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The Annals of Pharmacotherapy May 2016Approximately 50% of patients with alcohol dependence experience alcohol withdrawal. Severe alcohol withdrawal is characterized by seizures and/or delirium tremens,... (Review)
Review
OBJECTIVE
Approximately 50% of patients with alcohol dependence experience alcohol withdrawal. Severe alcohol withdrawal is characterized by seizures and/or delirium tremens, often refractory to standard doses of benzodiazepines, and requires aggressive treatment. This review aims to summarize the literature pertaining to the pharmacotherapy of severe alcohol withdrawal.
DATA SOURCES
PubMed (January 1960 to October 2015) was searched using the search termsalcohol withdrawal, delirium tremens, intensive care, andrefractory Supplemental references were generated through review of identified literature citations.
STUDY SELECTION AND DATA EXTRACTION
Available English language articles assessing pharmacotherapy options for adult patients with severe alcohol withdrawal were included.
DATA SYNTHESIS
A PubMed search yielded 739 articles for evaluation, of which 27 were included. The number of randomized controlled trials was limited, so many of these are retrospective analyses and case reports. Benzodiazepines remain the treatment of choice, with diazepam having the most favorable pharmacokinetic profile. Protocolized escalation of benzodiazepines as an alternative to a symptom-triggered approach may decrease the need for mechanical ventilation and intensive care unit (ICU) length of stay. Propofol is appropriate for patients refractory to benzodiazepines; however, the roles of phenobarbital, dexmedetomidine, and ketamine remain unclear.
CONCLUSIONS
Severe alcohol withdrawal is not clearly defined, and limited data regarding management are available. Protocolized administration of benzodiazepines, in combination with phenobarbital, may reduce the need for mechanical ventilation and lead to shorter ICU stays. Propofol is a viable alternative for patients refractory to benzodiazepines; however, the role of other agents remains unclear. Randomized, prospective studies are needed to clearly define effective treatment strategies.
Topics: Alcohol Withdrawal Delirium; Alcoholism; Benzodiazepines; Critical Care; Dexmedetomidine; Drug Therapy, Combination; Humans; Phenobarbital; Propofol; Randomized Controlled Trials as Topic; Respiration, Artificial; Retrospective Studies; Substance Withdrawal Syndrome
PubMed: 26861990
DOI: 10.1177/1060028016629161 -
Epilepsy & Behavior : E&B Aug 2015Drug-induced status epilepticus (SE) is a relatively uncommon phenomenon, probably accounting for less than 5% of all SE cases, although limitations in case... (Review)
Review
Drug-induced status epilepticus (SE) is a relatively uncommon phenomenon, probably accounting for less than 5% of all SE cases, although limitations in case ascertainment and establishing causation substantially weaken epidemiological estimates. Some antiepileptic drugs, particularly those with sodium channel or GABA(γ-aminobutyric acid)-ergic properties, frequently exacerbate seizures and may lead to SE if used inadvertently in generalized epilepsies or less frequently in other epilepsies. Tiagabine seems to have a particular propensity for triggering nonconvulsive SE sometimes in patients with no prior history of seizures. In therapeutic practice, SE is most commonly seen in association with antibiotics (cephalosporins, quinolones, and some others) and immunotherapies/chemotherapies, the latter often in the context of a reversible encephalopathy syndrome. Status epilepticus following accidental or intentional overdoses, particularly of antidepressants or other psychotropic medications, has also featured prominently in the literature: whilst there are sometimes fatal consequences, this is more commonly because of cardiorespiratory or metabolic complications than as a result of seizure activity. A high index of suspicion is required in identifying those at risk and in recognizing potential clues from the presentation, but even with a careful analysis of patient and drug factors, establishing causation can be difficult. In addition to eliminating the potential trigger, management should be as for SE in any other circumstances, with the exception that phenobarbitone is recommended as a second-line treatment for suspected toxicity-related SE where the risk of cardiovascular complications is higher anyways and may be exacerbated by phenytoin. There are also specific recommendations/antidotes in some situations. The outcome of drug-induced status epilepticus is mostly good when promptly identified and treated, though less so in the context of overdoses. This article is part of a Special Issue entitled "Status Epilepticus".
Topics: Animals; Anti-Bacterial Agents; Anticonvulsants; Humans; Nipecotic Acids; Phenobarbital; Phenytoin; Status Epilepticus; Tiagabine; gamma-Aminobutyric Acid
PubMed: 26210064
DOI: 10.1016/j.yebeh.2015.04.034 -
Annals of Neurology Dec 2022Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective...
OBJECTIVE
Seizures are more common in the neonatal period than at any other stage of life. Phenobarbital is the first-line treatment for neonatal seizures and is at best effective in approximately 50% of babies, but may contribute to neuronal injury. Here, we assessed the efficacy of phenobarbital versus the synthetic neurosteroid, ganaxolone, to moderate seizure activity and neuropathology in neonatal lambs exposed to perinatal asphyxia.
METHODS
Asphyxia was induced via umbilical cord occlusion in term lambs at birth. Lambs were treated with ganaxolone (5mg/kg/bolus then 5mg/kg/day for 2 days) or phenobarbital (20mg/kg/bolus then 5mg/kg/day for 2 days) at 6 hours. Abnormal brain activity was classified as stereotypic evolving (SE) seizures, epileptiform discharges (EDs), and epileptiform transients (ETs) using continuous amplitude-integrated electroencephalographic recordings. At 48 hours, lambs were euthanized for brain pathology.
RESULTS
Asphyxia caused abnormal brain activity, including SE seizures that peaked at 18 to 20 hours, EDs, and ETs, and induced neuronal degeneration and neuroinflammation. Ganaxolone treatment was associated with an 86.4% reduction in the number of seizures compared to the asphyxia group. The total seizure duration in the asphyxia+ganaxolone group was less than the untreated asphyxia group. There was no difference in the number of SE seizures between the asphyxia and asphyxia+phenobarbital groups or duration of SE seizures. Ganaxolone treatment, but not phenobarbital, reduced neuronal degeneration within hippocampal CA1 and CA3 regions, and cortical neurons, and ganaxolone reduced neuroinflammation within the thalamus.
INTERPRETATION
Ganaxolone provided better seizure control than phenobarbital in this perinatal asphyxia model and was neuroprotective for the newborn brain, affording a new therapeutic opportunity for treatment of neonatal seizures. ANN NEUROL 2022;92:1066-1079.
Topics: Animals; Humans; Infant, Newborn; Anticonvulsants; Asphyxia Neonatorum; Epilepsy; Phenobarbital; Seizures; Sheep; Animals, Newborn; Pregnanolone; Disease Models, Animal
PubMed: 36054160
DOI: 10.1002/ana.26493 -
Cold Spring Harbor Perspectives in... Jan 2016γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the cerebral cortex. GABAergic inhibition enables synchronization of activity in cortical... (Review)
Review
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the cerebral cortex. GABAergic inhibition enables synchronization of activity in cortical networks, and contributes to generation of variety of brain activity patterns. In relation to epilepsy, GABAergic inhibition has been traditionally viewed as the main mechanism counterbalancing glutamatergic excitation and preventing hypersynchronous neuronal discharges. Indeed, deficits in GABAergic functions most commonly result in a hyperexcitable epileptic state, and many of the currently used antiepileptic drugs act through enhancement of GABAergic functions. However, a number of observations show that some epileptiform activity patterns involve synchronization by GABAergic mechanisms. These include two main categories that will be reviewed here: (1) synchronization of epileptiform oscillations based on GABAergic inhibition, and (2) epileptiform events driven by depolarizing and excitatory GABA. The conclusion is reached that GABAergic control of spike timing, either through inhibition or excitation under certain conditions, may work as a powerful synchronizing mechanism during epilepsy.
Topics: Action Potentials; Animals; Anticonvulsants; Cortical Synchronization; Disease Models, Animal; Epilepsy; Humans; Nerve Net; Phenobarbital; Rats; Receptors, GABA; Synaptic Transmission; gamma-Aminobutyric Acid
PubMed: 26747834
DOI: 10.1101/cshperspect.a022764 -
Indian Pediatrics Aug 2019
Topics: Epilepsy; Humans; Infant, Newborn; Levetiracetam; Phenobarbital; Piracetam; Seizures
PubMed: 31477641
DOI: No ID Found -
The Annals of Pharmacotherapy Dec 2021To review the literature describing the use of adjunctive phenobarbital in the treatment of severe alcohol withdrawal syndrome (AWS). (Review)
Review
OBJECTIVE
To review the literature describing the use of adjunctive phenobarbital in the treatment of severe alcohol withdrawal syndrome (AWS).
DATA SOURCES
PubMed and EMBASE were searched using the following terms: , , , , and .
STUDY SELECTION AND DATA EXTRACTION
The search was limited to randomized controlled trials (RCTs) and cohort studies published in English.
DATA SYNTHESIS
Seven studies were identified in the emergency department (ED; RCT, n = 1; cohort, n = 2), general medicine ward (cohort, n = 1), and intensive care unit (ICU; cohort, n = 3) settings. For all studies set in the ED and general medicine ward and for 1 ICU study, phenobarbital plus symptom-guided benzodiazepine therapy was compared to symptom-guided benzodiazepine monotherapy. The other 2 ICU studies examined adjunctive phenobarbital before and after implementation of a protocol, meaning patients in both arms could have received phenobarbital. Overall risk of bias across all studies was low to moderate.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
The specific role of adjunctive phenobarbital in AWS is not clear because a majority of studies are retrospective cohorts with varying primary outcomes in different patient care settings.
CONCLUSIONS
In the ED and general medicine ward, phenobarbital demonstrated benzodiazepine-sparing effects. In the ICU, when a protocol guides phenobarbital use, the need for mechanical ventilation may be reduced. Adjunctive phenobarbital was well tolerated. Because of study limitations, it is challenging to provide specific recommendations for adjunctive phenobarbital use in severe AWS.
Topics: Alcohol Withdrawal Delirium; Alcoholism; Humans; Hypnotics and Sedatives; Phenobarbital; Substance Withdrawal Syndrome
PubMed: 33678057
DOI: 10.1177/1060028021999821 -
The Cochrane Database of Systematic... Oct 2023Newborn infants are more prone to seizures than older children and adults. The neuronal injury caused by seizures in neonates often results in long-term... (Review)
Review
BACKGROUND
Newborn infants are more prone to seizures than older children and adults. The neuronal injury caused by seizures in neonates often results in long-term neurodevelopmental sequelae. There are several options for anti-seizure medications (ASMs) in neonates. However, the ideal choice of first-, second- and third-line ASM is still unclear. Further, many other aspects of seizure management such as whether ASMs should be initiated for only-electrographic seizures and how long to continue the ASM once seizure control is achieved are elusive.
OBJECTIVES
1. To assess whether any ASM is more or less effective than an alternative ASM (both ASMs used as first-, second- or third-line treatment) in achieving seizure control and improving neurodevelopmental outcomes in neonates with seizures. We analysed EEG-confirmed seizures and clinically-diagnosed seizures separately. 2. To assess maintenance therapy with ASM versus no maintenance therapy after achieving seizure control. We analysed EEG-confirmed seizures and clinically-diagnosed seizures separately. 3. To assess treatment of both clinical and electrographic seizures versus treatment of clinical seizures alone in neonates.
SEARCH METHODS
We searched MEDLINE, Embase, CENTRAL, Epistemonikos and three databases in May 2022 and June 2023. These searches were not limited other than by study design to trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that included neonates with EEG-confirmed or clinically diagnosed seizures and compared (1) any ASM versus an alternative ASM, (2) maintenance therapy with ASM versus no maintenance therapy, and (3) treatment of clinical or EEG seizures versus treatment of clinical seizures alone.
DATA COLLECTION AND ANALYSIS
Two review authors assessed trial eligibility, risk of bias and independently extracted data. We analysed treatment effects in individual trials and reported risk ratio (RR) for dichotomous data, and mean difference (MD) for continuous data, with respective 95% confidence interval (CI). We used GRADE to assess the certainty of evidence.
MAIN RESULTS
We included 18 trials (1342 infants) in this review. Phenobarbital versus levetiracetam as first-line ASM in EEG-confirmed neonatal seizures (one trial) Phenobarbital is probably more effective than levetiracetam in achieving seizure control after first loading dose (RR 2.32, 95% CI 1.63 to 3.30; 106 participants; moderate-certainty evidence), and after maximal loading dose (RR 2.83, 95% CI 1.78 to 4.50; 106 participants; moderate-certainty evidence). However, we are uncertain about the effect of phenobarbital when compared to levetiracetam on mortality before discharge (RR 0.30, 95% CI 0.04 to 2.52; 106 participants; very low-certainty evidence), requirement of mechanical ventilation (RR 1.21, 95% CI 0.76 to 1.91; 106 participants; very low-certainty evidence), sedation/drowsiness (RR 1.74, 95% CI 0.68 to 4.44; 106 participants; very low-certainty evidence) and epilepsy post-discharge (RR 0.92, 95% CI 0.48 to 1.76; 106 participants; very low-certainty evidence). The trial did not report on mortality or neurodevelopmental disability at 18 to 24 months. Phenobarbital versus phenytoin as first-line ASM in EEG-confirmed neonatal seizures (one trial) We are uncertain about the effect of phenobarbital versus phenytoin on achieving seizure control after maximal loading dose of ASM (RR 0.97, 95% CI 0.54 to 1.72; 59 participants; very low-certainty evidence). The trial did not report on mortality or neurodevelopmental disability at 18 to 24 months. Maintenance therapy with ASM versus no maintenance therapy in clinically diagnosed neonatal seizures (two trials) We are uncertain about the effect of short-term maintenance therapy with ASM versus no maintenance therapy during the hospital stay (but discontinued before discharge) on the risk of repeat seizures before hospital discharge (RR 0.76, 95% CI 0.56 to 1.01; 373 participants; very low-certainty evidence). Maintenance therapy with ASM compared to no maintenance therapy may have little or no effect on mortality before discharge (RR 0.69, 95% CI 0.39 to 1.22; 373 participants; low-certainty evidence), mortality at 18 to 24 months (RR 0.94, 95% CI 0.34 to 2.61; 111 participants; low-certainty evidence), neurodevelopmental disability at 18 to 24 months (RR 0.89, 95% CI 0.13 to 6.12; 108 participants; low-certainty evidence) and epilepsy post-discharge (RR 3.18, 95% CI 0.69 to 14.72; 126 participants; low-certainty evidence). Treatment of both clinical and electrographic seizures versus treatment of clinical seizures alone in neonates (two trials) Treatment of both clinical and electrographic seizures when compared to treating clinical seizures alone may have little or no effect on seizure burden during hospitalisation (MD -1871.16, 95% CI -4525.05 to 782.73; 68 participants; low-certainty evidence), mortality before discharge (RR 0.59, 95% CI 0.28 to 1.27; 68 participants; low-certainty evidence) and epilepsy post-discharge (RR 0.75, 95% CI 0.12 to 4.73; 35 participants; low-certainty evidence). The trials did not report on mortality or neurodevelopmental disability at 18 to 24 months. We report data from the most important comparisons here; readers are directed to Results and Summary of Findings tables for all comparisons.
AUTHORS' CONCLUSIONS
Phenobarbital as a first-line ASM is probably more effective than levetiracetam in achieving seizure control after the first loading dose and after the maximal loading dose of ASM (moderate-certainty evidence). Phenobarbital + bumetanide may have little or no difference in achieving seizure control when compared to phenobarbital alone (low-certainty evidence). Limited data and very low-certainty evidence preclude us from drawing any reasonable conclusion on the effect of using one ASM versus another on other short- and long-term outcomes. In neonates who achieve seizure control after the first loading dose of phenobarbital, maintenance therapy compared to no maintenance ASM may have little or no effect on all-cause mortality before discharge, mortality by 18 to 24 months, neurodevelopmental disability by 18 to 24 months and epilepsy post-discharge (low-certainty evidence). In neonates with hypoxic-ischaemic encephalopathy, treatment of both clinical and electrographic seizures when compared to treating clinical seizures alone may have little or no effect on seizure burden during hospitalisation, all-cause mortality before discharge and epilepsy post-discharge (low-certainty evidence). All findings of this review apply only to term and late preterm neonates. We need well-designed RCTs for each of the three objectives of this review to improve the precision of the results. These RCTs should use EEG to diagnose seizures and should be adequately powered to assess long-term neurodevelopmental outcomes. We need separate RCTs evaluating the choice of ASM in preterm infants.
Topics: Infant; Child; Infant, Newborn; Adult; Humans; Adolescent; Phenytoin; Levetiracetam; Epilepsy; Phenobarbital; Seizures
PubMed: 37873971
DOI: 10.1002/14651858.CD014967.pub2 -
CNS & Neurological Disorders Drug... 2023Drug design is one of the critical aspects of the drug development process. The present review focused on different heterocyclic molecules having anticonvulsant activity... (Review)
Review
Drug design is one of the critical aspects of the drug development process. The present review focused on different heterocyclic molecules having anticonvulsant activity with structural diversity and common pharmacophoric features. For the first time (1995), Dimmock and his team introduced specific arrangements of three important pharmacophores for anticonvulsant activity. These pharmacophores include two hydrophobic binding sites and one hydrogen binding site. After a few years (2012), Pandeya modified Dimmock's concept by adding one more pharmacophoric feature as an electron donor in the previously suggested pharmacophoric arrangement of the anticonvulsant. As a result, numerous scientists designed anticonvulsant drugs based on Dimmock's and Pandeya's concept. In addition, marketed anticonvulsant preparation containing Riluzole, Phenobarbital, Progabide, Ralitoline, etc., also holds the suggested pharmacophores by Dimmock and Pandeya's pharmacophoric concept. This review mainly focuses on the compilation of reported scientific literature in the last decade on the pharmacophoric features of different heterocyclic anticonvulsants, which will help develop new anticonvulsants.
Topics: Humans; Anticonvulsants; Seizures; Pharmacophore; Electroshock; Phenobarbital
PubMed: 35366788
DOI: 10.2174/1871527321666220401115529 -
Archives of Disease in Childhood Apr 2016Therapeutic drug monitoring (TDM) aims to integrate drug measurement results into clinical decision making. The basic rules apply when using TDM in neonates... (Review)
Review
Therapeutic drug monitoring (TDM) aims to integrate drug measurement results into clinical decision making. The basic rules apply when using TDM in neonates (aminoglycosides, vancomycin, phenobarbital, digoxin), but additional factors should also be taken into account. First, due to both pharmacokinetic variability and non-pharmacokinetic factors, the correlation between dosage and concentration is poor in neonates, but can be overcome with the use of more complex, validated dosing regimens. Second, the time to reach steady state is prolonged, especially when no loading dose is used. Consequently, the timing of TDM sampling is important in this population. Third, the target concentration may be uncertain (vancomycin) or depend on specific factors (phenobarbital during whole body cooling). Finally, because of differences in matrix composition (eg, protein, bilirubin), assay-related inaccuracies may be different in neonates. We anticipate that complex validated dosing regimens, with subsequent TDM sampling and Bayesian forecasting, are the next step in tailoring pharmacotherapy to individual neonates.
Topics: Anti-Bacterial Agents; Anticonvulsants; Bayes Theorem; Dose-Response Relationship, Drug; Drug Monitoring; Humans; Infant, Newborn; Phenobarbital; Vancomycin
PubMed: 26803050
DOI: 10.1136/archdischild-2013-305309 -
European Journal of Internal Medicine Jun 2023Phenobarbital (PB) has been acknowledged among clinicians as a potential alternative to benzodiazepines (BZD) to decrease the need for hospital length of stay and...
BACKGROUND
Phenobarbital (PB) has been acknowledged among clinicians as a potential alternative to benzodiazepines (BZD) to decrease the need for hospital length of stay and complications associated with alcohol withdrawal syndrome (AWS). However, the level of evidence, including appropriate dosing, is unclear. We aim to summarize the evidence regarding PB used in AWS and provide future agendas for research.
METHODS
Following the PRISMA guidelines, we searched MEDLINE, EMBASE, ClinicalTrials.gov, and WHO ICTRP for all peer-reviewed articles and clinical trials using keywords including"alcohol withdrawal", "delirium tremens", "phenobarbital," and "barbiturate" from their inception to September 18, 2022.
RESULTS
We included 20 articles, nine in the emergency department (ED) and 11 in the general floors or intensive care units (ICUs). Studies performed in the ED included two RCTs, although both suffered from a considerably small sample size. Six studies done in the general floors or ICUs compared PB and BZD monotherapy, while four compared the utility of adjunct PB in addition to BZD compared with BZD monotherapy and one was a database study without specific dosing information. Overall, there was considerable heterogeneity in PB dosing, measured outcomes, and AWS severity measurement scales.
CONCLUSION
This systematic review summarizes the current evidence related to PB use in AWS. While considerable heterogeneity exists among studies available, PB as monotherapy without BZD may be a safe and effective alternative in AWS treatment. Future prospective studies or trials should focus on the standardization of PB dosing and outcomes.
Topics: Humans; Substance Withdrawal Syndrome; Alcoholism; Alcohol Withdrawal Delirium; Prospective Studies; Retrospective Studies; Phenobarbital; Benzodiazepines
PubMed: 36935249
DOI: 10.1016/j.ejim.2023.03.006