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A Practical Overview of Tizanidine Use for Spasticity Secondary to Multiple Sclerosis, Stroke, and Spinal Cord Injury

Posted on: Thursday, 3 April 2008, 03:00 CDT

By Kamen, Leonard Henney, Herbert R III; Runyan, Jacob D

Key words: Efficacy - Review - Safety - Spasticity - Tizanidine ABSTRACT

Objective: Tizanidine is an imidazoline central alpha^sub 2^- adrenoceptor agonist widely used to manage spasticity secondary to conditions such as multiple sclerosis (MS), stroke, and spinal cord injury (SCI). While there is widespread use of tizanidine in clinical practice, little practical information is available to assist preservers with the effective use of tizanidine for spasticity management. The aim of this review is to provide an up- to-date overview of tizanidine and its use in the management of spasticity associated with acquired (SCI), static (stroke), and progressive neurological (MS) diseases.

Scope: An unfiltered literature search of the term 'tizanidine' was undertaken on the Medline database resulting in 311 papers. As the review focused on tizanidine clinical pharmacokinetics, efficacy, and tolerability, with comparisons limited to the oral antispastic agents baclofen, diazepam, and dantrolene, 53 articles were selected for detailed assessment.

Findings: Tizanidine, an alpha^sub 2^-adrenoceptor agonist, is a short-acting drug with larger interpatient variability, and linear pharmacokinetics that is dosage form-dependent. Clinical trials have demonstrated that the efficacy of tizanidine is comparable to that of baclofen or diazepam with global tolerability data favoring tizanidine. A clinical case presentation demonstrated the effective use of tizanidine in combination with baclofen as a logical avenue for improved spasticity control.

Conclusions: There is a large body of evidence for the effective use of tizanidine monotherapy in the management of spasticity. A case study demonstrates that combination therapy can effectively control spasticity while better managing dose-dependant adverse events, although additional studies need to be performed to confirm these results.

Introduction

Spasticity is the result of involuntary muscle tension, stiffening, or contractions and is often associated with spinal cord injury, multiple sclerosis (MS), stroke, and traumatic brain injury, among other etiologies1. Classically, spasticity is described as a movement disorder characterized by excessive motor activity resulting from an upper motor neuron (UMN) syndrome or injury. In UMN disorders, nerve cells in the spinal cord no longer receive normal input from the brain, resulting in transmission of unregulated impulses to the muscles. The symptoms of UMN syndrome can include spasticity, weakness, fatigability, and decrease in coordination. The clinical consequences of spasticity can be extensive, including disfigurement, disability, and pain2. The majority of people with spinal cord injury (65-78%)3 or multiple sclerosis (84.3%)4 experience spasticity. While the incidence of spasticity is not known with a high degree of certainty, it is estimated to affect over half a million people in the USA alone, and over 12 million worldwide5. Until recently, the economic burden of multiple sclerosis was not well documented6-8. However, progress has been made to quantify the financial impact of the disease both in the United States and across Europe. Based on data from 1994, the annual cost of multiple sclerosis in the United States was estimated at over $34 000 per person9. At that time, the per person cost conservatively translated to an estimated national annual cost in the US of between $6.8 billion and $11.9 billion, excluding intangible losses (losses due to an individual's pain and suffering). The total lifetime cost per case was approximately 2.2 million9. Analysis of data from the North American Committee on Multiple Sclerosis Patient Registry (NARCOMS) indicates that in 2004 the estimated per-patient cost had risen to $47215 per year10. In 2005, the European mean annual per-patient resource consumption for MS adjusted for domestic purchasing power was approximately euro18000 for mild disease (Expanded Disability Status Scale (EDSS) < 4), euro36 500 for moderate MS (EDSS 4-6.5) and euro62000 for patients with severe MS (EDSS > 7)11. The influence of spasticity on these costs has not been documented.

Based on the recommendations developed by the Multiple Sclerosis Council for Clinical Practice Guidelines, pharmacological management of generalized spasticity is indicated when symptom severity cannot be controlled by other means such as health promotion strategies and skilled rehabilitation strategies12. Effective management of spasticity provides not only for symptomatic relief; it can also allow patients to more fully participate in physical and occupational therapies. At least 16 drugs have been purported to have some effect in controlling spasticity or the pain associated with spasticity12. Neuromuscular blockade is most appropriate for focal spasticity.

This overview of tizanidine has been limited to comparisons with other oral antispastic agents outlined in the evidence-based guidelines of the Consortium of Multiple Sclerosis Centers (CMSC)12. In addition to tizanidine, only diazepam, dantrolene, and baclofen received a rating high enough to substantiate clinical effectiveness in the management of spasticity.

Tizanidine is an orally administered alpha^sub 2^-adrenergic agonist developed in Europe during the 1980s and approved by the FDA in 1996 for the short-term management of spasticity. Despite widespread use in clinical practice, little information is available to inform prescribers about the effective use of tizanidine in the management of spasticity secondary to multiple sclerosis, stroke, and spinal cord injury.

In June 2007 the authors performed an unfiltered search of the Medline database for the term 'tizanidine' between 1966 through June 2007. Each of the 311 papers found in the search was screened for data pertaining to efficacy, tolerability, and comparisons with baclofen, diazepam, or dantrolene; 53 were human clinical trials available in English. Eliminating pharmacokinetic (PK) trials, off- label use, and data on healthy volunteers further reduced the available literature to 16 studies for review. Of the nine papers published where PK was the primary focus, all were reviewed, and data from eight are presented. The data in this manuscript were supported with supplementary published information covering non- drug related data including disease state etiology, epidemiology, economics, and test methodologies.

Mechanism of action and pharmacodynamics

Tizanidine (5-chloro-4-(2-imidozolin-2-ylamino)-2,1,3- benzothiodiazole hydrochloride) is an imidazoline derivative with central alpha^sub 2^-adrenoceptor agonist activity at both spinal and supraspinal levels. It has a chemical structure closely related to the antihypertensive clonidine, which has been reported to have antispastic properties13-15. The alpha^sub 2^-receptor IC^sub 50^ of clonidine is 1.2nmol compared to 6.9nmol for tizanidine16. To a limited degree, clonidine has been investigated in clinical studies in spasticity as single-agent therapy or combined with other oral agents, such as baclofen17. As expected, clonidine had significant cardiovascular effects that limited its usefulness in the treatment of spasticity. In animal studies, tizanidine has been shown to be about one-tenth to one-fiftieth the potency of clonidine in decreasing blood pressure or heart rate16.

The exact mechanism of action of tizanidine has not been fully clarified (for reviews see Coward16 and Wagstaff and Bryson18). It is believed that the pharmacodynamic effects of tizanidine are primarily linked to its alpha^sub 2^-adrenergic agonist properties, although its imidazoline receptor binding may play a role19,20. The predominant effect of tizanidine appears to occur presynaptically in the spinal cord21 by reducing release of the excitatory amino acids glutamate and aspartate from the presynaptic terminal of spinal interneurons. There is some evidence of postsynaptic action on excitatory amino acid receptors22. Tizanidine may also facilitate the action of glycine, an inhibitory neurotransmitter, which may result in the inhibition of facilitatory coeruleospinal pathways. Tizanidine reduces tonic stretch reflexes and polysynaptic reflex activity in the spinal transected cat, possibly presynaptically21,23. Myotonolytic activity of tizanidine has been demonstrated in animal models19,24 and patients with spastic paresis25-27, but unlike other muscle relaxants did not cause generalized muscle weakness as measured by British Medical Research Council Modified Scale of Muscle Strength (BMRC)28. Tizanidine has been shown to decrease blood pressure and heart rate during studies in animals19,29,30 and humans20,31, an effect which has been possibly linked to its imidazoline receptor binding29,32. In a single-dose study of 142 patients with multiple sclerosis, a statistically significant (p < 0.04) inverse correlation between tizanidine dose and blood pressure (r = -0.224) has been found31. In that study, tizanidine produced a clinically relevant decrease in mean blood pressure from 121/75mmHg to a mean nadir of 98/64.8 mmHg (p < 0.02). Animal studies have shown that tizanidine possesses antinociceptive activity33-35 and inhibits gastrointestinal (GI) transit36,37 and gastric acid secretion2938. Tizanidine does not have any known opioid, dopaminergic, or GABA receptor activity18. Pharmacokinetics

For more than two decades tizanidine has been available in the United States as an oral tablet and more recently as a multi- particulate capsule formulation. Tizanidine's use has, at times, been limited in patients not able to tolerate high enough doses to achieve adequate spasticity control. As a result, an attempt was made to alter the pharmacokinetics of the tablet formulation without having an adverse impact on effectiveness. The results of this effort yielded a multi-particulate capsule formulation. The capsule is made using proprietary technology starting with uniform spherical inert beads which are then coated with tizanidine.

The pharmacokinetic profile of tizanidine was initially defined using the conventional tablet formulation (for review see Wagstaff and Bryson18). Tizanidine is well absorbed (> 65%) after oral administration and mean maximum plasma concentration (C^sub max^) is reached after about 1-1.5 h (T^sub max^)20,25,39-42. Tizanidine is approximately 30% bound to plasma proteins16. Administration with food is known to increase the absorption of the tablet formulation43. At therapeutic doses, tizanidine pharmacokinetics are linear, although there is considerable interpatient variability25,42,44. Plasma concentrations appear correlated with antispastic activity25,44.

Tizanidine undergoes significant first-pass metabolism with an estimated bioavailability reported to be between 20 and 40%40,42,45. Tizanidine is known to be metabolized to four inactive metabolites which are excreted in urine and feces39,40,46. Mean elimination half- life has been generally estimated at 2-4 h20,39,42, although one study found a biphasic elimination, with a terminal phase of 22 h40. There is no significant excretion of unchanged tizanidine39,40,46 and mean renal clearance (CL^sub r^) has been calculated as 74mL/ min41. Renal impairment may increase plasma tizanidine concentrations18.

It has recently been demonstrated that tizanidine is mainly metabolized by cytochrome P450 1A247. CYP 1A2 inhibitors including ciprofloxacin, fluvoxamine, certain oral contraceptives and rofecoxib have a major effect on tizanidine kinetics, increasing plasma levels, therapeutic effects, and adverse effects48-51. No clinically significant interaction seems to occur when tizanidine is coadministered with acetaminophen18 or baclofen41. A single case report has shown that a tizanidine dose of 2 mg t.i.d. resulted in a 25% increase in phenytoin plasma concentration after 1 week of coadministration while the unbound percentage of serum phenytoin was unchanged52. Due to the nonlinear pharmacokinetics of phenytoin and the limited published information on this case, it is difficult to offer any general clinical guidance for the concurrent use of tizanidine and phenytoin.

The relative bioavailability of a single 4-mg dose of tizanidine tablet and a single 4-mg dose of tizanidine capsule administered after a high-fat meal has been compared in a randomized, crossover study in 18 adult subjects43. Mean In-transformed C^sub max^ (2.7 vs. 4.0ng/mL, p < 0.019; 90% CI 50.4-87.3) was reduced and mean T^sub max^ (2.6 +- 0.69 vs. 1.2 +- 0.656 h, p = 0.0001) was prolonged in the comparison between the capsule and tablet formulations, respectively, indicating that the formulations were not bioequivalent in the fed state. To establish bioequivalence, the 90% CI must have fallen between 80 and 125% for the In-transformed mean C^sub max^ and area under the plasma concentration time curve (AUC)53. The AUC^sub 0-last^ for capsule versus tablet (10.6 +- 7.0 and 11.7 +- 8.0ng-h/mL, respectively) was not statistically different. Single 8-mg doses of tizanidine tablet and capsule formulations were compared under fasting and non-fasting conditions in a randomized, crossover study in 96 adult subjects54. Tizanidine tablets and capsules were bioequivalent after fasting with a mean C^sub max^ of 5.5 +- 4.28 and 5.4 +- 4.17ng/mL, and AUC^sub 0-last^ of 16.0 +- 19.33 and 16.0 +- 16.41 ng.h/mL, respectively. When taken with food, the comparison between capsules and tablets resulted in decreases of 34 and 15% for mean C^sub max^ and AUC, respectively, while T^sub max^ was increased from 1.4 to 3.0 h (p < 0.0001) (Figure 1). Also in this study, the impact of tizanidine pharmacokinetics on cognitive impairment was studied using a computerized battery of tests (Power of Attention)55-62 that have previously been shown to assess aspects of attention and reflect the overall ability to focus and sustain attention. Power of Attention is defined by the mean reaction times of three tests: Simple Reaction Time, Digital Vigilance Task, and Choice Reaction Time. The prolongation of T^sub max^ when capsules were given with food compared to tablets regardless of time of administration or when capsules were given in a fasted state resulted in a delay in onset of cognitive impairment as measured by Power of Attention (Figure 2). The clinical implications of this finding are not clear, in part because the study was conducted with healthy volunteers and there was no up-titration to the 8-mg dose. The results should be confirmed with additional research in patients employing the Power of Attention test methodology.

Figure 1. Mean plasma concentrations of tizanidine (ng/mL) versus time following oral administration of tablet and capsule formulations (2 x 4 mg) under fed and fasted conditions in healthy volunteers (h = 81). T^sub max^ for capsule in fed state has a p < 0.0001 compared to all other treatments (reproduced with permission from Shah et al.54)

Figure 2. Mean change from baseline (ms) in Power of Attention versus time following oral administration of tablet and capsule formulations (2 x 4 mg) under fed and fasted conditions in healthy volunteers (n = 88) * p < 0.001 versus baseline (pre-dose). (Reproduced with permission from Shah et al.54)

In a randomized, crossover study in 28 adult subjects (unpublished results on file, Acorda Therapeutics, Inc.: biostudy 0400002), single 6-mg doses of the tizanidine capsule formulation were administered intact or sprinkled on applesauce after an overnight fast. Administration of the capsule contents sprinkled on applesauce resulted in a mean In-transformed C^sub max^ of 5.7ng/mL which was significantly higher than the mean C^sub max^ of 4.9ng/mL when the capsule was given intact (p = 0.035; 90% CI 103.95- 133.66). In addition, there were small, but statistically significant, increases in geometric mean In-transformed AUC^sub 0- last^ (p < 0.009; 90% CI 106.80-130.53) and AUC^sub 0-[infinity]^ (p < 0.013; 90% CI 105.47-127.01) for the sprinkled capsule contents compared to the intact capsule. The mean T^sub max^ for both treatment groups was approximately 1.3h. Although no data are available, it was presumed the differences found in this study were due, at least in large part, to the more rapid wetting of the drug- coated beads placed in applesauce which is mostly water with a pH [approximate] 3.5. Because of the statistically significant differences and based on FDA definition of bioequivalence, the capsule contents sprinkled were not found to be equivalent to the intact capsule. Despite the pharmacokinetic differences between the intact capsule and capsule contents sprinkled on soft foods, this may be an effective delivery method for patients who have difficulty swallowing.

Clinical efficacy

Open-label and placebo-controlled studies

Spinal cord injury

The efficacy and safety of tizanidine tablets up to 36 mg/day for 7 weeks has been investigated in a large-scale, multicenter (14 North American centers), randomized, double-blind, parallel-group, placebo-controlled trial in patients who had spinal cord injury for > 12 months and secondary spasticity63. Tizanidine was titrated to optimal effect in each of the 118 randomized patients over 3 weeks and maintained for a further 4 weeks (mean daily dose 31 mg administered in three divided doses). Compared to placebo after 4 weeks of stable dosing, and assessed by the most widely used standardized scale, Ashworth64 (passive muscle tone; scale: 0 = no increase in muscle tone to 4 = affected part is rigid in flexion or extension), tizanidine significantly reduced muscle tone (p = 0.0001) and video motion analysis of the pendulum test (p = 0.004). Performing the pendulum test requires that the patient be seated on an examination table with the lower legs hanging over the edge of the table. The tested leg is then raised and allowed to drop unassisted, swinging freely. The amplitude and duration of the first swing (of particular interest in patients with spasticity), the total number of times the leg swings, and the total duration of leg swinging are recorded and compared to normal parameters to assess the severity of spasticity65. The frequency of average daily count of daytime spasms as reported by patients was reduced by almost 50% at 7 weeks in the tizanidine group compared to baseline. There were no significant changes in muscle strength or vital signs in either treatment group.

Multiple sclerosis

There have been several large-scale, randomized, double-blind, placebo-controlled, parallel-group trials to establish the antispastic efficacy and tolerability of tizanidine in patients with multiple sclerosis.

A ten-center dose-response study was conducted using single 8- and 16-mg doses of tizanidine or placebo tablets in 142 patients with clinically defined multiple sclerosis and established spasticity31. A strong dose-response relationship was found between clinical improvement and plasma tizanidine concentration (r = 0.487, p < 0.001). When compared to placebo, there was a significant (p < 0.001) reduction in muscle tone with both Ashworth scores and knee swing amplitude in the pendulum test, with no reduction in muscle strength. Figure 3 shows the mean change in Total Ashworth score for four muscle groups up to 6 h after administration: there was a statistically significant (p < 0.001) improvement in Ashworth score for both tizanidine doses compared to placebo at 1, 2, and 3 h after dose administration that dissipates by 6 h. The most commonly reported adverse effects in this study were: somnolence, asthenia (defined as weakness, fatigue, and/or tiredness), dry mouth, and dizziness. Hypotension occurred more frequently in patients receiving tizanidine 16mg as compared to 8mg, and in contrast to previous studies25,63,66-70 where cardiovascular side-effects were rarely observed, tizanidine produced significant decreases in blood pressure (p < 0.02) compared to placebo as previously described. These effects generally returned to baseline by 6 h after tizanidine administration. The authors found a dose response for the following adverse events: dizziness, dry mouth, drowsiness and tiredness (p < 0.001, placebo vs. 16-mg dose group; p = 0.006, placebo vs. 8-mg group). The peak effect of these events ranged from 1 to 3 h post- dose and the duration was up to 6 h. The US Tizanidine Study Group69 performed a multicenter trial in 220 patients with stable spasticity secondary to multiple sclerosis. Patients were stratified for baseline spasticity severity at randomization to tizanidine (n = 109) or placebo tablets (n = 111). Dose was titrated to a maximum recommended dose of 36mg/day (12mg t.i.d.) over 2 weeks and this was maintained for a further 8 weeks. The drug dosing in relation to meals was not reported. Curiously, there was no statistically significant difference between the treatment groups at any point during the study, including the end of the stable dosing (week 13) with respect to decrease in muscle tone assessed by Ashworth score, the primary study endpoint. This is most likely due to an unexplained placebo effect of -2.84 in Total Ashworth relative to baseline at the end of the stable dosing phase. A post hoc analysis of Ashworth scores was performed, stratified by the time of Ashworth assessment (< 3 before or >/= 3 h after dosing). Again, there was no difference in the placebo group for change in Total Ashworth score compared to baseline depending on the time of dosing (-4.7 for both <3 and >/=3h). However, in the tizanidine group, Total Ashworth score decreased 4.8 points as compared to baseline if the dose was taken within 3 h of assessment but was unchanged if the dose was taken >/= 3 h prior to assessment. Due to the large placebo effect, the clinical relevance of this change was unclear. With respect to secondary efficacy assessments, both global efficacy and tolerability scores were significantly better in the tizanidine group compared to the placebo group when assessed by both physician/ prescriber (p = 0.043) and patient (p = 0.011). Patient diary data showed a significant reduction (p = 0.028) in daily spasms and clonus in the tizanidine group when compared to placebo. There was no significant change in muscle strength in either group. Follow-up was conducted on 161 patients from this study who went on to receive open-label treatment with tizanidine28. Cohorts of 134, 86, 48, and 15 were available at 1, 4, 8, and 12 months, respectively. Each cohort, analyzed separately, demonstrated statistically significant improvements in individual Total Ashworth scores (p-values not reported) decreasing from 15-20 at baseline to 8 (month 1), 11 (month 4), 9 (month 8), and a trend towards significance of 10 (month 12).

Figure 3. Mean change (+- 95% CI) in muscle tone from baseline as measured by Ashworth score after oral administration of a singb dose of tizanidine (8 or 16 mg) or placebo in patients with multiple sclerosis (h = 142). *p < 0.001 for both tizanidine doses compared to placebo at 1,2, and 3 h after dose administration [adapted from Nance et al.31]

The United Kingdom Tizanidine Trial Group70 conducted a prospective, double-blind, randomized, placebo-controlled, multicenter study in 187 patients with stable spasticity secondary to multiple sclerosis. Analysis of baseline demographics showed the groups were well matched. Dose was administered with food and titrated to a maximum of 36 mg/day (12 mg t.i.d.) over 3 weeks. Each patient's optimal dose was maintained for a further 9 weeks. The mean dose of tizanidine tablets at the end of titration was 30.7 mg/ day. Compared to baseline, the improvement in muscle tone (Ashworth score) at week 12 was significantly greater in patients receiving tizanidine versus those on placebo for both intention-to-treat (p = 0.004) and completer populations (p = 0.0001) (Table 1). Tizanidine achieved an approximately 20% mean reduction in Total Ashworth score as compared to placebo. An improvement in muscle tone defined as a decrease in Total Ashworth score >/=1 was attained in 71 % of patients receiving tizanidine compared to 50% of those receiving placebo; this difference was significant (p < 0.005). There was no statistically significant change in muscle strength in either treatment group and there was no statistically significant between- group difference with respect to spasm frequency. Both investigator (p = 0.00001) and patient (p = 0.012) assessment of overall efficacy favored tizanidine over placebo.

Stroke and traumatic brain injury

In an open-label study71, 47 patients, mean age 61 years, with either ischemic or hemorrhagic stroke and moderate spasticity received tizanidine tablets for 16 weeks. Each patient's dose was titrated to maximum tolerated dose over several weeks. The total daily dose was limited to a maximum of 36mg/day (12mg t.i.d.). The mean daily dose in this patient cohort was 20 mg/day. Relationship of dosing to food intake was not reported. There was a significant reduction in muscle tone assessed by Total Modified Ashworth score (from 9.30 +- 0.41 at baseline to 6.47 +- 0.54 at week 16, p < 0.0001), as well as improvement in pain (p = 0.0375), quality of life (p = 0.0001), and physician assessment of disability (p = 0.0001) at the end of stable dosing (16 weeks). There was no statistically significant change in muscle strength.

Table 1. Comparison of muscle tone (Ashworth score, mean +- SD) and percent change in multiple sclerosis patients treated with tizanidine or placebo for 12 weeks (reproduced with permission from the United Kingdom Tizanidine Trial Group70)

In a randomized, double-blind, placebo-controlled, crossover study72, 17 patients with acquired brain injury (eight traumatic brain injury, nine stroke) and established intractable spastic hypertonia received tizanidine tablets titrated to a maximum of 36 mg/day (mean 25 mg/day) for 8 weeks. Compared to placebo at 4 weeks, when patients reached maximum tolerated dose, tizanidine resulted in significant reductions in upper and lower extremity Ashworth score (p < 0.001), upper motor tone (p < 0.0006) and lower motor tone (p < 0.0007). Spasm scores achieved significance in lower extremities only (p < 0.046). After 6 weeks of treatment with tizanidine, there was a slight improvement in muscle strength (p = 0.009).

Comparison with other antispastic agents

The Medline search for this review did not reveal any published direct comparisons between tizanidine and dantrolene. Dantrolene, the only approved oral antispastic agent to work directly on the muscle, causes muscle weakness that generally limits its use to nonambulatory patients with severe spasticity due to cerebral damage73,74. Dantrolene is infrequently used in other patients with spasticity, in part because of a 1.8% overall incidence of dose- dependant hepatotoxicity which can be irreversible73-75. Women over 30 years of age, taking more than 300 mg per day for longer than 60 days appear to be at greatest risk74. There have been a number of clinical trials comparing tizanidine with other antispastic agents, primarily baclofen23,76-83 and diazepam82,84. Published in the 1980s, these trials were generally randomized, double-blind, parallel-group studies in patients with multiple sclerosis and employed titrated doses and total treatment periods ranging from 4 to 8 weeks. Reporting on relatively small studies of < 15 to 40 patients per treatment group, these trials were not generally powered to show statistically significant differences between treatments or demonstrate equivalence with any degree of rigor. Despite this limitation, the authors of these studies consistently report that fewer patients receiving tizanidine had subjective muscle weakness or withdrew from treatment because of muscle weakness as compared to baclofen77,78,80,82,83.

Comparative data can also be drawn from a meta-analysis often European, randomized, double-blind, comparative studies in 270 patients with spasticity related to multiple sclerosis or cerebrovascular lesions. To be included in the analysis, each trial had to be of at least 6 weeks' duration and was required to have three key outcome measures: Ashworth score for muscle tone, a measure of muscle strength, and a global tolerability rating as judged by the investigator. Patients received tizanidine tablets over a range of 4-36 mg daily versus baclofen 10-90mg daily or diazepam 5-40 mg daily46. The comparator was baclofen in seven of these studies and diazepam in three other studies. Tizanidine had similar spasticity-reducing effects at weeks 3 and 6 compared to both baclofen and diazepam as measured by Total Ashworth scores (Table 2). Similar results were documented using Total Lower Body Ashworth scores. Muscle strength based on a six-point ordinal scale for 32 upper- and lower-limb measurements was affected less by tizanidine than by either baclofen (mean difference at 3 weeks of 2 units, p = 0.023) or diazepam (mean difference at 6 weeks of 1 unit, p = ns). The global tolerability of tizanidine as judged by the investigators with a one-time assessment at the end of study participation across these ten studies was significantly better than that of either baclofen (p = 0.008) or diazepam (p = 0.001)46. In 2004, Chou et al.85 published the results of a systematic review of the comparative efficacy and safety of skeletal muscle relaxants for spasticity and musculoskeletal conditions. A total of 101 randomized clinical trials were included in their review. The primary conclusions were that tizanidine, baclofen, and dantrolene are effective when compared to placebo in patients with spasticity primarily due to multiple sclerosis regardless of the assessment tool used in each individual study. Control of spasticity, assessed most commonly by Ashworth scores, demonstrated that the efficacy of tizanidine and baclofen were not statistically different. There was insufficient evidence to determine the relative efficacy of dantrolene when compared to either tizanidine or baclofen. The overall incidence of reported adverse events was similar between tizanidine and baclofen. Tizanidine was associated with more dry mouth and baclofen with more muscle weakness. These adverse events are known to be dose-related31,73.

Table 2. Muscle tone change assessed using Total Ashworth score in patients receiving tizanidine as compared to baclofen or diazepam (reproduced with permission from Groves et al. 46)

Use in combination with other antispastic agents

Owing to the progressive nature of multiple sclerosis, clinical practice guidelines emphasize that treatment considerations should be individualized based on efficacy and side-effects12. However, initial treatment regimens often fail over time and require frequent dosage changes or the addition of other medications in order to effectively obtain management of spasticity.

The Clinical Practice Guidelines on Spasticity Management recommends initiation of therapy with a single drug: either tizanidine or baclofen. For patients who do not achieve adequate spasticity control, single-drug step therapy should then be undertaken12. Initial pharmacologie intervention entails up- titration to maximum tolerated doses and revaluation of therapy in order to maintain the same level of control, despite the increased incidence of adverse events associated with these higher doses. In situations where multiple attempts at monotherapy do not provide adequate control, combination therapy should be considered. However, current practice guidelines do not provide specific dosing recommendations for combination drug therapy12. A rational approach to combination therapy is to start up-titration of a second agent concurrent with down-titration of the initial agent in near equivalent doses. Although often difficult to use86,87, multidrug therapy has a place in the treatment of spasticity. Because each of the approved spasmolytic medications have a different mechanism of action, multidrug pharmacologie intervention at different receptor sites can maximize the anti-spastic effect of each.

Combination therapy may represent a more appropriate approach in some patients because it can reduce the dose-related adverse events and combine potential synergistic pharmacodynamic effects from each compound88. Table 3 outlines the most commonly used oral agents for the treatment of spasticity associated with multiple sclerosis along with their respective sites of action and most common adverse events. As expected, adverse events of each drug are more prevalent at higher doses. Tizanidine, an a-2 agonist, and baclofen, a GABA^sub B^ agonist, the two agents recommended for first line therapy in the management of spasticity12, are the logical choices for initial combination. However, multiple drug therapy must be approached cautiously. The following case report (L. Kamen, personal observation, May 2007) of a patient with multiple sclerosis experiencing adverse events with baclofen illustrates an effective method for initiating multiple drug therapy to successfully manage spasticity with lower doses of baclofen and the addition of tizanidine.

Table 3. Commonly used oral anti-spastic agents with dosing regimen, sites of action, and most common adverse events74,75

Case report

Mrs. B, a 53-year-old female former computer program consultant, was diagnosed with chronic slowly progressive multiple sclerosis in 1986. Prior medical history was remarkable for hypertension, chronic urinary tract infection, and chronic fatigue syndrome related to MS. Earlier MRI studies revealed CNS plaque formation. Mrs. B's chief complaint at initial assessment in 2005 was progressive weakness resulting in loss of ability to perform sit-to-stand or stand-pivot transfers independently over the previous 18 months. Severe spastic diplegia with nocturnal flexor spasms over the last two decades had prompted increasing doses of oral baclofen up to 160 mg daily. Intensive inpatient rehabilitation and home care physical therapy had failed to restore her previously independent transfers. As a result of her weakness and loss of independent transfers, the patient and her husband, a school teacher, were making plans to place her in a residential facility in order to allow her husband to continue working, as she was unsafe at home alone during the day.

In addition to baclofen 40 mg q.i.d., Mrs. B was receiving clonazepam 1 mg b.i.d., hydrochlorothiazide 12.5mg daily, oxybutynin 5mgq.i.d., methylphenidate 10 mg b.i.d., nitrofurantoin 50 mg daily, and interferon beta-1b IM every other day. Physical examination showed the following: spastic quadraparesis with Ashworth 3/4 grade spastic tone in both hip and knee flexors; sustained ankle clonus on rapid dorsiflexion stretch; motor strength was 3/5 in the right hand, 4/5 left hand, 4/5 in the proximal upper limbs, 2/5 strength in hip and knee flexors, 3/5 in knee extensors, 4/5 knee flexion, and 2/5 ankle dorsiflexion/plantar flexion without full range of motion; reflexes were +3 in lower limbs; and sensation was diminished to vibration below the knees. Mobility was dependent on a power wheelchair using joystick controls. Attempts at sit-to-stand transfers from her wheelchair required moderate to maximal assistance from her husband.

Mrs. B was under pressure to achieve independent transfer status before her husband returned to his teaching position. After her initial examination, baclofen was reduced from 160mg daily by 10-mg decrements every 2 days over 12 days to 100 mg. Dramatic improvement in strength was evident throughout the dose reduction, with return to complete independence for all transfers in and out of her wheelchair. Reassessment at this time indicated the recurrence of severe flexor spasms which prompted the concurrent introduction of tizanidine capsules started at 4 mg and up-titrated in 4-mg steps for each additional 10-mg drop in baclofen dose over the next 8 days. At stabilized doses of tizanidine 16mg daily in combination with baclofen 60 mg daily, Mrs. B resumed driving her adapted van and was participating in community-based activities. Her husband returned to work and reported reduction in his own back pain, as he no longer struggled to assist his wife's transfers.

Tizanidine reduces spasticity with less suppression of general strength than previously available oral antispasticity agents. In this case, therapy was initiated with baclofen for treatment of severe flexor spasticity. Gradual increases in dose levels suppressed spontaneous muscle spasm but were accompanied by depression of the ability to generate functional strength and essential transfer skills. This feature of the GABA inhibitor, baclofen, along with failure to recognize an associated loss of global strength, had been overlooked by several treating clinicians. Recognition of this phenomenon and the subsequent action of slowly down-titrating baclofen plus concurrently introducing and up- titrating tizanidine allowed effective spasticity management for this patient. In this case study, combination therapy of tizanidine plus baclofen resulted in improvement in mobility and basic self care, with return to community activities.

Safety

The tolerability of tizanidine was assessed during three of the largest randomized trials31,63,69, comparing a total of 264 patients with either MS or SCI, treated with tizanidine at doses up to 36mg/ day and 261 placebo-treated patients. In a combined analysis of these trials, the most frequently reported adverse events for tizanidine vs. placebo respectively were dry mouth (49 vs. 10%), somnolence (48 vs. 10%), asthenia (41 vs. 16%), and dizziness (16 vs. 4%)28. For the purpose of this analysis, asthenia included the adverse event terms: weakness, fatigue and/or tiredness. Approximately 75% of the more common events in these short-term trials (up to 15 weeks) were transient and graded by the investigator as mild-to-moderate in intensity45. The rate of discontinuation because of adverse events in three randomized, double-blind trials63,69,70 comparing tizanidine (up to 36mg/day) and placebo was 15.5% (41/264) and 6.1% (16/261), respectively. Based on meta-analysis of clinical trials data, the global tolerability of tizanidine has generally been considered superior to either baclofen (p = 0.008) or diazepam (p = 0.001)46,88. A summary of global tolerability assessed by investigators and patients is shown in Table 418. As noted above, patients receiving tizanidine reported muscle weakness less frequently or required treatment discontinuation as compared to either baclofen or diazepam.

Table 4. Global tolerability of tizanidine, baclofen, and diazepam in comparative clinical trials: summary of global tolerability assessments (by patients and investigators) in patients with spasticity associated with cerebral or spinal spasticity (reproduced with permission from Wagstaff and Bryson18)

Table 5. Summary of tizanidine adverse events based on product datasheet

A summary of the most common tizanidine adverse events, based on the product datasheet45, and their clinical management is provided in Table 5.

Transient elevations in hepatic transaminase levels (< 3 times the upper limit of normal) have been reported in approximately 5% of patients treated with tizanidine in controlled clinical trials45. In most cases, the elevated levels return to normal rapidly upon discontinuation of therapy with no reported sequelae. In addition there have been isolated case reports in the literature of drug- induced cholestasis89,90. Based on this information, liver enzymes should therefore be monitored for the first 6 months of treatment and periodically thereafter. It is unclear from the available literature what, if any, factors predispose patients to hepatic enzyme elevations or hepatic damage. These events do not appear to be dose-related. It is prudent to use tizanidine with extreme caution in patients with impaired liver function (creatinine clearance < 25 mL/min)45. In these instances, initial dosing should be reduced from the recommended 4-mg initial dose and up-titration should proceed slowly with close monitoring of patient response to therapy as well as laboratory assessment of liver function. In addition, patients should be closely monitored for common adverse events (dry mouth, somnolence, asthenia, and dizziness) as an additional sign of reduced tizanidine clearance45. Similarly, elderly patients, in whom renal clearance of tizanidine might be expected to be decreased, should be closely monitored for common adverse events45. Hypotension can be induced by tizanidine via its alpha^sub 2^-adrenergic agonist activity16. In a single-dose study with 8 mg of tizanidine tablets, a 20% reduction in either the systolic or diastolic blood pressure was associated, at times, with bradycardia (2%), hypotension (16%), lightheadedness/dizziness (22%), and rarely syncope (< 1%)45. The literature-reported rate of drug-induced hypotension is quite variable28,69,91. In single-dose trials31,92, the lack of dose up-titration more readily unmasked the hypotensive effects of tizanidine. In addition, the clinical occurrence of orthostatic hypotension is grouped with protocoldefined orthostatic hypotension (systolic BP decrease >/= 20 mmHg or diastolic BP decrease >/= 10 mmHg regardless of symptomatology).

The risk of significant hypotension may be limited by careful titration, close observation, and slowly moving the patient from a supine to fixed upright position. Concurrent administration of tizanidine with antihypertensive agents must be done with caution45. To minimize the risk of orthostatic hypotension when therapy is initiated in the presence of an antihypertensive drug, it is advisable to have patients rise slowly until the individual response to therapy is known. Due to the potential for a decrease in blood pressure, tizanidine should not be combined with other oc2- adrenergic agonists45.

Table 6. Prevalence of treatment-emergent adverse events reported in > 5% of subjects in any treatment group (reproduced with permission from Shah et al.54)

Tizanidine should only be given to pregnant women if the benefit clearly outweighs the risks (Category C); it should not be used by nursing mothers since it is expected that tizanidine might pass into breast milk because it is a lipid-soluble drug45. There are no adequate and well controlled studies to document the safety and efficacy of tizanidine in children45.

The most robust data comparing the tolerability of capsule and tablet formulations of tizanidine are derived from the previously described single 8-mg dose pharmacokinetic study in 96 healthy adult subjects, which primarily compared bioavailability under fed and fasted conditions54. Of the 96 subjects enrolled, data for all treatment periods were available from 81 subjects, to generate individual pharmacokinetic profiles. It is important to note that two subjects were excluded from analysis due to emesis. Adverse event reporting evaluated by number of subjects, irrespective of food intake, was 92% (87 subjects) and 83% (77 subjects) for subjects in the combined tablets group and combined capsules group respectively. Two subjects were withdrawn from the study due to adverse events. One was withdrawn due to an injury unrelated to the study and the other due to an oral abscess. The rate of adverse events found in the combined capsule groups was statistically lower than the rate in the combined tablet groups (p = 0.0253). All betweengroup differences are shown in Table 6: asthenia and somnolence were notably less common in subjects treated with capsules.

Drug interactions

Practitioners should use caution if tizanidine must be administered concurrently with other CYP 1A2 inhibitors such as antiarrhythmic agents (amiodarone, mexiletine, propafenone), cimetidine, fluoroquinolones (ciprofloxacin, norfloxacin), rofecoxib, oral contraceptives, and ticlopidine45. Alcohol may increase the side-effects of tizanidine as the CNS depressant effects of both are additive45.

A randomized, double-blind, crossover study49 was conducted in ten healthy subjects to assess the effects of a potent CYP 1A2 inhibitor, fluvoxamine, on the pharmacokinetics of tizanidine. Each subject received fluvoxamine 100mg once daily or placebo for 4 days and on day 4 ingested a single oral dose of tizanidine 4mg, 1 h after fluvoxamine administration. Fluvoxamine increased mean (+- SD) tizanidine AUC^sub 0-[infinity]^ from 6.6 +- 2.9 to 216.0 +- 51.6ng- h/mL (p = 0.000001) and C^sub max^ increased from 2.2 +- 0.9 to 26.6 +- 5.6ng/mL (p = 0.000002). This represents a 33-fold increase in AUC and 12-fold increase in C^sub max^. Mean t^sub 1/2^ was also significantly increased from 1.5 +- 0.1 to 4.3 +- 1.1 h (p = 0.00004). The pharmacodynamic effects of tizanidine were much stronger during co-administration with fluvoxamine, being statistically significant for systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR), drowsiness, subjective assessment of drug effect, and Digital Symbol Substitution Test (DSST) (all p

A randomized, double-blind, crossover study50 was conducted in ten healthy subjects to quantify the interaction between ciprofloxacin and tizanidine. Each subject received ciprofloxacin 500 mg twice daily or placebo for 3 days and on day 4 ingested a single oral dose of tizanidine 4 mg, 1 h after ciprofloxacin administration. Ciprofloxacin significantly increased mean (+- SD) tizanidine AUC^sub 0-[infinity]^ from 3.4 +- 2.3 to 33.1 +- 9.8ng-h/ mL (p < 0.001) and C^sub max^ from 1.2 +- 0.8 to 8.2 +- 2.6 ng/mL (p < 0.001). These changes represent a 10-fold increase in tizanidine AUC and 7-fold increase in tizanidine C^sub max^. Mean t^sub 1/2^ was also significantly increased from 1.5 +- 0.2 to 1.8 +- 0.3 h (p = 0.007). The pharmacodynamic effects of tizanidine were much more evident during co-administration with ciprofloxacin, being statistically significant for SBP, DBP, drowsiness, drug effect, and DSST (all p

In a parallel-group study48 of 15 healthy women using oral contraceptives (OCs) containing ethinyl estradiol 20-30 [mu]g and gestodene 75 [mu]g and 15 healthy women not receiving OCs, each subject ingested a single oral dose of tizanidine 4mg. OCs significantly (p < 0.001) increased mean tizanidine AUC^sub 0 - [infinity]^ and C^sub max^ by 3.9- and 3.0-fold, respectively. The pharmacodynamic effects of tizanidine were more evident during co- administration with OCs for SBP (p = 0.002) and DBP (p = 0.009). Subjective drug effect as measured by patient-assessed drowsiness on a visual analog scale was statistically greater in the OC group as compared to the control group (p = 0.01). Correlation coefficients were not reported for the potential relationship between plasma tizanidine concentrations and pharmacodynamic effects, except for SBP (r = -0.70, p < 0.001). The authors noted that all pharmacodynamic variables, except HR, correlated significantly with plasma tizanidine concentration. Details on possible adverse events were not reported.

Conclusion

Tizanidine is a short-acting drug used for the management of spasticity. It is available as 2- and 4-mg tablets as well as 2-, 4- , or 6-mg capsules. It is prudent to start treatment with single doses of 4 mg preferably at bedtime and increase the dose gradually in 2- to 4-mg steps until optimal effect (satisfactory reduction of muscle tone at a tolerated dose) is achieved. Up titration can be done as frequently as every 3-5 days except in patients with impaired hepatic or renal function. The dose can be repeated at 6-8- h intervals, as needed, to a maximum of three doses in 24 h. In clinical trials, patients have been successfully titrated to doses of >/= 24 mg in 3-4 weeks88. The total daily dose should not exceed 36 mg. The capsule can also be administered by sprinkling its contents on applesauce for patients who have difficulty in swallowing. The practitioner should be aware of the altered pharmacokinetics (faster time to peak and higher C^sub max^) when administering tizanidine in this manner. Because food has a differential effect on the pharmacokinetics of tizanidine between formulations, any switch between formulations and/or their mode of administration (intact or sprinkled capsule, with or without food) should be performed carefully, as these changes may result in increased adverse events or delayed/more rapid onset of activity, depending on the nature of the switch45. In addition, it is advisable to avoid abrupt withdrawal of tizanidine therapy, particularly in patients treated with higher doses due to the potential for rebound hypertension and hypertonia28. Tizanidine is an effective treatment for hypertonia and spasm in patients with spasticity. The efficacy of tizanidine is comparable to that of baclofen or diazepam. Tizanidine may reduce muscle pain71 and does not induce the muscle weakness often associated with baclofen and diazepam28. There are no direct comparative data of tizanidine versus dantrolene. Dantrolene, which works directly on the muscle, causes muscle weakness and is infrequently used in ambulatory patients with spasticity.

Global tolerability data favor tizanidine over baclofen and diazepam. Approximately 75% of adverse events with tizanidine are graded as mild-to-moderate by patients - the most common being dry mouth and somnolence or drowsiness, which might be alleviated by slow titration. Unlike diazepam, drug dependency has not been reported with tizanidine. Hallucinations have been reported in approximately 3% (5 of 170) of patients in clinical trials usually within the first 6 weeks of therapy45. One patient continued to have hallucinations for 2 weeks after discontinuation. It is of note that patients did not feel the need to act on the reported hallucinations, which responded to a reduction of dose or the passage of time28.

It has been suggested that tizanidine might be synergistically combined with another antispastic agent that acts by a different mechanism of action at lower doses that would be better tolerated88. There are no published data to confirm this assertion, although the case reported here in which tizanidine and baclofen therapy were combined is a practical test of this hypothesis that deserves further study. Tizanidine and baclofen do not appear to undergo any significant pharmacokinetic drug interaction. Because both tizanidine and diazepam are known to cause sedation, it would be prudent to reserve this combination of drugs in the management of spasticity for the more difficult cases.

In conclusion, each of the first-line drugs recommended by the CMSC guidelines has an important place in the pharmacotherapy of spasticity. Tizanidine, baclofen and diazepam are all equiefficacious. Therefore, selection of therapy should be based on clinically relevant differences. Although none of these agents are devoid of annoying and sometimes limiting adverse events, in clinical trials tizanidine has been found to be better tolerated. Tizanidine does not induce the muscle weakness associated with each of the other approved oral antispastic agents. Tizanidine is therefore a valuable drug for the front-line management of patients with spasticity associated with cerebral or spinal damage12.

Acknowledgment

Declaration of interest: The design and development of this manuscript was supported by Acorda Therapeutics, Inc. LK serves as a consultant to Acorda Therapeutics, Inc. Editorial assistance in the preparation of this article was provided by Tajut Ltd., Kaiapoi, New Zealand, and Kristina Christian from Acorda Therapeutics.

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