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Tizanidine

A Review of its Pharmacology, Clinical Efficacy and Tolerability in the Management of Spasticity Associated with Cerebral and Spinal Disorders

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Summary

Synopsis

The central α2 adrenoceptor agonist tizanidine is a myotonolytic agent used in the treatment of spasticity in patients with cerebral or spinal injury. Wide interpatient variability in the effective plasma concentrations of tizanidine means that the optimal dosage must be titrated over 2 to 4 weeks for each patient (dosages of 2 to 36 mg/day have been used in clinical trials). Maximum effects occur within 2 hours of administration.

Antispastic efficacy has been demonstrated for tizanidine in placebo-controlled trials, with reduction in mean muscle tone scores of 21 to 37% versus 4 to 9% for patients receiving placebo. Improvement in muscle tone occurred in 60 to 82% of tizanidine recipients, compared with 60 to 65% of baclofen and 60 to 83% of diazepam recipients. Spasm frequency and clonus are also reduced by tizanidine.

The most common adverse effects associated with tizanidine are dry mouth and somnolence/drowsiness. Muscle strength, as assessed by objective means, appears not to be adversely affected by tizanidine and subjective muscle weakness is reported less often by tizanidine recipients than by those receiving baclofen or diazepam. Global tolerability was assessed as good to excellent in 44 to 100% of patients receiving tizanidine, compared with 38 to 90% of baclofen and 20 to 54% of diazepam recipients.

In conclusion, tizanidine is an antispastic agent with similar efficacy to that of baclofen and a more favourable tolerability profile. While drowsiness is a frequently reported adverse effect with both agents, subjective muscle weakness appears to be less of a problem with tizanidine than with baclofen. Tizanidine, therefore, appears to be an attractive therapeutic alternative for patients with spasticity associated with cerebral or spinal damage.

Pharmacodynamic Properties

Tizanidine is a central α2 adrenoceptor agonist used as a myotonolytic agent in patients with spasticity associated with multiple sclerosis or cerebral or spinal damage. Muscle reflexes (particularly polysynaptic reflexes) are depressed by tizanidine, presumably via both spinal and supraspinal effects, and myotonolytic activity has been demonstrated in patients with spasticity. The precise mechanism of action of tizanidine is not known.

Clinical trials have demonstrated tizanidine-associated decreases in blood pressure (of 7 to 15% from baseline) and sedative and sympatholytic effects (but with a lack of psychological dependence potential). Animal studies demonstrated anticonvulsant effects of tizanidine and indicated that gastrointestinal motility may be inhibited by the drug. Tizanidine may offer some protection against drug-induced ulcers.

Pharmacokinetic Properties

Moderate interpatient variation has been demonstrated in the pharmacokinetics of tizanidine, but maximum plasma concentrations appear to be reached 0.75 to 2 hours after administration. Between 53 and 66% of the dose is absorbed and food has no effect on the pharmacokinetics of this drug.

The dosage, plasma concentration and antispastic activity of tizanidine are related in individual patients but not between patients. The bioavailability of tizanidine is estimated to be 21 % and there is a low propensity for plasma protein binding (about 30%).

Extensive first-pass metabolism of tizanidine occurs, with less than 3% of unchanged drug excreted. The metabolites have no pharmacological activity. Total recovery analysis indicated that 19 to 23% of the administered dose is excreted in the faeces, and 53 to 66% in the urine. The elimination half-life ranges from 2.1 to 4.2 hours in patients with normal renal function compared with a mean value of 13.6 hours in those with renal impairment (creatinine clearance <1.5 L/h).

Clinical Efficacy

The antispastic efficacy of tizanidine has been demonstrated in several placebo-controlled trials, with wide interpatient variation in effective and tolerated dosage (2 to 36 mg/day). Mean muscle tone scores (as measured by the Ashworth Scale) were decreased by 21 and 37% in tizanidine recipients and 4 and 9% in those receiving placebo. Spasm and clonus frequency were improved to a significantly greater extent in tizanidine than in placebo recipients.

In comparative trials, improvements in muscle tone occurred in 60 to 82% of tizanidine recipients, 60 to 65% of baclofen recipients and 60 to 83% of diazepam recipients. Spasm frequency and clonus were improved to a similar extent in patients receiving tizanidine or baclofen. Efficacy was maintained during continued use of tizanidine for at least 3 years.

Tolerability

The most common adverse effects associated with tizanidine are dry mouth (23 to 57% of patients) and somnolence/drowsiness (24 to 48%). In clinical trials, the incidence of somnolence/drowsiness was similar in patients receiving tizanidine and baclofen (15 to 67%) and somewhat lower than in those receiving diazepam (44 to 82%).

Subjective muscle weakness occurred more often among tizanidine recipients than among placebo recipients in clinical trials (18 to 48% vs 9 to 18%). However, in comparative trials with other antispastic agents, weakness occurred less often (2 to 47%) than among those receiving baclofen (15 to 79%) or diazepam (18 to 47%). Withdrawals because of muscle weakness occurred more often among baclofen and diazepam recipients than among tizanidine recipients. Muscle strength assessed by objective means appears not to be adversely affected by tizanidine.

Global tolerability was judged as good to excellent in 44 to 100% of patients receiving tizanidine ≤36 mg/day for up to 12 months, compared with 38 to 90% of baclofen (≤90 mg/day) and 20 to 54% of diazepam (≤30 mg/day) recipients.

There were no consistent changes in mean blood pressure compared with placebo in clinical trials with tizanidine, but a decrease in blood pressure was reported in 7 to 12% of individual patients.

Rare serious adverse effects reported with tizanidine treatment include hallucinations and liver function abnormalities.

Dosage and Administration

A titration period of 2 to 4 weeks is necessary for each patient beginning tizanidine treatment. The usual starting dosage is 4mg at 6- to 8-hour intervals, reduced to 2 mg/day in patients with renal insufficiency. Effective tolerated dosages have ranged from 2 to 36 mg/day in clinical trials. The daily dosage may be divided into smaller doses given more often if sedation is a problem.

Monitoring of liver function should be considered in patients receiving tizanidine. Patients receiving concomitant tizanidine and antihypertensive medication or phenytoin should also be monitored.

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    Antona J. Wagstaff & Harriet M. Bryson

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  1. Antona J. Wagstaff
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  2. Harriet M. Bryson
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Correspondence to Antona J. Wagstaff.

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Various sections of the manuscript reviewed by: P.J. Delwaide, University Department of Neurology, Hôpital de la Citadelle, Liège, Belgium; M. Eysette, Rééducation et Réadaptation Fonctionnelles, Hôpital Henry Gabrielle, Saint-Genis-Laval, France; I. Milanov, Third Neurological Clinic, University Hospital, IV Kilometer, Sofia, Bulgaria; P.W. Nance, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; R. Stien, Department of Neurology, Ullevål Hospital, Oslo, Norway; M. Taittonen, Department of Anaesthesiology, Turku University Hospital, Turku, Finland; R.R. Young, Department of Neurology, University of California, Irvine, California, USA.

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Wagstaff, A.J., Bryson, H.M. Tizanidine. Drugs 53, 435–452 (1997). https://doi.org/10.2165/00003495-199753030-00007

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