Overdoses of Muscle Relaxants



Overdoses of Muscle Relaxants

(From Maryland Poison Center)

Cyclobenzaprine (Flexeril


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 cyclobenzaprine’s 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 (Lioresal


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 (Robaxin


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 (Zanaflex


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 (Norflex™)

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

drug’s 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 (Skelaxin


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

® DSC)

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.

Management Options

The treatment of all muscle relaxant poisonings should begin with administration of activated charcoal

to limit absorption if the patient’s 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.

In conclusion…

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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