What are the side effects of prolonged tizanidine (Zanaflex) use?

Side Effects of Prolonged Tizanidine Use

Prolonged tizanidine use carries significant risks including persistent sedation, hypotension, hepatotoxicity requiring monitoring, and withdrawal syndrome upon discontinuation, with the most common chronic adverse effects being dry mouth (49%), somnolence (48%), asthenia (41%), and dizziness (16%). 1

Most Common Chronic Adverse Effects

The FDA-approved labeling identifies the following adverse effects in controlled trials, which persist with long-term use:

• Dry mouth occurs in 49% of patients on tizanidine versus 10% on placebo, making it the most frequent side effect 1
• Somnolence/sedation affects 48% of patients compared to 10% on placebo, representing a nearly 5-fold increase 1
• Asthenia (weakness, fatigue, tiredness) occurs in 41% of patients versus 16% on placebo 1
• Dizziness affects 16% of patients compared to 4% on placebo 1
• Three-quarters of patients rate these events as mild to moderate, while one-quarter rate them as severe, and these effects appear dose-related 1

Cardiovascular Risks with Chronic Use

• Hypotension occurs in 16-33% of patients depending on dose, with the lowest dose associated with hypotension being 28 mg 1, 2
• Bradycardia develops in 2-10% of patients, with heart rates dropping as low as 30 bpm in overdose scenarios 1, 2
• The American Academy of Neurology warns that tizanidine should be avoided in elderly patients due to significant hypotensive effects 3
• QT interval prolongation and bradycardia were noted in chronic toxicity studies at doses equivalent to maximum human doses 1

Hepatotoxicity Concerns

• Liver function test abnormalities occur in 3% of patients in controlled trials 1
• SGPT/ALT elevations occur in 3% of patients 1
• Mild elevations in liver function tests occur occasionally but improve in all patients with dose reduction or withdrawal 4
• Two patients in one study developed elevated liver function tests that decreased with cessation of therapy 5

Ophthalmologic Risks

• Dose-related retinal degeneration and corneal opacities have been found in animal studies at doses equivalent to the maximum recommended human dose 1
• Blurred vision (amblyopia) occurs in 3% of patients in controlled trials 1
• While no reports of corneal opacities or retinal degeneration emerged in clinical studies, the animal data warrants caution with prolonged use 1

Neuropsychiatric Effects

• Three patients from the double-blind database reported formed visual hallucinations, though all cleared and two continued tizanidine 4
• Speech disorders occur in 3% of patients 1
• Confusion affects 5 patients per 100 in overdose scenarios, suggesting risk with higher chronic doses 2

Withdrawal Syndrome - Critical Safety Concern

• The American Geriatrics Society specifically warns to avoid abrupt discontinuation due to central nervous system irritability 3
• Withdrawal symptoms include rebound hypertension, tachycardia, and hypertonia when discontinued abruptly in long-term users 3, 1
• Slow tapering is mandatory when discontinuing therapy, especially in patients on high doses for extended periods 3, 1

Special Population Risks

Renal Impairment

• Clearance is reduced by more than 50% in patients with creatinine clearance <25 mL/min, requiring dose reduction and close monitoring for adverse effects 1

Women on Oral Contraceptives

• Clearance is reduced by approximately 50% in women taking oral contraceptives, necessitating dose reduction during titration 1

Elderly Patients

• Older adults rarely tolerate doses greater than 30-40 mg per day 3, 6
• The American Geriatrics Society recommends careful consideration of sedation and somnolence risks, particularly regarding fall risk 3

Drug Interaction Risks with Prolonged Use

• Alcohol increases tizanidine AUC by 20% and Cmax by 15%, with additive CNS depressant effects 1
• CYP1A2 inhibitors significantly reduce tizanidine clearance, increasing adverse effect risk 3
• Combination with benzodiazepines poses life-threatening risks including severe sedation, respiratory depression, and potentially fatal outcomes 7
• Combination with opioids (e.g., oxycodone) carries significant hypotension risk due to additive blood pressure reduction effects 3

Discontinuation Rates

• 17% of patients discontinued treatment due to adverse events in controlled studies, compared to 5% on placebo 1
• The most frequent reasons for withdrawal were asthenia (3%), somnolence (3%), dry mouth (3%), increased spasm (2%), and dizziness (2%) 1

Monitoring Requirements for Long-Term Use

• The American Geriatrics Society recommends monitoring for muscle weakness, urinary function, cognitive effects, sedation, and orthostasis in all patients on chronic therapy 3
• Liver function tests should be monitored given the 3% incidence of abnormalities 1
• Blood pressure and heart rate monitoring is essential given cardiovascular risks 3, 1

Clinical Context

While tizanidine demonstrates efficacy with 60-82% of patients showing improvement in muscle tone 8, and global tolerability assessed as good to excellent in 44-100% of patients 8, the side effect profile with prolonged use requires careful patient selection and monitoring. The drug appears better tolerated than baclofen or diazepam regarding subjective muscle weakness 8, 4, but the persistent sedation, cardiovascular effects, and withdrawal risks demand ongoing clinical vigilance.