Toxicology Brief: Baclofen overdose in dogs


Toxicology Brief: Baclofen overdose in dogs

May 01, 2004

Baclofen (Lioresal—Novartis) is a centrally acting skeletal muscle relaxant. It is used to control spasticity and pain in people with multiple sclerosis and spinal disorders. Baclofen has also been used extralabel in dogs (1 to 2 mg/kg orally t.i.d.) to treat urinary retention by reducing urethral resistance.1 It is available in 10- and 20-mg tablets and as a parenteral injection.

Mechanism of action and pharmacokinetics

Baclofen mimics γ-aminobutyric acid (GABA) within the spinal cord and works by depressing monosynaptic and polysynaptic afferent reflex activity at the spinal cord level, thereby reducing skeletal muscle spasm caused by upper motor neuron lesions.2 The overall effect is a flaccid paralysis of skeletal muscles. When administered intrathecally, baclofen also inhibits substance P, a stimulatory compound within the brainstem, and it reduces myocardial epinephrine and norepinephrine content.2,3 At oral therapeutic concentrations, baclofen has virtually no central nervous system effects because of its poor ability to cross the blood-brain barrier, but in overdose situations, central nervous system effects are common.4

Baclofen is rapidly and completely absorbed from the gastrointestinal tract and reaches peak blood concentrations in two or three hours in people; however, in an overdose situation, absorption may be prolonged over several hours.2,5 The onset of clinical signs after acute oral exposure may be rapid (within 30 to 60 minutes) or may be delayed for several hours.2 In a survey of 40 dogs with baclofen toxicosis, the onset of signs occurred as early as 15 minutes after exposure and as late as seven hours after exposure (average of 1.9 hr) (ASPCA Animal Poison Control Center [APCC] Database: Unpublished data, 1994-2004).

The half-life of baclofen in people is two and a half to four hours, but in overdose situations the half-life has been reported to increase to as much as 34 hours because of saturation of metabolic and elimination mechanisms.5 The duration of clinical signs in animals with baclofen intoxication has varied from several hours to several days.4 Signs can continue long after serum baclofen concentrations have returned to normal because of the slow clearance from the central nervous system (ASPCA APCC Database: Unpublished data, 1994-2004). Baclofen has low protein-binding (30%) and a wide volume of distribution. About 80% of the drug is eliminated unchanged in the urine, with 15% to 20% undergoing hepatic metabolism and biliary excretion.4,6 Baclofen is principally metabolized by deamination in the liver, but there is also some deamination in the renal tubules.6

Clinical signs and toxicity

Table 1: Clinical Signs of Baclofen Toxicosis
Most cases of baclofen toxicosis reported to the ASPCA APCC have involved dogs ingesting their owners' medication (ASPCA APCC Database: Unpublished data, 1994-2004). The most common clinical signs of toxicosis are vomiting, ataxia, and vocalization or disorientation, but the most life-threatening signs are dyspnea, respiratory arrest, and seizures. Dyspnea and respiratory arrest are secondary to paralysis of the diaphragm and intercostal muscles. The mechanism for baclofen-induced seizures is thought to be decreased GABA release from presynaptic neurons, resulting in excessive postsynaptic firing.4 Other frequent clinical signs of baclofen toxicosis include salivation, depression, coma, weakness, recumbency, and hypothermia. Hypotension, bradycardia, hyperactivity or agitation, tremors, panting, mydriasis, diarrhea, respiratory arrest, pulmonary edema, and death have been reported less frequently (ASPCA APCC Database: Unpublished data, 1994-2004) (Table 1).

The oral LD50 in rats and mice is high (145 and 200 mg/kg, respectively),6 but dogs appear to be more sensitive. Doses as low as 1.3 mg/kg caused vomiting, depression, and vocalizing in a 3-month-old rottweiler (ASPCA APCC Database: Unpublished data, 1994-2004). There are no established lethal doses in dogs, but per the ASPCA APCC database, deaths in dogs have occurred at doses estimated to be between 8 and 16 mg/kg.