Topics in Clinical Pharmacology: Flumazenil, a Benzodiazepine Antagonist

Longmire, Atkinson W.; Seger, Donna

doi:10.1097/00000441-199307000-00012

Cited by 20 publications

(5 citation statements)

References 29 publications

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“…In Spain, 80% of the flumazenil-treated were reported non-comatose (9), and a Canadian study concluded that empirical use of flumazenil in intentional drug overdose of unknown aetiology was not cost effective (19). Flumazenil may cause seizures (20), but others consider flumazenil to be a safe and valid diagnostic tool (21). In our study, there were not significantly more convulsions in the group receiving only flumazenil, indicating that the present (over-) use was not harmful at the doses typically utilized.…”

Section: Use Of Antidotesmentioning

confidence: 99%

Acute poisonings treated in hospitals in Oslo: A one-year prospective study (II): Clinical outcome

Heyerdahl

Bjornas

Hovda

et al. 2008

Clinical Toxicology

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Section: Use Of Antidotesmentioning

confidence: 99%

Acute poisonings treated in hospitals in Oslo: A one-year prospective study (II): Clinical outcome

Heyerdahl

Bjornas

Hovda

et al. 2008

Clinical Toxicology

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“…A typical total dose is between 0.3 and 0.6 mg. 40 This titrated administration decreases the likelihood of failed antagonism, which has been reported in 5% of reversals in humans and could reflect inadequate agonist/antagonist ratio at the site of action, based on individual variability. 36 One rabbit in our study did not achieve ReRR as expected after FLU despite plasma drug levels comparable to the rest of the sample population. Administration of FLU in veterinary patients is mostly reported as single injection.…”

Section: Midazolam Alone (N = 13)mentioning

confidence: 50%

A Pharmacokinetic-Pharmacodynamic Study of Intravenous Midazolam and Flumazenil in Adult New Zealand White—Californian Rabbits (Oryctolagus cuniculus)

Rousseau-Blass

Cribb

Beaudry

et al. 2021

j am assoc lab anim sci

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Flumazenil, a competitive GABAAreceptor antagonist, is commonly used in rabbits to shorten sedation or postanestheticrecovery after benzodiazepine administration. However, no combined pharmacokinetic (PK) and pharmacodynamic (PD)data are available to guide its administration in this species. In a prospective, randomized, blinded, crossover study design,the efficacy of IV flumazenil (FLU; 0.05 mg/kg) or saline control (SAL; equal volume) to reverse the loss of righting reflex(LORR) induced by IV midazolam (1.2 mg/kg) was investigated in 15 New Zealand white rabbits (2.73 to 4.65 kg, 1 y old). Rabbits were instrumented with arterial (central auricular artery) and venous (marginal auricular vein) catheters. Afterbaseline blood sampling, IV midazolam was injected (T0). Flumazenil or saline (FLU/SAL) was injected 30 s after LORR.Arterial blood samples were collected at 1 and 3 min after midazolam injection, and at 1, 3, 6, 10, 15, 21, 28, 36, 45 and 60 min after injection with flumazenil. Plasma samples for midazolam, 1-OH-midazolam and flumazenil were analyzed using high performance liquid chromatography-high-resolution mass spectrometry and the time to return of righting reflex (ReRR) was compared between groups (Wilcoxon test). FLU terminal half-life, plasma clearance and volume of distribution were 26.3min [95%CI: 23.3 to 29.3], 18.74 mL/min/kg [16.47 to 21.00] and 0.63 L/kg [0.55 to 0.71], respectively. ReRR was 25 times faster in rabbits treated with FLU (23 [8 to 44] s) compared with SAL (576 [130 to 1141] s; 95%CI [425 to 914 s]). Return of sedation(lateral recumbency) occurred in both groups (7/13 in FLU; 12/13 in SAL) with return of LORR in a few animals (4/13 in FLU; 7/13 in SAL) at 1540 [858 to 2328] s. In the population and anesthesia protocol studied, flumazenil quickly and reliably reversed sedation induced by midazolam injection. However, the potential return of sedation after flumazenil administration warrants careful monitoring in the recovery period.

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“…-Optimization of the use of any adjuvants such as antidepressants and non-narcotic drugs The antiepileptic prophylaxis has made it possible to reduce the risk of convulsive episodes to less than 2% of the cases treated and is then continued after discharge for 2-3 weeks while clonazepam is possibly used only for the first 2-3 days and then suspended. Main exclusion criteria are pregnancy, severe uncompensated mental disorders and untreated poly-abuse of other substances, as well as patients with less severe BZD dependence (daily intake of less than five times the DDD) [21]. The presence of medical comorbidities, including epilepsy and substance abuse under appropriate treatment are not exclusion criteria.…”

Section: Discussionmentioning

confidence: 99%

Use of Flumazenil in Detoxification of High-Dose Benzodiazepine Users: A Mini Review of Pharmacological Basis and Clinical Studies

Morgillo¹,

Morgillo²

2022

J Drug Addi Ther

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Introduction: The use of benzodiazepines (BDZ) is notoriously associated with significant long-term problems and it is estimated that the long-term users (LTU) in Italy are over 3 million people, including many elderly people. Unfortunately, 40 to 80% of the LTUs develop dependence and many also have tolerance, with the need for a progressive increase in the daily dosage up to the point of tolerating daily megadoses. In recent years, the off-label use of continuous infusion subcutaneous flumazenil has established itself as a viable approach for rapid hospital detoxification of these sometimes very complex clinical cases. The purpose of the article is, starting from the pharmacological and biochemical bases, to describe the mechanism of action, the areas of applicability and the possible criticalities by analyzing the Italian data. Materials and Methods: A computerized research was carried out for the articles to be inserted through use of international databases PUBMED and RESEARCHGATE by typing in keywords such as “flumazenil, high dose benzodiazepine users, use of flumazenil for benzo detoxification” and related articles. We also used the PUBCHEM database to describe some chemical and pharmacological characteristics of flumazenil. Both Italian and international research articles have been selected, starting from 1980 to today. Discussion and Conclusions: The use of flumazenil in slow infusion remains off-label but, for almost 20 years, it has been in use (in Italy and beyond) to detoxify, in about a week of hospitalization, patients with equivalent daily doses of diazepam greater than 50 mg / day for more than 6 months (with a description of cases up to 350 mg / day of diazepam-equivalent). This would allow the GABA-Argic receptor resensitization in a short time and with minimal or absent withdrawal symptoms, being able to suspend megadoses of BDZ in a very short time. In Italy this approach is still used to a limited extent and it cannot be said that it is absolutely the best method but the analysis of various endpoints in published studies, such as acute withdrawal discomfort, discharge without prescription of benzodiazepines and relapses in the first 6-12 months of discharge, certainly makes us reflect on the possibility of extending this approach to various territorial hospitals.

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Topics in Clinical Pharmacology: Flumazenil, a Benzodiazepine Antagonist

Cited by 20 publications

References 29 publications

Acute poisonings treated in hospitals in Oslo: A one-year prospective study (II): Clinical outcome

Acute poisonings treated in hospitals in Oslo: A one-year prospective study (II): Clinical outcome

A Pharmacokinetic-Pharmacodynamic Study of Intravenous Midazolam and Flumazenil in Adult New Zealand White—Californian Rabbits (Oryctolagus cuniculus)

Use of Flumazenil in Detoxification of High-Dose Benzodiazepine Users: A Mini Review of Pharmacological Basis and Clinical Studies

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