12 Sept 2023
Lotfi El Bahri discusses the implications a specific human muscle relaxant can have on pets, using the case of a young poodle.
Lotfi El Bahri
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Image © cynoclub / Adobe Stock
You are presented with a six-month-old female poodle weighing 8.8kg at your emergency veterinary clinic.
A questionnaire to the dog’s owner revealed a prescription for baclofen and that the puppy ingested two 10mg tablets of the drug within two hours, before developing collapse with vocalisation, excessive salivation and muscle tremors.
Baclofen – or 4-amino-3-(4-chlorophenyl) butanoic acid – is a centrally acting skeletal muscle relaxant. It is a chiral molecule and has two potential configurations as (R)- and (S)- enantiomers.
Baclofen is marketed as a racemic mixture. The pharmaceutical activity of baclofen resides in the R- enantiomer only, which is 100 times more active than the S- enantiomer.
Baclofen, a lipid soluble derivative of β-aminobutyric acid (GABA), the main inhibitory neurotransmitter, is used for symptomatic relief of muscle spasm and to treat severe spasticity of cerebral and spinal origin in human medicine – especially in patients with multiple sclerosis, particularly to relieve flexor spasms and concomitant pain, or patients with spinal cord traumatic lesions or cerebral disorders.
It is administered orally or intrathecally via an implanted micro-infusion pump (more effective in relieving spasticity because baclofen is infused directly in the spinal fluid). Interest in high-dose baclofen treatment for alcohol dependence in chronic alcoholics has increased over the past few years.
In dogs, baclofen can be used extra label in dogs to treat urinary retention by decreasing striated urethral sphincter tone. It is also being recommended in treating gastro-oesophageal reflux disease because baclofen significantly reduces the duration of transient lower oesophageal sphincter relaxation. However, it is infrequently used because of its narrow margin of safety in dogs.
High oral toxicity. The oral median lethal doses (LD50s) of baclofen are 145mg/kg and 200mg/kg, in rats and mice, respectively.
Dogs are more sensitive. The therapeutic dose for dogs is 1 mg/kg to 2mg/kg orally every eight hours. Small amounts of baclofen can be toxic to dogs. Doses as low as 1.3mg/kg can cause vomiting, depressed mentation, vocalisation and ataxia. Deaths in dogs can occur at doses of 8mg/kg to 16mg/kg.
In cats, clinical signs have been reported with doses of baclofen as low as 3µg/kg to 10µg/kg. It is not recommended for use in cats.
In humans, the toxic effects of baclofen start at ingestion of as low as a single dose of 15mg. Patients with impaired renal function are at a higher risk of developing baclofen toxicosis, even at a lower dose.
Poisoning can occur when dogs accidentally ingest medication intended for their owners. The American Society for the Prevention of Cruelty to Animals’ Animal Poison Control Center named baclofen (number 3) in its top 10 deadliest pet toxins during 2021.
Baclofen is an agonist for GABAB receptors on pre-synaptic and post-synaptic neurons in the central nervous system (CNS) and peripheral nervous system. It mediates pre-synaptic and post-synaptic inhibition by decreasing calcium influx and increasing potassium influx, leading to hyper-polarisation of the neuronal membrane.
Distribution of the GABAB receptors includes the following:
Two major subunits of the GABAB receptor exist: GABAB1 and GABAB2, which are most often expressed at the same location. The GABAB receptor does not function without both these isoforms.
GABAB receptors expressed through the brain and the spinal cord are involved in various structures, including the regulation of the neurotransmitter systems, the respiratory control centre, the temperature-controlling centre and the anterior horn α-motoneurons; therefore, several mechanisms of toxicity baclofen exist.
High doses of baclofen cross the blood-brain barrier by passive diffusion and by large-neutral amino acid transporter 1 (one amino group, one carboxyl group; for example, glycine or tyrosine) found in the brain.
Significant drug concentrations can accumulate within the CNS, resulting in neurotoxic effects.
Baclofen seizures may result from the exertion of a complex regulation by GABAB receptors on both the GABAergic (main inhibitory neurotransmitter) and glutamatergic (main excitatory neurotransmitter) systems in the brain.
Baclofen penetrates into the CNS and may cause respiratory depressant effects due to activation of CNS GABAB receptors.
In acutely poisoned rats, baclofen significantly reduces the respiratory rate and rhythm, causing hypoventilation.
Multiple physiological mechanisms are involved in thermoregulation of the body, in coordination with the thermoregulation centre located in the anterior hypothalamus and the innervation of the brown adipose tissue (BAT). BAT burns carbohydrates and lipids to produce heat. Baclofen, as a GABA receptor agonist, replaces GABA, thereby directly inhibiting the hypothalamus nuclei, suppressing BAT activation. Suppressing BAT activation, baclofen in turn lowers the body temperature. In the rat, baclofen induces significant dose-dependent hypothermia.
Baclofen acts as a positive allosteric modulator (substances that modulate the effects of an agonist at a receptor) of GABAB receptors, facilitating the inhibition of α-motoneurons, a subtype of spinal motor neurons, located in the ventral horn of the spinal cord, that innervate skeletal muscle. Pre-synaptic and post-synaptic inhibition of GABAB receptors in the α-motoneurons within the spinal cord leads to a reduction in skeletal muscle tone and musculoskeletal weakness.
Cardiovascular toxicity, such as hypotension and bradycardia, noted in baclofen overdose are related to autonomic nervous system disturbances. The autonomic nervous system is a component of the peripheral nervous system that regulates physiological processes, including heart rate and blood pressure.
Baclofen overdose can cause hypoglycaemia in dogs. The exact mechanism is unknown, but hypoglycaemia may result from suppression of glucagon release by pancreatic α-cells.
Clinical signs of baclofen toxicosis may be rapid within 30 to 60 minutes, but can sometimes be delayed for several hours after ingestion and can persist for hours to days (delayed clearance of the drug from the CNS).
The general signs manifest as:
Hypoglycaemia (blood glucose levels below 3.3mmol/L) and hypokalaemia (reference range 3.5mEq/L to 5.5mEq/L) are also noted. Thrombocytopenia has been reported with prolonged partial thromboplastin time (PTT). Normal PTT is less than 20 seconds.
Death is a result of cardiopulmonary arrest.
In humans, ECG of a poisoned patient shows cardiac conduction abnormalities such as bradycardia, QT interval prolongation (normal QT criteria is 0.15 seconds to 0.25 seconds in dogs, depending on heart rate) and first degree heart block.
Prolongation of the QT interval is associated with high risk of ventricular arrhythmias and sudden cardiac death.
EEG of a poisoned patient shows abnormal waveforms, such as severe generalised slow triphasic waves with burst suppression that take up more than 50% of standard EEG.
Burst suppression is an EEG pattern observed in states of severely reduced brain activity that is characterised by periods of high-voltage electrical activity, alternating with periods of no activity in the brain.
No specific antidote exists. Baclofen toxicosis is a potentially life-threatening emergency. Treatment is aggressive and supportive care is intensive.
For controlling seizures, an IV catheter should be placed. Diazepam (0.5mg/kg to 2mg/kg IV bolus) should be administered and repeated, if necessary, within 20 minutes (serum half-life in dogs is 2.5 to 3.2 hours) and up to three times in a 24-hour period, or 1mg/kg to 2mg/kg rectally. This is contraindicated in patients with severe liver disease, however.
Alternatively, administer lorazepam (long-acting benzodiazepine – 0.2mg/kg IV bolus – because of its high affinity for benzodiazepine receptors in the CNS) or midazolam (0.2mg/kg to 0.4mg/kg IV); this may be repeated once.
Levetiracetam can be administered 30mg/kg IV across 5 to 15 minutes or 60mg/kg SC, or 40mg/kg rectally (minimal effects on the cardiovascular system).
Do not use phenobarbital in these patients because it can cause CNS and respiratory depression.
Ketamine is contraindicated because seizure-like effects have been reported, while valproic acid is not recommended (serum half-life in dogs is between 1.5 and two hours).
In case of refractory seizures, administer propofol (3mg/kg to 6mg/kg IV initial bolus) followed by 0.1/kg/min to 0.6mg/kg/min CRI. Alternatively, 2% to 2.5% concentrations of isoflurane alone with oxygen can be used. For maintenance, use 1.5% to 1.8% concentrations of isoflurane in oxygen.
Attention to airway and breathing is paramount. Affected animals should be intubated with a cuffed endotracheal tube to keep the airway clear, and provided oxygenation during convulsions. ECG and continuous cardiac monitoring should be performed.
The induction of emesis is contraindicated, as it stimulates seizures.
To prevent further absorption of baclofen from the intestinal tract, use activated charcoal (AC; 1g/kg to 4g/kg) mixed with water to make a 20% slurry (1g/5ml water) via nasogastric tube as soon as possible post-ingestion, and after the airway is secured. This may be repeated at eight-hour intervals for three days (reduces enterohepatic recirculation of baclofen). However, AC admitted orally is contraindicated in convulsing or comatose animals.
Because baclofen is lipid soluble (log P values of 1.3), consider lipid emulsion therapy – an initial IV lipid emulsion (ILE) 20% 1.5ml/kg IV bolus over one minute, followed by a CRI of 0.25ml/kg/min for the next 30 to 60 minutes.
In non-responsive patients, an additional intermittent bolus can be given IV slowly, up to 7ml/kg. If clinical signs do not improve after 24 hours, discontinue ILE.
ILE 20% preparations are isotonic and can be given by a peripheral vein, or in a central catheter using aseptic techniques.
Haemodialysis (HD) may be also the appropriate treatment because baclofen is a low protein-binding (30%), a small molecule (214 daltons) with a limited volume of distribution (1L/kg), enough to fit through the artificial kidney membrane.
Additional benefits with HD are the removal of both parent compounds and metabolites, as well as the removal of substances that have already been absorbed from the gut. HD may be also necessary for patients with impaired kidney function, as the estimated half-life in overdose can exceed 30 hours.
Slowly re-warm the patient using warm IV fluids, a circulating warm water blanket under the patient, or forced air warming systems. Body temperature must be monitored while these devices are in place because they can increase the temperature rapidly.
Severe vomiting should be treated by antiemetics such as maropitant (neurokinin-1 antagonist): 1mg/kg IV every 24 hours. Alternatively, administer an serotonergic antagonist such as ondansetron: 0.5mg/kg to 1mg/kg IV slow bolus (two to three minutes) every eight to 12 hours; or dolasetron: 0.6mg/kg IV slow bolus every 24 hours. Metoclopramide (dopaminergic antagonist) is contraindicated (excitatory effects can occur).
For emergency patients presenting with respiratory depression, mechanical ventilation is very expensive, requires full-time care and monitoring by specially trained veterinary professionals, as well as the use of heavy sedation or anaesthetics, and is not commonly available in most veterinary practices.
High-flow oxygen therapy (HFOT) is an effective alternative method of delivering high volumes and pressures of oxygen. HFOT is the administration of warm, humidified oxygen via nasal prongs. It allows the delivery of higher flow rates of oxygen (4L/min to 60L/min with some devices). The flow rate is set to meet or exceed the inspiratory flow demand of the patient.
In normal mesocephalic dogs (for example, the golden retriever, Labrador retriever and German shepherd dog), the average flow demand is approximately 500ml/seconds to 1,000ml/seconds.
Brachycephalic dogs (for example, the boxer and the bulldog) may have lower flow demands due to naturally occurring airway obstructions. HFOT bridges the gap to mechanical ventilation, is less invasive than ventilation, and is generally more cost effective.
The use of CNS respiratory stimulants is of questionable value.
Atropine sulfate is the first-line medication for the treatment of bradycardia (heart rate lower than 160 beats per minute in puppies, 100 beats per minute in small adult dogs and 60 beats per minute in large adult dogs). Administer 0.04mg/kg IV bolus. Can repeat every five minutes for a maximum of three doses.
To correct hypotension, IV fluids should be used. Maintain the patient on an IV-balanced crystalloid fluid, such as lactated Ringer’s solution 40ml/kg/hour to 90ml/kg/hour.
If you have a case of refractory hypotension, administer dopamine, an endogenous catecholamine, the immediate precursor to norepinephrine: 1µg/kg/min to 3µg/kg/min CRI.
Hypoglycaemia can be corrected using 5% dextrose: 40mg/kg IV every 24 hours. Blood glucose should be monitored every eight hours.
The immediate goal of treatment (raising serum potassium to a safe level) is the prevention of potentially life-threatening cardiac conduction disturbances and neuromuscular dysfunction.
Potassium is added as potassium chloride (KCl), and the dosage is dependent on the dog’s serum potassium levels (Table 1).
| Table 1. Guidelines of potassium dosage to add to IV fluids (Adapted from Sluijters, 2016) | |||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Serum potassium (mEq/L) | Potassium chloride to add to lactated Ringer’s solution (mEq/L) | Maximum infusion rate (ml/kg/hour) | |||||||||||||||||||||||||||||||
| < 2.0 | 75 | 6 | |||||||||||||||||||||||||||||||
| 2.1-2.5 | 55 | 8 | |||||||||||||||||||||||||||||||
| 2.6-3.0 | 35 | 12 | |||||||||||||||||||||||||||||||
| 3.1-3.5 | 23 | 16 | |||||||||||||||||||||||||||||||
Because the use of IV potassium increases the risk of hyperkalaemia and can cause pain and phlebitis, it should be reserved for patients with severe hypokalaemia. Administration of fluids with more than 60mEq/L of potassium through peripheral catheters is not recommended. The use of a central catheter is mandatory.
Potassium-containing fluids should never be used as a bolus or delivered at high rate of concentration. Do not exceed an IV administration rate of 0.5mmol/kg/hour of potassium, as toxicity and death may occur. Where possible, it is recommended to use infusion pumps to ensure accurate administration rates.
It is essential to mix added KCl thoroughly in the IV bag, as inadvertent K overdoses can occur and are often fatal.
Administer dexmedetomidine, the active enantiomer isolated from the racemic compound medetomidine, and a highly selective α2-adrenergic receptor agonist, which produces dose-dependent levels of sedation (moderate to profound) lasting to up 30 minutes: 5 micrograms/kg to 10 micrograms/kg IV. Dexmedetomidine does not cause respiratory suppression. Cyproheptadine, a histamine and non-specific serotonin antagonist, does have sedative properties. The patient requires excellent nursing care.
Baclofen causes loss of the gag reflex, putting the dog at high risk for aspiration. It will often drool excessively and can aspirate on its own saliva, so intermittent suctioning or using gauze to clean the mouth may be helpful. Maintain affected animals in a quiet environment. Noises can restart seizures.
The patient should be observed for a minimum of four days (in overdose, the elimination half-life of baclofen increases to 34.6 hours because of saturation of renal elimination). After a patient has recovered from baclofen toxicosis, no residual neurological damage is expected.
According to Regulation (EC) No.1907/2006 of the European Parliament, this substance/mixture contains no components considered to be persistent, bioaccumulative and toxic, or very persistent and very bioaccumulative at levels of 0.1% or higher.
Do not let the product enter drains. Prevent further leakage or spillage if safe to do so. Prevent entry into waterways, sewers, basements or confined areas. Owners should be advised to store all medications safely out of the reach of pets.
