Drugs discussed in this chapter are centrally acting skeletal muscle relaxants that exert their effects indirectly. Dantrolene, a direct acting skeletal muscle relaxer, is described in Section III. The drugs commonly used as skeletal muscle relaxants are listed in Table II-57. Carisoprodol and baclofen are often abused as recreational drugs.

1. Central nervous system. Most of these drugs cause generalized CNS depression.
   1. Baclofen is an agonist at the GABA_B receptor and can produce profound CNS and respiratory depression as well as paradoxical muscle hypertonicity and seizure-like activity.
   2. Spastic encephalopathy with increased muscle tone, hyperreflexia and myoclonus is common with carisoprodol overdose.
   3. Cyclobenzaprine and orphenadrine possess anticholinergic properties.
   4. Tizanidine, a centrally acting alpha₂ agonist, has effects similar to those of clonidine.
2. Cardiovascular effects. Hypotension may occur after overdose. Baclofen has caused bradycardia in up to 30% of ingestions. Orphenadrine has sodium channel blocking effects similar to tricyclic antidepressants. Massive orphenadrine ingestions have caused supraventricular and ventricular tachycardia.
3. Pharmacokinetics varies with the drug. Absorption may be delayed because of anticholinergic effects (see also Table II-63,).

The toxic dose varies considerably among drugs, depends largely on individual tolerance, and can be influenced by the presence of other drugs, such as ethanol. For most of these drugs, ingestion of more than 3-5 times the usual therapeutic dose may cause stupor or coma.

1. Baclofen. In adults, CNS depression, delirium, seizures, and hypertension occurred more frequently after ingestion of more than 200 mg. However, in children respiratory arrest was reported in a 22-month-old child who ingested 120 mg (10.9 mg/kg), and an estimated 60 mg of baclofen caused coma, flaccidity, hyporeflexia, bradycardia, and hypotension in a 3-year-old child.
2. Carisoprodol. Death was reported in a 4-year-old child who ingested approximately 3,500 mg, and a 2-year-old child who ingested two tablets (350 mg each) required intubation.
3. Orphenadrine. A 2-year-old child had seizures and tachycardia after ingesting 400 mg. In a series of 10 fatal cases, the mean amount ingested by 6 adults was 22 mg/kg and by 4 children was 72 mg/kg.
4. The lowest dose of tizanidine associated with coma in an adult was between 60 and 120 mg.

Onset of CNS depression usually is seen within 30-120 minutes of ingestion. Lethargy, slurred speech, ataxia, coma, and respiratory arrest may occur. Larger ingestions, especially when combined with alcohol, can produce unresponsive coma.

1. Baclofen overdose can cause profound coma, flaccid paralysis and absent brainstem reflexes lasting several days that may be mistaken for brain death. In addition to CNS and respiratory depression, baclofen overdose may cause myoclonus, seizure-like activity, bradycardia, hypotension or hypertension, and ECG abnormalities including first- and second-degree AV block and QTc prolongation. Nonconvulsive status epilepticus diagnosed by EEG, and prolonged delirium resulting in rhabdomyolysis have been reported. Hallucinations, seizures, and hyperthermia have occurred after abrupt withdrawal from baclofen, usually within 12-48 hours following discontinuation. While the withdrawal syndrome can occur from cessation of oral baclofen use, severe manifestations typically follow abruptly stopping intrathecal therapy.
2. Carisoprodol may cause paradoxical hyperreflexia, opisthotonus, and increased muscle tone. A withdrawal syndrome has been described with symptoms including agitation, insomnia, anxiety, ataxia, and hallucinations.
3. Cyclobenzaprine and orphenadrine can produce anticholinergic findings such as tachycardia, dilated pupils, and delirium. Despite its structural similarity to tricyclic antidepressants, cyclobenzaprine has not been reported to cause quinidine-like cardiotoxicity, although it can cause hypotension. Status epilepticus, ventricular tachycardia, and asystolic arrest have been reported after orphenadrine overdose.
4. Tizanidine is similar to clonidine and can cause coma, profound hypotension, and bradycardia; in addition, sinoatrial (SA) and atrioventricular (AV) nodal dysfunction was reported after an overdose. After abrupt cessation, withdrawal symptoms include hypertension, tachycardia, anxiety, and hypertonicity.

Usually is based on the history of ingestion and findings of CNS depression, often accompanied by muscle twitching or hyperreflexia. The differential diagnosis should include other sedative-hypnotic agents.

1. Specific levels. Many of these drugs can be detected on comprehensive urine toxicology screening. Quantitative drug levels do not always correlate with severity of intoxication, especially in patients who have tolerance to the drug or have also ingested other drugs or alcohol.
2. Other useful laboratory studies include electrolytes, glucose, serum ethanol, BUN, creatinine, creatine kinase, arterial blood gases, and chest radiography.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen.
   2. Treat coma, hypothermia, hypotension, and pulmonary edema if they occur. Hypotension usually responds promptly to supine position and IV fluids.
   3. Monitor patients for at least 6 hours after ingestion because delayed absorption may occur.
   4. The definitive treatment for baclofen withdrawal symptoms is reinstitution of baclofen therapy followed by a slow taper. Benzodiazepines or barbiturates can be helpful for the treatment of spasticity and CNS excitation.
2. Specific drugs and antidotes. There are no specific antidotes. Flumazenil is a specific antagonist of benzodiazepine receptors and would not be expected to be beneficial for skeletal muscle relaxants, but it reportedly has been used successfully for chlorzoxazone and carisoprodol overdose. Although physostigmine may reverse the anticholinergic symptoms associated with cyclobenzaprine and orphenadrine overdose, it is not generally needed and may potentially cause seizures.
3. Decontamination . Administer activated charcoal orally if conditions are appropriate (see Table I-37,). Gastric lavage is not necessary after small-to-moderate ingestions if activated charcoal can be given promptly.
4. Enhanced elimination. Because of extensive tissue distribution, hemodialysis and hemoperfusion are not very effective for most of the drugs in this group. Hemodialysis may significantly enhance baclofen clearance, particularly for patients with impaired renal function due to its predominant renal excretion (85%). The elimination half-life of baclofen decreased from 15.7 hours before dialysis to 3.1 hours during hemodialysis in a 55-year-old man with normal renal function who reportedly ingested 420 mg.