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The International Journal of... Apr 2021Transcranial direct current stimulation has shown promising clinical results, leading to increased demand for an evidence-based review on its clinical effects. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Transcranial direct current stimulation has shown promising clinical results, leading to increased demand for an evidence-based review on its clinical effects.
OBJECTIVE
We convened a team of transcranial direct current stimulation experts to conduct a systematic review of clinical trials with more than 1 session of stimulation testing: pain, Parkinson's disease motor function and cognition, stroke motor function and language, epilepsy, major depressive disorder, obsessive compulsive disorder, Tourette syndrome, schizophrenia, and drug addiction.
METHODS
Experts were asked to conduct this systematic review according to the search methodology from PRISMA guidelines. Recommendations on efficacy were categorized into Levels A (definitely effective), B (probably effective), C (possibly effective), or no recommendation. We assessed risk of bias for all included studies to confirm whether results were driven by potentially biased studies.
RESULTS
Although most of the clinical trials have been designed as proof-of-concept trials, some of the indications analyzed in this review can be considered as definitely effective (Level A), such as depression, and probably effective (Level B), such as neuropathic pain, fibromyalgia, migraine, post-operative patient-controlled analgesia and pain, Parkinson's disease (motor and cognition), stroke (motor), epilepsy, schizophrenia, and alcohol addiction. Assessment of bias showed that most of the studies had low risk of biases, and sensitivity analysis for bias did not change these results. Effect sizes vary from 0.01 to 0.70 and were significant in about 8 conditions, with the largest effect size being in postoperative acute pain and smaller in stroke motor recovery (nonsignificant when combined with robotic therapy).
CONCLUSION
All recommendations listed here are based on current published PubMed-indexed data. Despite high levels of evidence in some conditions, it must be underscored that effect sizes and duration of effects are often limited; thus, real clinical impact needs to be further determined with different study designs.
Topics: Brain Diseases; Evidence-Based Medicine; Humans; Mental Disorders; Pain; Practice Guidelines as Topic; Transcranial Direct Current Stimulation
PubMed: 32710772
DOI: 10.1093/ijnp/pyaa051 -
The Cochrane Database of Systematic... Jun 2018Migraine occurs in around 15% of adults and is ranked as the seventh most disabling disease amongst all diseases globally. Despite the available treatments many people... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Migraine occurs in around 15% of adults and is ranked as the seventh most disabling disease amongst all diseases globally. Despite the available treatments many people suffer prolonged and frequent attacks which have a major impact on their quality of life. Chronic migraine is defined as 15 or more days of headache per month, at least eight of those days being migraine. People with episodic migraine have fewer than 15 headache days per month. Botulinum toxin type A has been licensed in some countries for chronic migraine treatment, due to the results of just two trials.
OBJECTIVES
To assess the effects of botulinum toxins versus placebo or active treatment for the prevention or reduction in frequency of chronic or episodic migraine in adults.
SEARCH METHODS
We searched CENTRAL, MEDLINE & MEDLINE in Process, Embase, ClinicalTrials.gov and World Health Organization International Clinical Trials Registry (to December 2017). We examined reference lists and carried out citation searches on key publications. We sent correspondence to major manufacturers of botulinum toxin.
SELECTION CRITERIA
Randomised, double-blind, controlled trials of botulinum toxin (any sero-type) injections into the head and neck for prophylaxis of chronic or episodic migraine in adults. Eligible comparators were placebo, alternative prophylactic agent or different dose of botulinum toxin.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials and extracted data. For continuous outcomes we used mean change data when available. For dichotomous data we calculated risk ratios (RRs). We used data from the 12-week post-treatment follow-up time point. We assessed the evidence using GRADE and created two 'Summary of findings' tables.
MAIN RESULTS
Description of trialsWe found 90 articles describing 28 trials (4190 participants), which were eligible for inclusion. The longest treatment duration was three rounds of injections with three months between treatments, so we could not analyse long-term effects. For the primary analyses, we pooled data from both chronic and episodic participant populations. Where possible, we also separated data into chronic migraine, episodic migraine and 'mixed group' classification subgroups. Most trials (21 out of 28) were small (fewer than 50 participants per trial arm). The risk of bias for included trials was low or unclear across most domains, with some trials reporting a high risk of bias for incomplete outcome data and selective outcome reporting.Botulinum toxin versus placeboTwenty-three trials compared botulinum toxin with placebo. Botulinum toxin may reduce the number of migraine days per month in the chronic migraine population by 3.1 days (95% confidence interval (CI) -4.7 to -1.4, 4 trials, 1497 participants, low-quality evidence). This was reduced to -2 days (95% CI -2.8 to -1.1, 2 trials, 1384 participants; moderate-quality evidence) when we removed small trials.A single trial of people with episodic migraine (N = 418) showed no difference between groups for this outcome measure (P = 0.49).In the chronic migraine population, botulinum toxin reduces the number of headache days per month by 1.9 days (95% CI -2.7 to -1.0, 2 trials, 1384 participants, high-quality evidence). We did not find evidence of a difference in the number of migraine attacks for both chronic and episodic migraine participants (6 trials, N = 2004, P = 0.30, low-quality evidence). For the population of both chronic and episodic migraine participants a reduction in severity of migraine rated during clinical visits, on a 10 cm visual analogue scale (VAS) of 3.3 cm (95% CI -4.2 to -2.5, very low-quality evidence) in favour of botulinum toxin treatment came from four small trials (N = 209); better reporting of this outcome measure from the additional eight trials that recorded it may have improved our confidence in the pooled estimate. Global assessment and quality-of-life measures were poorly reported and it was not possible to carry out statistical analysis of these outcome measures. Analysis of adverse events showed an increase in the risk ratio with treatment with botulinum toxin over placebo 30% (RR 1.28, 95% CI 1.12 to 1.47, moderate-quality evidence). For every 100 participants 60 experienced an adverse event in the botulinum toxin group compared with 47 in the placebo group.Botulinum toxin versus other prophylactic agentThree trials studied comparisons with alternative oral prophylactic medications. Meta-analyses were not possible for number of migraine days, number of headache days or number of migraine attacks due to insufficient data, but individually trials reported no differences between groups for a variety of efficacy measures in the population of both chronic and episodic migraine participants. The global impression of disease measured using Migraine Disability Assessment (MIDAS) scores were reported from two trials that showed no difference between groups. Compared with oral treatments, botulinum toxin showed no between-group difference in the risk of adverse events (2 trials, N = 114, very low-quality evidence). The relative risk reduction (RRR) for withdrawing from botulinum toxin due to adverse events compared with the alternative prophylactic agent was 72% (P = 0.02, 2 trials, N = 119).Dosing trialsThere were insufficient data available for the comparison of different doses.Quality of the evidenceThe quality of the evidence assessed using GRADE methods was varied but mostly very low; the quality of the evidence for the placebo and active control comparisons was low and very low, respectively for the primary outcome measure. Small trial size, high risk of bias and unexplained heterogeneity were common reasons for downgrading the quality of the evidence.
AUTHORS' CONCLUSIONS
In chronic migraine, botulinum toxin type A may reduce the number of migraine days per month by 2 days compared with placebo treatment. Non-serious adverse events were probably experienced by 60/100 participants in the treated group compared with 47/100 in the placebo group. For people with episodic migraine, we remain uncertain whether or not this treatment is effective because the quality of this limited evidence is very low. Better reporting of outcome measures in published trials would provide a more complete evidence base on which to draw conclusions.
Topics: Adult; Botulinum Toxins, Type A; Chronic Disease; Female; Humans; Male; Migraine Disorders; Randomized Controlled Trials as Topic
PubMed: 29939406
DOI: 10.1002/14651858.CD011616.pub2 -
Cephalalgia : An International Journal... Dec 2022This meta-analysis evaluated the real-world effectiveness of onabotulinumtoxinA (BOTOX®), the first preventive treatment FDA-approved specifically for chronic migraine... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This meta-analysis evaluated the real-world effectiveness of onabotulinumtoxinA (BOTOX®), the first preventive treatment FDA-approved specifically for chronic migraine in 2010.
METHODS
We systematically reviewed onabotulinumtoxinA observational data in chronic migraine published between 1 January 2010 and 31 March 2021. Random-effects models evaluated available data for primary and secondary endpoints defined in onabotulinumtoxinA pivotal trials at approximately 24 weeks and 52 weeks.
RESULTS
Of the 44 full-text eligible studies (29 prospective; 13 retrospective; 2 other), seven evaluated change from baseline (mean[confidence interval]) at ∼24 weeks and ∼52 weeks, respectively, for onabotulinumtoxinA in: : (-10.64 [-12.31, -8.97]; -10.32 [-14.92, -5.73]); (-7.40 [-13.04, -1.77]; overlapping CIs at 52 weeks); (-11.70 [-13.86, -9.54]); -11.80 [14.70, -8.90]); and (MSQ; 23.60 [CI: 21.56, 25.64]; 30.90 [CI: 28.29, 33.51]). At ∼24 weeks onabotulinumtoxinA showed of 44.74 [28.50, 60.99] and of 46.57% [29.50%, 63.65%]. A sensitivity analysis at study-end suggested durability of onabotulinumtoxinA effectiveness on MSQ.
CONCLUSION
The meta-analysis reflecting real-world practice broadly corroborated with evidence from pivotal and long-term open-label studies of onabotulinumtoxinA in chronic migraine preventive treatment.
Topics: Humans; Botulinum Toxins, Type A; Retrospective Studies; Prospective Studies; Treatment Outcome; Chronic Disease; Migraine Disorders; Headache; Acute Pain
PubMed: 36081276
DOI: 10.1177/03331024221123058 -
Pain Physician Mar 2021Peripheral nerve stimulation (PNS) has been increasingly used to manage acute and chronic pain. However, the level of clinical evidence to support its use is not clear.
BACKGROUND
Peripheral nerve stimulation (PNS) has been increasingly used to manage acute and chronic pain. However, the level of clinical evidence to support its use is not clear.
OBJECTIVES
To assess the clinical evidence of PNS in the treatment of acute or chronic pain.
STUDY DESIGN
A systematic review of the efficacy and safety of PNS in managing acute or chronic pain.
METHODS
Data sources were PubMed, Cochrane Library, Scopus, CINAHL Plus, Google Scholar, and reference lists. The literature search was performed up to December 2019. Study selection included randomized trials, observational studies, and case reports of PNS in acute or chronic pain. Data extraction and methodological quality assessment were performed utilizing Cochrane review methodologic quality assessment and Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) and Interventional Pain Management Techniques-Quality Appraisal of Reliability and Risk of Bias Assessment for Nonrandomized Studies (IPM-QRBNR). The evidence was summarized utilizing principles of best evidence synthesis on a scale of 1 to 5. Data syntheses: 227 studies met inclusion criteria and were included in qualitative synthesis.
RESULTS
Evidence synthesis based on randomized controlled trials (RCTs) and observational studies showed Level I and II evidence of PNS in chronic migraine headache; Level II evidence in cluster headache, postamputation pain, chronic pelvic pain, chronic low back and lower extremity pain; and Level IV evidence in peripheral neuropathic pain, and postsurgical pain. Peripheral field stimulation has Level II evidence in chronic low back pain, and Level IV evidence in cranial pain.
LIMITATIONS
Lack of high-quality RCTs. Meta-analysis was not possible due to wide variations in experimental design, research protocol, and heterogeneity of study population.
CONCLUSIONS
The findings of this systematic review suggest that PNS may be effective in managing chronic headaches, postamputation pain, chronic pelvic pain, and chronic low back and lower extremity pain, with variable levels of evidence in favor of this technique.
Topics: Acute Pain; Chronic Pain; Humans; Pain Management; Peripheral Nerves; Reproducibility of Results; Transcutaneous Electric Nerve Stimulation
PubMed: 33740342
DOI: No ID Found -
Cells Dec 2022To perform a systematic review of real-world outcomes for anti-CGRP-mAbs. (Review)
Review
OBJECTIVE
To perform a systematic review of real-world outcomes for anti-CGRP-mAbs.
METHODS
Following the PRISMA guidelines, we searched PubMed for real-world data of erenumab, galcanezumab, fremanezumab, or eptinezumab in patients with migraines.
RESULTS
We identified 134 publications (89 retrospective), comprising 10 pharmaco-epidemiologic and 83 clinic-based studies, 38 case reports, and 3 other articles. None of the clinic-based studies provided follow-up data over more than one year in more than 200 patients. Findings suggest that there are reductions in health insurance claims and days with sick-leave as well as better treatment adherence with anti-CGRP-mAbs. Effectiveness, reported in 77 clinic-based studies, was comparable to randomized controlled trials. A treatment pause was associated with an increase in migraine frequency, and switching to another antibody resulted in a better response in some of the patients. Adverse events and safety issues were addressed in 86 papers, including 24 single case reports.
CONCLUSION
Real-world data on anti-CGRP-mAbs are limited by retrospective data collection, small patient numbers, and short follow-up periods. The majority of papers seem to support good effectiveness and tolerability of anti-CGRP-mAbs in the real-world setting. There is an unmet need for large prospective real-world studies providing long-term follow-ups of patients treated with anti-CGRP-mAbs.
Topics: Humans; Calcitonin Gene-Related Peptide; Prospective Studies; Retrospective Studies; Antibodies, Monoclonal; Migraine Disorders
PubMed: 36611935
DOI: 10.3390/cells12010143 -
European Neuropsychopharmacology : the... Nov 2023Psilocybin is increasingly studied for its antidepressant effect, but its optimal dosage for depression remains unclear. We conducted a systematic review and a... (Meta-Analysis)
Meta-Analysis Review
Psilocybin is increasingly studied for its antidepressant effect, but its optimal dosage for depression remains unclear. We conducted a systematic review and a dose-response meta-analysis to find the optimal dosage of psilocybin to reduce depression scores. Following our protocol (CRD 42022220190) multiple electronic databases were searched from their inception until February 2023, to identify double-blind randomized placebo-controlled (RCTs) fixed-dose trials evaluating the use of psilocybin for adult patients with primary or secondary depression. A one-stage dose-response meta-analysis with restricted cubic splines was used. Cochrane risk of bias was used to assess risk of bias. Our analysis included seven studies with a total of 489 participants. Among these, four studies focused on primary depression (N = 366), including one study with patients suffering from treatment-resistant depression. The remaining three studies examined secondary depression (N = 123). The determined 95% effective doses per day (ED95) were 8.92, 24.68, and 36.08 mg/70 kg for patients with secondary depression, primary depression, and both subgroups, respectively. We observed significant dose-response associations for all curves, each plateauing at different levels, except for the bell-shaped curve observed in the case of secondary depression. Additionally, we found significant dose-response associations for various side effects, including physical discomfort, blood pressure increase, nausea/vomiting, headache/migraine, and the risk of prolonged psychosis. In conclusion, we discovered specific ED95 values for different populations, indicating higher ED95 values for treatment-resistant depression, primary depression, and secondary depression groups. Further RCTs are necessary for each population to determine the optimal dosage, allowing for maximum efficacy while minimizing side effects.
Topics: Adult; Humans; Depression; Psilocybin; Antidepressive Agents; Psychotic Disorders; Randomized Controlled Trials as Topic
PubMed: 37557019
DOI: 10.1016/j.euroneuro.2023.07.011 -
Chiropractic & Manual Therapies Feb 2021A small proportion of chiropractors, osteopaths, and other manual medicine providers use spinal manipulative therapy (SMT) to manage non-musculoskeletal disorders....
The global summit on the efficacy and effectiveness of spinal manipulative therapy for the prevention and treatment of non-musculoskeletal disorders: a systematic review of the literature.
BACKGROUND
A small proportion of chiropractors, osteopaths, and other manual medicine providers use spinal manipulative therapy (SMT) to manage non-musculoskeletal disorders. However, the efficacy and effectiveness of these interventions to prevent or treat non-musculoskeletal disorders remain controversial.
OBJECTIVES
We convened a Global Summit of international scientists to conduct a systematic review of the literature to determine the efficacy and effectiveness of SMT for the primary, secondary and tertiary prevention of non-musculoskeletal disorders.
GLOBAL SUMMIT
The Global Summit took place on September 14-15, 2019 in Toronto, Canada. It was attended by 50 researchers from 8 countries and 28 observers from 18 chiropractic organizations. At the summit, participants critically appraised the literature and synthesized the evidence.
SYSTEMATIC REVIEW OF THE LITERATURE
We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health, and the Index to Chiropractic Literature from inception to May 15, 2019 using subject headings specific to each database and free text words relevant to manipulation/manual therapy, effectiveness, prevention, treatment, and non-musculoskeletal disorders. Eligible for review were randomized controlled trials published in English. The methodological quality of eligible studies was assessed independently by reviewers using the Scottish Intercollegiate Guidelines Network (SIGN) criteria for randomized controlled trials. We synthesized the evidence from articles with high or acceptable methodological quality according to the Synthesis without Meta-Analysis (SWiM) Guideline. The final risk of bias and evidence tables were reviewed by researchers who attended the Global Summit and 75% (38/50) had to approve the content to reach consensus.
RESULTS
We retrieved 4997 citations, removed 1123 duplicates and screened 3874 citations. Of those, the eligibility of 32 articles was evaluated at the Global Summit and 16 articles were included in our systematic review. Our synthesis included six randomized controlled trials with acceptable or high methodological quality (reported in seven articles). These trials investigated the efficacy or effectiveness of SMT for the management of infantile colic, childhood asthma, hypertension, primary dysmenorrhea, and migraine. None of the trials evaluated the effectiveness of SMT in preventing the occurrence of non-musculoskeletal disorders. Consensus was reached on the content of all risk of bias and evidence tables. All randomized controlled trials with high or acceptable quality found that SMT was not superior to sham interventions for the treatment of these non-musculoskeletal disorders. Six of 50 participants (12%) in the Global Summit did not approve the final report.
CONCLUSION
Our systematic review included six randomized clinical trials (534 participants) of acceptable or high quality investigating the efficacy or effectiveness of SMT for the treatment of non-musculoskeletal disorders. We found no evidence of an effect of SMT for the management of non-musculoskeletal disorders including infantile colic, childhood asthma, hypertension, primary dysmenorrhea, and migraine. This finding challenges the validity of the theory that treating spinal dysfunctions with SMT has a physiological effect on organs and their function. Governments, payers, regulators, educators, and clinicians should consider this evidence when developing policies about the use and reimbursement of SMT for non-musculoskeletal disorders.
Topics: Asthma; Colic; Dysmenorrhea; Female; Humans; Hypertension; Manipulation, Spinal; Noncommunicable Diseases
PubMed: 33596925
DOI: 10.1186/s12998-021-00362-9 -
BMJ Open Jan 2021To determine the effects of coenzyme Q10 (CoQ10) for reduction in the severity, frequency of migraine attacks and duration of headache in adult patients with migraine. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To determine the effects of coenzyme Q10 (CoQ10) for reduction in the severity, frequency of migraine attacks and duration of headache in adult patients with migraine.
DESIGN
Systematic review and meta-analysis.
DATA SOURCES
Cochrane Central Register of Controlled Trials, CENTRAL, MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Psychological Information Database (PsycINFO) from inception till December 2019.
STUDY SELECTION
All randomised control trials comparing CoQ10 with placebo or used as an adjunct treatment included in this meta-analysis. Cross-over designs and controlled clinical trials were excluded.
DATA SYNTHESIS
Heterogeneity at face value by comparing populations, settings, interventions and outcomes were measured and statistical heterogeneity was assessed by means of the I statistic. The treatment effect for dichotomous outcomes were using risk ratios and risk difference, and for continuous outcomes, mean differences (MDs) or standardised mean difference; both with 95% CIs were used. Subgroup analyses were carried out for dosage of CoQ10 and if CoQ10 combined with another supplementation. Sensitivity analysis was used to investigate the impact risk of bias for sequence generation and allocation concealment of included studies.
RESULTS
Six studies with a total of 371 participants were included in the meta-analysis. There is no statistically significant reduction in severity of migraine headache with CoQ10 supplementation. CoQ10 supplementation reduced the duration of headache attacks compared with the control group (MD: -0.19; 95% CI: -0.27 to -0.11; random effects; I statistic=0%; p<0.00001). CoQ10 usage reduced the frequency of migraine headache compared with the control group (MD: -1.52; 95% CI: -2.40 to -0.65; random effects; I statistic=0%; p<0.001).
CONCLUSION
CoQ10 appears to have beneficial effects in reducing duration and frequency of migraine attack.
PROSPERO REGISTRATION NUMBER
CRD42019126127.
Topics: Adult; Dietary Supplements; Humans; Migraine Disorders; Ubiquinone
PubMed: 33402403
DOI: 10.1136/bmjopen-2020-039358 -
Journal of Integrative Neuroscience Aug 2023Pharmacological treatment is the primary approach in chronic migraine (CM), although non-drug interventions such as physical therapy are used as adjunct treatments. We... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Pharmacological treatment is the primary approach in chronic migraine (CM), although non-drug interventions such as physical therapy are used as adjunct treatments. We aimed to review the efficacy of physical therapy and rehabilitation approaches for CM and their impact on quality of life (QoL) and disability.
METHODS
This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included randomized controlled trials (RCTs) in adults with CM. The primary outcomes were changes in intensity, frequency, duration of headache, disability, and QoL. Methodological quality was assessed using the Physiotherapy Evidence Database (PEDro) scale. Data synthesis and quantitative analysis were conducted on relevant studies.
RESULTS
Seven RCTs were included in the narrative review, and five of them were eligible for quantitative analysis. Aerobic exercise (AE), osteopathic manipulative treatment (OMT), occipital transcutaneous electrical stimulation (OTES), acupressure, hydrotherapy, instrument-assisted soft tissue mobilization (IASTM), facial proprioceptive neuromuscular facilitation (FPNF), and connective tissue massage (CTM) were used in CM. AE combined with pharmacological therapy reduced the frequency, duration, and intensity of headache. OMT combined with medication improved QoL and reduced disability, intensity of pain, and migraine days per month. Hydrotherapy combined with medication also resulted in improvements in the intensity of headache, frequency, and overall QoL. IASTM and OTES reduced the intensity of headache, alleviated neck pain, and improved QoL, although there were conflicting findings following OTES alone on disability and intensity of headache. Both FPNF and CTM reduced the intensity of headache. Acupressure as an adjunct to medication did not show additional benefits on the intensity of headache and QoL. Quantitative analysis of the data showed that manual physical therapy combined with medication reduced the intensity of headache ( = 0.0796), and manual or AE combined with medication reduced the headache days per month ( = 0.047).
CONCLUSIONS
A limited number of RCTs investigating the efficacy of physical therapy and rehabilitation approaches show promise in improving headache symptoms, reducing disability, and enhancing QoL in CM. Meta-analysis of the data also supported favorable outcomes for both intensity and headache days per month. Further research is needed to better understand the efficacy, optimal duration, and safety of physical therapy and rehabilitation approaches for CM, and to explore alternative interventions.
Topics: Adult; Humans; Physical Therapy Modalities; Migraine Disorders; Headache; Pain; Databases, Factual
PubMed: 37735140
DOI: 10.31083/j.jin2205126 -
Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.The Cochrane Database of Systematic... Apr 2022This is an updated version of the original Cochrane Review published in 2017. Epilepsy is a common neurological condition with a worldwide prevalence of around 1%.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an updated version of the original Cochrane Review published in 2017. Epilepsy is a common neurological condition with a worldwide prevalence of around 1%. Approximately 60% to 70% of people with epilepsy will achieve a longer-term remission from seizures, and most achieve that remission shortly after starting antiepileptic drug treatment. Most people with epilepsy are treated with a single antiepileptic drug (monotherapy) and current guidelines from the National Institute for Health and Care Excellence (NICE) in the United Kingdom for adults and children recommend carbamazepine or lamotrigine as first-line treatment for focal onset seizures and sodium valproate for generalised onset seizures; however, a range of other antiepileptic drug (AED) treatments are available, and evidence is needed regarding their comparative effectiveness in order to inform treatment choices.
OBJECTIVES
To compare the time to treatment failure, remission and first seizure of 12 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, eventrate, zonisamide, eslicarbazepine acetate, lacosamide) currently used as monotherapy in children and adults with focal onset seizures (simple focal, complex focal or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus).
SEARCH METHODS
For the latest update, we searched the following databases on 12 April 2021: the Cochrane Register of Studies (CRS Web), which includes PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Epilepsy Group Specialised Register and MEDLINE (Ovid, 1946 to April 09, 2021). We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators and experts in the field.
SELECTION CRITERIA
We included randomised controlled trials of a monotherapy design in adults or children with focal onset seizures or generalised onset tonic-clonic seizures (with or without other generalised seizure types).
DATA COLLECTION AND ANALYSIS
This was an individual participant data (IPD) and network meta-analysis (NMA) review. Our primary outcome was 'time to treatment failure', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', and 'time to first seizure post-randomisation'. We performed frequentist NMA to combine direct evidence with indirect evidence across the treatment network of 12 drugs. We investigated inconsistency between direct 'pairwise' estimates and NMA results via node splitting. Results are presented as hazard ratios (HRs) with 95% confidence intervals (CIs) and we assessed the certainty of the evidence using the CiNeMA approach, based on the GRADE framework. We have also provided a narrative summary of the most commonly reported adverse events.
MAIN RESULTS
IPD were provided for at least one outcome of this review for 14,789 out of a total of 22,049 eligible participants (67% of total data) from 39 out of the 89 eligible trials (43% of total trials). We could not include IPD from the remaining 50 trials in analysis for a variety of reasons, such as being unable to contact an author or sponsor to request data, data being lost or no longer available, cost and resources required to prepare data being prohibitive, or local authority or country-specific restrictions. No IPD were available from a single trial of eslicarbazepine acetate, so this AED could not be included in the NMA. Network meta-analysis showed high-certainty evidence that for our primary outcome, 'time to treatment failure', for individuals with focal seizures; lamotrigine performs better than most other treatments in terms of treatment failure for any reason and due to adverse events, including the other first-line treatment carbamazepine; HRs (95% CIs) for treatment failure for any reason for lamotrigine versus: eventrate 1.01 (0.88 to 1.20), zonisamide 1.18 (0.96 to 1.44), lacosamide 1.19 (0.90 to 1.58), carbamazepine 1.26 (1.10 to 1.44), oxcarbazepine 1.30 (1.02 to 1.66), sodium valproate 1.35 (1.09 to 1.69), phenytoin 1.44 (1.11 to 1.85), topiramate 1.50 (1.23 to 1.81), gabapentin 1.53 (1.26 to 1.85), phenobarbitone 1.97 (1.45 to 2.67). No significant difference between lamotrigine and eventrate was shown for any treatment failure outcome, and both AEDs seemed to perform better than all other AEDs. For people with generalised onset seizures, evidence was more limited and of moderate certainty; no other treatment performed better than first-line treatment sodium valproate, but there were no differences between sodium valproate, lamotrigine or eventrate in terms of treatment failure; HRs (95% CIs) for treatment failure for any reason for sodium valproate versus: lamotrigine 1.06 (0.81 to 1.37), eventrate 1.13 (0.89 to 1.42), gabapentin 1.13 (0.61 to 2.11), phenytoin 1.17 (0.80 to 1.73), oxcarbazepine 1.24 (0.72 to 2.14), topiramate 1.37 (1.06 to 1.77), carbamazepine 1.52 (1.18 to 1.96), phenobarbitone 2.13 (1.20 to 3.79), lacosamide 2.64 (1.14 to 6.09). Network meta-analysis also showed high-certainty evidence that for secondary remission outcomes, few notable differences were shown for either seizure type; for individuals with focal seizures, carbamazepine performed better than gabapentin (12-month remission) and sodium valproate (six-month remission). No differences between lamotrigine and any AED were shown for individuals with focal seizures, or between sodium valproate and other AEDs for individuals with generalised onset seizures. Network meta-analysis also showed high- to moderate-certainty evidence that, for 'time to first seizure,' in general, the earliest licensed treatments (phenytoin and phenobarbitone) performed better than the other treatments for individuals with focal seizures; phenobarbitone performed better than both first-line treatments carbamazepine and lamotrigine. There were no notable differences between the newer drugs (oxcarbazepine, topiramate, gabapentin, eventrate, zonisamide and lacosamide) for either seizure type. Generally, direct evidence (where available) and network meta-analysis estimates were numerically similar and consistent with confidence intervals of effect sizes overlapping. There was no important indication of inconsistency between direct and network meta-analysis results. The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders; however, reporting of adverse events was highly variable across AEDs and across studies.
AUTHORS' CONCLUSIONS
High-certainty evidence demonstrates that for people with focal onset seizures, current first-line treatment options carbamazepine and lamotrigine, as well as newer drug eventrate, show the best profile in terms of treatment failure and seizure control as first-line treatments. For people with generalised tonic-clonic seizures (with or without other seizure types), current first-line treatment sodium valproate has the best profile compared to all other treatments, but lamotrigine and eventrate would be the most suitable alternative first-line treatments, particularly for those for whom sodium valproate may not be an appropriate treatment option. Further evidence from randomised controlled trials recruiting individuals with generalised tonic-clonic seizures (with or without other seizure types) is needed.
Topics: Adult; Anticonvulsants; Child; Epilepsies, Partial; Epilepsy; Humans; Network Meta-Analysis; Phenytoin
PubMed: 35363878
DOI: 10.1002/14651858.CD011412.pub4