Current Medical Research and Opinion® 0300-7995

Vol. 24, No. 2, 2008, 425–439 doi:10.1185/030079908X261113

© 2008 LibraPharm Limited All rights reserved: reproduction in whole or part not permitted

REVIEW

A practical overview of tizanidine

use for spasticity secondary to
multiple sclerosis, stroke, and
spinal cord injury
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Leonard Kamen a, Herbert R. Henney III b and

Jacob D. Runyan b
a
Albert Einstein Medical Center, Moss Rehabilitation Outpatient Center,
Philadelphia, PA, USA
0 8
20
b
Acorda Therapeutics, Inc., Hawthorne, NY, USA

Address for correspondence: Herbert R. Henney III, PharmD, Vice President, Medical Affairs,
Acorda Therapeutics, Inc., 15 Skyline Drive, Hawthorne, NY 10532, USA. Tel.: +1 914 347 4300;
Fax: +1 914 347 4560; hhenney@acorda.com
Key words: Efficacy – Review – Safety – Spasticity – Tizanidine
For personal use only.

ABSTRACT

Objective: Tizanidine is an imidazoline central
α2-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 prescribers 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 α2-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 manage­
ment 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 syndrome or injury. In UMN disorders, nerve cells in

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)
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 pain 2. The majority of people with
spinal cord injury (65–78%) 3 or multiple sclerosis

Paper 4171 425

 (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 documented 6–8. 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 person 9. 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.
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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 $47 215 per year10. In 2005, the European
mean annual per-patient resource consumption for
MS adjusted for domestic purchasing power was
approximately €18 000 for mild disease (Expanded
Disability Status Scale (EDSS) < 4), €36 500 for
moderate MS (EDSS 4–6.5) and €62 000 for patients
with severe MS (EDSS > 7) 11 . The influence of
For personal use only.
spasticity on these costs has not been documented.
Based on the recommendations developed by the
Multiple Sclerosis Council for Clinical Practice Guide­
lines, pharmacological management of generalized
spasticity is indicated when symptom severity cannot
be controlled by other means such as health promotion
strategies and skilled rehabilitation strategies 12 .
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 α2‑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.
426 Review of tizanidine for spasticity
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, econ­
omics, 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 α2‑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
properties 13–15. The α 2‑receptor IC 50 of clonidine is
1.2 nmol compared to 6.9 nmol for tizanidine 16. 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 Coward 16
and Wagstaff and Bryson18). It is believed that the
pharmaco­dynamic effects of tizanidine are primarily
linked to its α2‑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 pre­s ynaptic 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
© 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
 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 121/75 mmHg to a mean
nadir of 98/64.8 mmHg ( p < 0.02). Animal studies
have shown that tizanidine possesses antinociceptive
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activity33–35 and inhibits gastro­intestinal (GI) transit36,37
and gastric acid secretion29,38. 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
For personal use only.
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 Bryson 18).
Tizanidine is well absorbed (> 65%) after oral
administration and mean maximum plasma
concentration (Cmax) is reached after about 1–1.5 h
(Tmax)20,25,39–42. Tizanidine is approximately 30% bound
to plasma proteins 16 . Administration with food
is known to increase the absorption of the tablet
formulation43. At therapeutic doses, tizanidine pharm­
aco­kinetics 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,
© 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
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 (CLr) has been calculated as 74 mL/min41.
Renal impairment may increase plasma tizanidine
concentrations18.
It has recently been demonstrated that tizanidine
is mainly metabolized by cytochrome P450 1A2 47.
CYP 1A2 inhibitors including ciprofloxacin, fluvox­
amine, 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 acetaminophen 18
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 non-
linear 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 ln-transformed Cmax (2.7 vs. 4.0 ng/mL,
p < 0.019; 90% CI 50.4–87.3) was reduced and mean
T 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 ln-transformed
mean Cmax and area under the plasma concentration
time curve (AUC)53. The AUC0–last for capsule versus
tablet (10.6 ± 7.0 and 11.7 ± 8.0 ng·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 Cmax of 5.5 ± 4.28 and 5.4 ±
4.17 ng/mL, and AUC0–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 Cmax and AUC,
respectively, while T 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
Review of tizanidine for spasticity Kamen et al. 427
 of Attention is defined by the mean reaction times of this finding are not clear, in part because the study
three tests: Simple Reaction Time, Digital Vigilance was conducted with healthy volunteers and there was
Task, and Choice Reaction Time. The prolongation of no up-titration to the 8‑mg dose. The results should
Tmax when capsules were given with food compared to be confirmed with additional research in patients
tablets regardless of time of administration or when employing the Power of Attention test methodology.
capsules were given in a fasted state resulted in a delay In a randomized, crossover study in 28 adult
in onset of cognitive impairment as measured by Power subjects (unpublished results on file, Acorda
of Attention (Figure 2). The clinical implications of Therapeutics, Inc.: biostudy 0400002), single 6‑mg

6
Plasma tizanidine concentration (ng/mL)

4
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0 2 4 6 8 10 12 14 16 18 20 22 24
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Time after drug administration (h)

Figure 1. Mean plasma concentrations of tizanidine (ng/mL) versus time following oral administration of tablet and
capsule formulations (2 × 4 mg) under fed and fasted conditions in healthy volunteers (n = 81). Tmax for capsule in fed state
has a p < 0.0001 compared to all other treatments (reproduced with permission from Shah et al.54)
Change from baseline in power of attention (ms)

Time after drug administration (h)

Figure 2. Mean change from baseline (ms) in Power of Attention versus time following oral administration of tablet
and capsule formulations (2 × 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)

428 Review of tizanidine for spasticity © 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
 doses of the tizanidine capsule formulation were
administered intact or sprinkled on applesauce after
an overnight fast. Admin­i stration of the capsule
contents sprinkled on applesauce resulted in a
mean ln-transformed C max of 5.7 ng/mL which was
significantly higher than the mean Cmax of 4.9 ng/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 ln-transformed AUC 0–last ( p < 0.009; 90% CI
106.80–130.53) and AUC 0–∞ ( p < 0.013; 90% CI
105.47–127.01) for the sprinkled capsule contents
compared to the intact capsule. The mean T max for
both treatment groups was approximately 1.3 h.
Although no data are available, it was presumed the
differences found in this study were due, at least in
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large part, to the more rapid wetting of the drug-
coated beads placed in applesauce which is mostly
water with a pH ≈ 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.
For personal use only.
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),
© 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
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 16 mg as compared to 8 mg, 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 Group 69 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 36 mg/day (12 mg t.i.d.) over 2 weeks and this was
maintained for a further 8 weeks. The drug dosing in
Review of tizanidine for spasticity Kamen et al. 429
 –5
Improvement in Ashworth score
–4
–3
–2
–1
1
0 1
Figure 3. Mean change (± 95% CI) in muscle tone from baseline as measured by Ashworth score after oral administration
of a single dose of tizanidine (8 or 16 mg) or placebo in patients with multiple sclerosis (n = 142). *p < 0.001 for both
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tizanidine doses compared to placebo at 1, 2, and 3 h after dose administration [adapted from Nance et al.31]
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
For personal use only.
–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 ≥ 3 h). 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
430 Review of tizanidine for spasticity
Placebo
8 mg tizanidine
16 mg tizanidine
*
* *
*
*
*
2 3 4 5 6
Hours post-dose
(month 1), 11 (month 4), 9 (month 8), and a trend
towards significance of 10 (month 12).
The United Kingdom Tizanidine Trial Group 70
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 improve­m ent 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.
© 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
 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)
Population analyzed Tizanidine (n = 94)
Week 0 Week 12
Intention-to-treat 18.5 ± 9.4 14.6 ± 10.1*
Completers 18.7 ± 9.3 14.3 ± 9.8†
Statistical significance: *p = 0.004 vs. placebo and †p = 0.0001 vs. placebo
Each patient’s dose was titrated to maximum tolerated
dose over several weeks. The total daily dose was
limited to a maximum of 36 mg/day (12 mg 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
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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.
In a randomized, double-blind, placebo-controlled,
crossover study 72, 17 patients with acquired brain
injury (eight traumatic brain injury, nine stroke) and
For personal use only.
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 improve­
ment 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 anti­
spastic agent to work directly on the muscle, causes
muscle weakness that generally limits its use to non-
ambulatory 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
© 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
Placebo (n = 93)
Change (%) Week 0 Week 12 Change (%)
21 16.8 ± 11.1 15.3 ± 10.0 9
24 15.8 ± 8.7 14.6 ± 9.1 7
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 differ­e nces 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
of ten 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 10–90 mg
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
Review of tizanidine for spasticity Kamen et al. 431
 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)

Tizanidine vs. baclofen

Tizanidine Baclofen Treatment
effect*
No. of patients Mean ± SD No. of patients Mean ± SD
Baseline 97 9.3 ± 5.4 99 9.6 ± 5.3
Week 3 94 6.9 ± 4.8 94 7.1 ± 5.2
Change 94 –2.3 ± 3.3 94 –2.3 ± 3.7 0.10 ± 0.35
( p = 0.785)
Week 6 90 5.9 ± 4.4 90 6.4 ± 5.4
Change 90 –3.2 ± 4.0 90 –3.0 ± 3.9 –0.11 ± 0.32
( p = 0.740)
Tizanidine vs. diazepam
Tizanidine Diazepam Treatment
effect
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No. of patients Mean ± SD No. of patients Mean ± SD

Baseline 36 13.5 ± 5.2 38 12.8 ± 5.1
Week 3 34 8.9 ± 4.9 38 9.3 ± 5.6
Change 34 –4.7 ± 3.2 38 –3.5 ± 4.8 –0.95 ± 0.93
( p = 0.313)
Week 6 33 7.9 ± 5.1 31 8.6 ± 4.9
Change 33 –5.6 ± 3.9 31 –4.0 ± 4.3 –1.32 ± 0.95
( p = 0.169)
*All within-group changes were statistically significant. A negative effect favored tizanidine and a positive one favored the control
For personal use only.

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.
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
pharmacologic 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 use 86,87, multidrug
therapy has a place in the treatment of spasticity.
Because each of the approved spasmolytic medications
have a different mech­a n­i sm of action, multidrug
pharmacologic inter­vention at different receptor sites
can maximize the anti-spastic effect of each.
Combination therapy may represent a more
appro­p riate 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

432 Review of tizanidine for spasticity © 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
 Table 3. Commonly used oral anti-spastic agents with dosing regimen, sites of action, and most common adverse events74,75
Mechanism of action
Baclofen Centrally acting GABAB agonist
Dantrolene Peripheral inhibition of calcium release*
Diazepam Centrally acting GABA BZ2 agonist
Tizanidine Centrally acting α2 agonist
GABAB, gamma-aminobutyric acid B receptor; BZ2, benzodiazepine 2 receptor; α2, alpha-2 adrenergic receptor
*Unlike calcium channel blockers (CCBs), dantrolene interferes with the release of calcium from the sarcoplasmic reticulum of the muscle
†Diarrhea may be severe and require withdrawal of therapy
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drug are more prevalent at higher doses. Tizanidine,
an α‑2 agonist, and baclofen, a GABAB 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
For personal use only.
spasticity with lower doses of baclofen and the addition
of tizanidine.
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
12.5 mg daily, oxybutynin 5 mg q.i.d., methylphenidate
10 mg b.i.d., nitrofurantoin 50 mg daily, and inter­
© 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
Common adverse events (prevalence where known)
Drowsiness (10–63%), dizziness (5–15%), weakness (5–15%), and
fatigue (2–4%)
Withdrawal seizures and hallucinations with abrupt discontinuation
Diarrhea†, dizziness, drowsiness, fatigue, general malaise, and weakness
(All transient, occurring early in treatment)
Hepatotoxicity (liver enzymes should be monitored)
Drowsiness, ataxia, and confusion
(All transient, occurring early in treatment)
Dry mouth (49%), somnolence (48%), asthenia (41%), and dizziness (16%)
Liver enzymes should be monitored
feron β‑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 wheel­
chair 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 160 mg daily by 10‑mg decrements
every 2 days over 12 days to 100 mg. Dramatic improve­
ment 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 16 mg 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 anti­
spasticity 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
Review of tizanidine for spasticity Kamen et al. 433
 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
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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 36 mg/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.
A summary of the most common tizanidine adverse

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 36 mg/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:
For personal use only.
events, based on the product datasheet 45, 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,

weakness, fatigue and/or tiredness. Approximately liver enzymes should therefore be monitored for the
75% of the more common events in these short-term first 6 months of treatment and periodically thereafter.

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)

Global tolerability (% patients)

Poor Moderate Good/excellent
Tizanidine ≤ 36 mg/day 0–19 0–50 44–100
Baclofen ≤ 90 mg/day 0–38 0–56 38–90
Diazepam ≤ 30 mg/day 27–28 18–53 20–54

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

Adverse reaction Incidence (%)45 Dose-related Clinical management

Dry mouth 49 Yes Reduce dose Titrate slowly
Sedation 48 Yes Reduce dose Titrate slowly
Asthenia 41 Yes Reduce dose Titrate slowly
Hypotension ≤ 33 Yes Reduce dose Titrate slowly
Dizziness 16 Yes Reduce dose Titrate slowly
Elevated hepatic 3–5 No Monitor LFTs at 0, 1, 3, and Discontinue drug
transaminases 6 months and routinely after
GI effects ≤4 No Monitor symptom
Hallucinations 3 No Ask if present Reduce dose or discontinue drug
LFT = liver function test

434 Review of tizanidine for spasticity © 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
 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
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adverse events45.
Hypotension can be induced by tizanidine via its
α2-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
For personal use only.
more readily unmasked the hypotensive effects of
tizanidine. In addition, the clinical occurrence of
orthostatic hypo­t ension is grouped with protocol-
defined orthostatic hypo­tension (systolic BP decrease
≥ 20 mmHg or diastolic BP decrease ≥ 10 mmHg regard­
less 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.
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)
Adverse event Tablet-fed
(n = 94)
Asthenia* 46 (48.9)
Somnolence 29 (30.9)
Headache 7 (7.4)
Dizziness 6 (6.4)
Dry mouth 5 (5.3)
Total‡ 76§
Values are no. (%) of subjects
*Weakness, fatigue, or tiredness
†p < 0.040 versus tablet-fed (McNemar test nominal [unadjusted])
‡Number of subjects who experienced ≥ 1 adverse event. Overall difference, p = 0.015 (Cochran Q test)
§p < 0.017 and p < 0.003 versus capsule-fed and capsule-fasted, respectively (McNemar test nominal [unadjusted])
© 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
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
α2‑adrenergic agonists45.
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 between-
group differences are shown in Table 6: asthenia and
somnolence were notably less common in subjects
treated with capsules.
Tablet-fasted Capsule-fed Capsule-fasted
(n = 90) (n = 91) (n = 91)
36 (40.0) 37 (40.7) 31 (34.1)†
28 (31.1) 21 (23.1) 21 (23.1)
8 (8.9) 9 (9.9) 6 (6.6)
5 (5.6) 5 (5.5) 4 (4.4)
5 (5.6) 4 (4.4) 6 (6.6)
65 62 58
Review of tizanidine for spasticity Kamen et al. 435
 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 contra­
ceptives, 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 100 mg once daily or placebo for 4 days
and on day 4 ingested a single oral dose of tizanidine
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4 mg, 1 h after fluvoxamine administration. Fluvoxamine
increased mean (± SD) tizanidine AUC0–∞ from 6.6 ±
2.9 to 216.0 ± 51.6 ng·h/mL ( p = 0.000001) and Cmax
increased from 2.2 ± 0.9 to 26.6 ± 5.6 ng/mL ( p =
0.000002). This represents a 33-fold increase in AUC
and 12-fold increase in Cmax. Mean t½ 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
For personal use only.
(SBP), diastolic blood pressure (DBP), heart rate
(HR), drowsiness, subjective assessment of drug effect,
and Digital Symbol Substitution Test (DSST) (all p ≤
0.007). There were significant correlations (Pearson’s
coefficient) between plasma tizanidine concentrations
and the change from baseline for SBP (r = –0.84), DBP
(r = –0.76), HR (r = –0.34), drowsiness (r = 0.64),
subjective assessment of drug effect (r = 0.84), and
DSST (r = –0.76) ( p < 0.0000001 in all cases). During
the fluvoxamine phase, all subjects reported being
somnolent and dizzy for 3–6 h after tizanidine intake and
had difficulties in fixating their eyes and concentrating
on the psychomotor tests. Muscle weakness and dry
mouth were also reported during the fluvoxamine
phase. Despite severe hypotension, HR was lowered and
the extremities were warm. The adverse effects were
much milder during the placebo phase. Urinary output
was also significantly reduced during the fluvoxamine
phase ( p = 0.004). The authors stated, ‘The clinical
significance of the fluvoxamine–tizanidine inter­action is
obvious. The therapeutic range of tizanidine seems to be
narrow and the concentration-effect relationship rather
steep (e.g., regarding blood pressure and psychomotor
function).’ Clinicians should be aware that fluvoxamine
can substantially increase the concen­tration-dependent
adverse effects of tizanidine and avoid the concurrent
use of these drugs.
A randomized, double-blind, crossover study50 was
conducted in ten healthy subjects to quantify the
436 Review of tizanidine for spasticity
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 0–∞ from 3.4 ± 2.3 to
33.1 ± 9.8 ng·h/mL ( p < 0.001) and Cmax 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 Cmax. Mean t½ 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 ≤
0.02). The Pearson’s coefficient correlations between
plasma tizanidine concentration and change from
baseline value in SBP (r = –0.78), DBP (r = –0.72),
drowsiness (r = 0.56), drug effect (r = 0.72), and
DSST (r = –0.55) were significant ( p < 0.001 in each
case). All parameters measured except HR had the
greatest change from baseline at 1–2 h after dosing.
All ten subjects reported being somnolent and dizzy
for about 3 h after ingestion of tizanidine during the
ciprofloxacin phase, with difficulties in fixating their
eyes and concentrating on psychomotor tests. Three
subjects reported mouth dryness. These adverse events
were much milder or undetectable with tizanidine
during the placebo phase.
In a parallel-group study48 of 15 healthy women using
oral contraceptives (OCs) containing ethinyl estradiol
20–30 µg and gestodene 75 µg and 15 healthy women
not receiving OCs, each subject ingested a single oral
dose of tizanidine 4 mg. OCs significantly ( p < 0.001)
increased mean tizanidine AUC0–∞ and Cmax 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 manage­
ment of spasticity. It is available as 2- and 4‑mg tablets
© 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
 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 Cmax) when administering tizanidine in
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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 personal use only.
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 diazepam 28. There are no direct
com­p arative 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
© 2008 LIBRAPHARM LTD – Curr Med Res 2008; 24(2)
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 recom­
mended 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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Paper CMRO-4171_6, 11:24-25.01.08
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Published Online: 31 December 2007
doi:10.1185/030079908X261113
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