Baclofen-Induced Neuro-Respiratory Toxicity in the Rat: Contribution of Tolerance and Characterization of Withdrawal Syndrome

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. Tolerance and withdrawal syndromes have been reported during prolonged treatment but their contribution to the variability of baclofen-induced neurotoxicity in overdose is unknown. We studied baclofen-induced effects on rat sedation, temperature, and ventilation and modeled baclofen pharmacokinetics and effect/concentration relationships aiming to investigate the consequences of repeated baclofen pretreatment and to characterize withdrawal syndrome. Baclofen-induced dose-dependent sedation (p <0.01), hypothermia (p <.001) and respiratory depression (p <.01) were altered in repeatedly baclofen-pretreated rats (p <.05). Repeatedly baclofen-pretreated rats did not exhibit respiratory depression following baclofen overdose due to limitations on baclofen-induced increase in inspiratory (p <.01) and expiratory times (p <.01). Only slight hypoxemia without respiratory acidosis was observed. Baclofen discontinuation resulted in hyperlocomotion and non-anxiogenic withdrawal symptoms. Regarding pharmacokinetics, repeated baclofen pretreatment increased the peak concentration (p <.05) and absorption constant rate (p <.05) and reduced the distribution volume (p <.0001) and elimination half-life (p <.05). Analysis of the effect/concentration relationships indicated that plasma baclofen concentration decreases more rapidly than all studied neuro-respiratory effects, in tolerant and non-tolerant rats. Taken together, our findings supported the role of brain distribution in baclofen-induced neurotoxicity expression and its probable involvement in tolerance-related attenuation in addition to physiological adaptations of ventilation. In conclusion, repeated pretreatment attenuates baclofen-attributed neurotoxicity in overdose and results in post-discontinuation withdrawal syndrome. Our findings suggest both pharmacodynamic and pharmacokinetic mechanisms whose relative contributions to the variability of baclofen-induced neurotoxicity in overdose remain to be established.

Pneumomediastinum: A case report of baclofen toxicity

“…Baclofen also blocks the inspiratory neurons of the pneumotaxic center's solitary tract nucleus, responsible for the automatic control of respiratory volume. It prevents phrenic nerve impulses from activating the diaphragm [ 10 ]. Overall, these findings support breathing difficulties and an increased risk of atelectasis in hypoxia [ 3 ].…”

Antiemetic effects of baclofen in a shrew model of postoperative nausea and vomiting: Whole‐transcriptome analysis in the nucleus of the solitary tract

“…In a separate study, 12 shrews were randomly assigned to two groups and treated as follows: the Baclofen group (n = 6), lower abdominal surgery followed by single‐dose 5 mg/kg intraperitoneal injection of baclofen (a GABA B receptor agonist); and the Vehicle group (n = 6), surgery followed by intraperitoneal injection of normal saline alone. The doses of drugs were determined in preliminary experiments based on previous reports 13,14 . Baclofen or normal saline was administered at 3 min before the start of the emetic behavioral test.…”

“…The doses of drugs were determined in preliminary experiments based on previous reports. 13,14 Baclofen or normal saline was administered at 3 min before the start of the emetic behavioral test.…”

Novel Agents for the Pharmacological Treatment of Alcohol Use Disorder

“…Baclofen's significant adverse side effects include drowsiness, sedation, headache, vertigo, confusion, perspiration, muscle stiffness and/or abnormal movements, slurred speech, and numbness [86][87][88]. Tolerance to baclofen may also develop with chronic administration [89,90]. Additionally, dose and sex may moderate baclofen tolerability and response; escalation of dosage in response to developing tolerance can increase sedative side effects, which affect women significantly more than men at the same dose [91].…”