Continuing Education Activity

Tizanidine is an FDA-approved drug for managing spasticity. It is a centrally acting alpha-2 receptor agonist. Tizanidine effectively works with spasticity caused by multiple sclerosis, an acquired brain injury, or a spinal cord injury. It has also been shown to be clinically effective in managing patients suffering from chronic neck and lumbosacral neuralgia with a myofascial component to their pain and regional musculoskeletal pain syndromes. 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. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, toxicity, and monitoring, of tizanidine so providers can direct patient therapy as part of the inter-professional team.

Objectives:

• Explain the mechanism of action of tizanidine.
• Identify the clinical indications for tizanidine use.
• Review the adverse reaction profile of tizanidine.
• Summarize inter-professional team strategies for improving care, coordination, and communication for improving patient outcomes related to tizanidine therapy.

Indications

Tizanidine is a centrally acting alpha-2 agonist. Tizanidine is widely used as an anti-spastic agent for multiple medical conditions.

FDA-approved Indication

• Tizanidine is indicated for spasticity management due to multiple sclerosis, spinal cord injury, stroke, amyotrophic lateral sclerosis, and traumatic brain injury.[1][2][3]

Off-label Use

• Chronic neck and lower back pain[4]
• Rebound headaches due to analgesic withdrawal[5]
• Chronic migraine headaches[6]
• Refractory insomnia in spastic quadriplegic patients[7]
• Regional musculoskeletal pain syndromes[4]

Clinical Studies

• Placebo-controlled studies confirm the significant efficacy of tizanidine in reducing spasticity in patients with spinal cord-induced spasticity. Literature suggests that patients with 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 compared to the controls. Furthermore, patients given tizanidine experienced fewer adverse effects than those using controlled substances.[8]
• Studies exhibit that tizanidine, baclofen, and diazepam effectively decreased excessive muscle tone in patients with multiple sclerosis or cerebrovascular lesions. Muscle strength improved in all three treatment groups, but the improvement was most significant with tizanidine. Shakespeare et al. also reported similar findings showing no differences in efficacy between tizanidine, baclofen, and dantrolene compared to diazepam. However, diazepam was associated with more sedation.[9] 
• Another study by Lataste et al. 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 tolerance is slightly better than diazepam and baclofen.[10]
• Groves et al. report no significant differences between tizanidine, baclofen, or diazepam for spasticity by Ashworth score. However, applying global tolerability to treatment favored tizanidine compared to baclofen and diazepam.[11] 
• Animal studies have shown that tizanidine provides benefits in the perioperative period and the management of neuropathic pain, such as trigeminal neuralgia, similar to the effects of clonidine under similar circumstances.
• A recent study indicates that tizanidine and other alpha-2 agonists can be used for medically supervised opioid withdrawal.[12]
• The American Academy of Neurology guidelines reports that tizanidine should be used for generalized spasticity in cerebral palsy, for segmental/localized spasticity treatment with botulinum toxin-A is more effective.[13]

Mechanism of Action

Tizanidine is an imidazoline derivative and a centrally acting alpha-2 receptor agonist. Tizanidine inhibits the release of excitatory amino acids like glutamate and aspartate from spinal interneurons. Consequently, tizanidine enhances the presynaptic inhibition of motor neurons. Tizanidine has significant action on spinal polysynaptic pathways.[14]

The overall effect of these actions is to reduce the facilitation of spinal motor neurons. Similarly, alpha-2 receptor-mediated inhibition of inter-neuronal activity appears to underlie tizanidine's additional anti-nociceptive and anti-convulsant activities. Spasm frequency and clonus are also reduced by tizanidine.[15]

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.[16]

Pharmacokinetics  

Absorption: Tizanidine has a significant, first-pass hepatic metabolism with an oral bioavailability of 20% to 34%. Tizanidine attains the steady-state concentration within 24 to 48 hours after administration. There is no noticeable change in its pharmacokinetic behavior with repeated intake.[17]

Distribution: Tizanidine has extensive tissue distribution; the volume of distribution is 2.4 L/kg. The plasma protein binding of tizanidine is approximately 30%.

Metabolism: Tizanidine is metabolized extensively in the liver by cytochrome P450-1A2 to inactive metabolites.

Excretion: Tizanidine has an elimination half-life of 2.5 hours, follows linear pharmacokinetics, and is excreted 60% through urine and 20% through feces.[18]

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 for 1 to 4 days in between until there is a noticeably significant reduction of spasticity. Maximum dosing is three doses every 24 hours, up to 36 mg daily.

If tizanidine is used for more than nine weeks or given in high doses ranging from 20 mg to 36 mg daily, taper the dose gradually. The recommendation is to taper the dose to 2 to 4 mg daily to reduce the risk of tachycardia, rebound hypertension, and increased spasticity.[19]

The patient may open the capsule and sprinkle the contents into food. Patients can take tizanidine with food or on an empty stomach. It is important to note that the extent of absorption is greater when taken with food. The tablet and capsule dosage forms are not bioequivalent when administered with food. Hence, the clinician should counsel the patient to take tizanidine with or without food but be consistent to avoid fluctuations in concentration.[20] It is also important to recognize that smoking decreases tizanidine's plasma concentration and exposure(AUC).[21]

Use in Specific Patient Population

Patients with Hepatic Impairment: The consequence of Hepatic impairment on the pharmacokinetics of tizanidine has not been evaluated. However, tizanidine is extensively metabolized by the liver; therefore, hepatic impairment would significantly influence the pharmacokinetics of tizanidine. Therefore, tizanidine should be avoided or used with extreme caution in patients with hepatic impairment.

Patients with Renal Impairment: Tizanidine should be used cautiously in patients with renal impairment (creatinine clearance < 25 mL/min), as clearance is decreased by more than 50%. Start with a low dose, evaluate the response to therapy, and if a higher dose is needed, the dose can be increased rather than increasing the frequency of administration. The clinician should monitor the patient closely for adverse drug reactions such as dry mouth, drowsiness, asthenia, and dizziness as indicators of toxicity.

Pregnancy Considerations: The use of tizanidine in managing spinal cord injury during pregnancy has been described in case reports.[22] However, it is important to note that tizanidine is a former FDA pregnancy category-C and should be used only if indicated after careful risk-benefit evaluation.

Breastfeeding Considerations: Tizanidine is a lipid-soluble drug; hypothetically, it may be present in breast milk; its use during lactation is not advised.

Adverse Effects

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

Common Adverse Drug Reactions

• Drowsiness
• Blurred vision
• Asthenia
• Constipation
• Dyskinesia
• Nervousness
• Hallucination
• Rhinitis
• Xerostomia[15]
• Dizziness[23]

Severe Adverse Drug Reactions

• Severe hepatotoxicity and liver failure[24] 
• Anaphylaxis
• Exfoliative dermatitis
• Severe hypotension[25]
• QT interval prolongation[26]
• Severe bradycardia[27]
• Stevens-Johnson syndrome[28]
• Refractory hypokalemia and potassium wasting nephropathy[29]

Withdrawal Symptoms 

• Tachycardia
• Rebound hypertension
• Increased spasticity 
• Withdrawal symptoms are more likely to occur when discontinuing the drug abruptly.[19]

Drug Interactions

• Concomitant use of tizanidine with fluvoxamine or ciprofloxacin is contraindicated due to significant hypotension and increased psychomotor impairment.[30] A recent retrospective analysis of the WHO pharmacovigilance database identified severe cardiac and nervous system adverse drug reactions. The study concluded that the concomitant use of ciprofloxacin with tizanidine should be avoided.[31]
• Because of potential drug interactions, using 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.[32]
• If tizanidine is clinically necessary, therapy should be initiated with 2 mg and increased to 2 to 4 mg daily based on patient response to therapy.
• Adverse reactions such as hypotension, bradycardia, or excessive sedation require gradual dose reduction or stopping therapy.
• Tizanidine should be used cautiously in patients on other alpha-2 adrenergic receptor agonists.
• Patients should avoid alcohol and benzodiazepines with tizanidine as it can lead to excessive sedation and myocardial toxicity in rare instances.[33]
• Vemurafenib used in BRAF mutation-positive malignancy is an inhibitor of CYP1A2 and can increase plasma concentration of tizanidine, leading to potential toxicity.[34]

Contraindications

• Hypersensitivity to tizanidine or its ingredients is a contraindication to the use of tizanidine.
• Tizanidine use requires caution in patients with hepatic impairment. Review articles on tizanidine report cases of severe hepatotoxicity, acute liver failure, and death.[24]
• According to product labeling, tizanidine use requires caution in patients with renal impairment (creatinine clearance < 25 mL/min). In such patients, decrease the dose. If high doses are necessary, increase the individual dosage rather than the dosage frequency.

Monitoring

• Creatinine and liver function tests require measurement at baseline, then one month after the maintenance dose is achieved. Periodically monitor liver function tests in patients managed with tizanidine chronically and in higher doses.[24]
• Monitor blood pressure and heart rate before increasing the dosage because of the risk of severe hypotension associated with the higher dose.[25]
• Monitor the level of spasticity by Ashworth and modified Ashworth Scales.[35] 
• In patients with multiple sclerosis, monitor spasticity using MS Spasticity Scale(MSSS-88).[36]

Toxicity

• The maximum recommended dose of tizanidine is 36 mg/day.[37]
• In the retrospective review, which included 45 patients, the mean dose ingested was 72 mg (Above the maximum recommended dose).

Clinical Features

• Lethargy
• Bradycardia
• Hypotension
• Agitation
• Confusion
• Vomiting
• Drowsiness
• Coma

Management

• There is no antidote for tizanidine toxicity.
• Tizanidine overdose management is by close monitoring of airways, administration of intravenous fluid, and vasopressors as necessary.[25]
• The pediatric case report described an overdose of tizanidine in spastic quadriplegia and toxicity presented with multiple organ dysfunction in the absence of sepsis.[37]
• A recent case report described the altered mental status and hemodynamic instability due to tizanidine overdose, and naloxone 10 mg IV administration improved Richmond Agitation-Sedation Scale(RASS).[38] The study concluded that naloxone could be used in tizanidine overdose in emergency settings; however, naloxone does not reverse the hemodynamic parameters.[39]

Enhancing Healthcare Team Outcomes

Tizanidine is a centrally acting alpha-2 agonist prescribed to manage spasticity caused by multiple sclerosis, stroke, and spinal cord injury. Tizanidine is also used off-label for managing patients suffering from chronic neck and back pain and chronic migraines. However, this drug can cause hypotension, bradycardia, and hepatotoxicity. Hence all healthcare providers need to understand indications, mechanisms, adverse effects, and their management. 

The clinician prescribes tizanidine for appropriate indication and should assess liver function tests at baseline and one month. In addition, the neurologist should evaluate the improvement in spasticity related to neurological disorders such as multiple sclerosis, stroke, and spinal cord injury. Nurses can check compliance, monitor for adverse events, and counsel patients for adherence to therapy. The pharmacist should verify the dosing regimen, perform medication reconciliation for drug interactions, and counsel the patient on adverse drug reactions. In addition, patients need to be warned not to combine it with antihypertensive medications. In the overdose of tizanidine, triage nurses should admit the patient, and the emergency department physicians should monitor blood pressure and heart rate and obtain 12 lead EKG. Additionally, a liver function test is required to assess for hepatotoxicity. The critical care physician should manage severe overdose, which requires vasopressors and fluids during the ICU stay.

As depicted above, there are multiple healthcare providers, including clinicians (MDs, DOs, NPs, PAs), specialists, pharmacists, and nurses, involved in taking care of the patient. Tizanidine can be an effective therapeutic agent, but it requires the entire interprofessional healthcare team to collaborate and communicate for therapy to be successful. In addition, a recent study noted that interprofessional care between clinicians, neurologists, pharmacists, nurses, physical therapists, speech and language therapists, and occupational therapists is crucial for providing patient-centered care in patients with multiple sclerosis.[40] [Level 5]