Introduction
Tizanidine is a centrally acting alpha-2 adrenergic agonist muscle relaxant used primarily for the management of spasticity. Originally developed in the 1980s, it has become a widely prescribed medication for neurological conditions characterized by increased muscle tone. Unlike other muscle relaxants, tizanidine's primary mechanism targets the central nervous system rather than acting directly on skeletal muscle.
Mechanism of Action
Tizanidine exerts its effects primarily through agonism of alpha-2 adrenergic receptors in the central nervous system. This action results in:
- Presynaptic inhibition of spinal motor neurons
- Reduction in the release of excitatory amino acids from spinal interneurons
- Facilitation of glycine-mediated inhibitory neurotransmission
- Suppression of polysynaptic reflex pathways
The net effect is reduced spasticity without significant reduction in muscle strength, distinguishing it from peripherally acting neuromuscular blockers.
Indications
FDA-approved indications:- Management of spasticity associated with multiple sclerosis
- Management of spasticity associated with spinal cord injury
- Chronic headache prevention (particularly migraine and tension-type headaches)
- Low back pain with muscle spasm
- Spasticity related to cerebral palsy, stroke, or traumatic brain injury
Dosage and Administration
Initial dosing: 2-4 mg orally every 6-8 hours as needed Titration: Increase by 2-4 mg increments every 1-4 days Maximum recommended dose: 36 mg per 24 hours (divided into 3-4 doses) Special populations:- Renal impairment (CrCl < 25 mL/min): Start with 2 mg once daily
- Hepatic impairment: Use with extreme caution; consider lower initial doses
- Elderly: Start with 2 mg once daily due to increased sensitivity
- Pediatric: Safety and efficacy not established
- May be taken with or without food, but consistency is important due to food effects on absorption
- Tablets should be swallowed whole
Pharmacokinetics
Absorption: Rapid but incomplete (20-40% bioavailability); significantly affected by food (increases AUC by 30%) Distribution: Vd: 2.4 L/kg; 30% protein bound Metabolism: Extensive hepatic metabolism via CYP1A2 (95%) with minor contributions from other CYP enzymes Elimination: Half-life: 2.5 hours; primarily renal excretion (60%) with 20% fecal elimination Active metabolites: None clinically significantContraindications
- Hypersensitivity to tizanidine or any component of the formulation
- Concurrent use with potent CYP1A2 inhibitors (fluvoxamine, ciprofloxacin)
- Severe hepatic impairment
Warnings and Precautions
Black Box Warning: None Important precautions:- Hypotension: Significant blood pressure lowering effects; monitor particularly with antihypertensives
- Sedation: May impair alertness; caution with driving or operating machinery
- Hepatotoxicity: Transaminase elevations in 5% of patients; monitor LFTs at baseline and periodically
- Hallucinations: May occur, particularly with rapid dose escalation
- Withdrawal: Abrupt discontinuation may cause rebound hypertension, tachycardia, and hypertonia
- Renal impairment: Requires dose adjustment
Drug Interactions
Major interactions:- CYP1A2 inhibitors: Fluvoxamine, ciprofloxacin, amiodarone, oral contraceptives - increase tizanidine levels 10-30 fold
- Other CNS depressants: Alcohol, benzodiazepines, opioids - additive sedation
- Antihypertensives: Additive hypotensive effects
- Acetaminophen: May prolong tizanidine's half-life
- CYP1A2 inducers: Smoking, omeprazole - may decrease efficacy
- Zileuton: Moderate CYP1A2 inhibition
Adverse Effects
Very common (>10%):- Dry mouth (49%)
- Somnolence (48%)
- Fatigue (41%)
- Dizziness (16%)
- Hypotension
- Nausea
- Constipation
- Liver enzyme elevations
- Weakness
- Insomnia
- Hepatotoxicity
- Hallucinations
- Syncope
- Bradycardia
- Severe hypotension
- Anaphylaxis
Monitoring Parameters
Baseline:- Liver function tests
- Renal function
- Blood pressure and heart rate
- Concomitant medications review
- Blood pressure (particularly during dose titration)
- Liver enzymes (periodically, especially with long-term use)
- Sedation levels and cognitive function
- Efficacy assessment (spasticity scales, functional improvement)
- Signs of hepatotoxicity (jaundice, dark urine, fatigue)
Patient Education
Key points to communicate:- Take exactly as prescribed; do not exceed recommended doses
- Consistency with food intake is important
- Avoid alcohol and other sedating medications
- Rise slowly from sitting/lying positions to prevent dizziness
- Do not stop abruptly; taper under medical supervision
- Report signs of liver problems: yellowing skin/eyes, dark urine, unusual fatigue
- Be cautious with activities requiring alertness until effects are known
- Inform all healthcare providers about tizanidine use
- Keep out of reach of children
References
1. FDA Prescribing Information: Zanaflex (tizanidine) [2023] 2. Nance PW, et al. Efficacy and safety of tizanidine in the treatment of spasticity in patients with spinal cord injury. Neurology. 1994;44(11 Suppl 9):S44-S52. 3. Gelber DA, et al. Open-label dose-titration safety and efficacy study of tizanidine hydrochloride in the treatment of spasticity associated with chronic stroke. Stroke. 2001;32(8):1841-1846. 4. Malanga GA, et al. Tizanidine is effective in the treatment of myofascial pain syndrome. Pain Physician. 2002;5(4):422-432. 5. Micromedex Solutions: Tizanidine Drug Information [2023] 6. Lexicomp Online: Tizanidine Monograph [2023] 7. Clinical Pharmacology: Tizanidine [2023] 8. Kamen L, et al. Management of spasticity associated pain with tizanidine in patients with spinal cord injury. Restor Neurol Neurosci. 2008;26(3):209-215.
This monograph is for educational purposes only and does not replace professional medical advice. Always consult a healthcare provider for medical decisions.