Baclofen-induced encephalopathy in overdose - Modeling of the electroencephalographic effect/concentration relationships and contribution of tolerance in the rat

Abstract

Baclofen, a γ-amino-butyric acid type-B receptor agonist with exponentially increased use at high-dose to facilitate abstinence in chronic alcoholics, is responsible for increasing poisonings. Baclofen overdose may induce severe encephalopathy and electroencephalographic (EEG) abnormalities. Whether prior prolonged baclofen treatment may influence the severity of baclofen-induced encephalopathy in overdose has not been established. We designed a rat study to characterize baclofen-induced encephalopathy, correlate its severity with plasma concentrations and investigate the contribution of tolerance. Baclofen-induced encephalopathy was assessed using continuous EEG and scored based on a ten-grade scale. Following the administration by gavage of 116 mg/kg baclofen, EEG rapidly and steadily impaired resulting in the successive onset of deepening sleep followed by generalized periodic epileptiform discharges and burst-suppressions. Thereafter, encephalopathy progressively recovered following similar phases in reverse. Periodic triphasic sharp waves, non-convulsive status epilepticus and even isoelectric signals were observed at the most critical stages. Prior repeated baclofen administration resulted in reduced severity (peak: grade 7 versus 9; peak effect length: 382 ± 40 versus 123 ± 14 min, P = 0.008) and duration of encephalopathy (18 versus > 24 h, P = 0.0007), supporting the acquisition of tolerance. The relationship between encephalopathy severity and plasma baclofen concentrations fitted a sigmoidal E_max model with an anticlockwise hysteresis loop suggesting a hypothetical biophase site of action. The baclofen concentration producing a response equivalent to 50% of E_max was significantly reduced (8947 μg/L, ±11.3% versus 12,728 μg/L, ±24.0% [mean, coefficient of variation], P = 0.03) with prior prolonged baclofen administration. In conclusion, baclofen overdose induces early-onset and prolonged marked encephalopathy that is significantly attenuated by prior repeated baclofen treatment. Our findings suggest a possible role for the blood-brain barrier in the development of tolerance; however, its definitive involvement remains to be demonstrated.

Keywords: Baclofen; Effect/concentration relationship; Electroencephalography; Encephalopathy; Epileptic activity; Tolerance.