investigate M1 Corticospinal Inhibition.

Contralateral silent period (cSP) is a period of suppression in the background electrical muscle activity captured by electromyography (EMG) after a motor evoked potential (MEP). To obtain this, an MEP is elicited by a suprathreshold transcranial magnetic stimulation (TMS) pulse delivered to the primary motor cortex (M1) of the target muscle selected, while the participant provides a standardized voluntary target muscle contraction. The cSP is a result of inhibitory mechanisms that occur after the MEP; it provides a broad temporal assessment of spinal inhibition in its initial ~50 ms, and cortical inhibition after. Researchers have tried to better understand the neurobiological mechanism behind the cSP to validate it as a potential diagnostic, surrogate, and predictive biomarker for different neuropsychiatric diseases. Therefore, this article describes a method to measure M1 cSP of lower and upper limbs, including a selection of target muscle, electrode placement, coil positioning, method of measuring voluntary contraction stimulation, intensity setup, and data analysis to obtain a representative result. It has the educational objective of giving a visual guideline in performing a feasible, reliable, and reproducible cSP protocol for lower and upper limbs and discussing practical challenges of this technique.

Temporal Summation in Fibromyalgia Patients: Comparing Phasic and Tonic Paradigms.

Introduction: Fibromyalgia (FM) is associated with dysfunctional pain modulation mechanisms, including central sensitization. Experimental pain measurements, such as temporal summation (TS), could serve as markers of central sensitization and have been previously studied in these patients, with conflicting results. Our objective in this study was to explore the relationships between two different protocols of TS (phasic and tonic) and test the associations between these measures and other clinical variables. Materials and Methods: In this cross-sectional analysis of a randomized clinical trial, patients were instructed to determine their pain-60 test temperature, then received one train of 15 repetitive heat stimuli and rated their pain after the 1st and 15th stimuli: TSPS-phasic was calculated as the difference between those. We also administered a tonic heat test stimulus at the same temperature continuously for 30 s and asked them to rate their pain levels after 10 s and 30 s, calculating TSPS-tonic as the difference between them. We also collected baseline demographic data and behavioral questionnaires assessing pain, depression, fatigue, anxiety, sleepiness, and quality of life. We performed univariable analyses of the relationship between TSPS-phasic and TSPS-tonic, and between each of those measures and the demographic and clinical variables collected at baseline. We then built multivariable linear regression models to find predictors for TSPS-phasic and TSPS-tonic, while including potential confounders and avoiding collinearity. Results: Fifty-two FM patients were analyzed. 28.85% developed summation during the TSPS-phasic protocol while 21.15% developed summation during the TSPS-tonic protocol. There were no variables associated TSPS phasic or tonic in the univariable analyses and both measures were not correlated. On the multivariate model for the TSPS-phasic protocol, we found a weak association with pain variables. BPI-pain subscale was associated with more temporal summation in the phasic protocol (ß = 0.38, p = 0.029), while VAS for pain was associated with less summation in the TSPS-tonic protocol (ß = -0.5, p = 0.009). Conclusion: Our results suggest that, using heat stimuli with pain-60 temperatures, a TSPS-phasic protocol and a TSPS-tonic protocol are not correlated and could index different neural responses in FM subjects. Further studies with larger sample sizes would be needed to elucidate whether such responses could help differentiating subjects with FM into specific phenotypes.

Severe Exacerbation of Multiple Sclerosis Following Withdrawal of Fingolimod.

BACKGROUND: Fingolimod is an effective therapy for multiple sclerosis (MS). Isolated reports of very aggressive MS rebound after discontinuation of fingolimod are drawing neurologists' attention to this potentially severe complication of the drug. OBJECTIVE: Our objective was to collect literature data on cases of MS rebound following fingolimod withdrawal. In addition, we report six new cases of this adverse event in Brazil. METHODS: We carried out a systematic review of published data on cases of MS rebound after fingolimod was discontinued. In addition, the study reports a retrospective data series of Brazilian patients presenting this rebound reaction. RESULTS: Twenty papers have been published reporting on 52 patients with severe MS rebound after fingolimod withdrawal. Six new patients are included in the present paper, all of them with aggressive rebound and accumulated disability sequelae. CONCLUSION: We recommend gradual discontinuation of fingolimod with replacement by other treatment. The washout period should not exceed 4 weeks.

Impact of Therapeutic Interventions on Pain Intensity and Endogenous Pain Modulation in Knee Osteoarthritis: A Systematic Review and Meta-analysis.

OBJECTIVE: To study the impact of therapeutic interventions on pain analgesia and endogenous pain modulation in knee osteoarthritis (KOA). DESIGN: Systematic review and meta-analysis. METHODS: We searched for KOA randomized clinical trials and observational studies with data on therapeutic interventions comparing pain intensity, temporal summation (TS), and conditioned pain modulation (CPM) scores relative to control. These data were pooled as Hedge's g. To study the relationship between pain intensity and TS/CPM, we performed metaregression with 10,000 Monte-Carlo permutations. RESULTS: We reviewed 11 studies (559 participants). On studying all the interventions together, we found no significant changes in pain modulation, TS, or CPM. Our findings show that this lack of difference is likely because surgical and nonsurgical interventions resulted in contrary effects. Metaregression significantly correlated pain reduction with normalization of TS and CPM. CONCLUSIONS: We demonstrate an association between pain reduction and TS/CPM normalization. Though we cannot directly compare these interventions, the results allow us to draw hypotheses on potential practice schemas. Recovering defective endogenous pain modulation mechanisms may help establish long-term analgesia. However, to validate these paradigms as robust clinical biomarkers, further investigation into their mechanisms would be necessary. The registration number for this review is CRD42017072066.

There is no benefit in the use of postnatal intravenous immunoglobulin for the prevention of relapses of multiple sclerosis: findings from a systematic review and meta-analysis.

OBJECTIVE: Multiple sclerosis (MS) is a complex autoimmune and neurodegenerative disease of the central nervous system. Since MS affects mostly fertile women, pregnancy issues often arise in daily practice. The present study assessed the use of postpartum intravenous immunoglobulin (IVIG) in MS. METHODS: The authors individually searched for records using PubMed, Medline, EMBASE, Cochrane, SciELO, LILACS, and Google Scholar, using the terms "multiple sclerosis" OR "MS" AND "pregnancy" OR "gestation" OR "partum" OR "post-partum" OR "puerperium" AND "immunoglobulin". RESULTS: The initial search returned 321 papers. There were 11 eligible articles selected for the review. In total, 380 patients had received post-natal IVIG to reduce the number of postpartum relapses. The unadjusted number needed to treat was 6.3 for the quantitative and 5.8 for the qualitative analyses. CONCLUSION: The therapeutic effect of IVIG for prevention of postnatal relapses in MS could not clearly be established in this meta-analysis.

There is no benefit in the use of postnatal intravenous immunoglobulin for the prevention of relapses of multiple sclerosis: findings from a systematic review and meta-analysis / Não há benefício do uso de imunoglobulina endovenosa para prevenção de surtos na esclerose múltipla: achados de revisão sistemática e meta-análise

ABSTRACT Multiple sclerosis (MS) is a complex autoimmune and neurodegenerative disease of the central nervous system. Since MS affects mostly fertile women, pregnancy issues often arise in daily practice. The present study assessed the use of postpartum intravenous immunoglobulin (IVIG) in MS. Methods The authors individually searched for records using PubMed, Medline, EMBASE, Cochrane, SciELO, LILACS, and Google Scholar, using the terms "multiple sclerosis" OR "MS" AND "pregnancy" OR "gestation" OR "partum" OR "post-partum" OR "puerperium" AND "immunoglobulin". Results The initial search returned 321 papers. There were 11 eligible articles selected for the review. In total, 380 patients had received post-natal IVIG to reduce the number of postpartum relapses. The unadjusted number needed to treat was 6.3 for the quantitative and 5.8 for the qualitative analyses. Conclusion The therapeutic effect of IVIG for prevention of postnatal relapses in MS could not clearly be established in this meta-analysis.

RESUMO Esclerose múltipla (EM) é uma complexa doença autoimune e neurodegenerativa do sistema nervoso central. Uma vez que EM afeta principalmente mulheres em idade fértil, assuntos relacionados à gravidez frequentemente surgem na prática diária. O presente estudo avaliou o uso pós-parto de imunoglobulina (IVIG) na EM. Métodos Os autores individualmente pesquisaram as bases de dados PubMed, Medline, EMBASE, Cochrane, SciELO, LILACS, e Google Scholar usando os termos "multiple sclerosis" OR "MS" AND "pregnancy" OR "gestation" OR "partum" OR "post-partum" OR "puerperium" AND "immunoglobulin". Resultados A pesquisa inicial retornou 321 artigos. Havia 11 artigos elegíveis para a revisão. No total, havia relato de 380 pacientes que receberam IVIG após a gravidez visando reduzir o número de surtos. O número necessário para tratar não ajustado foi 6,3 para análise quantitativa e 5,8 para análise qualitativa. Conclusão O efeito terapêutico da IVIG para prevenção dos surtos pós-parto na EM não pôde ser claramente estabelecida nesta meta-análise.

Augusta Marie Déjerine-Klumpke: much more than just Déjerine's wife.

Augusta Marie Déjerine-Klumpke (1859-1927) was a formidable neurologist, neuroanatomist and researcher in France. One of the first women to be accepted for medical internship, externship and research in Paris, Augusta made her name studying and teaching anatomy, histology and dissection, attending clinical activities in neurology, obstetrics, pediatrics and neurologic trauma, performing necropsies, and writing scientific papers and book chapters. Her main research in neurology awarded her an eponym for the avulsion of the lowest root of the brachial plexus (Klumpke's palsy). Married to her professor, the remarkable Dr. Joseph Jules Déjerine, Augusta continued her career and became the first female president of the French Society of Neurology.

Augusta Marie Déjerine-Klumpke: much more than just Déjerine's wife / Augusta Marie Déjerine-Klumpke: muito mais do que apenas a esposa de Déjerine

ABSTRACT Augusta Marie Déjerine-Klumpke (1859-1927) was a formidable neurologist, neuroanatomist and researcher in France. One of the first women to be accepted for medical internship, externship and research in Paris, Augusta made her name studying and teaching anatomy, histology and dissection, attending clinical activities in neurology, obstetrics, pediatrics and neurologic trauma, performing necropsies, and writing scientific papers and book chapters. Her main research in neurology awarded her an eponym for the avulsion of the lowest root of the brachial plexus (Klumpke's palsy). Married to her professor, the remarkable Dr. Joseph Jules Déjerine, Augusta continued her career and became the first female president of the French Society of Neurology.

RESUMO Augusta Marie Déjerine-Klumpke (1859-1927) foi uma formidável neurologista, neuroanatomista e pesquisadora na França. Uma das primeiras mulheres aceitas para estágios médicos internos e externos ao hospital, e pesquisa em Paris, Augusta fez seu nome estudando e ensinando anatomia, histologia e dissecção, participando de atividades clínicas em neurologia, obstetrícia, pediatria e trauma neurológico, participando de necrópsias, e escrevendo artigos científicos e capítulos de livros. Sua principal pesquisa em neurologia lhe rendeu um epônimo para a avulsão da raiz inferior do plexo braquial (paralisia de Klumpke). Casada com seu professor, o notável Dr. Joseph Jules Déjerine, Augusta continuou sua carreira e se tornou a primeira mulher presidente da Sociedade Francesa de Neurologia.

Mary Broadfoot Walker: 83 years since a historical discovery.

Mary Broadfoot Walker was a Scottish physician who, in 1935, described in great detail the effect of an anticholinesterase drug (physostigmine) on the signs and symptoms of myasthenia gravis. An original five-minutes movie is available online and the skepticism of her contemporary British medical doctors is understandable when the drastic effect of the treatment is shown in this movie. What Mary Walker taught us, more than eight decades ago, about myasthenia gravis continues to be the basis of a pharmacological diagnostic test and treatment of this disease.

Mary Broadfoot Walker: 83 years since a historical discovery / Mary Broadfoot Walker: 83 anos desde uma descoberta histórica

ABSTRACT Mary Broadfoot Walker was a Scottish physician who, in 1935, described in great detail the effect of an anticholinesterase drug (physostigmine) on the signs and symptoms of myasthenia gravis. An original five-minutes movie is available online and the skepticism of her contemporary British medical doctors is understandable when the drastic effect of the treatment is shown in this movie. What Mary Walker taught us, more than eight decades ago, about myasthenia gravis continues to be the basis of a pharmacological diagnostic test and treatment of this disease.

RESUMO Mary Broadfoot Walker foi uma médica escocesa que em 1935 descreveu em grande detalhe o efeito de uma droga anticolinesterásica (fisostigmina) nos sinais e sintomas da myasthenia gravis. Um filme original com cinco minutos de duração está disponível online e a reação cética dos colegas médicos contemporâneos de Mary é compreensível dado o drástico efeito terapêutico mostrado neste filme. O que Mary Walker nos ensinou mais de oito décadas atrás continua a ser a base de um teste diagnóstico farmacológico e do tratamento da myasthenia gravis.