Muscle relaxant and neurotoxic activities of intrathecal baclofen in rats

Abstract

Intrathecal baclofen therapy by the continuous intrathecal infusion of baclofen has been shown to be an effective treatment for spasticity in patients with spinal cord injury, cerebral palsy, traumatic brain injury, multiple sclerosis and other disorders. To demonstrate the efficacy and safety of intrathecal baclofen therapy, we investigated the muscle relaxant and neurotoxic activities of intrathecal baclofen in rats, compared with intravenous baclofen. Intrathecal and intravenous administration of baclofen dose-dependently inhibited the anemic decerebrate rigidity with ED 50 values of 0.31 μg/animal (=1.1–1.3 μg/kg) and 0.43 mg/kg, respectively. Intrathecal administration of baclofen induced no noticeable changes in a spontaneous electroencephalogram at 30 μg/animal. Intravenous administration of baclofen induced an abnormal electroencephalogram with flat waves in all the animals and the no-observed-effect level was estimated to be 5 mg/kg. In some animals, intravenous administration of baclofen induced sporadic spikes or sharp waves with background flat waves, indicating inhibitory and excitatory effects on the central nervous system. In conclusion, intrathecal administration of baclofen dose-dependently inhibited anemic decerebrate rigidity in rats and the effective dose was more than 300 times lower than that of intravenous baclofen. The safety margin of intrathecal baclofen was greater than that of intravenous baclofen (≥97 versus 12). These results suggest that intrathecal baclofen therapy is superior to systemic baclofen therapy in both efficacy and safety.