What is tizanidine used to treat. How does tizanidine work. What are the potential side effects of tizanidine. How should tizanidine be taken. What precautions should be considered when using tizanidine.

Understanding Tizanidine: A Comprehensive Overview

Tizanidine, known by the brand name Zanaflex, is a short-acting muscle relaxant that belongs to the class of skeletal muscle relaxants. This medication works by blocking nerve impulses, specifically pain sensations, that are sent to the brain. Its primary use is to treat spasticity by temporarily relaxing muscle tone.

Key Points About Tizanidine

• Generic name: tizanidine (tye-ZAN-i-deen)
• Brand name: Zanaflex
• Drug class: Skeletal muscle relaxants
• Primary use: Treatment of spasticity

The Mechanism of Action: How Does Tizanidine Work?

Tizanidine’s effectiveness lies in its ability to interfere with nerve signals. By blocking these impulses, it reduces the intensity of pain sensations reaching the brain. This mechanism results in temporary muscle relaxation, which is particularly beneficial for individuals experiencing spasticity.

Is tizanidine a long-lasting medication? No, tizanidine is considered a short-acting muscle relaxer. Its effects are most noticeable between 1 and 3 hours after ingestion, making it suitable for daily activities that require relief from muscle spasms.

Tizanidine Dosage and Administration Guidelines

The proper administration of tizanidine is crucial for its effectiveness and safety. Here are the key points regarding dosage:

• Starting dose: 2 mg every 6 to 8 hours
• Maximum frequency: Up to 3 doses in 24 hours
• Maximum daily dose: 36 mg in a 24-hour period

Can tizanidine be taken with or without food? Tizanidine can be taken with or without food, but it’s important to maintain consistency. Switching between taking it with food and without food can affect the medicine’s effectiveness or cause increased side effects.

Important Dosage Considerations

1. Follow your doctor’s instructions carefully.
2. Do not exceed the maximum recommended dose.
3. Be cautious when switching between tablets and capsules, as it may affect side effects or therapeutic effect.
4. Contact your doctor if you notice any changes in the medication’s effectiveness after altering your intake method.

Potential Side Effects and Safety Precautions

As with any medication, tizanidine can cause side effects. It’s essential to be aware of these potential reactions and take necessary precautions:

Common Side Effects

• Drowsiness
• Dizziness
• Dry mouth
• Weakness
• Fatigue

What should you avoid while taking tizanidine? It’s important to avoid alcohol consumption, as it can increase some of the side effects. Additionally, be cautious when performing activities that require alertness, such as driving or operating machinery, until you know how the medication affects you.

Serious Side Effects

Seek immediate medical attention if you experience:

• Signs of liver problems (e.g., yellowing of skin or eyes, dark urine)
• Unusual bleeding or bruising
• Severe dizziness or fainting
• Slow heartbeat
• Hallucinations

Contraindications and Drug Interactions

Certain conditions and medications can interact negatively with tizanidine. It’s crucial to inform your healthcare provider about your medical history and current medications.

Do Not Use Tizanidine If:

• You are allergic to it
• You are taking fluvoxamine (Luvox) or ciprofloxacin (Cipro)

What medical conditions should be disclosed before taking tizanidine? Inform your doctor if you have a history of liver disease, kidney disease, or low blood pressure.

Potential Drug Interactions

Tizanidine may interact with:

• Cold or allergy medicines
• Narcotic pain medications
• Sleeping pills
• Other muscle relaxers
• Medications for seizures, depression, or anxiety

These interactions can potentially increase drowsiness or other side effects.

Special Populations and Tizanidine Use

Certain groups may require special consideration when using tizanidine:

Pregnancy and Breastfeeding

Is tizanidine safe during pregnancy? The effects of tizanidine on unborn babies are not fully known. If you are pregnant or planning to become pregnant, consult your doctor before using this medication.

Regarding breastfeeding, it may not be safe to use tizanidine while nursing. Discuss the potential risks with your healthcare provider.

Elderly Patients

Older adults may be more sensitive to the side effects of tizanidine, particularly dizziness and drowsiness. Careful monitoring and potential dose adjustments may be necessary.

Monitoring and Long-Term Use Considerations

Long-term use of tizanidine requires careful monitoring:

Liver Function Tests

Regular blood tests to check liver function are necessary for individuals taking tizanidine, especially those on higher doses or long-term therapy.

Withdrawal Symptoms

Can stopping tizanidine suddenly cause withdrawal symptoms? Yes, abrupt discontinuation after long-term use may lead to withdrawal symptoms such as dizziness, fast heartbeats, tremors, and anxiety. Always consult your doctor for guidance on safely stopping the medication.

Proper Storage and Handling of Tizanidine

To maintain the effectiveness and safety of tizanidine:

• Store at room temperature
• Keep away from moisture and heat
• Keep out of reach of children
• Do not use expired medication

How should unused or expired tizanidine be disposed of? Follow your local guidelines for medication disposal, or consult your pharmacist for proper disposal methods.

Maximizing the Benefits of Tizanidine Therapy

To get the most out of your tizanidine treatment:

1. Take the medication exactly as prescribed
2. Be consistent with the timing of your doses
3. Keep track of any side effects and report them to your doctor
4. Attend all scheduled follow-up appointments
5. Combine medication use with other recommended therapies, such as physical therapy or exercise, as advised by your healthcare provider

How can you determine if tizanidine is working effectively? Monitor your symptoms and keep a log of any changes in muscle spasticity or pain levels. This information can help your doctor assess the medication’s effectiveness and make any necessary adjustments to your treatment plan.

Lifestyle Considerations

While taking tizanidine, consider the following lifestyle adjustments:

• Avoid activities that require full muscle strength and coordination during peak medication effects
• Ensure adequate rest and sleep to complement the medication’s muscle-relaxing effects
• Maintain a balanced diet and stay hydrated to support overall health and potentially minimize side effects
• Engage in gentle stretching or low-impact exercises as recommended by your healthcare provider to maintain flexibility and muscle function

By following these guidelines and working closely with your healthcare team, you can optimize the benefits of tizanidine while minimizing potential risks and side effects.

Tizanidine Uses, Dosage, Side Effects

Generic name: tizanidine [ tye-ZAN-i-deen ]
Brand name: Zanaflex
Drug class: Skeletal muscle relaxants

Medically reviewed by Sanjai Sinha, MD. Last updated on Jan 10, 2022.

What is tizanidine?

Tizanidine is a short-acting muscle relaxer. It works by blocking nerve impulses (pain sensations) that are sent to your brain.

Tizanidine is used to treat spasticity by temporarily relaxing muscle tone.

Tizanidine may also be used for purposes not listed in this medication guide.

Warnings

Tizanidine is a short-acting medication that should be taken only for daily activities that require relief from muscle spasticity.

You should not take tizanidine if you are also taking fluvoxamine (Luvox) or ciprofloxacin (Cipro).

Do not use tizanidine at a time when you need muscle tone for safe balance and movement during certain activities. In some situations, it may endanger your physical safety to be in a state of reduced muscle tone.

Switching between tablets and capsules, or changing the way you take it with regard to eating, can cause an increase in side effects or a decrease in therapeutic effect. Follow your doctor’s instructions carefully. After making any changes in how you take tizanidine, contact your doctor if you notice any change in how well the medicine works or if it causes increased side effects.

The recommended starting dose of tizanidine is 2 mg every 6 to 8 hours, up to a maximum of 3 doses in 24 hours. Do not take more than 36 mg of tizanidine in a 24-hour period. Too much of this medicine can damage your liver. Cold or allergy medicine, narcotic pain medicine, sleeping pills, other muscle relaxers, and medicine for seizures, depression or anxiety can add to sleepiness caused by tizanidine.

Avoid drinking alcohol. It can increase some of the side effects of this medicine.

Before taking this medicine

You should not use tizanidine if you are allergic to it, or if:

To make sure tizanidine is safe for you, tell your doctor if you have ever had:

• liver disease;

• kidney disease; or

• low blood pressure.

It is not known whether tizanidine will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

It may not be safe to breastfeed while using this medicine. Ask your doctor about any risk.

How should I take tizanidine?

Take tizanidine exactly as it was prescribed for you. Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Tizanidine is usually taken up to 3 times in one day, starting at 2mg per dose. Allow 6 to 8 hours to pass between doses. Do not take more than 36 mg in a 24-hour period. Too much of this medicine can damage your liver.

You may take tizanidine with or without food, but take it the same way each time. Switching between taking with food and taking it without food can make the medicine less effective or cause increased side effects.

Switching between tablets and capsules may cause changes in side effects or how well the medicine works.

If you make any changes in how you take tizanidine, tell your doctor if you notice any change in side effects or in how well the medicine works.

Tizanidine is a short-acting medication, and its effects will be most noticeable between 1 and 3 hours after you take it. You should take this medicine only for daily activities that require relief from muscle spasms.

You will need frequent blood tests to check your liver function.

If you stop using this medicine suddenly after long-term use, you may have withdrawal symptoms such as dizziness, fast heartbeats, tremors, and anxiety. Ask your doctor how to safely stop using this medicine.

Store at room temperature away from moisture and heat.

What happens if I miss a dose?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include weakness, drowsiness, confusion, slow heart rate, shallow breathing, feeling light-headed, or fainting.

What to avoid

Do not use tizanidine at a time when you need muscle tone for safe balance and movement during certain activities. In some situations, it may be dangerous for you to have reduced muscle tone.

Drinking alcohol with this medicine can cause side effects.

Avoid driving or hazardous activity until you know how this medicine will affect you. Your reactions could be impaired. Avoid getting up too fast from a sitting or lying position, or you may feel dizzy.

Tizanidine side effects

Get emergency medical help if you have signs of an allergic reaction to tizanidine: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

• a light-headed feeling, like you might pass out;

• weak or shallow breathing;

• confusion, hallucinations; or

• pain or burning when you urinate.

Common tizanidine side effects may include:

• drowsiness, dizziness, weakness;

• feeling nervous;

• blurred vision;

• flu-like symptoms;

• dry mouth, trouble speaking;

• abnormal liver function tests;

• runny nose, sore throat;

• urination problems, painful urination;

• vomiting, constipation; or

• uncontrolled muscle movements.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect tizanidine?

Taking tizanidine with other drugs that make you sleepy or slow your breathing can cause dangerous side effects or death. Ask your doctor before using opioid medication, a sleeping pill, a muscle relaxer, or medicine for anxiety or seizures.

Tell your doctor about all your other medicines, especially:

• acyclovir;

• ticlopidine;

• zileuton;

• birth control pills;

• an antibiotic – ciprofloxacin, levofloxacin, moxifloxacin, or ofloxacin;

• blood pressure medicine – clonidine, guanfacine, methyldopa;

• heart rhythm medicine – amiodarone, mexiletine, propafenone, verapamil; or

• stomach acid medicine – cimetidine, famotidine.

This list is not complete. Other drugs may interact with tizanidine, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

Popular FAQ

The maximum effect of tizanidine occurs about 1 hour to 2 hours after taking a dose. It wears off in about 3 to 6 hours after taking it. Tizanidine is typically given no more than 3 times a day.

Tizanidine is not listed as a controlled substance by the U.S. Drug Enforcement Administration (DEA). Abuse potential has not been evaluated in human studies.

Tizanidine can cause sleepiness, but it has not been approved by the U.S. Food and Drug Administration (FDA) to treat sleep disorders. Tizanidine is a skeletal muscle relaxant. It is approved by the FDA to help relieve muscle spasms.

Tizanidine is known to cause low blood pressure. In some cases, it may cause low blood pressure that is so low that you could faint or pass out. The chances of fainting can be lowered if your doctor raises the dose of tizanidine very slowly. You may also have to be careful when you move from a sitting position to a standing position. In clinical trials, the most common side effects of tizanidine were dry mouth, sleepiness, dizziness and asthenia (defined as weakness, fatigue and/or tiredness).

Tizanidine normally starts working 1 to 2 hours after taking it. It wears off about 3 hours to 6 hours after taking it. Tizanidine can be taken up to 3 times a day to help relieve muscle spasms.

Tizanidine may be addictive, but it has not been evaluated in human studies. Withdrawal symptoms have been reported after abruptly stopping tizanidine, but abuse of other medications concomitantly was suspected in these cases. Dosing should be tapered off to avoid possible withdrawal symptoms.

Tizanidine is not known to cause weight gain. In clinical trials, the most common side effects of tizanidine were dry mouth, sleepiness, dizziness and asthenia (defined as weakness, fatigue and/or tiredness).

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Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use tizanidine only for the indication prescribed.

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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.

Access free multiple choice questions on this topic.

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]

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• Access free multiple choice questions on this topic.

• Comment on this article.

References

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Disclosure: Shirin Ghanavatian declares no relevant financial relationships with ineligible companies.

Disclosure: Armen Derian declares no relevant financial relationships with ineligible companies.

Tizanidine – description of the substance, pharmacology, use, contraindications, formula

Contents

• Structural formula

• Russian name

• English name

• Latin name

• chemical name

• Gross formula

• Pharmacological group of the substance Tizanidine

• Nosological classification

• CAS code

• pharmachologic effect

• Characteristic

• Pharmacology

• The use of the substance Tizanidin

• Contraindications

• Use during pregnancy and lactation

• Side effects of tizanidine

• Interaction

• Overdose

• Dosage and administration

• Precautionary measures

• Information sources

• Trade names with the active substance Tizanidine

Structural formula

Russian name

Tizanidin

English name

Tizanidine

Latin name

Tizanidinum ( born Tizanidini)

Chemical name

5-Chloro-N-(4,5-dihydro-1H-imidazole- 2-yl)-2,1,3-benzothiadiazol-4-amine (as hydrochloride)

Gross formula

C ₉ H ₈ ClN ₅ S

Pharmacological substance group Tizanidin

Alpha-agonists

Drugs affecting neuromuscular transmission

Nosological classification

ICD-10 code list

CAS code

51322-75-9

Pharmacological action

Pharmacological action –

muscle relaxant , central .

Characteristics

White or almost white crystalline powder, odorless or with a slight characteristic odor. Slightly soluble in water and methanol, solubility in water decreases with increasing pH.

Pharmacology

Excites alpha ₂ -adrenergic receptors, mainly at the level of the spinal cord; reduces the release of excitatory amino acids from the intermediate neurons of the spinal cord, selectively suppresses the polysynaptic mechanisms responsible for muscle hypertonicity. Relaxes skeletal muscles in chronic spastic conditions of spinal and cerebral origin, eliminates acute painful muscle spasms and clonic convulsions. Reduces muscle resistance during passive movements, increases the strength of voluntary muscle contractions.

After oral administration, it is rapidly and almost completely absorbed. Absolute bioavailability is approximately 40%. max “> C _max is achieved in 1-2 hours. Plasma protein binding is about 30%. Biotransformed in the liver with the participation of the CYP1A2 isoenzyme to inactive or inactive metabolites. Excreted by 70% in the urine. T _1/2 – 3-5 hours

Application of the substance Tizanidine

Painful muscle spasms in diseases of the spine (including osteochondrosis, spondylosis, syringomyelia, hemiplegia, cervical and lumbar syndromes), after surgery for a herniated disc or osteoarthritis of the hip, spasticity and pain caused by neurological diseases: multiple sclerosis, chronic myelopathy, degenerative diseases of the spinal cord, cerebrovascular accidents, stroke, traumatic brain injury, cerebral palsy, convulsions of central origin.

Contraindications

Hypersensitivity, severe liver and kidney failure, pregnancy, lactation, childhood.

Pregnancy and Lactation Use

FDA Fetal Category C.

Breastfeeding should be discontinued during treatment (it is unknown if tizanidine is excreted in breast milk).

Side effects of the substance Tizanidine

From the side of the nervous system and sensory organs: drowsiness, fatigue, dizziness or vertigo, muscle weakness, anxiety, sleep disturbances, hallucinations.

From the CCC and blood (hematopoiesis, hemostasis): slight decrease in blood pressure (at low doses) or arterial hypertension, bradycardia.

From the gastrointestinal tract: dry mouth, nausea, gastrointestinal disorders, temporary increase in serum transaminase activity.

Interactions

Antihypertensive drugs, including diuretics, increase hypotension and bradycardia. Alcohol and sedatives deepen the depressive effect.

Overdose

Symptoms: nausea, vomiting, lowering blood pressure, dizziness, miosis, respiratory failure, coma.

Treatment: gastric lavage, activated charcoal, forced diuresis, maintenance of vital functions.

Dosage and administration

Inside. Dosing regimen should be selected individually. Tizanidine has a narrow therapeutic index and high variability in plasma levels of tizanidine in patients, so careful dose selection is required. Initial dose – 2-4 mg 3 times a day, in severe cases – an additional 2-4 mg at night. In case of neurologically caused spastic conditions, the initial dose should not exceed 6 mg per day in 3 doses with a gradual increase by 2-4 mg at intervals of 3-4 days – up to a week. The optimal therapeutic effect is usually achieved at a dose of 12-24 mg / day in 3-4 doses at regular intervals. Do not exceed a dose of 36 mg / day.

Precautions

Periodic monitoring of liver and kidney function is necessary and dose reduction if they worsen. A continuous increase in the activity of transaminases in the blood requires discontinuation. Due to possible drowsiness and weakness, it is recommended to limit the appointment to persons whose work requires a quick physical and mental reaction (operators, drivers of vehicles, etc. ).

Generalized materials www.grls.rosminzdrav.ru, 2014–2016.

Trade names with the active ingredient Tizanidine

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Dosage
All dosages 2 mg 250-1000 g 4 mg 6 mg No dosage

Manufacturer
All manufacturers Avexima Sibir LLC Berezovsky Pharmaceutical Plant CJSC (CJSC “BFZ”) Veropharm JSC Veropharm JSC J.P.En. Pharma Pvt. Irbit Chemical and Pharmaceutical Plant Novartis Neva OJSC Novartis Saglik LLC Gida ve Tarim Yuryunleri Sanayi ve Ticaret A.S. Novartis Pharmaceutical Ozone LLC Sun Pharmaceutical Industries Ltd. North Star NAO Simpeks Pharma Teva Pharmaceutical Plant JSC Teva Pharmaceutical Plant Private Co. Ltd Farmak

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Use of tizanidine (Sirdalud) in the treatment of pain and spasm | Danilov A.

B.

The drug tizanidin (Sirdalud) belongs to the centrally acting muscle relaxants (α2-adrenergic agonists) and implements its effect at the spinal and supraspinal level [4]. By stimulating presynaptic α2 receptors, it inhibits the release of excitatory amino acids that stimulate NMDA receptors. This leads to the suppression of the transmission of excitation through the polysynaptic reflexes of the spinal cord. The drug mainly inhibits the polysynaptic reflexes of the spinal cord responsible for muscle hypertonicity, which causes a decrease in the increased tone of the flexor and extensor muscles and a decrease in painful muscle spasms. In addition to muscle relaxant properties, tizanidine also has a central, moderately pronounced analgesic effect (by reducing the release of excitatory neurotransmitters in the brain at the level of the locus coeruleus). In animal studies, it has been shown that tizanidine (Sirdalud) can realize its effect through a decrease in central sensitization [11]. These properties of tizanidine allow it to be used both as a means to reduce muscle spasm, and for the treatment of a number of pain syndromes (associated with muscle spasm).

Tizanidin (Sirdalud)
for pain syndromes
Monotherapy with tizanidine (Sirdalud) for pain syndromes. Muscular tonic and myofascial pain syndromes are very often the main reason for patients to seek medical attention. In the treatment of muscular-tonic pain, the central place belongs to local influences aimed at relaxing the muscle (massage, applications of warming ointments, gels, wet compresses, etc.), and in the case of myofascial pain syndrome, on the destruction of trigger points using post-isometric relaxation, the introduction of dry needles or anesthetic into the trigger zone. The terms of therapy are significantly reduced with effective anesthesia of the patient. A common method of pain relief for myofascial pain is also the use of non-steroidal anti-inflammatory drugs (NSAIDs).
Muscle relaxants can be of great help in the treatment of muscular-tonic and myofascial pain syndromes by reducing the intensity of pain, reducing painful muscle tension, and improving motor activity. The use of muscle relaxants is justified by the recognition of the important role of muscle spasm in the pathogenesis of pain in the lower back. Pain of various origins (due to damage to the intervertebral discs, facet joints of the spine, the muscles themselves and other causes) increases the activity of the motor neurons of the spinal cord, which leads to muscle spasm, which in turn plays a significant role in maintaining the pain itself. Pathologically increased muscle tone has various mechanisms for increasing pain: direct irritation of muscle pain receptors, deterioration of blood supply to the muscles, which leads to the formation of a vicious circle leading to increased muscle spasm and accompanying pain. Muscle relaxants break the vicious circle of “pain – muscle spasm – pain” and, as a result, can accelerate the recovery period [6]. In European guidelines for the treatment of acute pain in the lower back, tizanidine, dantrolene, diazepam, baclofen are noted as effective muscle relaxants [19]. In our country, of these drugs, tizanidine (Sirdalud) is most commonly used [6].
The effective daily dose range of tizanidine (Sirdalud) for pain syndromes is 2–12 mg (the optimal dose is 6–8 mg/day). For mild pain syndromes, the appointment of tizanidine (Sirdalud) can be limited to taking the drug at night at a dose of 2-4 mg until the pain stops (usually 5-7 days). With a moderately severe pain syndrome, it is also better to prescribe the first dose at night at a dose of 2–4 mg (the patient will “oversleep” the side effects), then gradually increase the dose to 6–8 mg / day. In severe cases, an additional 2–4 mg of tizanidine (Sirdalud) at night can be added. A positive effect, as a rule, is already noted on the 3rd day of taking the drug. In chronic pain syndromes, a course of therapy is usually carried out lasting 2-4 weeks, adjusting the duration of treatment and the dose of the drug depending on the efficacy / tolerability.
It should be noted that for mild to moderate pain associated with muscle spasm (eg, acute pain in the neck or lower back), it may be sufficient to prescribe tizanidine (Sirdalud) as monotherapy.
The effectiveness of tizanidine monotherapy (Sirdalud) has been confirmed in many studies, incl. and in a multicenter study that included 2251 patients with acute pain caused by muscle spasm in the lower back, neck, or shoulder. 89% of patients rated the treatment outcome as “good” or “very good”. The study also noted a very good tolerability of the drug (90% of patients reported tolerability as “good” or “very good”). These results allowed the authors to recommend tizanidine as the drug of choice among muscle relaxants for the treatment of pain associated with muscle spasm [13].
Combination of tizanidine (Sirdalud) with NSAIDs. With more severe pain, or when it is based on inflammatory changes, it is advisable to use tizanidine and NSAIDs together. Studies show that the use of tizanidine potentiates the effect of NSAIDs [9,16]. In addition, taking tizanidine (Sirdalud) has a gastroprotective effect, which is associated with its adrenergic activity and antispasmodic effect. Tizanidin (Sirdalud) reduces basal and induced acid secretion in the stomach, eliminates the imbalance of glycoproteins in the gastric mucosa and gastric secretions [11,16].
In experimental studies, the use of tizanidine demonstrated a significant decrease in the ulcerogenic effect of acetylsalicylic acid, indomethacin, meloxicam, nimesulide and naproxen. The gastroprotective activity of tizanidine has also been proven in clinical studies. In patients receiving the combination of ibuprofen and tizanidine, the incidence of gastrointestinal side effects, including bleeding, was significantly (p=0.002) lower than in patients receiving the combination of ibuprofen and placebo [9]. Similar results were obtained when comparing the combination of diclofenac and tizanidine with the combination of diclofenac and placebo in a multicenter (12 centers), prospective, double-blind, placebo-controlled, randomized clinical trial conducted in 6 countries of the Asia-Pacific region and including 405 participants [16]. Gastropathy was reported in 12% of patients treated with a combination of diclofenac and tizanidine versus 32% of patients treated with diclofenac in combination with placebo (p<0.001). The frequency of positive fecal occult blood test results was 5% in the main group compared to 11% in the control group.
The gastroprotective effect of Sirdalud is especially important for the management of patients with chronic pain syndromes who take NSAIDs for a long period of time (for rheumatological diseases), which often leads to the development of erosive gastritis and gastric and duodenal ulcers [1].
Combination of tizanidine (Sirdalud) with antidepressants and anticonvulsants. The management of chronic pain is more complex than the management of acute pain and requires an integrated approach. The use of muscle relaxants here is only a component of treatment and should be justified by the presence of a therapeutic target – muscle spasm. In this regard, the patient’s expectations regarding the effect of a muscle relaxant should be correctly formed: the use of tizanidine (Sirdalud) can reduce pain, facilitate the patient’s movements, but will not stop the pain completely, because. in chronic pain, the muscle component is not the leading one.
In the treatment of chronic pain syndromes, anticonvulsants, antidepressants are used, so it is important to consider how tizanidine (Sirdalud) interacts with these drugs. There are works that show that tizanidine (Sirdalud) potentiates the action of tricyclic antidepressants (amitriptyline) [10]. At the same time, it must be remembered that tizanidine (Sirdalud) cannot be combined with fluvoxamine, an antidepressant from the SSRI group. Simultaneous administration of tizanidine (Sirdalud) and fluvoxamine can lead to a significant decrease in blood pressure and cause complications from the central nervous system.
Thus, due to high efficiency and minor side effects, a number of domestic and foreign experts consider tizanidine (Sirdalud) as the drug of choice for the treatment of acute and subacute myofascial pain in monotherapy and as the drug of first choice for the treatment of chronic myofascial syndrome in combination with other drugs [2 ,13].
Tizanidin (Sirdalud)
in neurological practice
Disturbances in muscle tone, associated pain syndromes, restrictions on motor functions, secondary changes in joints and muscles are part of the clinical manifestations of many diseases of the nervous system. As a rule, the problem of increasing muscle tone – hypertonicity or spasticity – acquires clinical significance [8]. However, the causes of hypertonicity and the mechanisms underlying it may be different, and therefore the treatment of spasticity requires differentiated approaches to treatment.
The use of tizanidine (Sirdalud) is most widely used in the treatment of spasticity in traumatic injuries of the brain and spinal cord, multiple sclerosis, and stroke. With spasticity associated with dystonic disorders, parkinsonism, it is more appropriate to use other drugs (for example, clonazepam, diazepam).
Spasticity leads to significant functional disorders and impaired quality of life of the patient. However, it should be remembered that spasticity itself does not always require treatment. For example, in some patients with severe paresis, the presence of spasticity in the muscles that anatomically oppose gravity (anti-gravity muscles) can make standing and walking easier. In addition, the presence of increased muscle tone can prevent the development of muscle atrophy, soft tissue edema and osteoporosis, as well as reduce the risk of thrombosis of the lower extremities. Indications for the treatment of spasticity are only those cases when, due to increased tone, the “functioning, positioning or comfort” of the patient is disturbed.
The use of tizanidine (Sirdalud) in stroke. In stroke, the main objectives of treatment are not only to reduce the severity of spasticity, but also to improve the functionality of paretic limbs, reduce pain and discomfort associated with high muscle tone, and facilitate care for a paralyzed patient.
The most effective means in the fight against spasticity are exercise therapy and physiotherapy, especially at an early stage. In cases where patients with post-stroke limb paresis have local spasticity, local administration of botulinum toxin preparations can be used. A significant contribution to the treatment of spasticity can be made by the use of anti-spastic drugs (muscle relaxants) for oral administration. The use of muscle relaxants can reduce muscle tone, improve motor functions, facilitate the care of an immobilized patient, relieve painful muscle spasms, enhance the effect of physical therapy and, as a result, prevent the development of contractures. In our country, tizanidine, baclofen, tolperisone, diazepam are used to treat post-stroke spasticity.
An analysis of 20 studies comparing the use of various antispastic agents in a variety of neurological diseases accompanied by spasticity showed that tizanidine, baclofen and diazepam are approximately equally able to reduce spasticity, but tizanidine (Sirdalud) is more effective than other antispastic agents in reducing clonus [14] . Unlike baclofen, tizanidin (Sirdalud) does not cause a decrease in muscle strength with a decrease in spasticity (which is very important for improving the functionality of the limb), it is better tolerated by patients than baclofen and diazepam (when using it, patients are less likely to stop treatment due to side effects) [14,15,20]. Among the side effects identified during the study of tizanidine in patients with post-stroke spasticity, conducted by Gelber (2001), the most common side effects were drowsiness, weakness, dizziness, dry mouth, orthostatic hypotension. These phenomena took place with the abolition or reduction of the dose of the drug. At the same time, no serious side effects were noted during treatment with tizanidine [Gelber, 2001], which allowed the authors to conclude that it is highly safe.
Authors who have conducted studies on the clinical effects of tizanidine (Sirdalud) and many clinicians agree that among muscle relaxants, tizanidine (Sirdalud) is the drug of first choice for the treatment of post-stroke spasticity [7,12,14,15,20].
For the treatment of spasticity due to neurological diseases, higher doses of tizanidine (Sirdalud) are usually used than for the treatment of pain syndromes. Usually the optimal therapeutic effect is achieved with a daily dose of 12 to 24 mg (effective dose range is 2-36 mg). However, given the dose-dependent increase in the risk of side effects with increasing doses of the drug, treatment should be started with small (2–6 mg / day) doses, then gradually increase the dose until a therapeutic effect is achieved, observing individual tolerance (usually 2– 4 mg every 3–7 days divided into 3 doses per day). If side effects occur, you can temporarily stop increasing the dose (if you do not increase the dose, in many cases the side effects disappear after a few days) and continue increasing the dose after the patient gets used to the drug. This allows, firstly, to select the most effective minimum dose of the drug for a particular patient (in some patients (due to individual variability), a sufficient therapeutic effect may occur when taking smaller doses than recommended standards), as well as to relieve unnecessary suffering of patients with individual poor tolerance to tizanidine (in patients with poor tolerance to tizanidine, side effects appear already at a dose of 2-4 mg / day). Dose titration usually takes 2-4 weeks. The duration of treatment is set individually (from several weeks to several months) [8].
The use of prolonged forms of tizanidine (Sirdalud MR). For long-term use, a dosage form of tizanidine in the form of modified-release capsules (Sirdalud MR), which is available in a dose of 6 mg, is convenient. Clinical experience shows that for most patients the optimal dose is 12 mg / day. (2 capsules), in rare cases, it may be necessary to increase the daily dose to 24 mg. Treatment also begins with a minimum dose of 6 mg (1 capsule), if necessary, gradually increasing the dose by 6 mg (1 capsule) at intervals of 3-7 days.
The use of tizanidine (Sirdalud) in traumatic brain injury. Among muscle relaxants, tizanidine (Sirdalud) is the most commonly used drug for the treatment of spasticity associated with traumatic brain injury [5]. The reasons for prescribing, dose selection tactics and warnings are the same as in the treatment of post-stroke spasticity.
The use of tizanidine (Sirdalud) in multiple sclerosis and spinal injury. Restriction of mobility in patients with multiple sclerosis is associated with a significant increase in spastic muscle tone, mainly in the lower extremities. The basis of the treatment of muscle tone disorders are special exercises that should be performed under the supervision of a specialist in physical therapy. Drug therapy plays a complementary role. Among the drugs used to treat spasticity are tolperisone, baclofen, tizanidine, diazepam. Drug treatment of spastic tone should be individual, controlled by the doctor and the patient himself. This is because most anti-tonus drugs increase the weakness of the paralyzed limbs and may worsen the patient’s condition. In this regard, the dose of the antispastic drug should be gradually increased from the minimum to the optimum, when spasticity decreases, but there is no increase in weakness. Sirdalud in this regard is more preferable than baclofen and diazepam (when using tizanidine (Sirdalud), muscle weakness develops less often; due to excessive relaxation of the sphincters of the bladder when using baclofen, patients often complain of an increase in pelvic disorders; the use of diazepam is associated with a greater frequency development of side effects, drug dependence) [3,17]. Sirdalud is more effective than other muscle relaxants against clonuses [14].
The optimal daily dose of Sirdalud for the treatment of spasticity in multiple sclerosis is 6–8 mg (maximum daily dose is 36 mg). It is also necessary to start treatment with the minimum dose, the step of increasing the dose is 2 mg [3].
In patients with spasticity due to spinal injury, tizanidine (Sirdalud) and baclofen are most commonly used, and diazepam is used to relieve painful muscle spasms. Treatment begins with a minimum dose (4-6 mg Sirdalud), which is gradually brought to a therapeutic dose over several days or weeks, trying to avoid unwanted side effects (muscle weakness and sedation). Baclofen is effective mainly when administered intrathecally; when administered orally, tizanidine (Sirdalud) gives a more pronounced positive effect and is better tolerated by patients than baclofen [18].
For other types of spasticity encountered in neurological practice (with parkinsonism, torsion dystonia, torticollis, ALS), the use of tizanidine (Sirdalud) is not justified. In these cases, the use of clonazepam and diazepam is more appropriate. These drugs have a higher likelihood of side effects, but their antispasmodic effect is more pronounced in these disorders.
Treatment Optimization
when using tizanidine
(Sirdaluda)
A sufficiently wide range of effective doses of tizanidine (Sirdalud) (from 2 to 36 mg / day) allows the use of the drug for short and long courses of treatment of pain syndromes and spasticity as monotherapy or in combination with other drugs. To improve clinical performance, the following recommendations for the practical use of tizanidine (Sirdalud) may be helpful.
Start treatment with small doses of the drug. The development of side effects with the use of tizanidine (Sirdalud) is dose-dependent (for example, the likelihood of side effects with a dose of 12-24 mg is 2 times higher than with a dose of 6-12 mg). At the same time, a sufficient therapeutic effect can sometimes be achieved at lower doses than recommended in the treatment standards. In this regard, it is recommended to start treatment with a minimum dose (2-4 mg), then gradually increase it, observing individual tolerance.
Gradual withdrawal of the drug. After prolonged use of tizanidine (Sirdalud), especially in large doses, it is necessary to gradually discontinue the drug, because. abrupt withdrawal can cause the development of muscle weakness (this is also characteristic of other muscle relaxants).
The use of tizanidine (Sirdalud) to normalize sleep
Side effects of tizanidine (Sirdalud) include increased drowsiness. Therefore, patients who experience drowsiness while taking tizanidine (Sirdalud) should avoid all activities that require increased concentration and responsiveness. At the same time, many patients, especially those with chronic pain syndromes, have disturbed sleep. This side effect of tizanidine (Sirdalud) can be used therapeutically by prescribing the drug at night to improve the patient’s sleep. Given that the effect of tizanidine (Sirdalud) is short-lived, some doctors, in order to maintain the patient’s social activity, prescribe the drug only at night or distribute the main daily dose of the drug in the afternoon and at night. This allows the patient to maintain social activity in the morning (work, drive a car), and in the evening helps to fall asleep, as well as “sleep” other side effects.
Use of tizanidine (Sirdalud) as an antihypertensive
funds
One of the side effects when using tizanidine (Sirdalud) is a moderate decrease in blood pressure. Simultaneous use with antihypertensive agents may enhance the antihypertensive effect. If long-term use of tizanidine (Sirdalud) is necessary (for example, in the treatment of post-stroke spasticity), the hypotensive effect of tizanidine (Sirdalud) can be used to reduce the dose or stop taking blood pressure-lowering drugs if the patient is receiving antihypertensive therapy.
Conclusion
Tizanidine is an effective drug both in the treatment of spasticity in a number of neurological disorders, and for the treatment of a wide range of pain syndromes associated with increased muscle tone. However, the success of the treatment in each particular case depends not only on the correct choice of a particular drug in terms of the symptoms described in the instructions for use and evidence-based studies on the effectiveness of the drug, but also on how the attending physician manages to correlate the features of pharmacokinetic properties of the drug with individual clinical manifestations of the disease in this (specific) patient.

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