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(Stroke. 2001;32:1841.)
© 2001 American Heart Association, Inc.

Original Contributions

Open-Label Dose-Titration Safety and Efficacy Study of Tizanidine Hydrochloride in the Treatment of Spasticity Associated With Chronic Stroke

David A. Gelber, MD; David C. Good, MD; Alexander Dromerick, MD; Stephen Sergay, MB, BCh Melissa Richardson, MD

From the Department of Neurology (D.A.G.), Southern Illinois University, Springfield, Ill; Departments of Neurology (D.C.G.) and Physical Medicine and Rehabilitation (M.R.), Wake Forest University, Winston-Salem, NC; Department of Neurology (A.D.), Washington University, St Louis, Mo; and Tampa Neurologic Associates (S.S.), Tampa, Fla.

Correspondence to David A. Gelber, MD, Springfield Clinic Neuroscience Institute, 455 W Carpenter, PO Box 19248, Springfield, IL 62794-9248. E-mail Dgelber{at}springfieldclinic.com

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion APPENDIX References

 
Background and Purpose—— Spasticity is a frequently observed motor impairment that develops after stroke; it can cause pain and disability in those affected. The objective of the present study was to evaluate the safety and efficacy of tizanidine, a centrally acting ₂-adrenergic agonist, in the treatment of stroke-related spasticity.

Methods—— Forty-seven patients, who were a minimum of 6 months poststroke and had significant spasticity, were studied at 4 centers. Tizanidine was administered in an open-label manner for 16 weeks, beginning at 2 mg/d and slowly titrated to a maximum of 36 mg/d. The Modified Ashworth Scale, muscle strength testing, functional assessments, and Pain and Functional Spasticity Questionnaires were administered at baseline and at 4, 8, 16, and 18 weeks (after 1 week off tizanidine).

Results—— Spasticity was significantly improved between baseline and week 16, with a decrease in total upper extremity Modified Ashworth Scale score of 2.80±0.47 (P<0.0001). No decline in strength was noted. Treatment with tizanidine resulted in a significant improvement in pain intensity (P=0.0375), quality of life (P=0.0001), and physician assessment of disability (P=0.0001). The most frequent side effects were somnolence (62%) and dizziness (32%). No serious adverse events were considered to be drug related. Ten of 47 patients (21%) were able to reach the maximum daily dosage of 36 mg.

Conclusions—— Overall, the data suggest that tizanidine is safe and efficacious in the treatment of stroke-related spasticity, preserving muscle strength while reducing muscle tone and painful spasms in affected patients.

Key Words: spasticity • stroke • tizanidine

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion APPENDIX References

 
More than 75% of stroke patients have motor impairments, often resulting in disability, such as impaired ambulation and inability to perform activities of daily living (ADLs).¹ In addition to motor weakness, 65% of stroke patients develop spasticity.² This is commonly defined as a velocity-dependent increase in muscle tone, associated with hyperreflexia and, at times, painful muscle spasms.³ Spasticity generally develops days to weeks after an acute stroke, and although it may eventually improve or resolve in some individuals, in others, it may be a permanent sequela.

Spasticity in and of itself is not necessarily detrimental. In fact, some patients use their increase in muscle tone to allow them to stand and ambulate. However, in others, spasticity can interfere with the ability to position comfortably, transfer, walk, perform ADLs, or maintain adequate hygiene, and it can be painful or predispose to the development of decubitus ulcers and contractures.⁴ In these individuals, treatment of spasticity is generally considered.

Patients with spasticity restricted to 1 or a few muscle groups may be best served by local treatment with botulinum toxin along with casting or splinting, whereas patients with generalized spasticity often require treatment with oral medications. The most commonly used medications have included baclofen, dantrolene, and the benzodiazepines, such as diazepam. Although effective, these medications are limited in their use by side effects.⁴ Diazepam is highly sedating and often causes tachyphylaxis and habituation. Baclofen is also sedating and tends to cause weakness, of both spastic and nonspastic muscles, which may lead to a worsening in function despite an improvement in muscle tone. Dantrolene also causes muscle weakness.

Tizanidine hydrochloride is a centrally acting -adrenergic agent that has been shown to be an effective treatment for spasticity, especially in patients with multiple sclerosis and spinal cord injury.^5–7 Unlike other drugs used to treat spasticity, tizanidine has not been shown to cause weakness.⁸ Overall, tizanidine has generally been better tolerated than these other drugs in comparative studies.⁹ Although several previous studies have included stroke patients,^10,11 the side-effect profile and effectiveness of tizanidine in the stroke population have not been definitively demonstrated.

The primary objective of this multicenter, open-label, 16-week treatment study was to evaluate the efficacy of tizanidine in the treatment of chronic spasticity after stroke. The study was also designed to evaluate the safety of tizanidine, to establish a safe and effective dosage range, and to evaluate the effects of the drug on muscle pain and on quality of life. In addition, the study was designed to evaluate the effect of tizanidine on muscle strength and functional abilities.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion APPENDIX References

 
Forty-seven patients who had experienced an ischemic or a hemorrhagic stroke 6 months earlier were enrolled across 4 study sites. For inclusion in the study, patients were required to have moderate spasticity, defined as a Modified Ashworth Scale (MAS)¹² score of 2 or 3 in 1 major muscle group in the affected upper extremity, and functional limitations as a result, including either muscle pain or mass spasms, limited passive range of motion, or impaired ADLs. Patients with debilitating concurrent medical conditions, significant language or cognitive deficits, fixed contractures, or a history of multiple strokes or those who had received botulinum toxin injections within the past 6 months or tizanidine previously were excluded. Antispasticity drugs (eg, baclofen, dantrolene, or benzodiazepines) were discontinued before study onset. Written consent for study participation was obtained from all patients

All patients received tizanidine in an open-label fashion. The initial dosage was 2 mg/d at bedtime. The dosage was increased by 2 mg every 7 days until the patient reached a dosage of 16 mg/d in 3 divided doses. The dosage was then increased more rapidly by 2 mg every 3 to 4 days to a maximum of 36 mg/d divided 3 times a day. If a patient could not tolerate a particular 2-mg increase because of side effects, he or she was maintained at the previous dosage for 1 additional week and the titration schedule was continued. At 16 weeks, patients were tapered off tizanidine over 1 week.

Before the initiation of drug treatment, all patients had baseline assessments that included a general physical examination, with vital signs measured while lying down and then repeated at 2 minutes while either sitting or standing, and the National Institutes of Health Stroke Scale (NIHSS).¹³ Spasticity of the elbow, wrist, finger, hip, and knee flexors and extensors was graded with the MAS independently by both the investigator and an occupational therapist; any discrepancy in scoring was discussed and resolved by consensus. The occupational therapist also evaluated muscle strength testing by using the British Medical Research Council (BMRC) scale,¹⁴ grip strength was measured with a hand-held dynamometer, upper extremity function was assessed with the Action Research Arm Test (ARAT),¹⁵ and lower extremity function and ambulation were assessed with the timed Up and Go Test.¹⁶ Global functional abilities were measured with the Barthel Index (BI).¹⁷ Quality-of-life issues were evaluated with a Functional Spasticity Questionnaire, the effect of spasticity-related pain was evaluated with the newly constructed Pain Questionnaire, and disability was evaluated with a physician rating scale (see Appendix). These assessments were repeated at weeks 4, 8, 16, and 18 (after 1 week off tizanidine). The safety profile of tizanidine was assessed through recording of adverse events, laboratory values, and vital signs.

The primary outcome measure was the change in spasticity from baseline to week 16, evaluated by adding individual MAS scores to give a total MAS score for the upper extremity. Additional outcome measures included change from baseline to week 16 for pain (Pain Questionnaire scale), quality of life (Functional Spasticity Questionnaire scale), strength (BMRC scale and dynamometry), ambulation and need for assistive devices for ambulation (Up and Go Test), ability to perform ADLs (BI), and upper extremity function (ARAT).

A modified intent-to treat data set was used for all efficacy analyses. All hypothesis testing was performed at an level of 0.05 and was 2-tailed. All changes from baseline were each separately tested with a dependent sample t test.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion APPENDIX References

 
Forty-seven patients were enrolled in the study. Demographic data are given in detail in Table 1. The mean age of the patients was 60.9 years, and the mean time from stroke to study entry was 29.8 months. A total of 32 patients completed the study; 13 patients dropped out due to adverse events, 1 was lost to follow-up, and 1 was discontinued at baseline because of a high creatinine level.

View this table: [in this window] [in a new window]   Table 1. Demographic Features and Baseline Characteristics of Study Patients

A summary of the mean change in the total MAS for the upper extremity for all of the subjects between baseline, week 16, and week 18 (off medication) is presented in Table 2. A linear dose-response relationship up to week 16 was seen (Figure). At week 18, after the discontinuation of tizanidine, there remained a significant improvement in spasticity from baseline (decrease in MAS of 1.59±0.40, P=0.0003), although some of the spasticity had returned.

View this table: [in this window] [in a new window]   Table 2. Total MAS Scores During Study

View larger version (17K): [in this window] [in a new window]   Mean change from baseline to follow-up in the total upper extremity for the MAS.

There was no decline in muscle strength, as assessed with the BMRC and grip dynamometry, over the course of the study. In fact, a modest improvement was seen in the wrist, elbow, and finger flexors (Table 3). As well, there was no significant change in functional abilities, as measured with the BI and ARAT. BI scores (mean±SEM) on admission were 80.2±2.7 and 81.1±2.9 at week 16. ARAT data are presented in Table 4. Although there was no difference in the frequency of pain, a significant improvement in pain intensity (P=0.0375) from baseline to week 16 was found (Table 5). A significant improvement for overall quality of life, as assessed by the patients, and in physician assessment of functional disability also were reported during the study (P=0.0001) (Table 5).

View this table: [in this window] [in a new window]   Table 3. Change in Muscle Strength Associated With Tizanidine Treatment (BMRC Results)

View this table: [in this window] [in a new window]   Table 4. ARAT Results

View this table: [in this window] [in a new window]   Table 5. Pain and Functional Spasticity Questionnaires Results

The percentage of patients requiring a cane to walk decreased from 65% at baseline to 59% at week 16; the percentage needing an orthosis decreased from 73% to 66%. The mean time to perform the Up and Go Test increased from 31.5 seconds at baseline to 37.1 seconds at week 16.

The average daily dose of tizanidine between baseline and week 4 was 4.7±0.2 mg. This increased to 11.5±0.5 mg from week 5 to week 8 and to 20.2±1.3 mg from week 9 to week 16. A total of 10 of 47 patients (21%) reached the maximum daily dose of 36 mg.

Vital signs were recorded at all study visits. Eleven percent of patients developed measurable orthostatic hypotension during the course of the study.

Eighty-nine percent of patients experienced 1 side effect that was possibly related to tizanidine, including complaints of somnolence (62%), dizziness (32%), asthenia (30%), dry mouth (21%), and hypotension (13%). Thirteen patients (28%) discontinued study medication because of an adverse event. One patient was discontinued from the study when he was diagnosed with metastatic pancreatic carcinoma, thought to be unrelated to tizanidine. Two patients (4%) developed elevated transaminases (5x to 8x baseline). In both cases, the elevation was noted midway through the study, at a dosage of 14 mg/d. The liver function values returned to normal after the tizanidine was discontinued. Seven patients discontinued tizanidine because of intolerable dizziness, lethargy, or hypotension. All of these patients developed these side effects early in the course of the study, at low dosages of 2 to 4 mg/d. Three patients dropped out of the study: 1 patient after constipation developed, 1 because of increasing leg weakness, and 1 after a swollen cheek developed. It was unclear, in these 3 cases, whether these adverse events were related to tizanidine.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion APPENDIX References

 
Spasticity is a common sequela of central nervous system disorders, including stroke, due to lesions that affect descending tracts in the brain and spinal cord that normally inhibit spinal reflex pathways. Spasticity, defined as a velocity-dependent increase in muscle tone, is often accompanied by an increase in muscle stretch reflexes, muscle weakness, painful spasms, poor dexterity, and cocontraction of agonist and antagonist muscles.^18,19 Treatment of spasticity is considered when it interferes with function, such as ambulation, transfers, and ADLs, or is painful.⁴ Conservative interventions, such as physical therapy, splints, and orthoses, are often prescribed initially; however, when these measures are ineffective, medications are often necessary.

A number of drugs have been used in the treatment of spasticity caused by stroke. Although effective in reducing muscle tone and painful spasms, the use of the medications is often limited by side effects. Baclofen is an agonist of -aminobutyric acid (GABA) and inhibits both monosynaptic and polysynaptic spinal cord reflexes.²⁰ It is effective in the treatment of spasticity of both spinal and cerebral origin.²¹ However, the use of baclofen is limited by sedative side effects. In stroke patients, it often causes sedation and confusion, especially in those with underlying cognitive dysfunction, and because of this is, it is generally poorly tolerated in the stroke population.^22,23 In addition, baclofen causes muscle weakness, especially at moderate and high doses, which is of obvious concern in stroke patients who are hemiparetic.⁴ Studies have reported that >10% of patients discontinue baclofen therapy because of muscle weakness.²⁴

Benzodiazepines, such as diazepam and clonazepam, reduce muscle tone and painful spasms by increasing the affinity of GABA receptors for endogenous GABA, predominantly at the spinal cord level.²⁵ Benzodiazepines have been shown to be as effective as baclofen,²⁶ but their use is also limited by side effects, including habituation and tachyphylaxis. Of greatest concern for stroke patients is that benzodiazepines are sedating and can cause confusion.⁴

Dantrolene reduces muscle tone through its action on skeletal muscle; it interferes directly with the excitation-coupling reaction.²⁷ It is effective in reducing spasticity of both cerebral and spinal origin. Unfortunately, the use of dantrolene is also limited by its side effects, which include muscle weakness and hepatotoxicity.⁴

Botulinum toxin is a neurotoxin produced by the clostridium botulinum bacterium. There are 7 antigenically distinct serotypes that inhibit the neuronal release of acetylcholine, producing functional denervation of muscle fibers.⁴ Botulinum toxins appear to be useful in the treatment of focal spasticity,^28,29 although additional studies in this area are warranted.

Tizanidine is the newest medication formally approved for the treatment of spasticity caused by cerebral and spinal cord disorders. It is an imidazoline derivative, active at ₂-receptors in the brain and spinal cord. Tizanidine decreases the excitability of and motor neurons in the spinal cord by reducing the release of excitatory neurotransmitters in the spinal cord and decreasing the action of these excitatory neurotransmitters at their receptors.³⁰ Tizanidine also inhibits the release of substance P from small sensory afferent nerve fibers, and it has been shown to slow the firing of the locus ceruleus, which normally facilitates spinal cord reflexes through descending ceruleospinal pathways.³¹ Through these actions, tizanidine has been shown to preferentially decrease polysynaptic spinal cord reflexes, resulting in a reduction in flexor and extensor muscle tone and painful spasms.

There have been 3 multicenter, double-blind, randomized, placebo-controlled trials of tizanidine in the treatment of spasticity and painful spasms in patients with multiple sclerosis and spinal cord disorders.^5–7 A combined analysis for the 525 patients in these studies demonstrated a significant improvement in muscle tone and spasms for the patients treated with tizanidine.⁸ Tizanidine was not shown to cause any muscle weakness.⁸

Several series have reported tizanidine to be effective in treating spasticity in stroke patients. However, these studies have been limited because of small sample size,^11,32 inclusion of mixed diagnoses,¹⁰ and evaluation of only low to mid range tizanidine doses.^10,11,32

Approximately 20 studies have compared the efficacy of tizanidine with other antispasticity medications in patients with a variety of neurological disorders, and a combined analysis of results from these trials has been published.²⁴ In these comparative studies, tizanidine was shown to be as effective as baclofen and diazepam in tone reduction and more effective in reducing clonus. In contrast to baclofen, tizanidine was not shown to cause muscle weakness. Overall, patients tolerated tizanidine better than they did the other medications. Fewer patients who were receiving tizanidine dropped out of the study, and physicians generally rated tizanidine better than baclofen or diazepam in terms of medication tolerability.²⁴

The major objective of the present study was prospectively evaluate the safety and efficacy of tizanidine, specifically in the stroke population. Forty-seven patients from 4 centers were evaluated. Only patients who experienced stroke 6 months earlier were enrolled; this was to minimize the effect of "natural recovery" on the outcome measures. In this open-label 16-week treatment trial with tizanidine, there was a statistically significant improvement in upper extremity spasticity as measured with the MAS. A dosage effect was evident (Figure); as the dosage of tizanidine was increased, there was a greater decrease in muscle tone. As expected, spasticity worsened after tizanidine was withdrawn. Treatment with tizanidine also resulted in a significant improvement in pain intensity and quality-of-life measures, as reported by the patients.

Although not statistically significant, it actually took more time for patients to perform the Up and Go Test at week 16 than at baseline. This may be related to the reduced use of canes and orthotic devices at the end of the study. Similar to the results of other studies, the use of tizanidine was not associated with an increase in weakness in this stroke population.

A limitation of this study was the fact that there was no control group; therefore, the possibility of a placebo effect cannot be excluded. However, the improvement in spasticity and pain was of the same magnitude seen in prior double-blind placebo-controlled trials of tizanidine in patients with multiple sclerosis and spinal cord disorders.^5–7 In addition, the linear correlation of tizanidine dosage to spasticity reduction seen in this study further supports a true medication effect.

Of particular concern in this study was whether older stroke patients would be able to tolerate tizanidine as well as the younger patients with multiple sclerosis or spinal cord injuries who were previously studied. For this reason, the dosage escalation was slow, increasing by 2 mg every week. Surprisingly, many of the patients were able to tolerate high doses of tizanidine; 21% were able to reach the maximum dosage of 36 mg/d.

The side effects seen with tizanidine in this study were similar to those previously reported.⁸ The most common were sedation (62%), dizziness (32%), dry mouth (21%), and hypotension (13%). Seven of the 47 patients withdrew from the study because of these side effects. All of these patients developed these side effects at very low doses of tizanidine, 2 to 4 mg/d, suggesting that patients who do not tolerate tizanidine can generally be identified early in the treatment course.

There have been previous reports of elevated transaminases associated with tizanidine treatment.⁸ In these series, the liver enzyme values returned to normal after discontinuation of the drug. Two patients in our series developed elevated transaminases (5x to 8x baseline values) midway through the study, at tizanidine dosages of 14 mg/d. Both of these patients were withdrawn from the study, and their liver enzyme values subsequently returned to baseline.

In summary, in this multicenter open-label trial, tizanidine was shown to be effective in reducing spasticity and pain and in improving the quality of life in stroke patients. Overall, the findings were similar to those previously reported for patients with multiple sclerosis or spinal cord injuries. The initial dosage of tizanidine in this study was 2 mg/d. With a slow dose escalation schedule of 2 mg per week, the drug was tolerated reasonably well, with almost one fourth of patients able to tolerate a maximum dosage of 36 mg/d. Similar to findings reported previously, tizanidine did not cause muscle weakness. Therefore, it might be preferable over other antispasticity medications that do cause weakness, such as baclofen and dantrolene, especially in patients whose strength is already compromised by neurological disease. This results of this study suggest that tizanidine should be considered a first-line treatment for patients with stroke-related spasticity.

	APPENDIX

Top Abstract Introduction Subjects and Methods Results Discussion APPENDIX References

 

View this table: [in this window] [in a new window]   Table A1.

	Acknowledgments

 
This work was funded by a grant from Elan Pharmaceuticals.

Received October 18, 2000; revision received May 3, 2001; accepted May 15, 2001.

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