The Pharmacological Management of Spasticity

Michael Saulino, MD PhD; Beth W. Jacobs, RN CRRN CCM

Disclosures

J Neurosci Nurs. 2006;38(6):456-459. 

In This Article

Pharmacological Approaches

Three medications have spasticity reduction as their primary indication: baclofen (Lioresal®), dantrolene (Dantrium®), and tizanidine (Zanaflex®). These drugs represent the mainstays of pharmaceutical treatment for hypertonicity. Table 1 summarizes their important features. The decision process for pharmacological intervention should integrate several factors. The course of neurological dysfunction can influence the choice of modality. A progressive disease such as multiple sclerosis might be better managed using an intervention that can escalate as the disease advances, such as an intrathecal baclofen pump. The areas of the body affected by the neurological disease can dictate treatment. For example, a focal intervention such as a botulinum toxin injection might benefit a stroke patient with focal hypertonicity but would not be appropriate for a patient with global hypertonicity resulting from a traumatic spinal cord injury. Concurrent medical problems should also be considered in the decision process. For patients with known liver dysfunction, medications that are known to affect hepatic function should be avoided. Similarly, for a patient who is chronically colonized by microbial agents, the use of implanted devices must be approached with caution, given the possibility that infectious agents could directly infect the device. For example, infection of an implanted intrathecal pump can lead to meningitis. Such problems are becoming more common (Teddy, Jamous, Gardner, Wang, & Silver, 1992).

Baclofen is a classic medication for spasticity management. It exerts its clinical effects by interacting with neurons that use gamma aminobutyric acid (GABA) as a neurotransmitter. It acts both pre- and postsynaptically to inhibit spinal reflexes. Baclofen is rapidly and completely absorbed following enteral administration. It has a mean half-life of 3.5 hours. Baclofen is metabolized by the liver and eliminated by renal excretion. Because baclofen readily crosses the blood-brain barrier, sedation, fatigue, dizziness, lowering of the seizure threshold, and cognitive dysfunction are common adverse effects. The typical starting dose is 5-10 mg two or three times per day, and the dosage can be increased by 5-10 mg per week. Although 80 mg per day is a commonly accepted maximum, dosing up to 200 mg per day has been used safely and effectively. A baclofen withdrawal syndrome can occur with rapid cessation of usage. Withdrawal symptoms include a rebound increase in spasticity, fever, altered mental status, seizures, malignant hyperthermia, and, very rarely, death. Baclofen withdrawal is typically treated by gradual reinstitution of oral baclofen. In the case of serious withdrawal, intravenous benzodiazepines can be used. Baclofen overdose syndrome can also occur. It is characterized by sedation, depressed arousal, and respiratory suppression and is treated by temporarily stopping or tapering off baclofen. Intravenous physostigmine, flumazenil, or both may be used in severe cases. Repeated dosing may be needed, because these agents have a shorter half-life than baclofen.

Dantrolene is unique among the oral agents in that its site of action is the peripheral muscle rather than the central neurotransmitter systems. This medication inhibits the release of calcium from the sarcoplasmic reticulum during muscle contraction. The usual starting dose is 25 mg twice per day, and it can be increased by 25-50 mg per day per week. The commonly accepted maximum dosage is 400 mg per day, although use of as much as 800 mg per day has been reported. The half-life of oral dantrolene is 15 hours. Liver abnormalities can be seen with this agent; thus, liver enzymes must be monitored periodically. Abnormal liver enzymes are observed in approximately 2% of patients, with fatal hepatic failure seen in 0.3% of cases. Hepatotoxicity can usually be reversed by ceasing treatment. Laboratory monitoring of liver enzymes (i.e., AST, ALT) is recommended at the initiation of treatment and periodically thereafter. Other reported adverse effects of dantrolene include weakness, nausea, diarrhea, and paresthesias. Dantrolene is the initial medication of choice for spasticity of cerebral origin, because it acts at the level of the peripheral muscle with minimal untoward central effects.

The newest drug for spasticity modulation is tizanidine. This agent is chemically similar to the antihypertension medication clonidine. It acts through agonist effects on the alpha-2 adrenergic system at both the spinal and supraspinal levels to reduce spasm. Peak plasma levels occur 1 hour after oral administration, with a half-life of 2.5 hours. The typical starting dose is 1-4 mg as a single dose at bedtime. The typical maximum daily dosage is 36 mg. This drug is extensively metabolized by the liver to inactive compounds and is then excreted by the kidneys. As with dantrolene, liver function should be monitored during treatment, although no cases of hepatic failure have been reported with tizanidine. Common adverse effects of this agent include sedation, dizziness, hypotension, nausea, and dry mouth. Some studies have suggested that tizanidine has pain relief properties in addition to its antispasticity effects (Elovic, 2001).

Several other agents, while not carrying primary indications for spasticity reduction, are occasionally used in appropriate patients. These agents include gabapentin (Neurontin®), tiagabine (Gabitril®), diazepam (Valium®), and clonidine (Catapres®). Gabapentin exerts its therapeutic effects by binding to a calcium channel receptor that resides on neurons. Tiagabine and diazepam similarly exert their effects through interactions on the GABA neurotransmitter systems (Francisco, Kothari, & Huls, 2001). Clonidine, a well-known antihypertension medication, is an agonist to the alpha2 adrenergic system. Its effects are similar to those of tizanidine. The centrally acting muscle relaxants, such as cyclobenzaprine (Flexeril®), carisoprodol (Soma®), methocarbamol (Robaxin®), metaxalone (Skelaxin®), and chlorzoxazone (Parafon Forte®), are more commonly used to treat painful musculoskeletal conditions rather than spasticity. Their mechanisms of action are poorly understood. All of these medications are considered second-line agents and are valuable treatment options (Kita & Goodkin, 2000).

Alternative techniques for administering oral medications can be quite useful in the appropriate patient setting. Both diazepam and dantrolene have intravenous formulations that can be effectively substituted while a patient is temporarily unable to use oral medication (e.g., during a hospitalization or prolonged procedure). Intravenous diazepam can also be useful in managing baclofen withdrawal. Clonidine is available as a transdermal patch that is applied every 3 days. The long duration of action and continuous administration also can be useful for patients with limited personal assistance or limited hand function. Both baclofen and clonidine can be delivered directly to the nervous system via implanted intrathecal pump. Intrathecal baclofen therapy is indicated for patients with severe spasticity who have not responded to conservative procedures or cannot tolerate other spasticity interventions or who require the precise dosing administration that the pump system affords (Ivanhoe, Tilton, & Francisco, 2001; Remy-Neris, Tiffreau, Bouillard, & Bussel, 2003).

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