Along with new therapeutic interventions that have emerged in the growing field of physical medicine and rehabilitation, pharmacologic agents continue to play an important role in management of the patient’s rehabilitation course. This chapter reviews an array of medications that are often used for conditions frequently managed in physiatric practice. Detailed discussion of each of these conditions—spasticity, traumatic brain injury, pain, and venous thromboembolism (deep vein thrombosis)—is found elsewhere in this book, and readers are referred to those chapters for additional information.

In spasticity, a motor neuron disorder (most often involving the upper motor neuron) leads to an abnormal increase in muscle tone secondary to hyperexcitability of the stretch reflex. (See Chapter 6 for additional information.) Current pharmacologic treatment utilizes oral antispasmodic medications and invasive chemodenervation agents. The choice of agents involves consideration of benefits versus complications of spasticity and expectations of the antispasmodic, such as functional benefit or pain relief.

Oral Antispasticity Agents

A variety of oral antispasmodic agents is available; however, only four medications are approved by the U.S. Food and Drug Administration (FDA) for spasticity management: baclofen, diazepam, tizanidine, and dantrolene. These oral agents have a systemic effect, reducing generalized muscle tone; however, all are associated with significant systemic side effects. Because all four medications involve a degree of hepatic metabolism, caution is advised in patients with liver disease. Table 10–1 contrasts key features of these medications.

A. Baclofen

Baclofen is a centrally acting antispasmodic agent that binds to the presynaptic and postsynaptic γ-aminobutyric acid B (GABA_B) receptors as a GABA agonist. Activation of the GABA_B receptors suppresses excitatory neurotransmitters and reduces γ motor neuron excitability and muscle spindle sensitivity. Side effects include sedation and weakness; therefore, baclofen is started at a low dose and titrated to a tolerable dose. Other potential side effects include lowering of the seizure threshold. The greatest risk with this medication is sudden withdrawal, which can lead to seizures, hallucinations, rebound spasticity, and fever. In addition, patients with renal disease may require a dosage adjustment since baclofen is renally excreted. Overdose of baclofen can be treated with physostigmine.

B. Diazepam

Diazepam is a centrally acting antispasmodic agent that binds to the GABA_A receptors and causes membrane hyperpolarization by opening membrane chloride channels. The most common side effect is sedation. Other side effects include memory impairment, addiction with withdrawal, cognitive impairment, decreased rapid eye movement (REM) sleep, and muscle weakness. Because of the cognitive side effects, diazepam is usually not administered to patients with traumatic brain injury. Overdose of diazepam can be treated with flumazenil.

C. Tizanidine

Tizanidine is a centrally acting antispasmodic agent that binds to the α₂-adrenergic receptors, acting as an agonist. Activation of the α₂-adrenergic receptors leads to an increase in presynaptic motor neuron inhibition, suppressing excitatory neurotransmitters and reducing spinal reflexes. Tizanidine has a rapid onset and a very short half-life, which requires frequent dosing. The major side effect is sedation. Other side effects include muscle weakness, hypotension, liver toxicity, dry mouth, bradycardia, and dizziness. Similarly, clonidine can be used as an antispasmodic agent, in addition to its use in hypertension. Clonidine is unique in that it can also be administered as a transdermal patch. Clonidine has greater antihypertensive properties when compared with tizanidine.

D. Dantrolene

Dantrolene is a peripherally acting antispasmodic agent that inhibits the release of calcium from the sarcoplasmic reticulum in striated muscles, rather than affecting neurotransmitters. By interfering with calcium release, dantrolene reduces muscle contraction (particularly the extrafusal muscle fiber and fast-twitch fibers) and muscle spindle sensitivity. It has some minor effects on smooth and cardiac muscle. Sedation is a lesser effect with dantrolene compared with the other oral antispasmodic agents due to its peripheral action. In addition, dantrolene has the potential to cause liver toxicity; however, the literature reflects a low 1.8% occurrence.

Injectable Antispasticity Agents

A. Phenol

Phenol is an alcohol-based chemical neurolytic agent that denatures neural protein and induces axonal destruction. When injected to the nerve, phenol demyelinates the γ fibers and destroys the axons. A 5% concentration is generally used for spasticity management; however, reports have demonstrated effects with concentrations between 2% and 7%. In addition, lower concentrations of phenol produce a transient anesthetic effect. Advantages of phenol are its inexpensive cost and immediate onset of effects. These effects may last up to 6 months. Side effects include dysesthesia, muscle pain, weakness, and systemic reactions, including convulsions and cardiovascular compromise.

B. Botulinum Toxin

Botulinum toxin is a neurotoxin produced by the bacterium Clostridium botulinum. The neurotoxin, which is subdivided into seven serotypes (A–G), inhibits the release of acetylcholine (ACh) at the neuromuscular junction. The mechanism of action of the toxin involves proteolytic cleavage of the SNARE complex (soluble NSF attachment protein receptor) at the presynaptic axon terminal. The SNARE complex consists of mainly synaptobrevin, SNAP-25, and syntaxin. The toxin cleaves the vesicles containing ACh, thereby preventing the release of ACh to the synaptic cleft. Toxin serotypes A, C, and E proteolytically cleave SNAP-25, whereas serotypes B, D, F, and G cleave synaptobrevin, and serotype C also cleaves syntaxin. This ultimately results in denervation and improvement of spasticity.

Currently, toxin serotypes A and B are being administered for spasticity management. Serotype A formulations include onabotulinumtoxinA (Botox), abobotulinumtoxinA (Dysport), and incobotulinumtoxinA (Xeomin); serotype B is rimabotulinumtoxinB (Myobloc). Dosing of serotypes A and B is not equivalent without a direct formula conversion. Dosage is dependent on the type of botulinum toxin and the patient’s weight, muscle size, level of spasticity, and treatment goal. The response is generally dose-dependent; thus, the more toxin is injected, the greater is the resulting muscle weakness.

The effects of botulinum toxin usually occur within 24–72 hours after injection. The medication peak effect occurs at approximately 4–6 weeks and has a duration of 2–6 months. This 2- to 6-month duration is the timeframe for collateral sprouting of the axon. The side effects and complications of botulinum toxin are weakness, pain at the injection site, infection, flulike syndrome, dysphagia with cervical injections, nerve injury, respiratory failure, and antibody formation.

For additional discussion of the various agents used in the treatment of spasticity, and nonpharmacologic treatment measures, refer to Chapter 6.

Traumatic brain injury occurs in approximately 1.7 million people every year with an estimated cost of 60 billion dollars. Individuals who survive the brain injury sustain physical, cognitive, and neurobehavioral deficits. Current pharmacologic agents play an important role in modulating the traumatic brain-injured individual’s neurochemistry in order to improve cognition, attention, and arousal. Chapter 13 explores a range of management issues relating to rehabilitation of patients with traumatic brain injury. The focus here is on pharmacologic agents that aid in postinjury recovery and rehabilitation.

Treatment of patients with traumatic brain injury may include medications administered with the goal of improving the patient’s consciousness and arousal state. Five such agents are described below and contrasted in Table 10–2. There is currently insufficient evidence to support the use of a single pharmacologic agent or combination of agents for this purpose. However, recent evidence has suggested the important role of amantadine for patients emerging from low-response states.