A randomised, controlled trial of cognitive and psychomotor recovery from midazolam sedation following reversal with oral flumazenil

Abstract

Flumazenil is traditionally administered intravenously to reverse the adverse effects of over sedation with benzodiazepines. The aim of this study was to test postoperative cognitive and psychomotor recovery from midazolam conscious sedation, following reversal with orally administered flumazenil. It was hypothesised that when administered by the oral route, flumazenil may enhance recovery over a prolonged period, thus increasing safety. Eighteen patients requiring intravenous midazolam sedation for dental treatment completed a randomised, double-blind, crossover trial. Following treatment the patients' sedation was reversed using either flumazenil or saline (as placebo), administered orally, on alternate appointments. Assessment of mood and cognitive function were undertaken using ClinPhone.cdr(R), a highly sensitive and specific computerised battery of cognitive tests administered by telephone prior to sedation and every hour for seven hours post reversal. Results indicate that within 20 min of administration, oral flumazenil is capable of partially reversing some cognitive and psychomotor impairments but the attentional and stimulus discrimination effects of midazolam sedation still remain.

Cognitive testing in early phase clinical trials: outcome according to adverse event profile in a Phase I study

“…Cognitive testing was initiated 5 min postdosing and identified significant decline on tests of simple and choice reaction time, immediate and delayed recall, as well as word and picture recognition tasks when compared to a no-drug control condition. Other recent studies have observed similar results (Girdler et al, 2002;Rogers et al, 2002). The timecourse of oral midazolam is well-established, with time to maximum plasma concentration (C max ) occurring within 1 hr post-dosing, and a good correlation observed between plasma levels and clinical effects (Kanto, 1985).…”

Tolerability of Midazolam to treat acute agitation in elderly demented patients: A systematic review

“…Midazolam seems to be a suitable pharmacological agent for the treatment of agitation in this population, considering that the preferred drugs are those with short-term effectiveness that contribute to tranquilization but do not delay recovery; all the more so as an effective antidote exists. 45 The two main adverse reactions reported in our review appear to be more common in the populations of patients with mean age over 60 years but also in the situations where Midazolam was used in combination with other drugs. However, rates of these adverse effects remain lower than those described with neuroleptic drugs whose adverse effects rates are age-dependent and not dose-dependent.…”

“…Midazolam seems to be a suitable pharmacological agent for the treatment of agitation in this population, considering that the preferred drugs are those with short‐term effectiveness that contribute to tranquilization but do not delay recovery; all the more so as an effective antidote exists …”

Pharmacokinetics and Safety of Sublingual Flumazenil (CRLS035) in Healthy Adults (Potential Therapy for Hepatic Encephalopathy)

“…Flumazenil is currently available only for intravenous (IV) injection and in a low concentration formulation, a fact that limits its use for some important indications [9]. However, it was found to be effective when used by other routes of administration such as oral [10][11][12] , intranasal [13,14] , intraoral injection [15] , endotracheal [16] , and sublingual [17] . The onset of flumazenil action following IV injection is rapid and effective as shown for the treatment of HE [6,7].…”