Tizanidine

[Gallichio JE. Pharmacologic management of spasticity following stroke. Phys Ther. 2004;84:973-981.]

Key Words: Drugs, Spasticity, Stroke.

Spasticity is a pervasive and debilitating condition that frequently occurs following upper motor neuron (UMN) lesions. Although the exact incidence of spasticity is unknown, it is likely that it affects more than half a million people in the United States alone, and more than 12 million people worldwide.1 Following stroke, approximately 65% of individuals develop spasticity.2

The definition of spasticity is variable among health care professionals. To some, spasticity simply refers to a velocity-dependent resistance to movement. For others, spasticity is part of a central motor neuron syndrome that includes hyperactive deep tendon reflexes, increased resistance to passive movement, flexed posturing of the upper extremity and extension of the lower extremity, excessive contraction of antagonist muscles, and synergistic movement patterns.3 In 1980, Lance published this frequently cited definition: "Spasticity is a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes (muscle tone) with exaggerated tendon jerks, resulting from hyper-excitability of the stretch reflex, as one component of the upper motoneuron syndrome."4(p485)

This definition emphasizes the fact that spasticity is just one component of a UMN syndrome. Although the strongest association may be made between spasticity and the hyperactive stretch reflex arc, clinicians are acutely aware of abnormal reflexive movements observed in patients with a UMN lesion that are not in response to stretch. The neurophysiologic mechanisms underlying spasticity are complex, but the phenomenon occurs when supraspinal inhibition is lost because of a lesion in the brain or spinal cord,5,6 resulting in a stretch reflex that comes on sooner and stronger than it should.7 Spasticity alone does not cause disability, but it is one component that contributes to functional impairments in people following a brain or spinal cord injury. For the purposes of this review, the term "spasticity" is used as it was defined by Lance.4

Various techniques for the management of spasticity have been proposed, including positioning, cryotherapy, splinting and casting, biofeedback, electrical stimulation, and education on causative factors, most of which have little evidence to support their application.8 Medical management via pharmacological agents, however, has been implemented and more extensively researched. The purpose of this article is to review the neurophysiologic mechanisms, intervention effects, dosages, side effects, and research related to the current pharmacologic agents utilized in the management of spasticity following stroke.

General Pharmacologic Principles

The exact mechanism and anatomic sites of action of drugs used to manage spasticity are not completely understood. Currently, some drugs are thought to act on neurotransmitters or neuromodulators within the central nervous system (CNS), whereas other drugs appear to affect the peripheral neuromuscular sites (Tab. 1).9 There are numerous medications proven to reduce stretch reflexes, but none have been established as consistently useful in reducing disability following stroke.10 In addition, each pharmacologic agent has the potential for adverse drug reactions that must be considered prior to administration. Dosing schedules for drugs also must be taken into account, especially for people with cognitive impairments (Tab. 2). Adherence to medication schedules may be adversely affected by decreased memory. The side effects of the drug, lethargy or sedation, also may impair a person's ability to adhere to the dosing schedule. Therefore, efficacy, side effects, and dosing regimen are important considerations when choosing a medication to manage spasticity.

Oral Drug Therapy

Historically, the most commonly administered oral medications for managing spasticity of cerebral origin are diazepam, dantrolene sodium, and baclofen.11 More recently, tizanidine has been used in people following stroke.12 Other drugs such as clonidine,13 an antihypertensive, and gabapentin,14 an anticonvulsant, have been used for the management of spasticity, but there is limited research conducted on these drugs for use in people after stroke.

Contrary to expectation, a reduction in spasticity does not necessarily improve function.

Diazepam

Diazepam (Valium*), a long-acting benzodiazepine, is the oldest medication still in widespread use for the management of spasticity. Originally developed for the management of anxiety, diazepam exhibits its effect by increasing the inhibitory effects of the ncurotransmitter, gamma-aminobulyric acid (GABA), at CNS synapses.15 These inhibitory synapses contain membrane protein complexes that have binding sites for GABA, binding sites for benzodiazepines, and ion channels specific for ions such as chloride.16 This system is typically referred to as the GABA-benzodiazepine-chloride ion channel complex.

There are at least 3 types of receptors for GABA: GABA-a, GABA-b, and GABA-c. GABA-a and GABA-c receptors produce an inhibitory effect by increasing chloride conductance through the channel, whereas GABA-b receptors cause inhibition by increasing potassium efflux from GNS neurons.17

Diazepam potentiates the inhibitory effect of GABA by binding to the benzodiazepine receptor site in the complex. Diazepam binds in both the brainstem reticular formation and the spinal polysynaptic pathways, with a greater impact on the reticular formation.18 It is well absorbed through the gastrointestinal tract, reaching a peak blood level 1 hour after administration, and has a half-life of 20 to 80 hours.9 Its effects can be seen within 15 to 45 minutes.

Diazepam can produce fatigue and drowsiness at the higher dosages required to manage spasticity because of its depressive CNS effects. Diazepam's effects are similar to those of alcohol in that it can provoke sedation, reduce motor coordination, and impair intellect, attention, and memory.19 One of the more serious adverse effects of diazepam is physiologic addiction.

Two double-blind, placebo-controlled studies19,20 have examined the effects of diazepam in people with hemiplegia. In 1967, Cocchiarella et al,19 studying 19 subjects, 16 of whom had post-stroke spasticity, determined that 6- or 15-mg/d doses of diazepam decreased grip force but failed to decrease spasticity as measured by the leg-drop test and range-of-motion (active and passive) tests. Many of the participants experienced fatigue and drowsiness, which resulted in 5 subjects dropping out of the study while taking diazepam.

In a study of 12 subjects done in 1964, diazepam decreased spasticity as measured by an increase in knee passive range of motion, but ambulation speed was negatively affected.20 The author, however, attributed the slowing of gait to the newly acquired improvements in motor control caused by the drug therapy. The subjects focused on improving the quality of their gait, which caused the decrease in gait speed. Fatigue caused one subject to withdraw from the study.

To my knowledge, there are no recent controlled studies that have examined the use of diazepam in people with post-stroke spasticity. However, when a new drug for managing spasticity is developed, it is often compared with diazepam. For example, when compared with ketazolam, a more recent medication that also acts at the benzodiazepine receptor site, diazepam was no worse in producing side effects (as measured by the number of participants who withdrew from the study due to fatigue).21 Due to the lack of advantage of ketazolam over diazepam, diazepam therapy has not been replaced by the newer tranquilizer.

The effect of diazepam on spasticity for people with hemiplegia appears to be less dramatic than for those with spinal cord injuries or cerebral palsy (or at least more often the therapeutic effects are overshadowed by the adverse effects). With the advent of newer drugs to manage spasticity with fewer sedative side effects, in my opinion, the use of diazepam will likely diminish.

Diazepam therapy is typically initiated with a bedtime dose of 5 mg, which can be increased to 10 mg as needed. Daytime dosage typically starts with 2 mg twice daily, which can be titrated up to a maximum dose of 60 mg/d.9 When discontinuing the medication at higher doses, a drug taper is required to prevent withdrawal.

Dantrolene Sodium

Dantrolene sodium (Dantrium[dagger]) is a peripherally acting muscle relaxant that exerts its effect directly on skeletal muscle cells by altering the chemistry of muscle contraction. It is unique in that it acts on the muscle fiber rather than at the neuronal level, like most drugs used to manage spasticity. Dantrolene sodium interferes with the release of calcium from the sarcoplasmic reticulum onto the muscle's contractile filaments. Due to less calcium, initiation of cross-bridge formation between actin and myosin filaments is reduced, thus reducing nmscle contractility.22 For unknown reasons, dantrolene sodium does not exhibit an effect on cardiac or smooth muscle tissue.9

Because dantrolene sodium is a peripherally acting agent, it is preferred for its lack of adverse effects on the CNS. It cannot selectively target spastic muscles so it can produce the negative side effect of generalized muscle weakness. Therefore, the benefit of the drug therapy may be counterproductive if the resulting weakness impedes function. Dantrolene sodium is largely metabolized in the liver, and hepatotoxicity is among the greatest risks of its use, occurring in approximately 1.8% of people using the drug.23 Liver function tests should be performed prior to drug therapy initiation and repeated over the course of treatment. Some researchers24,25 also have cited fatigue as an adverse drug reaction.

The use of dantrolene sodium is common in the management of spasticity of cerebral origin. Chyatte et al26 demonstrated a reduction in resistance to passive range of motion, clonus, and deep tendon reflexes in a double-blind, placebo-controlled study of 9 subjects. However, a decline in gross motor performance as measured by muscle force and stair climbing was noted. In another double-blind, placebo-controlled study of people with acute spasticity, Katrak et al24 found that Dantrium at 200-mg/d doses reduced muscle force in the unaffected limbs but not in the paretic limbs. There were no improvements or declines in resting muscle contractility or functional outcome measures. These results contradict the results of the study by Chyatte et al, examined people with chronic spasticity. Katrak and colleagues acknowledged that the drug dose used in their study may have been insufficient to achieve the desired therapeutic effects.

In an efficacy and long-term safety study using a double-blind, placebo controlled design,27 the 9 subjects post-stroke who received a placebo noted an increase in deficits, 7 or whom requested to terminate the placebo phase and resume intervention with dantrolenc sodium. In this study, 93% of the subjects had improved performance in activities of daily living with the initiation of drug therapy as measured by transfer, personal hygiene, and dressing abilities and had no adverse long-term side effects during follow-up lasting 12 weeks to 2.5 years.

Dosage is typically initiated at 25 mg, which can be incrementally increased to 100 mg 2 to 4 times per day. The maximum recommended daily dose is 400 mg.9,17,23 following stroke, most patients can effectively manage their spasticity with doses of 200 mg/d or less.23 Drug therapy should be started with a low dose, with the dosage slowly increased, to reduce the chance of side effects.

Oral Boclofen

Baclofen (Lioresal[double dagger]) is a structurally similar derivative of the previously discussed inhibitory neurotransmitter, GABA, and it is capable of inhibiting both monosynaptic and polysynaptic reflexes at the spinal level. It was first introduced as an oral drug in 1966 and as an implantable drug in 1984.28 Baclofen appears to selectively bind to GABA-b receptors. Although its exact mechanism of action remains unclear, baclofen appears to increase inhibition both presynaptically and postsynaptically. Baclofen binds with the GABAergic presynaptic receptor, causing hyperpolarization of the membrane and limiting the influx of calcium into the presynaptic terminal. These events result in a reduction in the release of the excitatory endogenous transmitter.10 Whether the inhibition occurs though presynaptic inhibition of excitatory neurons that synapse with alpha motoneurons or through postsynaptic inhibition directly on the alpha motoneuron, or a combination of both, the net effect is decreased activation of the alpha motoneuron.17

Baclofen has limited ability to cross the blood-brain barrier.29 Oral administration is frequently ineffective in controlling severe spasticity because of dosing limitations and systemic side effects.30 At doses that reduce spasticity, as many as 25% to 30% of people experience drowsiness, confusion, headache, and lethargy.11 There are limited studies examining the effects on spasticity and function in patients with stroke following oral administration of baclofen, but drug therapy appears more effective in managing spasticity caused by spinal cord damage than by cerebral damage because of the patients' increased susceptibility to adverse side effects9,17,31 and baclofen's limited ability to cross the blood-brain barrier.29

The recommended dosing regimen is initiated with 5 mg 3 times a day. It can be increased by 15-mg/d increments at 3-day intervals as needed. Dosing should not exceed 80 mg/d.17

Tizanidine Hydrochloride

Tizanidine hydrochloride (Zanaflex,§ Sirdalud||) is a centrally acting α^sub 2^-adrenergic agonist that inhibits both presynaptically and postsynaptically. These α^sub 2^-adrenergic receptors are found at various sites in the brain and spinal cord, including the presynaptic and postsynaptic membrane of spinal interneurons that control alpha motoneuron excitability.17 The drug increases the presynaptic inhibition of excitatory spinal interneurons, which decreases the amount of excitatory neurotransmitter release and thus the excitatory input onto the postsynaptic alpha motoneurons.32

Tizanidine is closely related to the cardiac medication, clonidine (Catapres#), but is preferred in the management of spasticity due to its lack of cardiovascular side effects.17 Clonidine acts additionally on the brainstem α^sub 2^-adrenergic receptors, causing antihypertensive effects.17 The most frequently cited side effects associated with tizanidine are dizziness, sedation, and dry mouth.33,34

Several studies12,34-37 that examined the effects of tizanidine in people with stroke demonstrated its efficacy. In a double-blind study of 105 subjects with spasticity of cerebral origin, Bes and colleagues12 established that people taking tizanidine showed functional improvements in ambulation distance on flat ground (572.63± 175.00 m [X±SD] before intervention versus 796.00±247.48 m [X±SD] after intervention). Both tizanidine and diazapam reduced the duration of contractions and increased the angle at which contraction occurred; however, fewer people who took tizanidine discontinued intervention as a result of the side effects as compared with people who took diazepam.

Tizanidine also has been shown to be effective in reducing spasticity as measured by the Modified Ashworth Scale, in reducing pain intensity, and in improving quality-of-life scores without decreasing muscle force as measured by the British Medical Research Council Scale and dynamometric grip force in a study of 47 people with chronic spasticity following stroke.34 Thirteen subjects, however, discontinued the study because of adverse events such as hypotension, dizziness, and lethargy. Despite these dropout rates, the use of tizanidine has been promoted over oral baclofen37 and diazepam12 due to its more favorable side effect profile and tolerability.

Dosing of tizanidine requires titration. Initial dosage typically starts with 2 to 4 mg at bedtime and is progressively increased by 2 to 4 mg every 2 to 4 days, with a maximum recommended dose of 36 mg/d.9 Dosages of 4 to 8 mg 3 times daily are felt to be most efficacious.36 The drug's peak effect occurs approximately 2 hours after ingestion and has a half-life of 2.5 hours. Tizanidine is pharmokinetically and physiologically safe if combined with baclofen.38

Intrathecal Drug Therapy

The term "intrathecal" refers to the administration of pharmacologic agents directly into the subarachnoid space of the CNS. This technique requires implantation of a programmable pump device into the subcutaneous tissue of the abdominal wall. The benefit of intrathecal drug therapy over oral administration is that a constant dose can be delivered continuously, avoiding peak and valley drug effects.

Intrathecal Baclofen

As previously mentioned, oral forms of baclofen are ineffective at crossing the blood-brain barrier at low doses.29 Intrathecal baclofen (ITB) is suited for individuals with severe spasticity who either do not benefit from the oral form or do not tolerate the adverse effects. Direct administration into the CNS results in fewer systemic side effects because the drug remains in the area of the spinal cord rather than circulating in the bloodstream and causing adverse effects on other tissues.17 However, complications such as infection, impaired wound healing, catheter dislocation, and pump malfunction exist. Catheter complications have been reported to be as high as 62%,39 but the rate is between 20% and 25% in most clinical studies.40 Pump malfunction resulting in overdose can result in respiratory depression, decreased cardiac function, and coma; abrupt stoppage of drug administration can result in withdrawal.41

Several studies29,42-45 have examined the effect of ITB on spasticity of cerebral origin; however, few studies have examined the diagnosis of stroke specifically.29,45 In a review article, Campbell et al42 provided an abundance of evidence in support of ITB in the management of spasticity, with functional improvement documented in 60% to 70% of the studies. Campbell et al found that documentation of improved quality of life is typically anecdotal.

In a recent study, Francisco and Boake,29 using a case-series design with 10 subjects, examined functional gains following ITB administration and found improved walking speed, functional mobility ratings, and spasticity while maintaining the muscle force in the uninvolved extremities. Remy-Neris et al,43 examining gait kinematics in people with spastic hemiplegia, found increases in knee extension and ankle flexion in 7 subjects 4 hours after initiating ITB therapy. In that study, Ashworth scale scores decreased in the quadriceps femoris and triceps muscles and maximum walking speed improved; however, preferred walking speed remained unchanged.

The intrathecal dose of baclofen is approximately 1% of the oral dose.46 Dosing typically is initiated at an infusion rate of 25 µg/d and titrated up to an average of 400 to 500 µg/d.9 Tolerance to ITB is a concern and may differ according to diagnosis.47 Several researchers48-50 have reported that doses must be progressively increased over periods of months to years in order to maintain ITB's effect.

Other Intratecal Drugs

Morphine sulphate (Infumorph**) and fentanyl have been successfully implemented for the management of spasticity,51-53 but indications for their use appear to be severe pain as a result of spasticity52,53 or tolerance to ITB.51 The studies of their use are limited to case reports and appear to be more promising for spasticity of spinal origin versus stroke.

Focal Treatment

Chemical Neurolytics

Chemical neurolysis is the destruction of a portion of a nerve in order to impair conduction. Two neurolytic agents are ethyl alcohol and benzyl alcohol (phenol). Relatively few reports of adverse effects of intramuscular and perineural ethyl alcohol injections compared with phenol injections exist, which may be due to a better safety profile of ethyl alcohol or to more extensive use of phenol over the last 3 decades.54

Phenol Injections

Phenol causes chemical denervation by denaturing protein, which results in Wallerian denervation. The extent of damage and length of effects are associated with the concentration of phenol in the injected solution.55 Phenol injections are typically used for larger proximal muscle groups because the nerve injected often supplies multiple muscles and therefore can have a greater effect using a lesser dose.54 Injections of phenol can be administered perineurally or intramuscularly. Perineural injection of a motor nerve may have a longer effect than intramuscular injection but has the additional risk of permanent causalgia due to sensory nerve injury.54 Intramuscular nerve blocking may be more painful but may allow for easier titration of the weakening effect. Phenol typically induces a short-term anesthetic effect followed by a longer-duration neuromuscular block.55 The improvement following either type of phenol injection may last from a few weeks to years.3

Phenol injections for people with acquired spasticity have been examined,56-59 including 2 studies of people with stroke. Kirazli and colleagues57 compared 3 mL of 5% phenol injections with 400 units of botulinum toxin (BTX) type A injections for the management of the spastic foot in 20 subjects. Both groups had a decrease in Ashworth scale scores and clonus duration, but subjects in the BTX group had more improvement than subjects in the phenol group at weeks 2 and 4, although there was no difference between groups at weeks 8 and 12. In a follow-up study,58 phenol was found to affect the M-response amplitude, whereas BTX type A affected the amplitude of the tendon response. The authors suggested that both agents reduce spasticity but by different mechanisms. Phenol affects the alpha motoneuron fibers within the tibial nerve, and BTX type A affects the fusimotor system and the muscle spindle. More diagnosis-specific and placebo-controlled studies are needed to draw conclusions regarding the safety and efficacy of phenol injections.

Botulinum Toxin

Botulinum toxin is a potent neurotoxin produced by the bacterium Clostridium botulinum. Two types of BTX are-available: type A (Botox,[dagger][dagger] Dysport[double dagger][double dagger]) and type B (Neurobloc§). Botulinum toxin works by binding to the presynaptic acetylcholine vesicles at the neuromuscular junction of skeletal muscles and preventing the release of the excitatory neurotransmitter.60 Subsequently, the muscle undergoes relaxation while leaving axonal conduction intact. Botulinum toxin is a focal intervention for specific dystonic or spastic muscles. It is typically reserved for smaller muscles that can be selectively targeted.

The reduction of spasticity after BTX injection begins within 3 to 7 days and may last for 2 to 6 months. Repeated injections often are necessary. Return of the abnormal resting muscle contractility is likely due to regeneration of fusion proteins and collateral sprouting of the nerve endings.3

Several studies61-78 have confirmed the efficacy of BTX injections for the management of spasticity after stroke, with all studies revealing a reduction in spasticity, but relatively few studies showing functional improvements as a result of decreased spasticity. The majority of the studies addressed spasticity in the upper extremity. Bakheit et al61 examined 83 subjects with spasticity in the upper extremity in a randomized, double-blind, placebo-controlled trial. Despite a decrease in spasticity as measured by the Modified Ashworth Scale, disability as measured by the Rivermead Motor Assessment (RMA) and the Barthel Index (BI) did not improve. Rousseaux and colleagues,69 however, found improvements in RMA scores but not in Nine-Hole Peg Test scores. Predictive factors for improvement in function may include higher baseline hand function prior to injection. In the study by Rousseaux and colleagues, subjects with more severe spasticity at baseline demonstrated improved comfort levels following BTX type A injections. In 2 studies of 6 and 8 subjects, Das and Park75,76 showed a substantial reduction in spasticity using the Oswestry Scale, with only some improvement in BI scores. The overall lack of functional improvements demonstrated in people post-stroke may be the result of the chronicity of the condition in the subjects studied, insensitivity of the measurement scales used, or suboptimal muscles used for treatment.79

In a study of 12 people with spasticity of the plantar flexors,73 improvements in gait characteristics of vertical ground reaction forces, speed, stride length, and stance symmetry were demonstrated. Seven subjects demonstrated better loading, advancement of the body, and push-off of the affected lower extremity; however, the improvements waned after 8 weeks.

Botulinum toxin is not a cure for spasticity in that its effect is temporary. Intervention is limited by the number of muscles that can be injected during a given treatment and the amount of BTX that can be administered. Although it has been reported that repeated BTX type A injections show unchanging effectiveness,65 it is plausible that some patients may lose the effect after repeated injections. However, BTX type B does not have cross-reactivity with BTX type A and, therefore, is effective in individuals who do not respond adequately or have developed resistance to BTX type A.8 Intervention using BTX versus phenol may possess the distinct benefits of not requiring exact localization of the injection, less pain at the time of administration, and the absence of permanent muscle transformations or vascular reactivity.54

When examining dosage, one must consider that Botox is 4 times more potent than Dysport; 100 units of Botox is nearly equivalent to 400 units of Dysport.3 A total amount of 200 to 300 units of Botox is typical for one treatment session, with the maximum dose of 400 units every 3 months. There are minimal adverse effects associated with BTX injections. The most frequently cited adverse effects are pain at the injection site and increased weakness in the treated muscle.

Conclusion

Several options exist for the pharmacologic management of spasticity after stroke, each with its own potential benefits and drawbacks. The decision regarding whether, when, and how to manage spasticity is influenced by many factors and may not simply follow the strategy of conservative to aggressive interventions.80 Factors to consider include distribution of spasticity, chronicity, severity, cause, concomitant medical conditions, and cost.80 The goals of intervention must be clearly established prior to choosing the intervention. A team approach to spasticity management should be used to maximize the outcome. Contrary to expectation, a reduction in spasticity does not necessarily improve , function.20,24,26,75,76

* Roche Pharmaceuticals, Roche Products Inc, Manati, Puerto Rico 00674.

[dagger] Proctor & Gamble Pharmaceuticals Inc, Health Care Research Center, 8700 Mason Montgomery Rd, Mason, oil 45040.

[double dagger] Manufactured by Novartis Pharma AG, Basel, Switzerland, for Medtronic Inc, 710 Medtronic Pkwy NK, Minneapolis, MN 55432-5604.

§ Elan Biopharmaceuticals, 7475 Lusk Blvd, San Diego, CA 92121.

|| Novartis Pharma AG, Hasel, Switzerland.

# Boehringer Ingelheim Pharmaceutical Inc, a subsidiary of Boehringer Ingelheim Corp, 900 Ridgebury Rd, PO Box 368, Ridgefield, CT 06877-0368.

** No manufacturer's information available.

[dagger][dagger] Allergan Inc, 2525 Dupont Or, PO Box 19534, Irvine, CA 92623-9354.

[double dagger][double dagger] Ipsen Ltd, 190 Bath Rd, Slough, Berkshire SL1 3XE, United Kingdom.

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JE Gallichio, PT, MPT, is Senior Physical Therapist, Montefiore Medical Center-The Jack D Weiler Hospital of the Albert Einstein College of Medicine, 1825 Easlchesier Rd, Bronx, NY 10461 (USA) (gallich33@aol.com).

The author thanks Sum Harlgraves, PT, PhD, for his support and critique of the manuscript.

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