A Retrospective Review of Supratherapeutic Modafinil Exposures

Modafinil is a non-amphetamine wakefulness-promoting agent used for the treatment of various sleep disorders characterized by excessive daytime sleepiness. There is little information in the medical literature with respect to supratherapeutic doses of this medication. We performed a retrospective review of the California Poison Control System database for all cases of single-substance ingestion of modafinil with follow-up to a known outcome for the time period 1998–2008. Data collected included age, gender, dose ingested, clinical effects, and medical outcome. There were a total of 87 patients, 53 (61%) of which were female. Patient ages ranged from 1.25 to 72 years with a mean of 30 years; 17 (20%) patients were aged 6 years or less. Thirty-three (38%) were intentional overdoses. Most commonly reported effects were tachycardia (n = 23), agitation (n = 14), anxiety (n = 11), headache (n = 8), hypertension (n = 6), dystonia/tremor (n = 6), and dizziness (n = 5). Forty-nine patients (56%) were managed at home, and 38 (44%) were managed in a healthcare setting. Therapies administered included activated charcoal (n = 8), benzodiazepines (n = 7), antihistamines (n = 2), intravenous fluids (n = 2), haloperidol (n = 2), and beta-blockers (n = 1). Effects were classified as none (n = 22), minor (n = 54), and moderate (n = 11). No major effects and no deaths occurred. Effects of modafinil overdose appear to be mild in most cases, with tachycardia and CNS symptoms predominating. Clinically significant effects requiring treatment occurred in a small number of patients.     

A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users

Rationale: Preclinical studies of the benzodiazepine antagonist flumazenil (Romazicon^®) have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use; when administered to animals chronically pretreated with benzodiazepines, flumazenil precipitates a withdrawal syndrome. However, few controlled clinical studies have been conducted. Objectives: The objective was to characterize the effects of flumazenil in long-term users of therapeutic doses of benzodiazepines. Methods: The acute physiological, participant-rated, and observer-rated effects of intravenously administered flumazenil (1 mg/70 kg) and caffeine (300 mg/70 kg; active drug control) were evaluated in an experimental group of 13 long-term users (mean 4.6 years) of low therapeutic doses (mean 11.2 mg/day diazepam equivalent) relative to a matched group of 13 volunteers without prior exposure to benzodiazepines in a double-blind, placebo-controlled, mixed design. Results: Whereas the experimental group did not differ from the control group with respect to the effects of placebo, and both groups showed some changes in response to caffeine (e.g., increased blood pressure and anxiety scores), only the experimental group showed considerable changes in physiological measures, participant ratings (e.g., increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch), and observer ratings in response to flumazenil; in addition, four participants developed panic attacks. Conclusions: This study clearly demonstrates that flumazenil can precipitate symptoms commonly associated with benzodiazepine withdrawal in chronic low-dose benzodiazepine users.     

Return Encounters in Emergency Department Patients Treated with Phenobarbital Versus Benzodiazepines for Alcohol Withdrawal

IntroductionPhenobarbital has been successfully used in the emergency department (ED) to manage symptoms of alcohol withdrawal, but few studies have reported outcomes for ED patients who receive phenobarbital and are discharged. We compared return encounter rates in discharged ED patients with alcohol withdrawal who were treated with benzodiazepines and phenobarbital.MethodsThis is a retrospective cohort study conducted at a single academic medical center utilizing chart review of discharged ED patients with alcohol withdrawal from July 1, 2016, to June 30, 2019. Patients were stratified according to ED management with benzodiazepines, phenobarbital, or a combination of both agents. The primary outcome was return ED encounter within three days of the index ED encounter. Multivariate logistic regression identified significant covariates of an ED return encounter.ResultsOf 470 patients who were discharged with the diagnosis of alcohol withdrawal, 235 were treated with benzodiazepines, 133 with phenobarbital, and 102 with a combination of both. Baseline characteristics were similar among the groups. However, patients who received phenobarbital were provided significantly more lorazepam equivalents compared to patients who received benzodiazepines alone. Treatment with phenobarbital, alone or in combination with benzodiazepines, was associated with significantly lower odds of a return ED visit within three days compared with benzodiazepines alone [AOR 0.45 (95% CI 0.23, 0.88) p = 0.02 and AOR 0.33 (95% CI 0.15, 0.74) p = 0.007].ConclusionsPatients who received phenobarbital for alcohol withdrawal were less likely to return to the ED within three days of the index encounter. Despite similar baseline characteristics, patients who received phenobarbital, with or without benzodiazepines, were provided greater lorazepam equivalents the ED.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13181-021-00863-2.     

Attenuation of Ethanol Withdrawal by Ceftriaxone-Induced Upregulation of Glutamate Transporter EAAT2

Alcohol withdrawal syndrome (AWS) is a potentially fatal outcome of severe alcohol dependence that presents a significant challenge to treatment. Although AWS is thought to be driven by a hyperglutamatergic brain state, benzodiazepines, which target the GABAergic system, comprise the first line of treatment for AWS. Using a rat model of ethanol withdrawal, we tested whether ceftriaxone, a β-lactam antibiotic known to increase the expression and activity of glutamate uptake transporter EAAT2, reduces the occurrence or severity of ethanol withdrawal manifestations. After a 2-week period of habituation to ethanol in two-bottle choice, alcohol-preferring (P) and Wistar rats received ethanol (4.0 g/kg) every 6 h for 3–5 consecutive days via gavage. Rats were then deprived of ethanol for 48 h during which time they received ceftriaxone (50 or 100 mg/kg, IP) or saline twice a day starting 12 h after the last ethanol administration. Withdrawal manifestations were captured by continuous video recording and coded. The evolution of ethanol withdrawal was markedly different for P rats vs Wistar rats, with withdrawal manifestations occurring >12 h later in P rats than in Wistar rats. Ceftriaxone 100 mg/kg per injection twice per day (200 mg/kg/day) reduced or abolished all manifestations of ethanol withdrawal in both rat variants and prevented withdrawal-induced escalation of alcohol intake. Finally, ceftriaxone treatment was associated with lasting upregulation of ethanol withdrawal-induced downregulation of EAAT2 in the striatum. Our data support the role of ceftriaxone in alleviating alcohol withdrawal and open a novel pharmacologic avenue that requires clinical evaluation in patients with AWS.     

Pharmacokinetic Evaluation of Intranasally Administered Vinyl Polymer-Coated Lorazepam Microparticles in Rabbits

The intranasal (IN) administration of lorazepam is desirable in order to maximize speed of onset and minimise carry-over sedation; however, this benzodiazepine is prone to chemical hydrolysis and poor airway retention, and thus, innovative epithelial presentation is required. The aim of this study was to understand how the in situ self-assembly of a mucoretentive delivery system, formed by the dissolution of vinyl polymer-coated microparticles in the nasal mucosa, would influence lorazepam pharmacokinetics (PK). IN administration of the uncoated lorazepam powder (particle size, 6.7 ± 0.1 μm) generated a biphasic PK profile, which was indicative of sequential intranasal and oral absorption (n = 6; dose, 5 mg/kg). Coating the drug with the vinyl polymer, MP1 (9.9 ± 0.5 μm with 38.8 ± 14.0%, w/w lorazepam) and MP2 (10.7 ± 0.1 μm with 47.0 ± 1.0%, w/w lorazepam), allowed rapid systemic absorption (MP1, T_max 14.2 ± 4.9 min; MP2, T_max 9.3 ± 3.8 min) in rabbits and modified the PK profiles in a manner that suggested successful nasal retention. The poly(vinyl pyrrolidone)-rich MP2 system provided the best comparative bioavailability, it prolonged the early-phase nasal drug absorption and minimised drug mucociliary clearance, which correlated well with the intermolecular hydrogen-bond-driven vinyl polymer interactions observed in vitro.KEY WORDS: intranasal, lorazepam, microparticles, pharmacokinetics, poly(vinyl alcohol)     

Long-term Alcohol Consumption Increases Pro-Matrix Metalloproteinase-9 Levels via Oxidative Stress

Matrix metalloproteinases (MMPs) play an important role in alcoholic liver disease. In this study, we evaluated the relationship between pro MMP-9 (pMMP-9) and oxidative stress in plasma of rat exposed to chronic alcohol consumption. Twenty four rats were divided into four groups. Rats in the control group (n = 6) were subjected to physiologic saline by intragastric (i.g.) route. Group Ethanol (n = 6) was given 1 ml of 80% ethanol (v/v) in distilled water through i.g. route. Group Vitamin E (Vit E), (n = 6) was given vitamin E (100 mg kg⁻¹ day⁻¹) by intra peritonealy. Group Vitamin E + Ethanol (n = 6) was given vitamin E 2 h before the administration of ethanol. At the end of 4 weeks, blood samples were taken and plasma malondialdehyde (MDA), protein carbonyls (PCs), aspartate aminotransferase (AST), tumor necrosis factor-α (TNF-α) and pMMP-9 levels were measured. Chronic ethanol administration increased the AST, MDA, PCs, TNF-α and pMMP-9 levels when compared to those in control group (p < 0.05, p < 0.01, p < 0.01, p < 0.05, p < 0.05, respectively). Vitamin E treatment was found to decrease lipid peroxidation and protein oxidation (p < 0.01, p < 0.01, respectively). Also TNF-α and pMMP-9 levels returned to normal by vitamin E treatment. Within all subjects, there was positive correlation between pMMP-9 levels and MDA, PCs levels (p = 0.045, r = 0.454; p = 0.004, r = 0.574, respectively). We conclude that since antioxidant supplementation decreases the alcohol-induced pMMP-9 levels, oxidative stress could be one of the mediators of the generation of MMP-9.     

Flumazenil-precipitated withdrawal in healthy volunteers following repeated diazepam exposure

Rationale Parametric preclinical studies of the benzodiazepine antagonist flumazenil have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use. However, few parametric studies have been conducted in human participants.Objective This study was designed to assess the effect of duration of benzodiazepine exposure on the intensity of flumazenil-precipitated withdrawal in healthy volunteers.Method Participants were randomly assigned to receive either oral diazepam (15 mg/70 kg; n=10) or placebo (n=8) capsules nightly for 28 days. Effects of flumazenil (1 mg/70 kg, intravenously administered) were assessed in challenge sessions conducted before capsule ingestion, and after 1, 7, 14, and 28 days of capsule ingestion.Results Flumazenil produced a profile of participant-rated effects consistent with benzodiazepine withdrawal that peaked immediately after completion of the 5-min flumazenil injection and rapidly dissipated thereafter. The magnitude of these effects was comparable after 7, 14, and 28 days of diazepam. Flumazenil also produced modest elevations in blood pressure and decreases in skin temperature in the diazepam group, both of which were sustained throughout the approximate 60-min session.Conclusions These findings support previous human research studies indicating that flumazenil precipitates withdrawal after short chronic exposure to benzodiazepines and suggests that duration of exposure does not influence the intensity of withdrawal beyond the first week of exposure.     

Chronic Treatment with Naltrexone Prevents Memory Retention Deficits in Rats Poisoned with the Sarin Analog Diisopropylfluorophosphate (DFP) and Treated with Atropine and Pralidoxime

Humans and rats poisoned with sarin develop chronic neurological disabilities that are not prevented with standardized antidotal therapy. We hypothesized that rats poisoned with the sarin analogue diisopropylfluorophosphate (DFP) and resuscitated with atropine and pralidoxime would have long-term memory deficits that were preventable with naltrexone treatment. Long Evans rats (250–275 g) were randomized to: DFP (N = 8): single subcutaneous (SC) injection of DFP (5 mg/kg). Treatment (N = 9): DFP (5 mg/kg) followed by chronic naltrexone (5 mg/kg/day × 12 weeks). Control (N = 12): single SC injection of isopropyl alcohol, (DFP vehicle) followed by chronic naltrexone (5 mg/kg/day). If toxicity developed after injection, antidotal therapy was initiated with atropine (2 mg/kg) and pralidoxime (25 mg/kg) and repeated as needed. After 12 weeks, rats underwent testing for place learning (acquisition) across 5 days of training using the Morris Water Maze. On day 6 a memory retention test was performed. Statistical analysis was performed using IBM SPSS Statistics. Rats receiving DFP rapidly developed toxicity requiring antidotal rescue. No differences in acquisition were seen between the DFP vs. DFP + naltrexone rats. During memory testing, DFP-poisoned rats spent significantly less time (29.4 ± 2.11 versus 38.5 ± 2.5 s, p < 0.05) and traveled less distance (267 ± 24.6 versus 370 ± 27.5 cm, p < 0.05) in the target quadrant compared to the treatment group. Treatment rats performed as well as control rats (p > 0.05) on the test for memory retention. Poisoning with DFP induced impaired memory retention. Deficits were not prevented by acute rescue with atropine and pralidoxime. Chronic naltrexone treatment led to preserved memory after DFP poisoning.     

Clinical Experience of Life-Threatening Dabigatran-Related Bleeding at a Large,Tertiary Care,Academic Medical Center: a Case Series

Introduction

Dabigatran, an oral direct thrombin inhibitor, is FDA approved for the prevention of stroke in patients with nonvalvular atrial fibrillation. No agent exists for the reversal of dabigatran-related major bleeding. Prothrombin complex concentrate (PCC) has been studied in reversal but was not shown to affect the surrogate markers of bleeding such as the thrombin time, ecarin clotting time, or activated partial thromboplastin time (aPTT). Recombinant factor VIIa (rFVIIa) may provide benefit in patients with life-threatening or major bleeding; however, it has not been studied in dabigatran-related bleeding. PCC and rFVIIa are agents utilized at our institution for major bleeding in patients receiving anticoagulant therapy. Due to the high cost and thrombogenic risk of both rVIIa and PCC and lack of a clear reversal strategy, we reviewed the management of all reported cases of dabigatran-related bleeding.

Methods

This was a retrospective chart review of patients admitted to UMass Memorial Medical Center with a bleeding event and also receiving dabigatran therapy.

Results

Eleven patients on dabigatran admitted for bleeding were identified. Seven were admitted for an intracranial hemorrhage (ICH) and four for a gastrointestinal hemorrhage (GIH). The baseline characteristics are as follows: mean age was 74.55 years (range, 63–89), and seven were male. Admission mean hemoglobin was 11.88 g/dl (range, 6.1–18), mean international normalized ratio (INR) was 2.2 (range, 1.1–7.1), and mean aPTT was 42.21 s (range, 36–81.4). Interventions received included fresh frozen plasma (n = 6), platelets (n = 3), packed red blood cells (n = 4), rFVIIa (n = 2), intravenous fluids (n = 10), surgical intervention (n = 3), and dialysis (n = 2). No patients received PCC. Four patients survived in the ICH group, and four patients survived in the GIH group.

Conclusion

Reversal strategies for dabigatran-related bleeding events at our institution are highly variable. Intracranial hemorrhage in patients on dabigatran was associated with 43 % mortality. Patients with severe dabigatran-related bleeding may benefit from a standardized approach to treatment.     

Reversal of triazolam- and zolpidem-induced memory impairment by flumazenil

The effects of flumazenil, a benzodiazepine receptor antagonist, on triazolam- and zolpidem-induced memory impairment were investigated. Sixty subjects received oral triazolam 0.5 mg, zolpidem 20.0 mg, or placebo at 10 a.m. (n=20 per drug). Ninety minutes later, half of the subjects (n=10) in each oral drug group were administered flumazenil 1.0 mg, while the remaining half received placebo (normal saline), through indwelling venous catheters. Learning/memory tests (including Simulated Escape, Restricted Reminding, Paired-Associates, and Repeated Acquisition) were administered at that time, and at 1.5-h intervals over the next 6 h. Triazolam/placebo and zolpidem/placebo drug combinations impaired memory on all tests (allPs<0.05). However, the triazolam/flumazenil and zolpidem/flumazenil groups showed no evidence of impairment during any test session. These results demonstrate that flumazenil 1.0 mg rapidly and lastingly reverses memory impairment caused by agonists of the benzodiazepine receptor. Furthermore, nonsignificant trends suggested that performance of the placebo/flumazenil group was consistently better than that of the placebo/placebo group, denoting a possible role of endogenous benzodiazepine agonists in natural sleep/wake processes.     

Impact of an alcohol withdrawal syndrome practice guideline on surgical patient outcomes

STUDY OBJECTIVE: To standardize treatment of alcohol withdrawal syndrome (AWS) in surgical patients using an AWS practice guideline with a symptom-triggered approach. DESIGN: Prospective interventional (pilot group) and retrospective (comparison group). SETTING: University teaching hospital. PATIENTS: Thirty-eight trauma, orthopedic, and general surgery patients identified at risk for AWS in the pilot group, and 34 patients who were managed using nonstandardized approaches. INTERVENTIONS: At-risk patients in the pilot group were assessed using the AWS Type Indicator. They received lorazepam, clonidine, or haloperidol, based on AWS Type Indicator assessment and AWS practice guideline criteria. MEASUREMENTS AND MAIN RESULTS: A standardized symptom-triggered approach to managing AWS was expected to decrease the use of benzodiazepines, avoid undertreatment of adrenergic hyperactivity and delirium, decrease the need for sitters and physical restraints, and reduce hospital length of stay. Pilot patients received a mean of 23 mg less benzodiazepine (p=0.01), 0.1 mg more clonidine (p=0.01), and 20 mg less haloperidol (p=0.06) than comparison patients. Pilot patients also required significantly fewer sitter hours (p=0.04) and hours of restraint use (p=0.09) than comparison patients. No significant differences were found between groups for length of stay (p=0.77). CONCLUSIONS: This pilot project suggests that trauma, orthopedic, and general surgery patients at risk for AWS can be safely and effectively managed with a standardized, symptom-triggered approach. Moreover, this approach decreased the amounts of benzodiazepines and haloperidol administered to patients at risk for AWS.     

Propofol for Treatment of Refractory Alcohol Withdrawal Syndrome: A Review of the Literature

The authors evaluated all available evidence on the use of propofol as an adjuvant for the treatment of resistant alcohol withdrawal syndrome (AWS) in comparison to other therapies. A comprehensive PubMed search (1966–December 2015) was conducted using the search terms propofol, alcohol withdrawal, and drug therapy. Articles were cross‐referenced for other citations. Clinical studies, case series, and case reports published in the English language assessing the use of propofol in adult patients for treatment of AWS were reviewed for inclusion. Propofol is a sedative‐hypnotic that exerts its actions through agonism of GABA_A receptors at a different binding site than benzodiazepines and reduces glutamatergic activity through N‐methyl‐d ‐aspartase (NMDA) receptor blockade. Dosages from 5 to 100 μg/kg/minute reduced AWS symptoms with frequent development of hypotension and requirement for mechanical ventilation. Patients on propofol often experienced longer durations of mechanical ventilation and length of stay, which may be attributed to more‐resistant cases of AWS. When propofol was compared with dexmedetomidine as adjuncts in AWS, both agents showed similar benzodiazepine‐ and haloperidol‐sparing effects. Dexmedetomidine was associated with more numerical rates of bradycardia, while propofol was associated with more numerical instances of hypotension. Dexmedetomidine was used more frequently in nonintubated patients. The available data assessing the utility of propofol for AWS exhibited significant heterogeneity. Propofol may be useful in a specific population of patients with AWS, limited to those who are not clinically responding to first‐line therapy with benzodiazepines. Specifically, propofol should be considered in patients who are refractory to or not candidates for other adjuvant therapies, patients already requiring mechanical ventilation, or those with seizure activity or refractory delirium tremens. In severe, refractory AWS, adjuvant therapy with propofol may be considered but requires further research to recommend its use either preferentially or as monotherapy.     

Stereoselective discriminative stimulus effects of zopiclone in rhesus monkeys

Abstract Rationale. The behavioral effects of racemic zopiclone are similar to those of benzodiazepines that positively modulate GABA at the GABA_A receptor complex; however, it is not clear how enantiomers or metabolites of zopiclone contribute to the benzodiazepine-like behavioral effects of racemic zopiclone. Objectives. Racemic zopiclone, its (R)- and (S)- enantiomers, and the (S)-N-desmethyl metabolite, were evaluated for discriminative stimulus effects in untreated and diazepam treated rhesus monkeys. Methods. One group of monkeys discriminated the benzodiazepine midazolam and another group, treated daily with the benzodiazepine diazepam (5.6 mg/kg, PO), discriminated the benzodiazepine antagonist flumazenil. Results. (RS)-Zopiclone (0.32–17.8 mg/kg) and (S)-zopiclone (0.1–10 mg/kg) substituted with similar potencies for midazolam (≥80% midazolam-appropriate responding). The midazolam-like discriminative stimulus effects of (RS)-zopiclone were antagonized by flumazenil (pK _B=7.52). (R)-Zopiclone occasioned a maximum 45% midazolam-appropriate responding at a dose of 100 mg/kg; (S)-desmethylzopiclone produced saline-appropriate responding up to a dose of 100 mg/kg. All four test compounds occasioned predominantly vehicle-appropriate responding in diazepam treated monkeys discriminating flumazenil. (RS)-Zopiclone (10 mg/kg) attenuated the discriminative stimulus effects of flumazenil in diazepam treated monkeys. Conclusions. These results clearly demonstrate that in rhesus monkeys the discriminative stimulus effects of zopiclone are stereoselective and qualitatively similar to those of midazolam. These results fail to show any benzodiazepine-like or benzodiazepine antagonist-like discriminative stimulus effects for (S)-N-desmethylzopiclone, suggesting that any behavioral (e.g. anxiolytic) effects of this compound are not the result of actions at benzodiazepine receptors. Electronic Publication     

Benzodiazepine dependence and its treatment with low dose flumazenil

Globally benzodiazepines remain one of the most prescribed medication groups, especially in the primary care setting. With such high levels of prescribing it is not surprising that benzodiazepine dependence is common, cutting across all socioeconomic levels. Despite recognition of the potential for the development of iatrogenic dependence and the lack of any effective treatment, benzodiazepines continue to be widely prescribed in general practice. Conventional dependence management, benzodiazepine tapering, is commonly a protracted process over several weeks or months. It is often associated with significant withdrawal symptoms and craving leading to patient drop out and return to use. Accordingly, there is a worldwide need to find effective pharmacotherapeutic interventions for benzodiazepine dependence. One drug of increasing interest is the GABA_A benzodiazepine receptor antagonist/partial agonist, flumazenil. Multiple bolus intravenous infusions of low dose flumazenil used either with or without benzodiazepine tapering can reduce withdrawal sequelae, and/or longer term symptoms in the months following withdrawal. Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for 4 days significantly reduces acute benzodiazepine withdrawal sequelae. The subcutaneous infusion was shown to be tissue compatible so the development of a longer acting (i.e. several weeks) depot flumazenil formulation has been explored. This could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae. Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future.     

Longitudinal imaging of metabotropic glutamate 5 receptors during early and extended alcohol abstinence

Chronic alcohol use has important effects on the glutamate system. The metabotropic glutamate 5 (mGlu5) receptor has shown promise in preclinical models as a target to reduce drinking-related behaviors and cue-induced reinstatement, motivating human studies of mGlu5 receptor negative allosteric modulators. The goal of this work was to measure levels of mGlu5 receptor availability with positron emission tomography (PET) imaging using the mGlu5 receptor-specific radiotracer [¹⁸F]FPEB during early and extended alcohol abstinence. Subjects who met DSM-5 criteria for alcohol use disorder (AUD; n = 17) were admitted inpatient for the study duration. [¹⁸F]FPEB PET scans were acquired first during early abstinence (6 ± 4 days after last drink) and a second time during extended abstinence (n = 13; 27 ± 6 days after last drink). A single scan was acquired in healthy controls matched for sex and smoking status (n = 20). [¹⁸F]FPEB total volumes of distribution (V_T) corrected for partial volume effects were measured using equilibrium analysis throughout the brain. A linear mixed model controlling for smoking status and sex identified significantly higher [¹⁸F]FPEB V_T in AUD subjects at early abstinence compared to controls (F_(1,32) = 7.23, p = 0.011). Post-hoc analyses revealed this effect to occur in cortical brain regions. No evidence for significant changes in [¹⁸F]FPEB V_T over time were established. These findings provide human evidence consistent with a robust preclinical literature supporting mGlu5 receptor drugs as pharmacotherapies for AUD.Subject terms: Addiction, Predictive markers     

Evaluation of an alcohol withdrawal protocol and a preprinted order set at a tertiary care hospital

Background:

Alcohol withdrawal protocols involving symptom-triggered administration of benzodiazepine have been established to reduce the duration of treatment and the cumulative benzodiazepine dose (relative to usual care). However, the effects of a protocol combining fixed-schedule and symptom-triggered benzodiazepine dosing are less clear.

Objective:

To assess the efficacy and safety of a combination fixed-scheduled and symptom-triggered benzodiazepine dosing protocol for alcohol withdrawal, relative to usual care, for medical inpatients at a tertiary care hospital.

Methods:

A chart review of admissions to the internal medicine service for alcohol withdrawal was conducted to compare treatment outcomes before (October 2005 to April 2007) and after (October 2007 to April 2009) implementation of the combination protocol. The primary outcome was duration of benzodiazepine treatment for alcohol withdrawal. The secondary outcomes were cumulative benzodiazepine dose administered, safety implications, and use of adjunctive medications.

Results:

A total of 159 patients met the inclusion criteria. Assessable data were available for 71 charts from the pre-implementation period and 72 charts from the post-implementation period. The median duration of benzodiazepine treatment was 91 h before implementation and 57 h after implementation (p < 0.001). Use of the protocol was also associated with a significant reduction in severe complications of alcohol withdrawal (50% versus 33%, p = 0.019), median cumulative benzodiazepine dose (in lorazepam equivalents) (20.0 mg versus 15.5 mg, p = 0.026), and use of adjunctive medications (65% versus 38%, p = 0.001). The incidence of serious adverse outcomes of treatment with benzodiazepines was not significantly different between the 2 groups.

Conclusions:

Implementation of an alcohol withdrawal protocol with a combination of fixed-schedule and symptom-triggered benzodiazepine dosing in a medical ward was associated with a shorter duration of benzodiazepine use and a lower incidence of severe complications of alcohol withdrawal.     

Rapid Delivery of Diazepam from Supersaturated Solutions Prepared Using Prodrug/Enzyme Mixtures: Toward Intranasal Treatment of Seizure Emergencies

Current treatments for seizure emergencies, such as status epilepticus, include intravenous or rectal administration of benzodiazepines. While intranasal delivery of these drugs is desirable, the small volume of the nasal cavity and low drug solubility pose significant difficulties. Here, we prepared supersaturated diazepam solutions under physiological conditions and without precipitation, using a prodrug/enzyme system. Avizafone, a peptide prodrug of diazepam, was delivered with—Aspergillus oryzae (A.O.) protease, an enzyme identified from a pool of hydrolytic enzymes in assay buffer, pH 7.4 at 32°C. This enzyme converted avizafone to diazepam at supersaturated concentrations. In vitro permeability studies were performed at various prodrug/enzyme ratios using Madin-Darby canine kidney II-wild type (MDCKII-wt) monolayers, a representative model of the nasal epithelium. Monolayer integrity was examined using TEER measurement and the lucifer yellow permeability assay. Prodrug/drug concentrations were measured using HPLC. Enzyme kinetics with avizafone-protease mixtures revealed K_M = 1,501 ± 232 μM and V_max = 1,369 ± 94 μM/s. Prodrug-protease mixtures, when co-delivered apically onto MDCKII-wt monolayers, showed 2–17.6-fold greater diazepam flux (S = 1.3–15.3) compared to near-saturated diazepam (S = 0.7). Data for prodrug conversion upstream (apical side) and drug permeability downstream (basolateral side) fitted reasonably well to a previously developed in vitro two compartment pharmacokinetic model. Avizafone-protease mixtures resulted in supersaturated diazepam in less than 5 min, with the rate and extent of supersaturation determined by the prodrug/enzyme ratio. Together, these results suggest that an intranasal avizafone-protease system may provide a rapid and alternative means of diazepam delivery.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9596-5) contains supplementary material, which is available to authorized users.KEY WORDS: avizafone enzyme activation, diazepam delivery, hydrophobic drugs, MDCK monolayers, rapid absorption, seizure emergencies, supersaturation