Spasticity

Oral Medications

Traditional Pharmacological Treatments for Spasticity Part II: General and Regional Treatments
Jean-Michel Gracies, MD, PhD; Elie Elovic, MD; John McGuire, MD; David Simpson, MD
MF Brin, MD, editor
Muscle Nerve 1997; 20 (suppl 6): S92-S120.

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Oral Medications For Spasticity Management: Overview

There are two clinical types of spasticity that can develop in response to injury to the central nervous system–phasic and tonic. Phasic spasticity is often the initial manifestation of spasticity and tonic spasticity may occur months to years later. The muscle has a normal lengthening reaction in phasic spasticity but the muscle shows a decreased amount of stretch in tonic spasticity. This decreased amount of muscle stretch can lead to the gradual development of contractures. Thus, spasticity must be aggressively managed in the early stages to prevent permanent deformities and joint contracture.

The use of oral medications for treatment of spasticity may be very effective. Benzodiazepines, baclofen, dantrolene sodium, and tizanidine are the most widely used agents for reduction of spasticity. The challenge is to establish a treatment plan that will strike a vital balance between improved function, patient satisfaction, and possible side effects. At high dosages, oral medications can cause unwanted side effects that include sedation, as well as changes in mood and cognition.

The following suggestions may be helpful in the management of spasticity:

• Carefully assess the extent to which muscle overactivity impacts patients' function, hygiene, comfort, and care. Target the patient's most bothersome dysfunction.


• Be aware of the complications of spasticity such as pressure sores, contractures, pain, poor hygiene and deconditioning.


• Some degree of spasticity may be beneficial in maintaining postural control and ambulation, so global reduction of tone may be destabilizing.


• Consider factors that may aggravate spasticity including intercurrent medical illness, certain classes of medications known to increase muscle tone (e.g. neuroleptic agents) and finally emotional stressors.


• Contemplate pharmacotherapy early in severe cases of spasticity where secondary problems often develop.


• Combination therapy using oral medications and focal injections of botulinum toxin, or other chemodenervating agents, may allow for the best control of spasticity with the least side effects.


• Use the team approach to spasticity management, through which realistic goals and expectations of the patients, families and caregivers can be established.

Benzodiazepines—Diazepam/Valium® and Clonazepam/Klonopin®, Rivotril®
The benzodiazepines are centrally acting agents that increase the affinity of GABA to its receptor. They have been shown to bind in the brain stem and at the spinal cord level. Diazepam is the oldest and most frequently used oral agent for managing spasticity related to spinal cord injury, cerebral palsy, and cerebral vascular accident. The clinical effects of diazepam include improved passive range of motion and reduction in hyperreflexia as well as painful spasms. These agents also cause sedation and improve anxiety. Diazepam has a half-life of 20-80 hours and active metabolites that prolong its effectiveness. Clonazepam's half-life ranges from 18-28 hours. Sedation, weakness, hypotension, GI symptoms, memory impairment, incoordination, confusion, depression, and ataxia are possible side effects of benzodiazepine treatment. Tolerance and dependency from these agents may occur and withdrawal phenomena have been associated with abrupt cessation of therapy. Tolerance may also lead to unacceptable dosage escalation to continue obtaining good clinical response. Benzodiazepines should be carefully monitored when used with similar agents, such as baclofen or tizanidine, that may potentiate sedation and other central depressant properties.

Baclofen/Lioresal®
Baclofen has been widely used for spasticity since 1967. It is a GABA agonist that has presynaptic and postsynaptic effects on monosynaptic and polysynaptic pathways. The primary site of action is the spinal cord where baclofen reduces the release of excitatory neurotransmitters. Most studies indicate that baclofen improves clonus, spasm frequency and joint range of motion resulting in improved functional status for the patient. The dose ranges from 30-100 mg/day in divided amounts. Tolerance to the medication may develop. Baclofen must be slowly weaned to prevent withdrawal effects such as seizures, hallucinations and increased spasticity. It must be used with care in patients with renal insufficiency as its clearance is primarily renal. Side effects are predominantly from central depressant properties including sedation, ataxia, weakness and fatigue. These side effects may be minimized by direct intrathecal infusion of baclofen because the concentration gradient favors higher levels at the spinal cord versus the brain. Intrathecal baclofen is approved in the U.S. by the FDA for treatment in spasticity of spinal or cerebral origin. When baclofen is used in combination with tizanidine or benzodiazepines the patient should be monitored for unwanted depressant effects.

Dantrolene Sodium/Dantrium®
Unlike all other oral agents for spasticity, dantrolene sodium acts peripherally at the level of the muscle fiber. It affects the release of calcium from the sarcoplasmic reticulum of skeletal muscle and thus reduces muscle contraction. Dantrolene sodium is generally indicated for spasticity of supra spinal origin. Patients with cerebral palsy and traumatic brain injury seem to respond best. The medication has peak effect at 4-6 hours with a half-life of 6-9 hours. There is a linear correlation between blood levels and spasmolytic effect. The dose range is between 25-400 mg/day in divided doses (children, dose range between 0.5 mg/kg/day - 3.0 mg/kg/day). It is less likely than the other agents to cause drowsiness, confusion and other central effects because of its mechanism of action. Dantrolene sodium has been shown to decrease muscle tone, clonus and muscle spasm. The action of dantrolene sodium is not selective for spastic muscles and it may cause generalized weakness, including weakness of the respiratory muscles. The side effects include drowsiness, dizziness, weakness, fatigue and diarrhea. In addition, there is potential hepatotoxicity that occurs in < 1% of patients who take dantrolene sodium. This increase in liver function tests is seen particularly in adolescents and women who have a duration of treatment for greater than sixty days and dosages greater than 300 mg/day. This agent should not be used in combination with other agents known to cause hepatotoxicity, including tizanidine. If no benefit is seen after forty-five days of treatment with dantrolene sodium at maximal therapeutic doses, then it should be discontinued.

Tizanidine/Zanaflex® (Sirdalud® outside the US)

Overview
Recently approved in the United States, tizanidine has been available in other countries since 1977 for the treatment of spasticity caused by multiple sclerosis and spinal cord injury. As a central alpha-2 noradrenergic agonist, tizanidine facilitates short-term vibratory inhibition of the H-reflex, associated with antispasticity effects without muscle weakness. Although the exact mechanism of action is not yet known, it does differ from other antispasticity agents, enabling the avoidance of certain drug dependence, intolerance and interactions.

Objective measures of muscle strength demonstrate no adverse effects from tizanidine. Patients report less muscle weakness from tizanidine than from baclofen or diazepam. The efficacy of tizanidine in reducing muscle tone based on various placebo-controlled studies is comparable to that of baclofen and better than that of diazepam. When combined with baclofen, tizanidine presents the opportunity to maximize therapeutic effects and minimize side effects by reducing the dosage of both drugs. If tizanidine is prescribed in conjunction with baclofen or benzodiazepines, the patient should be advised of possible potential additive effects, including possibly severe orthostatic hypotension and sedation. In addition, when tizanidine is prescribed with benzodiazepines, liver enzymes should be monitored closely since the combination may increase the possibility of liver toxicity.

While spasms and clonus are reduced in patients using tizanidine, the Ashworth Scale does not reveal significant differences from placebo groups. However, the long-term impact of tizanidine on spasms and clonus does show antispasticity value.

The antispasticity effects of tizanidine, using traditional tests, demonstrate a striking relationship to the plasma concentration, which peaks at 1-2 hours and dissipates between 3 to 6 hours after oral use. Since there is broad patient variability in titrating the optimal therapeutic dosage of tizanidine, an initial treatment dosage regimen of 2 to 4 weeks is required. Global tolerability scores were significantly higher among patients taking tizanidine than patients using baclofen, dantrolene or diazepam—the most commonly used antispasticity agents. Dry mouth, somnolence, asthenia and dizziness are the most common adverse events associated with tizanidine. Liver function problems and hallucinations are rare tizanidine-related serious adverse events.

From a review of 50 clinical trials, tizanidine appears to be a new and effective therapeutic option in the limited number of approaches to managing spasticity due to cerebral or spinal damage.

Dosing Guidelines
Tizanidine hydrochloride is a short-acting drug with extensive first-pass hepatic metabolism to inactive compounds following an oral dose. Its short duration of action is due to the liver's inactivation by oxidation and conjugation and elimination by the kidneys (70%) and the gut (30%).

Tizanidine is available in two oral formulations—tablets and capsules. These formulations are not interchangeable, and caution is urged when prescribing tizanidine to not inadvertently switch formulations for individual patients. Under fasting conditions, tizanidine tablets and capsules are bioequivalent, with time to peak plasma concentration of 1 hour and a half-life of 2 hours. However, under fed conditions, the two forms of tizanidine are not bioequivalent. With tablets, the mean peak plasma concentration is increased by 30%, with the time to peak plasma concentration increasing to 1 hour, 25 minutes. With capsules, the mean peak plasma concentration is decreased by 20%, with the median time to peak plasma concentration increasing to 3 hours. Absorption is about 80% higher with the use of tablets, as compared with capsules, in the fed condition. When capsules are opened and the contents sprinkled on applesauce, the CMAX increases by 15% to 20%, and the time to peak concentration decreases by an additional 15 minutes over the intact capsule form.

The therapeutic and side effects of tizanidine dissipate within 3-6 hours. Therefore, use must be directed to those activities and times when relief of spasticity is most important and titrated to avoid intolerance.

The absorption and metabolism of tizanidine is quite variable, requiring the initiation of therapy at a low dose, 2-4 mg (using 4 mg scored tablet) of the immediate-release formulation preferably at bedtime. It should be carefully titrated for each patient, increasing the dosage slowly and gradually by 2-4 mg every two to four days, until the desired therapeutic goals are achieved with minimal side effects. The plasma concentration is linear to the drug's beneficial antispasticity effects and the severity of side effects. In both single-dose and multiple-dose studies, mean changes in muscle tone, using the Ashworth Scale, improved significantly (-2 to -3) from a baseline of zero.

Somnolence/drowsiness may be reduced by titrating the dosage over the day. Some clinicians recommend a larger nighttime loading dose, particularly for patients with MS, to minimize side effects and maximize spasticity control and sleep throughout the night. The average maintenance dosage of tizanidine is 18-24 mg per day. The maximum recommended dose is 36 mg per day. Women taking an oral contraceptive appear to reach and maintain higher than average plasma concentrations, requiring more gradual dosage titration. Patients with impaired kidney function also require gradual titration, since they show a 2-fold increase in plasma concentration. Significant improvements in patients with cerebrovascular and mild to moderate spasticity have been reported after using tizanidine 3-9 mg per day.

The use of tizanidine is contraindicated in patients taking fluvoxamine (Luvox®) or ciprofloxacin (Cipro®). Concomitant use of these drugs has been shown to potentiate the hypotensive and sedative effects of tizanidine and may lead to psychomotor impairment. Caution is also urged with the use of tizanidine and other CYP142 inhibitors, such as zileuton, fluoroquinolones, amiodarone, mexiletine, propafenone, and verapamil, cimetidine, famotidine, acyclovir, and ticlopidine. Tizanidine clearance is decreased by about 50% in women taking oral contraceptives. Physicians should counsel patients who take tizanidine to inform all of their healthcare providers and pharmacists when any medication is added or removed from their regimen. Tizanidine should ordinarily be avoided or used with extreme caution in patients with hepatic impairment.