Neurotoxicity following prolonged therapy is most often related to cumulative dose and duration of treatment. Most dogs that develop neurologic signs secondary to metronidazole administration have received weeks to months of therapy, but I have seen possible toxicity after short-term therapy at relatively low dosages (<60 mg/kg/day). In general, higher dosages may produce signs in a shorter time period than moderate to low dosages. Reversible CNS dysfunction may produce signs including ataxia, recumbency, opisthotonus, positional nystagmus, muscle spasms and occasionally seizures.

The mechanisms of metronidazole neurotoxicity are unknown, but proposed mechanisms include inhibition of neuronal protein synthesis by binding to RNA and thiamine antagonism.

Most dogs affected with metronidazole neurotoxicity recover within one to two weeks of drug withdrawal. In a study in the Journal of Veterinary Internal Medicine [17:304-310], Evans et al suggest that dogs treated with diazepam had a more rapid resolution of clinical signs than dogs treated with supportive therapy alone. In this study, the authors evaluated potential differences in the recovery time between dogs with metronidazole toxicosis treated with diazepam and a similar group that did not receive diazepam as part of the therapy. Treated animals received 0.25-0.5 mg/kg diazepam IV followed by a similar dose PO TID for three days. The recovery time for treated versus untreated dogs was 38 hours and 11.6 days, respectively.

Results of this investigation demonstrated that diazepam appeared to facilitate and speed recovery for dogs with metronidazole toxicosis. From the similarities in the plasma half-life of metronidazole and the average response time of the diazepam-treated group, the authors speculated that once metronidazole is displaced from the benzodiazepine receptor by diazepam, normal metabolism of the displaced drug then occurs, resulting in the rapid clinical improvement observed. Furthermore, once metronidazole is displaced, the exogenous benzodiazepine not only restores, but also improves, normal benzodiazepine-induced chloride conductance, thereby enhancing an inhibitory effect on excitatory neurons.