Safety, tolerability, and nocebo phenomena during transcranial magnetic stimulation: a systematic review and meta‐analysis of placebo‐controlled clinical trials

Background The methodology used for the application of repetitive transcranial magnetic stimulation (TMS) is such that it may induce a placebo effect. Respectively, adverse events (AEs) can occur when using a placebo, a phenomenon called nocebo. The primary aim of our meta‐analysis is to establish the nocebo phenomena during TMS. Safety and tolerability of TMS were also studied. Methods After a systematic Medline search for TMS randomized controlled trials (RCTs), we assessed the number of patients reporting at least one AE and the number of discontinuations because of AE in active and sham TMS groups. Results Data were extracted from 93 RCTs. The overall pooled estimate of active TMS and placebo treated patients who discontinued treatment because of AEs was 2.5% (95% CI 1.9%‐3.2%) and 2.7% (95% CI 2.0%‐3.5%), respectively. The pooled estimate of active TMS and placebo treated patients experiencing at least one AE was 29.3% (95% CI 19.0%‐22.6%) and 13.6% (95% CI 11.6%‐15.8%), respectively, suggesting that the odds of experiencing an AE is 2.60 times higher (95% CI 1.75‐3.86) in the active treatment group compared to placebo (p < 0.00001). The most common AE was headache, followed by dizziness. Secondary meta‐analyses in depression and psychotic disorders showed that the odds of experiencing an AE is 3.98 times higher (95% CI 2.14‐7.40) and 2.93 times higher (95% CI 1.41‐6.07), respectively, in the active treatment groups compared to placebo. Conclusions TMS is a safe and well‐tolerated intervention. Nocebo phenomena do occur during TMS treatment and should be acknowledged during clinical trial design and daily clinical practice

European Headache Federation recommendations for placebo and nocebo terminology

Background and aim Despite recent publications, practitioners remain unfamiliar with the current terminology related to the placebo and nocebo phenomena observed in clinical trials and practice, nor with the factors that modulate them. To cover the gap, the European Headache Federation appointed a panel of experts to clarify the terms associated with the use of placebo in clinical trials. Methods The working group identified relevant questions and agreed upon recommendations. Because no data were required to ans

Add-on topiramate in the treatment of refractory partial-onset epilepsy: Clinical experience of outpatient epilepsy clinics from 11 general hospitals

SummaryAn open, prospective, observational study was performed to assess efficacy and adverse-event profile of topiramate as add-on therapy in epilepsy. Outpatient neurology clinics from 11 general hospitals in Greece participated in the study. In total, 211 patients with treatment resistant partial-onset seizures who met the inclusion criteria, were studied. After baseline evaluation, topiramate was given at a target dose of 200mg/day over a 1-month titration period. In the subsequent maintenance period, the topiramate dose could be varied according to the clinical results. Patients were followed for in total 6 months, with monthly visits and regular physical, neurological and laboratory examinations. Seizure frequencies decreased to 35–40% of baseline values following 3 months of treatment and remained relatively constant thereafter. The average monthly seizure frequency over the 6-month study period was 4.61, compared to 9.21 at baseline. The number of responders (patients with at least 50% reduction in seizure frequency) followed a similar pattern, i.e., increase during the first 3 months levelling off at a final 80–85% response rate. Of those completing the study, 30% had been seizure-free for at least 3 months and 12% for 5 months. Topiramate was well tolerated, no deviations in laboratory values were found. Adverse events appeared to occur less frequently, and antiepileptic effects were more pronounced in this prospective open-label study than in earlier reports from randomised controlled trials. The nature of the patient population and the application of individualised dose optimisation are proposed as contributing factors to explain the favourable results of this study

Comparing the efficacy of disease-modifying therapies in multiple sclerosis

Establishing the relative efficacy and safety of the different disease modifying therapies (DMTs) in multiple sclerosis (MS) is critical to the choice of agent that clinicians recommend for individual MS patients. The best evidence for the relative efficacy of the different DMTs comes from head-to-head randomized clinical trials (RCTs). Understanding that outcome-measures with the best established validity are the relapse rate and the actual (not the “confirmed”) change in the extended disability status scale (EDSS), we conclude from these head-to-head RCTs that interferon-beta (IFNβ) given subcutaneously multiple times per week (either IFNβ-1b or IFNβ-1a) and glatiramer acetate (GA) are about equivalent in terms of efficacy and that both of these agents, as well as many of the other DMTs, are superior to weekly intramuscular IFNβ-1a. Nevertheless, as ever-newer agents with novel mechanisms of action are brought to the marketplace, such direct head-to-head trials are becoming increasingly impractical, raising the need for alternative methods to draw reasonable inferences from less rigorous clinical data. One possible approach to judging comparative efficacy is to make comparisons across clinical trials using the complimentary analytic methods of calculating both the relative risk/rate and the absolute risk/rate reductions. A consideration and application of this analytic approach is undertaken here. It is only with an understanding of the safety and efficacy of the different agents that we can select, together with the patient, the right agent for the right person. © 201

Correction to: Oral Disease-Modifying Treatments for Relapsing Multiple Sclerosis: A Likelihood to Achieve No Evidence of Disease Activity or Harm Analysis (CNS Drugs, (2018), 32, 11, (1069-1078), 10.1007/s40263-018-0547-z)

NEDA was evaluated as the proportion of patients free of relapses, 3-month confirmed disability progression, and free of new or newly enlarging T2 lesion and Gadolinium enhancing lesions. © 2018, Springer Nature Switzerland AG

Therapies targeting CGRP signaling for medication overuse headache

PURPOSE OF REVIEW: Medication overuse headache (MOH) affects more than 60 million individuals worldwide causing enormous personal and social burden. Only repurposed drugs are available for MOH that share limited evidence for efficacy. The preclinical data suggesting that activation of the calcitonin gene-related peptide (CGRP) pathway is involved in headache chronification along with clinical evidence that monoclonal antibodies targeting CGRP (anti-CGRP mAbs) have good efficacy in preventing chronic migraine, triggered this review that aims to summarize the current data on the effectiveness and safety of mAbs against CGRP in MOH. RECENT FINDINGS: Post hoc analyses of phase-3 trials of erenumab, fremanezumab, galcanezumab, and eptinezumab for the prevention of chronic migraine revealed that patients with MOH benefit from the treatment over placebo. Several real-world studies confirm the efficacy of erenumab and galcanezumab in patients with MO. However, all published trials evaluated treatments in patients with chronic migraine with MO collectively, not in patients with MOH exclusively. SUMMARY: The available data indicate that anti-CGRP mAbs represent a good mechanism-based and disease-specific therapeutical option with for MOH as long as detoxification and additional nonpharmaceutical interventions are operated. Future research should focus on long-term-controlled trials in MOH populations exclusively. Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved