Tizanidine


Article Author:
Shirin Ghanavatian


Article Editor:
Armen Derian


Editors In Chief:
Rodrigo Kuljis
Oleg Chernyshev
Aninda Acharya


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
3/5/2019 5:22:58 PM

Indications

Tizanidine is a myotonolytic agent FDA-approved for the management of spasticity, which may be caused by multiple sclerosis, an acquired brain injury, or a spinal cord injury. It has also been shown to be clinically effective in the management of patients suffering from chronic neck and lumbosacral neuralgia with a myofascial component to their pain and regional musculoskeletal pain syndromes.[1] Animal studies have shown that tizanidine provides benefit in the perioperative period and in the management of neuropathic pain such as trigeminal neuralgia, in accordance with the effects of clonidine under similar circumstances. It is also prescribed off-label for migraine headaches, insomnia, and as an anticonvulsant. Tizanidine can also be applied as part of a detoxification therapy regimen in patients exhibiting analgesic rebound headaches to assist with analgesic withdrawal.

Clinical Studies

Spasticity is a common symptom of upper motor neuron disorders. Tizanidine is widely used as a spasmolytic agent for the management of these debilitating conditions. However, the data regarding the efficacy and safety of tizanidine compared to other approved skeletal muscle relaxants such as baclofen, dantrolene, and diazepam is limited and of older date.

Placebo-controlled studies confirm the significant efficacy of tizanidine in reducing spasticity in patients with spinal cord-induced spasticity. Literature suggests that patients with more severe spasticity are more likely to benefit from the therapy. Drug comparison studies have shown no differences in the efficacy of tizanidine compared with baclofen or diazepam. The Tizanidine treatment group did not report increased weakness when compared with controls. Furthermore, patients using tizanidine experienced fewer adverse effects than those using the control medications. [2]

Other comparison studies showed that tizanidine, baclofen, and diazepam were equally effective in decreasing excessive muscle tone in patients with multiple sclerosis or cerebrovascular lesions. Muscle strength improved in all three treatment groups, but the improvement was greatest with tizanidine. [3]

Similar findings are also reported by by Shakespeare et al.[4] showing no differences in efficacy between tizanidine, baclofen, and dantrolene when compared to diazepam. However, diazepam was associated with more sedation. Another study by Lataste et al.[5] showed no significant differences between tizanidine and baclofen or diazepam for muscle tone, muscle spasms, clonus, muscle strength, or overall anti-spastic effect. However, tizanidine was tolerated slightly better than diazepam and baclofen.

Groves et al.[3] report no significant differences between tizanidine or baclofen or diazepam for spasticity by “Ashworth score.” However, applying “global tolerability to treatment” favored tizanidine compared to baclofen and diazepam. Wallace et al.[2] evaluated the efficacy and tolerability of tizanidine, baclofen, and diazepam and reported increased withdrawal symptoms due to adverse events to tizanidine. 

Mechanism of Action

Tizanidine, an imidazoline derivative is a central acting noradrenergic alpha-2 receptor agonist resulting in impairment of excitatory amino acids like glutamate- and aspartate-release from spinal interneurons and increasing presynaptic inhibition of motor neurons with the greatest effect on spinal polysynaptic pathways.[6] The overall effect of these actions is thought to reduce the facilitation of spinal motor neurons. Similar alpha-2 receptor-mediated inhibition of interneuronal activity appears to underlie the additional anti-nociceptive and anticonvulsant activities of tizanidine. Spasm frequency and clonus are also reduced by tizanidine.[7] Tizanidine also has an affinity for the alpha-1 receptors but to a lesser degree, which may explain its mild and transitory effect on the cardiovascular system compared to clonidine despite their structural and biochemical similarity.[6]

Pharmacokinetics  

Tizanidine has a large, first-pass hepatic metabolism with an oral bioavailability of 20% to 34%. Tizanidine has an elimination half-life of 2.5 hours, and it follows linear pharmacokinetic principles. The steady-state concentration of tizanidine is reached within 24 to 48 hours after administration, and there is no noticeable change in its pharmacokinetic behavior with repeated intake. [8]

Tizanidine is metabolized extensively in the liver by CYP450: 1A2 to inactive metabolites and excreted 60% through urine and 20% through feces.

Administration

Tizanidine is administrated orally as 2 mg, 4 mg, and 6 mg capsules or as 2 mg and 4 mg tablets. Dosage starts with 2 mg orally and may repeat every 6 to 8 hours as needed. The dosage may gradually increase by 2 to 4 mg per dose of 1 to 4 days in between until a significant reduction of spasticity is noticed. Maximum dosing is three doses every 24 hours, up to 36 mg daily. Tizanidine can be taken with food or on an empty stomach. If it is used for more than 9 weeks or given in high doses ranging 20 mg to 36 mg daily, then one may consider discontinuing by tapering the dose 2 to 4 mg per day to reduce the risk of tachycardia, rebound hypertension, and increased spasticity. The capsule may be opened, and its content sprinkled into food. However, absorption of the drug is increased significantly when it is administered under fasting conditions.

Adverse Effects

Tizanidine is generally well-tolerated. However, potential adverse effects on several organs such as cutaneous, gastrointestinal, neurologic, cardiovascular, endocrine and respiratory systems are reported.

Common adverse effects include xerostomia, drowsiness, asthenia, dizziness, hypotension, bradycardia, constipation, urinary frequency, blurred vision, dyskinesia, nervousness, hallucination, and rhinitis.

Serious adverse effects include hepatotoxicity, severe bradycardia, QT interval prolongation, severe hypotension, syncope, Stevens-Johnson syndrome, anaphylaxis, and exfoliative dermatitis. tachycardia, rebound hypertension, and increased spasticity may be experienced when it is discontinued abruptly. 

Drug Interactions

Concomitant use of tizanidine with fluvoxamine or ciprofloxacin is contraindicated due to significant hypotension and increased psychomotor impairment.

Because of potential drug interactions, using of tizanidine with other CYP1A2 inhibitors such as oral contraceptives containing ethinyl estradiol and gestodene, dronedarone, pimozide, saquinavir, cimetidine, famotidine, acyclovir, and ticlopidine should be avoided due to decreased clearance of tizanidine. If tizanidine is clinically necessary, therapy should be initiated with 2 mg and increased 2 to 4 mg daily based on patient response to therapy. If adverse reactions such as hypotension, bradycardia, or excessive sedation occur, the dose should be reduced or discontinued. Use with alcohol should be avoided. Tizanidine should be used cautiously in patients on other alpha-2 adrenergic receptor agonists.

Contraindications

Tizanidine is contraindicated in patients reporting allergies to the drug itself or any other component of the formulation used.

Tizanidine should be used with caution in patients with hepatic or renal impairment. In such patients, individual dosing should be decreased. If high doses are required, increase the individual dose rather than the dose frequency. 

Monitoring

Creatinine and liver function tests are first measured at baseline, then one month after the maintenance dose is achieved. Periodically monitor liver function tests in patients managed with tizanidine on a chronic basis and in higher doses. Monitor signs and symptoms of hypotension before increasing the dose.

Toxicity

There is no antidote for tizanidine toxicity. Tizanidine overdose is managed with close monitoring of airways, administration of intravenous fluid, and catecholamines as necessary. 

Enhancing Healthcare Team Outcomes

Tizanidine is a myotonolytic agent often prescribed by the nurse practitioner, primary care provider, emergency department physicians and internists for the management of spasticity, which may be caused by multiple sclerosis, an acquired brain injury, or a spinal cord injury. It has also been shown to be clinically effective in the management of patients suffering from chronic neck and lumbosacral neuralgia with a myofascial component to their pain and regional musculoskeletal pain syndromes.[1] The drug does relieve some spasticity but practitioners need to monitor the patient's liver and renal function. The drug can also cause hypotension and the patient's need to be warned not to combine it with antihypertensive medications.


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Tizanidine - Questions

Take a quiz of the questions on this article.

Take Quiz
What type of medication is tizanidine?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Tizanidine is primarily excreted by which organ?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What are serious side effects expected by abrupt discontinuation of tizanidine?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
Which medication is an absolute contraindication to combine with tizanidine?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the antidote for tizanidine toxicity?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
For what type of receptors does tizanidine affinity?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
What is the most common side effect of tizanidine?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Tizanidine - References

References

Malanga G,Reiter RD,Garay E, Update on tizanidine for muscle spasticity and emerging indications. Expert opinion on pharmacotherapy. 2008 Aug     [PubMed]
Wallace JD, Summary of combined clinical analysis of controlled clinical trials with tizanidine. Neurology. 1994 Nov     [PubMed]
Groves L,Shellenberger MK,Davis CS, Tizanidine treatment of spasticity: a meta-analysis of controlled, double-blind, comparative studies with baclofen and diazepam. Advances in therapy. 1998 Jul-Aug     [PubMed]
Shakespeare DT,Boggild M,Young C, Anti-spasticity agents for multiple sclerosis. The Cochrane database of systematic reviews. 2001     [PubMed]
Lataste X,Emre M,Davis C,Groves L, Comparative profile of tizanidine in the management of spasticity. Neurology. 1994 Nov     [PubMed]
Coward DM, Tizanidine: neuropharmacology and mechanism of action. Neurology. 1994 Nov     [PubMed]
Wagstaff AJ,Bryson HM, Tizanidine. A review of its pharmacology, clinical efficacy and tolerability in the management of spasticity associated with cerebral and spinal disorders. Drugs. 1997 Mar     [PubMed]
Tse FL,Jaffe JM,Bhuta S, Pharmacokinetics of orally administered tizanidine in healthy volunteers. Fundamental     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of Neurology. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for Neurology, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in Neurology, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of Neurology. When it is time for the Neurology board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study Neurology.