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CNS Drugs Sep 2022Status epilepticus (SE) is an acute, life-threatening medical condition that requires immediate, effective therapy. Therefore, the acute care of prolonged seizures and... (Review)
Review
Status epilepticus (SE) is an acute, life-threatening medical condition that requires immediate, effective therapy. Therefore, the acute care of prolonged seizures and SE is a constant challenge for healthcare professionals, in both the pre-hospital and the in-hospital settings. Benzodiazepines (BZDs) are the first-line treatment for SE worldwide due to their efficacy, tolerability, and rapid onset of action. Although all BZDs act as allosteric modulators at the inhibitory gamma-aminobutyric acid (GABA) receptor, the individual agents have different efficacy profiles and pharmacokinetic and pharmacodynamic properties, some of which differ significantly. The conventional BZDs clonazepam, diazepam, lorazepam and midazolam differ mainly in their durations of action and available routes of administration. In addition to the common intravenous, intramuscular and rectal administrations that have long been established in the acute treatment of SE, other administration routes for BZDs-such as intranasal administration-have been developed in recent years, with some preparations already commercially available. Most recently, the intrapulmonary administration of BZDs via an inhaler has been investigated. This narrative review provides an overview of the current knowledge on the efficacy and tolerability of different BZDs, with a focus on different routes of administration and therapeutic specificities for different patient groups, and offers an outlook on potential future drug developments for the treatment of prolonged seizures and SE.
Topics: Anticonvulsants; Benzodiazepines; Clonazepam; Diazepam; Humans; Lorazepam; Midazolam; Seizures; Status Epilepticus; gamma-Aminobutyric Acid
PubMed: 35971024
DOI: 10.1007/s40263-022-00940-2 -
The New England Journal of Medicine Nov 2014
Review
Topics: Alcohol Withdrawal Delirium; Benzodiazepines; Central Nervous System Depressants; Diazepam; Disease Management; Humans; Lorazepam; Thiamine
PubMed: 25427113
DOI: 10.1056/NEJMra1407298 -
The New England Journal of Medicine Mar 2006
Review
Topics: Aged; Anti-Anxiety Agents; Antipsychotic Agents; Delirium; Dementia; Diagnosis, Differential; Humans; Lorazepam; Quality of Health Care; Risk Factors; Trazodone
PubMed: 16540616
DOI: 10.1056/NEJMra052321 -
British Journal of Anaesthesia May 1979Diazepam and lorazepam differ in potency and in the time-course of their action. As a sedative, diazepam 10 mg is equivalent to lorazepam 2-2.5 mg. Diazepam is better... (Clinical Trial)
Clinical Trial Comparative Study
Diazepam and lorazepam differ in potency and in the time-course of their action. As a sedative, diazepam 10 mg is equivalent to lorazepam 2-2.5 mg. Diazepam is better absorbed after oral than after i.m. administrations but this does not apply to lorazepam. The clinical effect and amnesia begin more rapidly with diazepam, but last longer following lorazepam. Lorazepam is more effective than diazepam in blocking the emergence sequelae from ketamine. Lorazepam i.v. is followed by a lesser frequency of venous thrombosis.
Topics: Amnesia; Anti-Anxiety Agents; Diazepam; Humans; Lorazepam; Middle Aged; Preanesthetic Medication; Time Factors
PubMed: 36117
DOI: 10.1093/bja/51.5.439 -
The New England Journal of Medicine Feb 2012Early termination of prolonged seizures with intravenous administration of benzodiazepines improves outcomes. For faster and more reliable administration, paramedics... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Early termination of prolonged seizures with intravenous administration of benzodiazepines improves outcomes. For faster and more reliable administration, paramedics increasingly use an intramuscular route.
METHODS
This double-blind, randomized, noninferiority trial compared the efficacy of intramuscular midazolam with that of intravenous lorazepam for children and adults in status epilepticus treated by paramedics. Subjects whose convulsions had persisted for more than 5 minutes and who were still convulsing after paramedics arrived were given the study medication by either intramuscular autoinjector or intravenous infusion. The primary outcome was absence of seizures at the time of arrival in the emergency department without the need for rescue therapy. Secondary outcomes included endotracheal intubation, recurrent seizures, and timing of treatment relative to the cessation of convulsive seizures. This trial tested the hypothesis that intramuscular midazolam was noninferior to intravenous lorazepam by a margin of 10 percentage points.
RESULTS
At the time of arrival in the emergency department, seizures were absent without rescue therapy in 329 of 448 subjects (73.4%) in the intramuscular-midazolam group and in 282 of 445 (63.4%) in the intravenous-lorazepam group (absolute difference, 10 percentage points; 95% confidence interval, 4.0 to 16.1; P<0.001 for both noninferiority and superiority). The two treatment groups were similar with respect to need for endotracheal intubation (14.1% of subjects with intramuscular midazolam and 14.4% with intravenous lorazepam) and recurrence of seizures (11.4% and 10.6%, respectively). Among subjects whose seizures ceased before arrival in the emergency department, the median times to active treatment were 1.2 minutes in the intramuscular-midazolam group and 4.8 minutes in the intravenous-lorazepam group, with corresponding median times from active treatment to cessation of convulsions of 3.3 minutes and 1.6 minutes. Adverse-event rates were similar in the two groups.
CONCLUSIONS
For subjects in status epilepticus, intramuscular midazolam is at least as safe and effective as intravenous lorazepam for prehospital seizure cessation. (Funded by the National Institute of Neurological Disorders and Stroke and others; ClinicalTrials.gov number, ClinicalTrials.gov NCT00809146.).
Topics: Adolescent; Adult; Anticonvulsants; Child; Child, Preschool; Double-Blind Method; Emergency Medical Services; Female; Humans; Hypnotics and Sedatives; Infant; Infusions, Intravenous; Injections, Intramuscular; Lorazepam; Male; Midazolam; Middle Aged; Recurrence; Status Epilepticus; Time Factors; Treatment Outcome
PubMed: 22335736
DOI: 10.1056/NEJMoa1107494 -
The Cochrane Database of Systematic... Jan 2018Tonic-clonic convulsions and convulsive status epilepticus (currently defined as a tonic-clonic convulsion lasting at least 30 minutes) are medical emergencies and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tonic-clonic convulsions and convulsive status epilepticus (currently defined as a tonic-clonic convulsion lasting at least 30 minutes) are medical emergencies and require urgent and appropriate anticonvulsant treatment. International consensus is that an anticonvulsant drug should be administered for any tonic-clonic convulsion that has been continuing for at least five minutes. Benzodiazepines (diazepam, lorazepam, midazolam) are traditionally regarded as first-line drugs and phenobarbital, phenytoin and paraldehyde as second-line drugs. This is an update of a Cochrane Review first published in 2002 and updated in 2008.
OBJECTIVES
To evaluate the effectiveness and safety of anticonvulsant drugs used to treat any acute tonic-clonic convulsion of any duration, including established convulsive (tonic-clonic) status epilepticus in children who present to a hospital or emergency medical department.
SEARCH METHODS
For the latest update we searched the Cochrane Epilepsy Group's Specialised Register (23 May 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO, 23 May 2017), MEDLINE (Ovid, 1946 to 23 May 2017), ClinicalTrials.gov (23 May 2017), and the WHO International Clinical Trials Registry Platform (ICTRP, 23 May 2017).
SELECTION CRITERIA
Randomised and quasi-randomised trials comparing any anticonvulsant drugs used for the treatment of an acute tonic-clonic convulsion including convulsive status epilepticus in children.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed trials for inclusion and extracted data. We contacted study authors for additional information.
MAIN RESULTS
The review includes 18 randomised trials involving 2199 participants, and a range of drug treatment options, doses and routes of administration (rectal, buccal, nasal, intramuscular and intravenous). The studies vary by design, setting and population, both in terms of their ages and also in their clinical situation. We have made many comparisons of drugs and of routes of administration of drugs in this review; our key findings are as follows:(1) This review provides only low- to very low-quality evidence comparing buccal midazolam with rectal diazepam for the treatment of acute tonic-clonic convulsions (risk ratio (RR) for seizure cessation 1.25, 95% confidence interval (CI) 1.13 to 1.38; 4 trials; 690 children). However, there is uncertainty about the effect and therefore insufficient evidence to support its use. There were no included studies which compare intranasal and buccal midazolam.(2) Buccal and intranasal anticonvulsants were shown to lead to similar rates of seizure cessation as intravenous anticonvulsants, e.g. intranasal lorazepam appears to be as effective as intravenous lorazepam (RR 0.96, 95% CI 0.82 to 1.13; 1 trial; 141 children; high-quality evidence) and intranasal midazolam was equivalent to intravenous diazepam (RR 0.98, 95% CI 0.91 to 1.06; 2 trials; 122 children; moderate-quality evidence).(3) Intramuscular midazolam also showed a similar rate of seizure cessation to intravenous diazepam (RR 0.97, 95% CI 0.87 to 1.09; 2 trials; 105 children; low-quality evidence).(4) For intravenous routes of administration, lorazepam appears to be as effective as diazepam in stopping acute tonic clonic convulsions: RR 1.04, 95% CI 0.94 to 1.16; 3 trials; 414 children; low-quality evidence. Furthermore, we found no statistically significant or clinically important differences between intravenous midazolam and diazepam (RR for seizure cessation 1.08, 95% CI 0.97 to 1.21; 1 trial; 80 children; moderate-quality evidence) or intravenous midazolam and lorazepam (RR for seizure cessation 0.98, 95% CI 0.91 to 1.04; 1 trial; 80 children; moderate-quality evidence). In general, intravenously-administered anticonvulsants led to more rapid seizure cessation but this was usually compromised by the time taken to establish intravenous access.(5) There is limited evidence from a single trial to suggest that intranasal lorazepam may be more effective than intramuscular paraldehyde in stopping acute tonic-clonic convulsions (RR 1.22, 95% CI 0.99 to 1.52; 160 children; moderate-quality evidence).(6) Adverse side effects were observed and reported very infrequently in the included studies. Respiratory depression was the most common and most clinically relevant side effect and, where reported, the frequency of this adverse event was observed in 0% to up to 18% of children. None of the studies individually demonstrated any difference in the rates of respiratory depression between the different anticonvulsants or their different routes of administration; but when pooled, three studies (439 children) provided moderate-quality evidence that lorazepam was significantly associated with fewer occurrences of respiratory depression than diazepam (RR 0.72, 95% CI 0.55 to 0.93).Much of the evidence provided in this review is of mostly moderate to high quality. However, the quality of the evidence provided for some important outcomes is low to very low, particularly for comparisons of non-intravenous routes of drug administration. Low- to very low-quality evidence was provided where limited data and imprecise results were available for analysis, methodological inadequacies were present in some studies which may have introduced bias into the results, study settings were not applicable to wider clinical practice, and where inconsistency was present in some pooled analyses.
AUTHORS' CONCLUSIONS
We have not identified any new high-quality evidence on the efficacy or safety of an anticonvulsant in stopping an acute tonic-clonic convulsion that would inform clinical practice. There appears to be a very low risk of adverse events, specifically respiratory depression. Intravenous lorazepam and diazepam appear to be associated with similar rates of seizure cessation and respiratory depression. Although intravenous lorazepam and intravenous diazepam lead to more rapid seizure cessation, the time taken to obtain intravenous access may undermine this effect. In the absence of intravenous access, buccal midazolam or rectal diazepam are therefore acceptable first-line anticonvulsants for the treatment of an acute tonic-clonic convulsion that has lasted at least five minutes. There is no evidence provided by this review to support the use of intranasal midazolam or lorazepam as alternatives to buccal midazolam or rectal diazepam.
Topics: Administration, Inhalation; Administration, Oral; Administration, Rectal; Anticonvulsants; Child; Diazepam; Epilepsy, Tonic-Clonic; Humans; Injections, Intramuscular; Injections, Intravenous; Lorazepam; Midazolam; Randomized Controlled Trials as Topic; Status Epilepticus
PubMed: 29320603
DOI: 10.1002/14651858.CD001905.pub3 -
Nature Nov 2015At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands,...
At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.
Topics: Allosteric Regulation; Allosteric Site; Animals; Anti-Anxiety Agents; Benzyl Alcohols; Conditioning, Classical; Drug Discovery; Fear; Female; HEK293 Cells; Humans; Ligands; Lorazepam; Male; Memory; Mice; Mice, Knockout; Models, Molecular; Receptors, G-Protein-Coupled; Signal Transduction; Triazines
PubMed: 26550826
DOI: 10.1038/nature15699 -
JAMA Sep 2017The use of benzodiazepines to control agitation in delirium in the last days of life is controversial. (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
The use of benzodiazepines to control agitation in delirium in the last days of life is controversial.
OBJECTIVE
To compare the effect of lorazepam vs placebo as an adjuvant to haloperidol for persistent agitation in patients with delirium in the setting of advanced cancer.
DESIGN, SETTING, AND PARTICIPANTS
Single-center, double-blind, parallel-group, randomized clinical trial conducted at an acute palliative care unit at MD Anderson Cancer Center, Texas, enrolling 93 patients with advanced cancer and agitated delirium despite scheduled haloperidol from February 11, 2014, to June 30, 2016, with data collection completed in October 2016.
INTERVENTIONS
Lorazepam (3 mg) intravenously (n = 47) or placebo (n = 43) in addition to haloperidol (2 mg) intravenously upon the onset of an agitation episode.
MAIN OUTCOMES AND MEASURES
The primary outcome was change in Richmond Agitation-Sedation Scale (RASS) score (range, -5 [unarousable] to 4 [very agitated or combative]) from baseline to 8 hours after treatment administration. Secondary end points were rescue neuroleptic use, delirium recall, comfort (perceived by caregivers and nurses), communication capacity, delirium severity, adverse effects, discharge outcomes, and overall survival.
RESULTS
Among 90 randomized patients (mean age, 62 years; women, 42 [47%]), 58 (64%) received the study medication and 52 (90%) completed the trial. Lorazepam + haloperidol resulted in a significantly greater reduction of RASS score at 8 hours (-4.1 points) than placebo + haloperidol (-2.3 points) (mean difference, -1.9 points [95% CI, -2.8 to -0.9]; P < .001). The lorazepam + haloperidol group required less median rescue neuroleptics (2.0 mg) than the placebo + haloperidol group (4.0 mg) (median difference, -1.0 mg [95% CI, -2.0 to 0]; P = .009) and was perceived to be more comfortable by both blinded caregivers and nurses (caregivers: 84% for the lorazepam + haloperidol group vs 37% for the placebo + haloperidol group; mean difference, 47% [95% CI, 14% to 73%], P = .007; nurses: 77% for the lorazepam + haloperidol group vs 30% for the placebo + haloperidol group; mean difference, 47% [95% CI, 17% to 71%], P = .005). No significant between-group differences were found in delirium-related distress and survival. The most common adverse effect was hypokinesia (3 patients in the lorazepam + haloperidol group [19%] and 4 patients in the placebo + haloperidol group [27%]).
CONCLUSIONS AND RELEVANCE
In this preliminary trial of hospitalized patients with agitated delirium in the setting of advanced cancer, the addition of lorazepam to haloperidol compared with haloperidol alone resulted in a significantly greater reduction in agitation at 8 hours. Further research is needed to assess generalizability and adverse effects.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT01949662.
Topics: Adult; Aged; Aged, 80 and over; Anti-Anxiety Agents; Antipsychotic Agents; Delirium; Double-Blind Method; Drug Therapy, Combination; Female; Haloperidol; Hospitalization; Humans; Lorazepam; Male; Middle Aged; Neoplasms; Palliative Care
PubMed: 28975307
DOI: 10.1001/jama.2017.11468 -
JAMA Psychiatry May 2019Although several pharmacological interventions for delirium have been investigated, their overall benefit and safety remain unclear. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Although several pharmacological interventions for delirium have been investigated, their overall benefit and safety remain unclear.
OBJECTIVE
To evaluate evidence regarding pharmacological interventions for delirium treatment and prevention.
DATA SOURCES
PubMed, Embase, ProQuest, ScienceDirect, Cochrane Central, Web of Science, ClinicalKey, and ClinicalTrials.gov from inception to May 17, 2018.
STUDY SELECTION
Randomized clinical trials (RCTs) examining pharmacological interventions for delirium treatment and prevention.
DATA EXTRACTION AND SYNTHESIS
To extract data according to a predetermined list of interests, the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines were applied, and all meta-analytic procedures were conducted using a random-effects model.
MAIN OUTCOMES AND MEASURES
The primary outcomes were treatment response in patients with delirium and the incidence of delirium in patients at risk of delirium.
RESULTS
A total of 58 RCTs were included, in which 20 RCTs with 1435 participants (mean age, 63.5 years; 65.1% male) compared the outcomes of treatment and 38 RCTs with 8168 participants (mean age, 70.2 years; 53.4% male) examined the prevention of delirium. A network meta-analysis demonstrated that haloperidol plus lorazepam provided the best response rate for delirium treatment (odds ratio [OR], 28.13; 95% CI, 2.38-333.08) compared with placebo/control. For delirium prevention, the ramelteon, olanzapine, risperidone, and dexmedetomidine hydrochloride groups had significantly lower delirium occurrence rates than placebo/control (OR, 0.07; 95% CI, 0.01-0.66 for ramelteon; OR, 0.25; 95% CI, 0.09-0.69 for olanzapine; OR, 0.27; 95% CI, 0.07-0.99 for risperidone; and OR, 0.50; 95% CI, 0.31-0.80 for dexmedetomidine hydrochloride). None of the pharmacological treatments were significantly associated with a higher risk of all-cause mortality compared with placebo/control.
CONCLUSIONS AND RELEVANCE
This network meta-analysis demonstrated that haloperidol plus lorazepam might be the best treatment and ramelteon the best preventive medicine for delirium. None of the pharmacological interventions for treatment or prophylaxis increased the all-cause mortality.
Topics: Antipsychotic Agents; Delirium; Drug Therapy, Combination; Haloperidol; Humans; Indenes; Lorazepam; Network Meta-Analysis; Treatment Outcome
PubMed: 30810723
DOI: 10.1001/jamapsychiatry.2018.4365