Overdoses of Muscle Relaxants
(From Maryland Poison Center)
Cyclobenzaprine is a tricyclic amine, which is structurally similar to the tricyclic antidepressants (TCAs).
In fact, cyclobenzaprine exposure can result in a false positive urine toxicology screen for TCAs. Its
skeletal muscle relaxant effect is thought to be mediated through inhibition of brain stem somatic
neuron activity. The typical adult dose is 10 mg three times daily. Clinical effects seen in overdose are
related to cyclobenzaprines anticholinergic (specifically, antimuscarinic), antihistaminic, and sedative
properties. Despite the similarities to TCAs, one 5-year review of 402 cyclobenzaprine exposures
found the major toxicity to be anticholinergic effects with less neurologic and cardiovascular effects.
Patients may present with CNS depression or agitation, delirium, and hallucinations. Tachycardia may
be noted in addition to hypertension, hyperthermia, flushed skin, dry mucous membranes, dilated
pupils, urinary retention, and decreased bowel sounds.
Baclofen is a structural analogue of gamma-aminobutyric acid (GABA). It binds to presynaptic GABA
receptors in the brain and spinal cord and decreases neurotransmitter (e.g., catecholamines,
glutamate, substance P) release from excitatory pathways. Baclofen also binds to postsynaptic GABA
receptors and similarly results in inhibition. These actions block the excitatory effects of the sensory
input from limb muscles. Baclofen is used orally and intrathecally to control muscle spasticity, restless
leg syndrome, hiccups, and pain. The normal oral adult dose is 40 to 80 mg/day. Intrathecal doses of
300 to 800 mcg/day are used for spasticity of spinal cord origin, and can be administered continuously
by a pump. Because approximately 85% of an oral dose is excreted unchanged in the urine, dose
adjustments must be made in patients with renal dysfunction. Common clinical effects seen after an
acute baclofen overdose include lethargy and confusion. In severe oral or intrathecal overdose, coma,
seizures, respiratory depression, bradycardia, hypotension, and rarely conduction disturbances and
dysrhythmias may develop.
Abrupt discontinuation of intrathecal baclofen can result in withdrawal symptoms such as hyperthermia,
tachycardia, altered mental status (i.e., hallucinations, delirium), and muscle rigidity. In rare cases
symptoms may progress to rhabdomyolysis, multiple organ-system failure, and death. Withdrawal can
be prevented by reintroducing the patient to baclofen.
Baclofen is abused, mainly by adolescents. Hypothermia, bradycardia, mild hypertension, seizures,
and respiratory and CNS depression have been described following recreational use.
Methocarbamol is similar to carisoprodol and meprobamate. It is hepatically metabolized. It is believed
that methocarbamol acts at the interneurons of the spinal cord where it blocks multisynaptic
reflexes. The usual adult dose is 6 to 8 g/day in divided doses. The onset of effects is about 30
minutes and can last up to 24 hours. Although overdose data are limited, CNS depression is the most
likely manifestation. Drowsiness and dizziness are common at therapeutic doses.
Tizanidine is an imidazole derivative similar to clonidine, which acts through central alpha-2 receptor
agonism. The usual adult dose is 4 to 8 mg three times daily. At therapeutic doses, tizanidine has
minimal antihypertensive effects compared to clonidine and is much less potent. It undergoes extensive
first-pass metabolism, which contributes to its 40% bioavailability. Following overdoses, patients
Overdoses of Muscle Relaxants
may present with hypotension and bradycardia, along with coma and respiratory depression. Miosis,
agitation, and hyposalivation are also possible.
Orphenadrine is an analogue of diphenhydramine (Benadryl®). Its pharmacologic action is similar to
cyclobenzaprine (i.e. inhibition of brain stem somatic neuron activity). The normal adult dose is 100
mg twice daily. Oral bioavailability is nearly 100%; however, absorption may be delayed due to the
drugs anticholinergic effects on gastric motility. Peak plasma levels usually occur within 2 to 4 hours
after ingestion. Orphenadrine produces marked anticholinergic effects in overdose including mydriasis,
tachycardia, agitation, CNS depression, hallucinations, hyperthermia, dry mouth, decreased
gastrointestinal motility, urinary retention, and dry, flushed skin. Cardiac dysrhythmias have also
been reported with orphenadrine overdoses and may be due to its sodium channel blocking effects,
similar to the class 1A antiarrhythmics.
Metaxalone most likely exerts its muscle relaxant effects through CNS depression, rather than directly
affecting skeletal muscles. The typical adult dose is 800 mg three to four times daily. Onset of
effects is usually within 1 hour with a duration of 4 to 6 hours. Little information is available regarding
poisonings with metaxalone. Sedation and CNS depression are the primary expected effects.
Chlorzoxazone (Parafon Forte
Chlorzoxazone inhibits reflex pathways in the spinal cord that produce and maintain muscle tone.
The usual adult dose is 250 to 750 mg three or four times daily. Chlorzoxazone is 100% bioavailable
orally with an onset of action within one hour. It is metabolized by cytochrome P450 2E1. Overdose
data are limited, but CNS and respiratory depression requiring intubation have been reported.
The treatment of all muscle relaxant poisonings should begin with administration of activated charcoal
to limit absorption if the patients mental status can tolerate it and the ingestion is recent. Intubation
and mechanical ventilation secondary to respiratory depression may be required with some
agents. Patients with persistent neurologic symptoms need to be admitted to the hospital. Muscle
relaxant-induced seizures or anticholinergic agitation and delirium usually respond to benzodiazepines
and barbiturates. EKG monitoring is recommended for orphenadrine. If the QRS interval is
prolonged beyond 100 msec, sodium bicarbonate should be administered. IV fluids should be used
for hypotension, and for refractory hypotension, vasopressors such as dopamine and/or
norepineprhine can be added. Symptomatic bradycardia can be reversed with atropine. Naloxone
has been used with relative success to reverse the neurologic effects of clonidine, thus it may be of
use in tizanidine overdoses. Hemodialysis can be considered in cases of life-threatening overdoses
of baclofen, but its use is rarely reported.
Skeletal muscle relaxant overdoses are commonly encountered, with carisoprodol and
cyclobenzaprine being the most frequently reported. All overdoses to muscle relaxants will present
with some degree of CNS impairment, but there are some notable differences. Cyclobenzaprine and
orphenadrine can produce profound anticholinergic effects, while tizanidine can cause hypotension
and bradycardia and baclofen can cause seizures.
References for this article are available on request.
(From Maryland Poison Center)
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