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CNS Drugs Feb 2017Benzodiazepines ameliorate or prevent the symptoms and complications of moderate to severe alcohol withdrawal, which can include autonomic hyperactivity, agitation,... (Comparative Study)
Comparative Study Review
Benzodiazepines ameliorate or prevent the symptoms and complications of moderate to severe alcohol withdrawal, which can include autonomic hyperactivity, agitation, combativeness, hallucinations, seizures, delirium, and death. The benzodiazepines most commonly used for this purpose are lorazepam, chlordiazepoxide, oxazepam, and diazepam. It is widely asserted that no member of this group is superior to the others for treatment of alcohol withdrawal. However, of these, diazepam has the shortest time to peak effect, which facilitates both rapid control of symptoms and accurate titration to avoid over-sedation. Furthermore, diazepam and its active metabolite, desmethyldiazepam, have the longest elimination half-lives, so their levels decrease in a gradual, self-tapering manner, resulting in a smoother withdrawal, i.e., a lower incidence and severity of both breakthrough symptoms and rebound phenomena, including a possibly decreased seizure risk. Importantly, the fear of increased risk of over-sedation with diazepam compared with other benzodiazepines is based on a misunderstanding of its pharmacokinetics and is unfounded. Similarly, the notion that diazepam should be avoided in patients with liver disease and elderly patients to avoid prolonged over-sedation is based on no more than conjecture. In fact, there is clinical evidence that diazepam is safe for the treatment of alcohol withdrawal in these patients when administered using a simple symptom-based approach. There is one instance in which diazepam should not be used: when intramuscular administration is the only option, the lipophilicity of diazepam can result in slow absorption-either lorazepam or, when rapid control of symptoms is required, midazolam should be used. The comparative pharmacokinetics of the benzodiazepines used in the treatment of alcohol withdrawal together with a comprehensive review of the literature on their use strongly suggest that diazepam should be the preferred benzodiazepine for the treatment of patients experiencing moderate to severe alcohol withdrawal under most circumstances.
Topics: Alcohol Withdrawal Delirium; Alcohol Withdrawal Seizures; Benzodiazepines; Diazepam; Half-Life; Humans; Hypnotics and Sedatives; Severity of Illness Index
PubMed: 28101764
DOI: 10.1007/s40263-016-0403-y -
Current Opinion in Neurology Apr 2022The purpose of this review is to provide a succinct evaluation of the current rescue medications and action plans available to our patients with seizure clusters in the... (Review)
Review
PURPOSE OF REVIEW
The purpose of this review is to provide a succinct evaluation of the current rescue medications and action plans available to our patients with seizure clusters in the outpatient setting.
RECENT FINDINGS
The main themes of the recent findings are that rescue medications and seizure action plans (SAPs) are underutilized, particularly in the adult population. The safety and efficacy of intranasal midazolam and intranasal diazepam is comparable with rectal diazepam for the treatment of seizure clusters. Additionally, this intranasal formulation has the benefit of a more socially acceptable route of administration and ease of use.
SUMMARY
The implication of these findings is a greater variety and awareness in the rescue medications available to our patients suffering from seizure clusters.
Topics: Administration, Intranasal; Adult; Anticonvulsants; Diazepam; Epilepsy; Humans; Seizures
PubMed: 35153281
DOI: 10.1097/WCO.0000000000001038 -
Neurologic Clinics Nov 2022Treatment of seizure clusters endeavors to prevent additional seizures and avoid progression to conditions such as prolonged seizures and status epilepticus. Rescue... (Review)
Review
Treatment of seizure clusters endeavors to prevent additional seizures and avoid progression to conditions such as prolonged seizures and status epilepticus. Rescue therapies are key components of seizure action plans (SAPs) for individuals with seizure clusters. Three rescue therapies are approved in the United States for the treatment of seizure clusters: diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray. Diazepam rectal gel is an effective rescue therapy for seizure clusters, though adults and adolescents may have social reservations regarding its administration. Intranasal delivery of midazolam or diazepam is a promising alternative to rectal administration because these formulations offer easy, socially acceptable administration exhibit a rapid onset, and allow for the possibility of self-administration. Off-label benzodiazepines, such as orally disintegrating lorazepam and intranasal use of an intravenous (IV) formulation of midazolam via nasal atomizer, are less well characterized regarding bioavailability and tolerability compared with approved agents.
Topics: Adult; Adolescent; Humans; Lorazepam; Midazolam; Anticonvulsants; Nasal Sprays; Seizures; Status Epilepticus; Diazepam; Benzodiazepines
PubMed: 36270699
DOI: 10.1016/j.ncl.2022.03.016 -
SAAD Digest Jan 2016
Topics: Anti-Anxiety Agents; Benzodiazepines; Diazepam; GABA Modulators; History, 20th Century; History, 21st Century; Humans; Hypnotics and Sedatives; Midazolam
PubMed: 27145551
DOI: No ID Found -
The Cochrane Database of Systematic... Aug 2017Baclofen shows potential for rapidly reducing symptoms of severe alcohol withdrawal syndrome (AWS) in people with alcoholism. Treatment with baclofen is easy to manage... (Review)
Review
BACKGROUND
Baclofen shows potential for rapidly reducing symptoms of severe alcohol withdrawal syndrome (AWS) in people with alcoholism. Treatment with baclofen is easy to manage and rarely produces euphoria or other pleasant effects, or craving for the drug. This is an updated version of the original Cochrane Review published in 2015, Issue 4.
OBJECTIVES
To assess the efficacy and safety of baclofen for people with AWS.
SEARCH METHODS
We updated our searches of the following databases to March 2017: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, PubMed, Embase, and CINAHL. We also searched registers of ongoing trials. We handsearched the references quoted in the identified trials, and sought information from researchers, pharmaceutical companies, and relevant trial authors about unpublished or uncompleted trials. We placed no restrictions on language.
SELECTION CRITERIA
We included all randomised controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for people with AWS. We excluded uncontrolled, non-randomised, or quasi-randomised trials. We included both parallel group and cross-over studies.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included three RCTs with 141 randomised participants. We did not perform meta-analyses due to the different control interventions. For the comparison of baclofen and placebo (1 study, 31 participants), there was no significant difference in Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) scores (very low quality evidence). For the comparison of baclofen and diazepam (1 study, 37 participants), there was no significant difference in CIWA-Ar scores (very low quality evidence), adverse events (risk difference (RD) 0.00, 95% confidence interval (CI) -0.10 to 0.10; very low quality evidence), dropouts (RD 0.00, 95% CI -0.10 to 0.10; very low quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.10 to 0.10; very low quality evidence). For the comparison of baclofen and chlordiazepoxide (1 study, 60 participants), there was no significant difference in CIWA-Ar scores (mean difference (MD) 1.00, 95% CI 0.70 to 1.30; very low quality evidence), global improvement (MD 0.10, 95% CI -0.03 to 0.23; very low quality evidence), adverse events (RD 2.50, 95% CI 0.88 to 7.10; very low quality of evidence), dropouts (RD 0.00, 95% CI -0.06 to 0.06; very low quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.06 to 0.06; very low quality evidence).
AUTHORS' CONCLUSIONS
No conclusions can be drawn about the efficacy and safety of baclofen for the management of alcohol withdrawal because we found insufficient and very low quality evidence.
Topics: Alcohol-Induced Disorders; Baclofen; Chlordiazepoxide; Diazepam; Ethanol; GABA Agonists; Humans; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome
PubMed: 28822350
DOI: 10.1002/14651858.CD008502.pub5 -
The Journal of Pediatrics May 2021
Topics: Candy; Child; Diazepam; Humans; Illicit Drugs; Male; Tablets; Tranquilizing Agents
PubMed: 33388304
DOI: 10.1016/j.jpeds.2020.12.075 -
Epilepsy & Behavior : E&B Aug 2015Most seizure emergencies occur outside of the hospital, and there is a need for treatment interventions that can be administered quickly and safely by nonclinical... (Review)
Review
Most seizure emergencies occur outside of the hospital, and there is a need for treatment interventions that can be administered quickly and safely by nonclinical caregivers. Intranasal benzodiazepine administration does not require intravenous access and offers rapid seizure cessation. Intranasal midazolam is faster at aborting seizure activity than rectal diazepam and quicker to administer than intravenous diazepam. Although time to seizure cessation varies from study to study, intranasal midazolam is efficacious when administered not only by emergency department personnel but also by paramedics and caregivers in out-of-hospital and home settings. Absorption of midazolam intranasal formulations appears to be relatively rapid compared to diazepam formulations. Its shorter elimination half-life may also be beneficial in that patients may more quickly return to normal function because of rapid offset of effect. On the other hand, the faster rate of elimination of midazolam may expose patients to a higher rate of seizure recurrence compared with diazepam. Two diazepam formulations and one midazolam formulation are being currently developed for intranasal use. This article is part of a Special Issue entitled "Status Epilepticus".
Topics: Acute Disease; Administration, Intranasal; Anticonvulsants; Diazepam; Humans; Lorazepam; Midazolam; Seizures
PubMed: 26022649
DOI: 10.1016/j.yebeh.2015.04.027 -
Nature Chemical Biology Dec 2021Small molecule drugs form the backbone of modern medicine's therapeutic arsenal. Often less appreciated is the role that small molecules have had in advancing basic... (Review)
Review
Small molecule drugs form the backbone of modern medicine's therapeutic arsenal. Often less appreciated is the role that small molecules have had in advancing basic biology. In this Review, we highlight how resistance mutations have unlocked the potential of small molecule chemical probes to discover new biology. We describe key instances in which resistance mutations and related genetic variants yielded foundational biological insight and categorize these examples on the basis of their role in the discovery of novel molecular mechanisms, protein allostery, physiology and cell signaling. Next, we suggest ways in which emerging technologies can be leveraged to systematically introduce and characterize resistance mutations to catalyze basic biology research and drug discovery. By recognizing how resistance mutations have propelled biological discovery, we can better harness new technologies and maximize the potential of small molecules to advance our understanding of biology and improve human health.
Topics: Alleles; Animals; Diazepam; Drug Discovery; Drug Resistance; Humans; Mutant Proteins; Mutation; Pharmaceutical Preparations; Protein Binding; Protein Conformation; Signal Transduction; Sulfonamides
PubMed: 34799733
DOI: 10.1038/s41589-021-00865-9 -
The Cochrane Database of Systematic... Apr 2015The treatment baclofen shows potential for rapidly reducing symptoms of severe alcohol withdrawal syndrome (AWS) in people with alcoholism. Treatment with baclofen is... (Review)
Review
BACKGROUND
The treatment baclofen shows potential for rapidly reducing symptoms of severe alcohol withdrawal syndrome (AWS) in people with alcoholism. Treatment with baclofen is easy to manage and rarely produces euphoria or other pleasant effects, or craving for the drug. This is an updated version of the original Cochrane review published in Issue 2, 2013.
OBJECTIVES
To assess the efficacy and safety of baclofen for people with AWS.
SEARCH METHODS
We searched the Cochrane Drugs and Alcohol Group Specialised Register (searched 13 January 2015), the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 1), MEDLINE (1966 to January 2015), EMBASE (1980 to January 2015), and CINAHL (1982 to January 2015). We also searched registers of ongoing trials, including ClinicalTrials.gov, the ISRCTN registry, and the European Clinical Trials Database. At the same time, we handsearched the references quoted in the identified trials, and sought information from researchers, pharmaceutical companies, and relevant trial authors about unpublished or uncompleted trials. We placed no restrictions on language.
SELECTION CRITERIA
We included all randomised controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for people with AWS. We excluded uncontrolled, non-randomised, or quasi-randomised trials. We included both parallel group and cross-over studies.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed references retrieved for possible inclusion. Any disagreements were resolved by an independent party. We contacted study authors for additional information where needed. We collected adverse effects information from the trials.
MAIN RESULTS
Two RCTs with a total of 81 participants were eligible according to the inclusion criteria. One study suggested that both baclofen and diazepam significantly decreased the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) score, without any significant difference between the two interventions. The other study showed no significant difference in CIWA-Ar score between baclofen and placebo, but a significantly decreased dependence on high-dose benzodiazepines with baclofen compared to placebo. Only one study reported on the safety of baclofen, without any side effects.
AUTHORS' CONCLUSIONS
The evidence for recommending baclofen for AWS is insufficient. We therefore need more well-designed RCTs to prove its efficacy and safety.
Topics: Alcohol-Induced Disorders; Baclofen; Diazepam; Ethanol; GABA Agonists; Humans; Randomized Controlled Trials as Topic; Substance Withdrawal Syndrome
PubMed: 25836263
DOI: 10.1002/14651858.CD008502.pub4 -
Expert Opinion on Pharmacotherapy Jan 2021Status epilepticus (SE) is a common neurological and medical emergency. It has high mortality and morbidity rates, which typically correlate with seizure semiology and... (Review)
Review
INTRODUCTION
Status epilepticus (SE) is a common neurological and medical emergency. It has high mortality and morbidity rates, which typically correlate with seizure semiology and duration; therefore, prompt and proper pharmacological intervention is paramount. In a pre-hospital setting, establishing venous access can be difficult, so other routes of drug administration should be considered.
AREAS COVERED
The paper summarizes the data from the literature and provides an evaluation of the efficacy and safety of intramuscular midazolam (IM MDZ) as it pertains to the management of acute seizures and SE.
EXPERT OPINION
The cascade of events involved in the genesis and sustenance of seizures, if not promptly stopped, lead to the perpetuation of the condition and may contribute to the refractoriness of pharmacological treatment. Hence, non-venous routes for drug administration were developed to allow untrained personnel to rapidly stop seizures. Among benzodiazepines (BDZs), IM MDZ is at least as effective and safe as other intravenously administered BDZs. Moreover, thanks to IM MDZ's favorable pharmacodynamic and pharmacokinetic profile, it is a promising alternative to other non-venous drugs such as intranasal-MDZ, buccal-MDZ, and rectal-diazepam in the pre-hospital management of SE cases with motor features.
Topics: Anticonvulsants; Diazepam; Humans; Injections, Intramuscular; Midazolam; Status Epilepticus
PubMed: 32840150
DOI: 10.1080/14656566.2020.1810236