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Neurology. Clinical Practice Aug 2020To systematically review and evaluate the available evidence supporting or refuting clinical use of therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) in... (Review)
Review
OBJECTIVE
To systematically review and evaluate the available evidence supporting or refuting clinical use of therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) in patients with epilepsy.
METHODS
We searched MEDLINE, Embase, BIOSIS, Cochrane, PubMed, Africa-Wide Information, Web of Science, and grey literature. Randomized controlled studies and observational studies that compared the clinical outcomes of TDM vs non-TDM were included. Two reviewers independently extracted the data. The primary outcome was seizure control; adverse effects were considered as secondary outcomes. The PROSPERO ID of this systematic review's protocol is CRD42018089925.
RESULTS
Sixteen studies were identified meeting eligibility requirements. Four randomized controlled trials (RCTs), 1 meta-analysis, and 11 quasiexperimental (QE) studies were included in the systematic review. Results from the analysis of RCTs showed no significant positive effect of TDM on seizure outcome (only 25% positive effect of phenytoin). However, some of the QE studies found that TDM was associated with better seizure control or lower rates of adverse effects. The existing evidence from various designs has shown various methodological implications, which warrants inconclusive results and highlights the requirement of more number of studies in this line.
CONCLUSIONS
If optimally implemented, TDM may enhance clinical care, particularly for phenytoin and other AEDs with complex pharmacokinetics. However, the ideal method for implementation is unclear, and serum drug levels should be considered in context with patient-reported clinical data regarding seizure control and adverse events.
PubMed: 32983615
DOI: 10.1212/CPJ.0000000000000722 -
The Cochrane Database of Systematic... Sep 2014Status epilepticus is a medical emergency associated with significant mortality and morbidity that requires immediate and effective treatment. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Status epilepticus is a medical emergency associated with significant mortality and morbidity that requires immediate and effective treatment.
OBJECTIVES
(1) To determine whether a particular anticonvulsant is more effective or safer to use in status epilepticus compared to another and compared to placebo.(2) To delineate reasons for disagreement in the literature regarding recommended treatment regimens and to highlight areas for future research.
SEARCH METHODS
For the latest update of this review, the following electronic databases were searched on 15/08/2013: the Cochrane Epilepsy Group's Specialized Register, CENTRAL The Cochrane Library July 2013, Issue 7, and MEDLINE (Ovid) 1946 to 15/08/2013.
SELECTION CRITERIA
Randomised controlled trials of participants with premonitory, early, established or refractory status epilepticus using a truly random or quasi-random allocation of treatments were included.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials for inclusion, assessed trial quality and extracted data.
MAIN RESULTS
Eighteen studies with 2755 participants were included. Few studies used the same interventions. Intravenous diazepam was better than placebo in reducing the risk of non-cessation of seizures (risk ratio (RR) 0.73, 95% confidence interval (CI) 0.57 to 0.92), requirement for ventilatory support (RR 0.39, 95% CI 0.16 to 0.94), or continuation of status epilepticus requiring use of a different drug or general anaesthesia (RR 0.73, 95% CI 0.57 to 0.92). Intravenous lorazepam was better than placebo for risk of non-cessation of seizures (RR 0.52, 95% CI 0.38 to 0.71) and for risk of continuation of status epilepticus requiring a different drug or general anaesthesia (RR 0.52, 95% CI 0.38 to 0.71). Intravenous lorazepam was better than intravenous diazepam for reducing the risk of non-cessation of seizures (RR 0.64, 95% CI 0.45 to 0.90) and had a lower risk for continuation of status epilepticus requiring a different drug or general anaesthesia (RR 0.63, 95% CI 0.45 to 0.88). Intravenous lorazepam was better than intravenous phenytoin for risk of non-cessation of seizures (RR 0.62, 95% CI 0.45 to 0.86). Diazepam gel was better than placebo gel in reducing the risk of non-cessation of seizures (RR 0.43 95% CI 0.30 to 0.62)For pre-hospital treatment, intramuscular midazolam is at least as effective as (probably more effective than) intravenous lorazepam in control of seizures (RR1.16, 95% CI 1.06 to 1.27) and frequency of hospitalisation (RR 0.88, 95% CI 0.79 to 0.97) or intensive care admissions (RR 0.79, 95% CI 0.65 to 0.96). It was uncertain whether Intravenous valproate was better than intravenous phenytoin in reducing risk of non-cessation of seizures (RR 0.75, 95% CI 0.28 to 2.00). Both levetiracetam and lorazepam were equally effective in aborting seizures (RR 0.97, 95% CI 0.44 to 2.13). Results for other comparisons of anticonvulsant therapies were uncertain due to single studies with few participants.The body of randomised evidence to guide clinical decisions is small. It was uncertain whether any anticonvulsant therapy was better than another in terms of adverse effects, due to few studies and participants identified. The quality of the evidence from the included studies is not strong but appears acceptable. We were unable to make judgements for risk of bias domains incomplete outcome reporting (attrition bias) and selective outcome reporting (selection bias) due to unclear reporting by the study authors.
AUTHORS' CONCLUSIONS
Intravenous lorazepam is better than intravenous diazepam or intravenous phenytoin alone for cessation of seizures. Intravenous lorazepam also carries a lower risk of continuation of status epilepticus requiring a different drug or general anaesthesia compared with intravenous diazepam. Both intravenous lorazepam and diazepam are better than placebo for the same outcomes. For pre hospital management, midazolam IM seemed more effective than lorazepam IV for cessation of seizures, frequency of hospitalisation and ICU admissions however,it was unclear whether the risk of recurrence of seizures differed between treatments. The results of other comparisons of anticonvulsant therapies versus each other were also uncertain. Universally accepted definitions of premonitory, early, established and refractory status epilepticus are required. Diazepam gel was better than placebo gel in reducing the risk of non-cessation of seizures. Results for other comparisons of anticonvulsant therapies were uncertain due to single studies with few participants.
Topics: Anticonvulsants; Diazepam; Humans; Injections, Intravenous; Lorazepam; Midazolam; Phenobarbital; Phenytoin; Randomized Controlled Trials as Topic; Status Epilepticus
PubMed: 25207925
DOI: 10.1002/14651858.CD003723.pub3 -
Medicine Dec 2018In this study, we aimed to review the literature on phenytoin intoxication induced by compound phenytoin sodium, ephedrine hydrochloride and theophylline tablets...
OBJECTIVE
In this study, we aimed to review the literature on phenytoin intoxication induced by compound phenytoin sodium, ephedrine hydrochloride and theophylline tablets (CPEHTT).
METHOD
A literature search was performed in the following databases: WANFANG DATA, HowNet, National Library Reference and Consultation Alliance, Full-text Database of Foreign Medical Journals, PubMed and Ovid. The search terms were "Compound Phenytoin Sodium, ephedrine Hydrochloride and Theophylline Tablets," and "poisoning," or "toxicity," in Chinese and in English.
RESULT
Ten articles including 104 patients with CPEHTT intoxication were identified. The ages of the patients ranged from 52 to 82 years. Sixty-seven patients were male and thirty-seven patients were female (the male/female ratio, approximately 2:1). The most common clinical manifestations were dizziness (85%) and ataxia (85%), followed by limb weakness (65%), diplopia (25%), binocular horizontal nystagmus (24%), limb numbness (13%), nausea and vomiting (12%), somnolence (10%), tremor and high muscle tension (7%), lag in response (5%), dysarthria (6%), choking cough (2%), auditory hallucination and visual fantasy (1%), and involuntary movement (1%). All patients had chronic lung disease, and the most common disease was chronic bronchitis. The dosage ranged 4 to 15 tablets per day with medication duration of more than 1 year for most patients.
CONCLUSION
The CPEHTT intoxication caused by phenytoin toxicity represents a drug safety problem in China. The common clinical manifestations, serum phenytoin concentrations, and associated factors of CPEHTT intoxication are important for diagnosis and prevention. These findings may help guide clinicians to correctly attend to the use of CPEHTT and avoid its toxicity.
Topics: Bronchodilator Agents; China; Drug Combinations; Ephedrine; Humans; Phenytoin; Tablets; Theophylline
PubMed: 30572493
DOI: 10.1097/MD.0000000000013689 -
Seizure Oct 2021Serotonin syndrome (SS) is a drug‑induced, potentially fatal, clinical syndrome resulting from drugs that have serotonergic properties. Several antiepileptic drugs... (Review)
Review
Serotonin syndrome (SS) is a drug‑induced, potentially fatal, clinical syndrome resulting from drugs that have serotonergic properties. Several antiepileptic drugs (AEDs) are known to have serotonergic properties and it can be hypothesized that such AEDs can cause SS. This study aims to review the literature on SS in patients receiving AEDs. We performed a systematic review of Scopus and MEDLINE/PUBMED for case reports and case series of SS where patients had received at least one AED at the onset of symptoms. The cases published in the English literature between 1 January 1991 and 1 April 2021 were included. Initial search identified 1263 articles of which 63 (76 patients) were included in the final analysis. Most of the included cases (53 cases, 70%) have been published in the last 10 years. The mean age of the 76 patients was 40.6 ± 17.8 years, and 51% of cases were females. These patients had been exposed to a total of 8 different types of AEDs. Valproic acid was the most common drug (29, 38%), followed by lamotrigine (22, 29%), gabapentin (16, 21%), pregabalin (seven, 9%), topiramate (five, 7%) and carbamazepine (two, 3%). There has been one case each with phenytoin and oxcarbazepine. Seven (9%) patients received more than one AEDs. Most patients (67, 88%) also received other serotoninergic agents. Only nine (12%) patients were on AEDs alone. The most common clinical condition for using AEDs was psychiatric disorders (36 patients, 47.3%), followed by migraine (17, 22.4%), other painful conditions (15, 19.7%), epilepsy (7, 9.2%), and perioperative conditions (8, 10.5%). Death was reported in two patients. We suggest that AEDs, because of their serotonergic properties, may induce SS, especially in patients who are on another serotonergic agent.
Topics: Adult; Anticonvulsants; Carbamazepine; Female; Humans; Middle Aged; Oxcarbazepine; Serotonin Syndrome; Topiramate; Young Adult
PubMed: 34153897
DOI: 10.1016/j.seizure.2021.06.004 -
The Cochrane Database of Systematic... Apr 2020This is an updated version of the Cochrane Review previously published in 2018. The incidence of seizures following supratentorial craniotomy for non-traumatic pathology...
BACKGROUND
This is an updated version of the Cochrane Review previously published in 2018. The incidence of seizures following supratentorial craniotomy for non-traumatic pathology has been estimated to be between 15% to 20%; however, the risk of experiencing a seizure appears to vary from 3% to 92% over a five-year period. Postoperative seizures can precipitate the development of epilepsy; seizures are most likely to occur within the first month of cranial surgery. The use of antiepileptic drugs (AEDs) administered pre- or postoperatively to prevent seizures following cranial surgery has been investigated in a number of randomised controlled trials (RCTs).
OBJECTIVES
To determine the efficacy and safety of AEDs when used prophylactically in people undergoing craniotomy and to examine which AEDs are most effective.
SEARCH METHODS
For the latest update we searched the following databases on 29 September 2019: Cochrane Epilepsy Group Specialized Register, CENTRAL, MEDLINE, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). We did not apply any language restrictions.
SELECTION CRITERIA
We included RCTs of people with no history of epilepsy who were undergoing craniotomy for either therapeutic or diagnostic reasons. We included trials with adequate randomisation methods and concealment; these could either be blinded or unblinded parallel trials. We did not stipulate a minimum treatment period, and we included trials using active drugs or placebo as a control group.
DATA COLLECTION AND ANALYSIS
Three review authors (JW, JG, YD) independently selected trials for inclusion, extracted data and assessed risk of bias. We resolved any disagreements through discussion. Outcomes investigated included the number of participants experiencing seizures (early (occurring within first week following craniotomy), and late (occurring after first week following craniotomy)), the number of deaths and the number of people experiencing disability and adverse effects. Due to the heterogeneous nature of the trials, we did not combine data from the included trials in a meta-analysis; we presented the findings of the review in narrative format. Visual comparisons of outcomes are presented in forest plots.
MAIN RESULTS
We included 10 RCTs (N = 1815), which were published between 1983 and 2015. Three trials compared a single AED (phenytoin) with placebo or no treatment. One, three-armed trial compared two AEDs (phenytoin, carbamazepine) with no treatment. A second three-armed trial compared phenytoin, phenobarbital with no treatment. Of these five trials comparing AEDs with placebo or no treatment, two trials reported a statistically significant advantage for AED treatment compared to controls for early seizure occurrence; all other comparisons showed no clear or statistically significant differences between AEDs and control treatment. None of the trials that were head-to-head comparisons of AEDs (phenytoin versus sodium valproate, phenytoin versus phenobarbital, levetiracetam versus phenytoin, zonisamide versus phenobarbital) reported any statistically significant differences between treatments for either early or late seizure occurrence. Only five trials reported incidences of death. One trial reported statistically significantly fewer deaths in the carbamazepine and no-treatment groups compared with the phenytoin group after 24 months of treatment, but not after six months of treatment. Incidences of adverse effects of treatment were poorly reported; however, three trials did show that significantly more adverse events occurred on phenytoin compared to valproate, placebo, or no treatment. No trials reported any results relating to functional outcomes such as disability. We considered the evidence to be of low certainty for all reported outcomes due to methodological issues and variability of comparisons made in the trials.
AUTHORS' CONCLUSIONS
There is limited, low-certainly evidence to suggest that AED treatment administered prophylactically is either effective or not effective in the prevention of postcraniotomy (early or late) seizures. The current evidence base is limited due to the different methodologies employed in the trials and inconsistencies in the reporting of outcomes including deaths and adverse events. Further evidence from good-quality, contemporary trials is required in order to assess the clinical effectiveness of prophylactic AED treatment compared to placebo or no treatment, or other AEDs in preventing postcraniotomy seizures in this select group of patients.
Topics: Anticonvulsants; Carbamazepine; Craniotomy; Humans; Isoxazoles; Levetiracetam; Phenobarbital; Phenytoin; Piracetam; Postoperative Complications; Randomized Controlled Trials as Topic; Seizures; Valproic Acid; Zonisamide
PubMed: 32343399
DOI: 10.1002/14651858.CD007286.pub5 -
Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.The Cochrane Database of Systematic... Jun 2017Epilepsy 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... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
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 partial 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 withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus).
SEARCH METHODS
We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016.
SELECTION CRITERIA
We included randomised controlled trials of a monotherapy design in adults or children with partial 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) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to-head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events.
MAIN RESULTS
IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 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.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than both current first-line treatments carbamazepine and lamotrigine; lamotrigine performed better than all other treatments (aside from levetiracetam), and carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first-line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure types (moderate- to high-quality evidence).Generally, direct evidence and network meta-analysis estimates (direct plus indirect evidence) were numerically similar and consistent with confidence intervals of effect sizes overlapping.The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders.
AUTHORS' CONCLUSIONS
Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first-line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity.
Topics: Adult; Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Epilepsies, Partial; Epilepsy; Epilepsy, Generalized; Fructose; Gabapentin; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Network Meta-Analysis; Oxcarbazepine; Phenobarbital; Phenytoin; Piracetam; Remission Induction; Topiramate; Triazines; Valproic Acid; Zonisamide; gamma-Aminobutyric Acid
PubMed: 28661008
DOI: 10.1002/14651858.CD011412.pub2 -
Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data.The Cochrane Database of Systematic... Dec 2017Epilepsy 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... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
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 partial 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 withdrawal of allocated treatment, remission and first seizure of 10 AEDs (carbamazepine, phenytoin, sodium valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures (simple partial, complex partial or secondary generalised) or generalised tonic-clonic seizures with or without other generalised seizure types (absence, myoclonus).
SEARCH METHODS
We searched the following databases: Cochrane Epilepsy's Specialised Register, CENTRAL, MEDLINE and SCOPUS, and two clinical trials registers. We handsearched relevant journals and contacted pharmaceutical companies, original trial investigators, and experts in the field. The date of the most recent search was 27 July 2016.
SELECTION CRITERIA
We included randomised controlled trials of a monotherapy design in adults or children with partial 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) review and network meta-analysis. Our primary outcome was 'time to withdrawal of allocated treatment', and our secondary outcomes were 'time to achieve 12-month remission', 'time to achieve six-month remission', 'time to first seizure post-randomisation', and 'occurrence of adverse events'. We presented all time-to-event outcomes as Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs). We performed pairwise meta-analysis of head-to-head comparisons between drugs within trials to obtain 'direct' treatment effect estimates and we performed frequentist network meta-analysis to combine direct evidence with indirect evidence across the treatment network of 10 drugs. We investigated inconsistency between direct estimates and network meta-analysis via node splitting. Due to variability in methods and detail of reporting adverse events, we have not performed an analysis. We have provided a narrative summary of the most commonly reported adverse events.
MAIN RESULTS
IPD was provided for at least one outcome of this review for 12,391 out of a total of 17,961 eligible participants (69% of total data) from 36 out of the 77 eligible trials (47% of total trials). We could not include IPD from the remaining 41 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.We were able to calculate direct treatment effect estimates for between half and two thirds of comparisons across the outcomes of the review, however for many of the comparisons, data were contributed by only a single trial or by a small number of participants, so confidence intervals of estimates were wide.Network meta-analysis showed that for the primary outcome 'Time to withdrawal of allocated treatment,' for individuals with partial seizures; levetiracetam performed (statistically) significantly better than current first-line treatment carbamazepine and other current first-line treatment lamotrigine performed better than all other treatments (aside from levetiracetam); carbamazepine performed significantly better than gabapentin and phenobarbitone (high-quality evidence). For individuals with generalised onset seizures, first-line treatment sodium valproate performed significantly better than carbamazepine, topiramate and phenobarbitone (moderate- to high-quality evidence). Furthermore, for both partial and generalised onset seizures, the earliest licenced treatment, phenobarbitone seems to perform worse than all other treatments (moderate- to high-quality evidence).Network meta-analysis also showed that for secondary outcomes 'Time to 12-month remission of seizures' and 'Time to six-month remission of seizures,' few notable differences were shown for either partial or generalised seizure types (moderate- to high-quality evidence). For secondary outcome 'Time to first seizure,' for individuals with partial seizures; phenobarbitone performed significantly better than both current first-line treatments carbamazepine and lamotrigine; carbamazepine performed significantly better than sodium valproate, gabapentin and lamotrigine. Phenytoin also performed significantly better than lamotrigine (high-quality evidence). In general, the earliest licenced treatments (phenytoin and phenobarbitone) performed better than the other treatments for both seizure types (moderate- to high-quality evidence).Generally, direct evidence and network meta-analysis estimates (direct plus indirect evidence) were numerically similar and consistent with confidence intervals of effect sizes overlapping.The most commonly reported adverse events across all drugs were drowsiness/fatigue, headache or migraine, gastrointestinal disturbances, dizziness/faintness and rash or skin disorders.
AUTHORS' CONCLUSIONS
Overall, the high-quality evidence provided by this review supports current guidance (e.g. NICE) that carbamazepine and lamotrigine are suitable first-line treatments for individuals with partial onset seizures and also demonstrates that levetiracetam may be a suitable alternative. High-quality evidence from this review also supports the use of sodium valproate as the first-line treatment for individuals with generalised tonic-clonic seizures (with or without other generalised seizure types) and also demonstrates that lamotrigine and levetiracetam would be suitable alternatives to either of these first-line treatments, particularly for those of childbearing potential, for whom sodium valproate may not be an appropriate treatment option due to teratogenicity.
Topics: Adult; Amines; Anticonvulsants; Carbamazepine; Child; Cyclohexanecarboxylic Acids; Epilepsies, Partial; Epilepsy; Epilepsy, Generalized; Fructose; Gabapentin; Humans; Isoxazoles; Lamotrigine; Levetiracetam; Network Meta-Analysis; Oxcarbazepine; Phenobarbital; Phenytoin; Piracetam; Remission Induction; Topiramate; Triazines; Valproic Acid; Zonisamide; gamma-Aminobutyric Acid
PubMed: 29243813
DOI: 10.1002/14651858.CD011412.pub3 -
The Cochrane Database of Systematic... Feb 2017Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 4% of children in Great Britain and the United States and recur in... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Febrile seizures occurring in a child older than one month during an episode of fever affect 2% to 4% of children in Great Britain and the United States and recur in 30%. Rapid-acting antiepileptics and antipyretics given during subsequent fever episodes have been used to avoid the adverse effects of continuous antiepileptic drugs.
OBJECTIVES
To evaluate primarily the effectiveness and safety of antiepileptic and antipyretic drugs used prophylactically to treat children with febrile seizures; but also to evaluate any other drug intervention where there was a sound biological rationale for its use.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2016, Issue 7); MEDLINE (1966 to July 2016); Embase (1966 to July 2016); Database of Abstracts of Reviews of Effectiveness (DARE) (July 2016). We imposed no language restrictions. We also contacted researchers in the field to identify continuing or unpublished studies.
SELECTION CRITERIA
Trials using randomised or quasi-randomised participant allocation that compared the use of antiepileptic, antipyretic or other plausible agents with each other, placebo or no treatment.
DATA COLLECTION AND ANALYSIS
Two review authors (RN and MO) independently applied predefined criteria to select trials for inclusion and extracted the predefined relevant data, recording methods for randomisation, blinding and exclusions. For the 2016 update a third author (MC) checked all original inclusions, data analyses, and updated the search. Outcomes assessed were seizure recurrence at 6, 12, 18, 24, 36, and 48 months and at age 5 to 6 years in the intervention and non-intervention groups, and adverse medication effects. We assessed the presence of publication bias using funnel plots.
MAIN RESULTS
We included 40 articles describing 30 randomised trials with 4256 randomised participants. We analysed 13 interventions of continuous or intermittent prophylaxis and their control treatments. Methodological quality was moderate to poor in most studies. We found no significant benefit for intermittent phenobarbitone, phenytoin, valproate, pyridoxine, ibuprofen or zinc sulfate versus placebo or no treatment; nor for diclofenac versus placebo followed by ibuprofen, acetaminophen or placebo; nor for continuous phenobarbitone versus diazepam, intermittent rectal diazepam versus intermittent valproate, or oral diazepam versus clobazam.There was a significant reduction of recurrent febrile seizures with intermittent diazepam versus placebo or no treatment, with a risk ratio (RR) of 0.64 (95% confidence interval (CI) 0.48 to 0.85 at six months), RR of 0.69 (95% CI 0.56 to 0.84) at 12 months, RR 0.37 (95% CI 0.23 to 0.60) at 18 months, RR 0.73 (95% CI 0.56 to 0.95) at 24 months, RR 0.58 (95% CI 0.40 to 0.85) at 36 months, RR 0.36 (95% CI 0.15 to 0.89) at 48 months, with no benefit at 60 to 72 months. Phenobarbitone versus placebo or no treatment reduced seizures at 6, 12 and 24 months but not at 18 or 72 month follow-up (RR 0.59 (95% CI 0.42 to 0.83) at 6 months; RR 0.54 (95% CI 0.42 to 0.70) at 12 months; and RR 0.69 (95% CI 0.53 to 0.89) at 24 months). Intermittent clobazam compared to placebo at six months resulted in a RR of 0.36 (95% CI 0.20 to 0.64), an effect found against an extremely high (83.3%) recurrence rate in the controls, which is a result that needs replication.The recording of adverse effects was variable. Lower comprehension scores in phenobarbitone-treated children were found in two studies. In general, adverse effects were recorded in up to 30% of children in the phenobarbitone-treated group and in up to 36% in benzodiazepine-treated groups. We found evidence of publication bias in the meta-analyses of comparisons for phenobarbitone versus placebo (eight studies) at 12 months but not at six months (six studies); and valproate versus placebo (four studies) at 12 months, with too few studies to identify publication bias for the other comparisons.Most of the reviewed antiepileptic drug trials are of a methodological quality graded as low or very low. Methods of randomisation and allocation concealment often do not meet current standards; and treatment versus no treatment is more commonly seen than treatment versus placebo, leading to obvious risks of bias. Trials of antipyretics and zinc were of higher quality.
AUTHORS' CONCLUSIONS
We found reduced recurrence rates for children with febrile seizures for intermittent diazepam and continuous phenobarbitone, with adverse effects in up to 30%. Apparent benefit for clobazam treatment in one trial needs to be replicated to be judged reliable. Given the benign nature of recurrent febrile seizures, and the high prevalence of adverse effects of these drugs, parents and families should be supported with adequate contact details of medical services and information on recurrence, first aid management and, most importantly, the benign nature of the phenomenon.
Topics: Anticonvulsants; Antipyretics; Child; Child, Preschool; Humans; Infant; Randomized Controlled Trials as Topic; Recurrence; Seizures, Febrile
PubMed: 28225210
DOI: 10.1002/14651858.CD003031.pub3 -
The Cochrane Database of Systematic... Sep 2020Antisocial personality disorder (AsPD) is associated with rule-breaking, criminality, substance use, unemployment, relationship difficulties, and premature death.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Antisocial personality disorder (AsPD) is associated with rule-breaking, criminality, substance use, unemployment, relationship difficulties, and premature death. Certain types of medication (drugs) may help people with AsPD. This review updates a previous Cochrane review, published in 2010.
OBJECTIVES
To assess the benefits and adverse effects of pharmacological interventions for adults with AsPD.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, 13 other databases and two trials registers up to 5 September 2019. We also checked reference lists and contacted study authors to identify studies.
SELECTION CRITERIA
Randomised controlled trials in which adults (age 18 years and over) with a diagnosis of AsPD or dissocial personality disorder were allocated to a pharmacological intervention or placebo control condition.
DATA COLLECTION AND ANALYSIS
Four authors independently selected studies and extracted data. We assessed risk of bias and created 'Summary of findings tables' and assessed the certainty of the evidence using the GRADE framework. The primary outcomes were: aggression; reconviction; global state/global functioning; social functioning; and adverse events.
MAIN RESULTS
We included 11 studies (three new to this update), involving 416 participants with AsPD. Most studies (10/11) were conducted in North America. Seven studies were conducted exclusively in an outpatient setting, one in an inpatient setting, and one in prison; two studies used multiple settings. The average age of participants ranged from 28.6 years to 45.1 years (overall mean age 39.6 years). Participants were predominantly (90%) male. Study duration ranged from 6 to 24 weeks, with no follow-up period. Data were available from only four studies involving 274 participants with AsPD. All the available data came from unreplicated, single reports, and did not allow independent statistical analysis to be conducted. Many review findings were limited to descriptive summaries based on analyses carried out and reported by the trial investigators. No study set out to recruit participants on the basis of having AsPD; many participants presented primarily with substance abuse problems. The studies reported on four primary outcomes and six secondary outcomes. Primary outcomes were aggression (six studies) global/state functioning (three studies), social functioning (one study), and adverse events (seven studies). Secondary outcomes were leaving the study early (eight studies), substance misuse (five studies), employment status (one study), impulsivity (one study), anger (three studies), and mental state (three studies). No study reported data on the primary outcome of reconviction or the secondary outcomes of quality of life, engagement with services, satisfaction with treatment, housing/accommodation status, economic outcomes or prison/service outcomes. Eleven different drugs were compared with placebo, but data for AsPD participants were only available for five comparisons. Three classes of drug were represented: antiepileptic; antidepressant; and dopamine agonist (anti-Parkinsonian) drugs. We considered selection bias to be unclear in 8/11 studies, attrition bias to be high in 7/11 studies, and performance bias to be low in 7/11 studies. Using GRADE, we rated the certainty of evidence for each outcome in this review as very low, meaning that we have very little confidence in the effect estimates reported. Phenytoin (antiepileptic) versus placebo One study (60 participants) reported very low-certainty evidence that phenytoin (300 mg/day), compared to placebo, may reduce the mean frequency of aggressive acts per week (phenytoin mean = 0.33, no standard deviation (SD) reported; placebo mean = 0.51, no SD reported) in male prisoners with aggression (skewed data) at endpoint (six weeks). The same study (60 participants) reported no evidence of difference between phenytoin and placebo in the number of participants reporting the adverse event of nausea during week one (odds ratio (OR) 1.00, 95% confidence interval (CI) 0.06 to 16.76; very low-certainty evidence). The study authors also reported that no important side effects were detectable via blood cell counts or liver enzyme tests (very low-certainty evidence). The study did not measure reconviction, global/state functioning or social functioning. Desipramine (antidepressant) versus placebo One study (29 participants) reported no evidence of a difference between desipramine (250 to 300 mg/day) and placebo on mean social functioning scores (desipramine = 0.19; placebo = 0.21), assessed with the family-social domain of the Addiction Severity Index (scores range from zero to one, with higher values indicating worse social functioning), at endpoint (12 weeks) (very low-certainty evidence). Neither of the studies included in this comparison measured the other primary outcomes: aggression; reconviction; global/state functioning; or adverse events. Nortriptyline (antidepressant) versus placebo One study (20 participants) reported no evidence of a difference between nortriptyline (25 to 75 mg/day) and placebo on mean global state/functioning scores (nortriptyline = 0.3; placebo = 0.7), assessed with the Symptom Check List-90 (SCL-90) Global Severity Index (GSI; mean of subscale scores, ranging from zero to four, with higher scores indicating greater severity of symptoms), at endpoint (six months) in men with alcohol dependency (very low-certainty evidence). The study measured side effects but did not report data on adverse events for the AsPD subgroup. The study did not measure aggression, reconviction or social functioning. Bromocriptine (dopamine agonist) versus placebo One study (18 participants) reported no evidence of difference between bromocriptine (15 mg/day) and placebo on mean global state/functioning scores (bromocriptine = 0.4; placebo = 0.7), measured with the GSI of the SCL-90 at endpoint (six months) (very low-certainty evidence). The study did not provide data on adverse effects, but reported that 12 patients randomised to the bromocriptine group experienced severe side effects, five of whom dropped out of the study in the first two days due to nausea and severe flu-like symptoms (very low-certainty evidence). The study did not measure aggression, reconviction and social functioning. Amantadine (dopamine agonist) versus placebo The study in this comparison did not measure any of the primary outcomes.
AUTHORS' CONCLUSIONS
The evidence summarised in this review is insufficient to draw any conclusion about the use of pharmacological interventions in the treatment of antisocial personality disorder. The evidence comes from single, unreplicated studies of mostly older medications. The studies also have methodological issues that severely limit the confidence we can draw from their results. Future studies should recruit participants on the basis of having AsPD, and use relevant outcome measures, including reconviction.
Topics: Adult; Aggression; Alcohol-Related Disorders; Amantadine; Antisocial Personality Disorder; Anxiety; Bromocriptine; Desipramine; Female; Humans; Male; Middle Aged; Nortriptyline; Phenytoin; Placebos; Psychotropic Drugs; Randomized Controlled Trials as Topic
PubMed: 32880105
DOI: 10.1002/14651858.CD007667.pub3 -
Wounds : a Compendium of Clinical... Feb 2024Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound...
BACKGROUND
Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound care remains limited.
OBJECTIVE
To conduct a comprehensive review to assess the efficacy of topical phenytoin compared with standard and alternative treatments for different wound types.
MATERIALS AND METHODS
The authors last searched Cochrane Library, PubMed, PubMed Central, and MEDLINE in June 2023. All English-language human RCTs and NRCTs from any time were included. The RoB 2 was used to assess quality of randomized trials, and the ROBINS-I was used to assess the quality of nonrandomized trials. Studies with a low risk of bias or some concerns in no more than 1 domain were included. Data collected and analyzed included wound type, interventions, sample size, outcome measures, and adverse effects.
RESULTS
The search yielded 101 studies, of which 17 RCTs and 8 NRCTs were eligible for inclusion. Of the included studies, 56% had a low risk of bias in all domains. The sample sizes varied between 20 and 130 (median, 60), with a total sample size of 1653 patients. Phenytoin improved wound healing in 17 of the 24 studies that evaluated it (71%), increased granulation tissue in 9 of the 10 studies that evaluated it (90%), provided analgesic effects in 7 of the 13 studies that evaluated it (54%), and inhibited bacterial contaminants in 6 of the 8 studies that evaluated it (75%). Adverse effects were rare (29%), minimal, and transient.
CONCLUSION
Phenytoin enhances wound healing and offers analgesic and antibacterial properties with minimal adverse effects. Further research is needed on optimal dosage of phenytoin, as well as frequency, delivery vehicles, and effects on other postoperative wounds.
BACKGROUND
Although phenytoin's potential benefits in wound healing, pain relief, and infection control across various wound types have been previously reported, its use in wound care remains limited.
OBJECTIVE
To conduct a comprehensive review to assess the efficacy of topical phenytoin compared with standard and alternative treatments for different wound types.
MATERIALS AND METHODS
The authors last searched Cochrane Library, PubMed, PubMed Central, and MEDLINE in June 2023. All English-language human RCTs and NRCTs from any time were included. The RoB 2 was used to assess quality of randomized trials, and the ROBINS-I was used to assess the quality of nonrandomized trials. Studies with a low risk of bias or some concerns in no more than 1 domain were included. Data collected and analyzed included wound type, interventions, sample size, outcome measures, and adverse effects.
RESULTS
The search yielded 101 studies, of which 17 RCTs and 8 NRCTs were eligible for inclusion. Of the included studies, 56% had a low risk of bias in all domains. The sample sizes varied between 20 and 130 (median, 60), with a total sample size of 1653 patients. Phenytoin improved wound healing in 17 of the 24 studies that evaluated it (71%), increased granulation tissue in 9 of the 10 studies that evaluated it (90%), provided analgesic effects in 7 of the 13 studies that evaluated it (54%), and inhibited bacterial contaminants in 6 of the 8 studies that evaluated it (75%). Adverse effects were rare (29%), minimal, and transient.
CONCLUSION
Phenytoin enhances wound healing and offers analgesic and antibacterial properties with minimal adverse effects. Further research is needed on optimal dosage of phenytoin, as well as frequency, delivery vehicles, and effects on other postoperative wounds.
Topics: Humans; Phenytoin; Anti-Bacterial Agents; Wound Healing; Analgesics; Pain
PubMed: 38479432
DOI: No ID Found