What are the guidelines for long-term use of tizanidine (Zanaflex) for muscle spasms?

Long-Term Use of Tizanidine: Guidelines and Recommendations

Long-term use of tizanidine above 24 mg/day has extremely limited clinical data, with the FDA explicitly warning that experience beyond 8-16 mg single doses or 24-36 mg total daily doses is insufficient to identify all potential adverse events. 1

Critical Safety Limitations for Long-Term Use

Limited Evidence Base

• Clinical experience with long-term tizanidine use is restricted: approximately 75 patients have been exposed to individual doses of 12 mg or more for at least one year, and approximately 80 patients have received total daily doses of 30-36 mg/day for at least one year. 1
• There is essentially no long-term experience with single daytime doses of 16 mg, meaning only adverse events with relatively high incidence have been identified. 1
• The FDA specifically states this limited database means the full safety profile for chronic use at higher doses remains unknown. 1

Mandatory Monitoring Requirements

Hepatotoxicity surveillance is non-negotiable: monitoring of aminotransferase levels is required during the first 6 months of treatment due to risk of liver injury. 1

• Approximately 5% of patients in controlled trials had liver function test elevations to greater than 3 times the upper limit of normal (or 2 times if baseline was elevated), compared to 0.4% in controls. 1
• Three deaths associated with liver failure have been reported in postmarketing experience, including one case of multilobular necrosis with fatal hepatic coma occurring after 2 months of treatment at 6 mg three times daily. 1
• Most cases resolve rapidly upon drug withdrawal, but symptomatic cases with nausea, vomiting, anorexia, and jaundice have occurred. 1

Cardiovascular Risks in Chronic Use

Hypotension is dose-related and persistent: two-thirds of patients treated with 8 mg experienced a 20% reduction in diastolic or systolic blood pressure, peaking 2-3 hours after dosing and sometimes associated with bradycardia, orthostatic hypotension, lightheadedness, and rarely syncope. 1

• The American Geriatrics Society recommends monitoring for muscle weakness, urinary function, cognitive effects, sedation, and orthostasis in all patients. 2
• Tizanidine should be avoided in patients with hepatic or renal dysfunction and in elderly patients due to significant sedative and hypotensive effects. 3

Appropriate Long-Term Use Scenarios

FDA-Approved Indications

Tizanidine is approved for management of spasticity, and treatment should be reserved for daily activities and times when relief of spasticity is most important due to its short duration of effect. 1

Chronic spasticity from upper motor neuron disorders represents the primary appropriate long-term indication:

• The American Heart Association recommends tizanidine for treating spasticity resulting in pain, poor skin hygiene, or decreased function in patients with chronic stroke. 4
• Long-term efficacy has been demonstrated in a 50-week double-blind study where 87% of patients showed improvement in excessive muscle tone with tizanidine. 5

Off-Label Use Duration Limits

For acute low back pain, treatment duration should not exceed 2 weeks: clinical trials for non-FDA approved indications such as low back pain typically used treatment durations of 2 weeks or less. 4

• The American College of Physicians recognizes tizanidine only for short-term relief of acute low back pain. 4
• One study showed initial pain relief on the 2nd day and complete relief after 4 days in back pain with muscle spasm. 6

Dosing Parameters for Long-Term Therapy

Standard Dosing Approach

• The American Geriatrics Society recommends starting at 2 mg up to three times daily, with older persons rarely tolerating doses greater than 30-40 mg per day. 2
• Optimal dosage must be titrated over 2-4 weeks for each patient, with dosages of 2-36 mg/day used in clinical trials. 7
• Maximum effects occur within 2 hours of administration. 7

Special Population Adjustments

Renal impairment requires dose reduction: tizanidine clearance is reduced by more than 50% in patients with creatinine clearance <25 mL/min. 1

• During titration in renally impaired patients, individual doses should be reduced rather than dosing frequency. 1
• These patients require close monitoring for dry mouth, somnolence, asthenia, and dizziness as indicators of potential overdose. 1

Women taking oral contraceptives have 50% lower clearance of tizanidine and require individual dose reductions during titration. 1

Discontinuation Protocol

Abrupt discontinuation is contraindicated: if therapy needs to be discontinued, especially in patients receiving high doses for long periods, the dose must be decreased slowly to minimize risk of withdrawal and rebound hypertension, tachycardia, and hypertonia. 1

• The American Geriatrics Society specifically warns to avoid abrupt discontinuation due to central nervous system irritability. 2
• If tizanidine needs to be discontinued in long-term users, slow tapering is required due to risk of withdrawal symptoms. 3

Drug Interactions Affecting Long-Term Safety

Contraindicated Combinations

• Tizanidine should not be used with other α2-adrenergic agonists. 1
• Caution is required when used with concurrent antihypertensive therapy due to additive hypotensive effects. 1

Significant Interactions

CYP1A2 inhibitors significantly reduce tizanidine clearance, increasing risk of adverse effects. 3

• Alcohol increases tizanidine AUC by approximately 20% and Cmax by 15%, associated with increased side effects and additive CNS depressant effects. 1
• Rofecoxib may potentiate adverse effects, with eight postmarketing case reports of hallucinations, psychosis, somnolence, hypotonia, hypotension, tachycardia, and bradycardia. 1

Common Pitfalls to Avoid

• Do not use tizanidine for hypotonia (reduced muscle tone): it is specifically for spasticity (increased muscle tone) and would worsen hypotonia. 8
• Do not assume benzodiazepines are interchangeable: unlike diazepam or other benzodiazepines, tizanidine is not contraindicated during stroke recovery, as benzodiazepines may have deleterious effects on recovery. 3
• Do not overlook polypharmacy risks: concurrent use of other CNS depressants such as pregabalin, quetiapine, and duloxetine can have additive sedative effects. 3
• Do not continue long-term use for non-spasticity indications: the American Geriatrics Society notes that traditional muscle relaxants have nonspecific effects not truly related to muscle relaxation, and if true muscle spasm is suspected, baclofen or benzodiazepines may be more appropriate. 3