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Tizanidine

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Tizanidine
Clinical data
Pronunciation/taɪˈzænɪdiːn/ tye-ZAN-i-deen
Trade namesZanaflex, Sirdalud, and others
Other namesAN-021; DS 103-282
AHFS/Drugs.comMonograph
MedlinePlusa601121
License data
Routes of
administration		Oral (tablets, capsules)[1]
Drug classα2-Adrenergic receptor agonist; Muscle relaxant; Sedative; Hypnotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability~40%[2][1]
Protein binding~30%[1]
MetabolismExtensive (>95%), primarily via CYP1A2[1]
Elimination half-lifeTizanidine: 2.5 hours[2][1]
Inactive metabolites: 20–40 hours[2][1]
ExcretionUrine (60%), feces (20%)[1]
Identifiers
  • 5-chloro-N-(4,5-dihydro-1H-imidazol-2-yl)benzo[c][1,2,5]thiadiazol-4-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.125.400 Edit this at Wikidata
Chemical and physical data
FormulaC9H8ClN5S
Molar mass253.71 g·mol−1
3D model (JSmol)
  • Clc1ccc3nsnc3c1NC/2=N/CCN\2
  • InChI=1S/C9H8ClN5S/c10-5-1-2-6-8(15-16-14-6)7(5)13-9-11-3-4-12-9/h1-2H,3-4H2,(H2,11,12,13) checkY
  • Key:XFYDIVBRZNQMJC-UHFFFAOYSA-N checkY
  (verify)

Tizanidine, sold under the brand names Zanaflex and Sirdalud among others, is an α2-adrenergic receptor agonist and muscle relaxant which is used to treat muscle spasticity due to spinal cord injury, multiple sclerosis, and spastic cerebral palsy.[1][3][4] Its effectiveness appears to be similar to that of other muscle relaxants like baclofen or diazepam.[5] The drug is taken orally.[6][1]

Common side effects of tizanidine include sleepiness, dry mouth, asthenia, dizziness, low blood pressure, and low heart rate.[6][1] Serious side effects may include dangerously low blood pressure, liver problems, and psychosis.[6][1] It is unclear if use in pregnancy and breastfeeding is safe.[7] The drug is an α2-adrenergic receptor agonist, but how it works is not entirely clear.[6]

Tizanidine was approved for medical use in the United States in 1996.[6] It is available as a generic medication.[3] In 2023, it was the 81st most commonly prescribed medication in the United States, with more than 8 million prescriptions.[8][9]

Medical uses

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Muscle spasticity

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Tizanidine is approved and used as a muscle relaxant to treat muscle spasticity.[1] It has been found to be as effective as other muscle relaxants and is more tolerable than baclofen and diazepam.[5] Due to its short elimination half-life and duration, tizanidine is generally taken once every 6 to 8 hours as needed, with a maximum of 3 doses per 24 hours.[1]

Other uses

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Tizanidine may be used off-label in the treatment of insomnia and for certain other uses.[10][11][12][13]

Available forms

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Tizanidine is available in the form of oral tablets and capsules.[1]

Contraindications

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Contraindications of tizanidine include concomitant use with strong CYP1A2 inhibitors and known hypersensitivity to tizanidine or its excipients.[1] Tizanidine is contraindicated with strong CYP1A2 inhibitors as these drugs profoundly increase tizanidine levels.[1] Warnings and precautions for tizanidine include hypotension, liver injury, sedation, and hallucinations and psychotic-like symptoms.[1]

Side effects

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The most common side effects of tizanidine (>10%) include somnolence, dry mouth, asthenia (including weakness, fatigue, and/or tiredness), dizziness, hypotension, and bradycardia.[1] At doses of 8 to 16 mg, the rates of these side effects were 78–92% for somnolence, 76–88% for dry mouth, 67–78% for asthenia, 22–45% for dizziness, 16–33% for hypotension, and 2–10% for bradycardia.[1] Additional side effects of tizanidine may include drowsiness, nervousness, confusion, hallucinations, strange dreams, depression, vomiting, constipation, diarrhea, stomach pain, heartburn, increased muscle spasms, back pain, rash, sweating, and tingling sensations in the arms, legs, hands, and feet.[14]

Tizanidine can cause withdrawal symptoms upon abrupt discontinuation and should be gradually tapered to avoid and minimize such symptoms.[1] Withdrawal symptoms include rebound hypertension, tachycardia, hypertonia, tremor, and anxiety.[1]

Overdose

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Symptoms of overdose with tizanidine have been reported to include lethargy, somnolence, bradycardia, hypotension, respiratory depression, agitation, confusion, vomiting, and coma.[15][1]

Interactions

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Concomitant use of tizanidine and moderate or potent CYP1A2 inhibitors (such as zileuton, certain antiarrhythmics (amiodarone, mexiletine, propafenone, verapamil), cimetidine, famotidine, aciclovir, ticlopidine and oral contraceptives) is contraindicated. Concomitant use of tizanidine with fluvoxamine, a potent CYP1A2 inhibitor in humans, resulted in a 33-fold increase in the tizanidine AUC (plasma drug concentration-time curve).[2] For this reason fluvoxamine and tizanidine should not be taken at the same time. Fluoroquinolone antibiotics such as moxifloxacin, levofloxacin, and ciprofloxacin should also be avoided due to an increased serum concentration of tizanidine when administered concomitantly.[16]

Tizanidine has the potential to interact with other central nervous system depressants.[1] Alcohol should be avoided, particularly as it can upset the stomach. The CNS-depressant effects of tizanidine and alcohol are additive.[2]

Caution with the following interactions:[17][18][19]

Pharmacology

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Pharmacodynamics

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Site Ki (nM) Species Ref
α2A 62 Human [20]
α2B 75 OK [20]
α2C 76 Rat [20]

Tizanidine is an α2-adrenergic receptor agonist and is closely related to clonidine. It has approximately one-tenth to one-fifteenth of the blood pressure-lowering effect or potency of clonidine. The relation between the α2-adrenergic receptor agonism and spasmolytic action of tizanidine is still not fully understood.[4]

Pharmacokinetics

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Absorption

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Tizanidine is essentially completely absorbed with oral administration.[1] The oral bioavailability of tizanidine is approximately 40%.[1] It is subject to extensive first-pass metabolism and this is responsible for its incomplete bioavailability.[1] The pharmacokinetics of tizanidine are linear across a dose range of 1 to 20 mg.[1] The time to peak levels with tizanidine under fasting conditions is 1 hour and under fed conditions is 1.5 to 3 hours.[1] The pharmacokinetics of tizanidine with oral tablet and capsule formulations are the same under fasting conditions but diverge and are non-equivalent under fed conditions.[1] The pharmacokinetics of tizanidine also change when capsules are opened and it is sprinkled onto applesauce versus intact capsules.[1][21]

Distribution

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Tizanidine is extensively distributed throughout the body.[1][2] Its volume of distribution is 2.4 L/kg following intravenous injection.[1] The drug's plasma protein binding is approximately 30%.[1]

Metabolism

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More than 95% of a dose of tizanidine is metabolized.[1] The primary cytochrome P450 enzyme involved in the metabolism of tizanidine is CYP1A2.[1] Strong CYP3A4 inhibitors such as fluvoxamine and ciprofloxacin can increase tizanidine exposure by 10- to 33-fold, indicating the key involvement of CYP1A2 in the metabolism of the drug.[1] The metabolites of tizanidine are thought to be inactive.[1]

Elimination

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Tizanidine is eliminated 60% in urine and 20% in feces.[1] Its elimination half-life is approximately 2.5 hours.[1] The inactive metabolites of tizanidine have half-lives of 20 to 40 hours.[1]

Chemistry

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Synthesis

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Tizanidine is a derivative of 2,1,3-benzothiadiazole and its first published synthesis was reported in a patent.[22] The 5-chloro-2,1,3-benzothiadiazol-4-amine intermediate was a known compound, produced in three steps from 4-chlorophenylenediamine as shown.[23] Treatment with two equivalents of thionyl chloride in pyridine formed the heterocycle, which was nitrated with sodium nitrate in sulfuric acid and reduced using iron and acetic acid.

The amine intermediate was treated with benzoyl chloride and ammonium thiocyanate followed by alkaline hydrolysis to form a thiourea. This was activated as its isothiuronium salt before being treated with ethylene diamine to give tizanidine.[22][24]

Analogues

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Analogues of tizanidine include clonidine and dexmedetomidine, among others.

History

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Tizanidine was approved for medical use in the United States in 1996.[1]

Society and culture

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Names

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Tizanidine is the generic name of the drug and its INNTooltip International Nonproprietary Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française.[25][26][27] In the case of the hydrochloride salt, its generic name is tizanidine hydrochloride and this is its USANTooltip United States Adopted Name and BANMTooltip British Approved Name.[27] Developmental code names of tizanidine include AN-021 and DS 103-282 and its major brand names include Zanaflex and Sirdalud.[25][26][27][28]

Research

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In addition to muscle spasticity, tizanidine was under development for the treatment of fibromyalgia and migraine, but development for these indications was discontinued.[28] Several other formulations have also been developed for various indications, including spastic paralysis, musculoskeletal pain, and back pain, but likewise have not been marketed.[29][30][31][32][33] An intranasal formulation was in phase 3 clinical trials for back pain as of 2017.[32]

References

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  1. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 "Highlights of prescribing information - ZANAFLEX (tizanidine) capsules, for oral use" (PDF). www.accessdata.fda.gov.
  2. 1 2 3 4 5 6 "Zanaflex (tizanidine hydrochloride) Capsules and Tablets for Oral Use. Full Prescribing Information" (PDF). Acorda Therapeutics Inc. Ardsley, NY 10502. Retrieved 1 September 2016.
  3. 1 2 British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 1094. ISBN 978-0-85711-338-2.
  4. 1 2 Katzung BG (30 November 2017). Basic & clinical pharmacology (14th ed.). New York: McGraw Hill Education. p. 487. ISBN 978-1-259-64115-2. OCLC 1015240036.
  5. 1 2 Kamen L, Henney HR, Runyan JD (February 2008). "A practical overview of tizanidine use for spasticity secondary to multiple sclerosis, stroke, and spinal cord injury". Current Medical Research and Opinion. 24 (2): 425–439. doi:10.1185/030079908X261113. PMID 18167175. S2CID 73086671.
  6. 1 2 3 4 5 "Tizanidine Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
  7. ↑ "Tizanidine Pregnancy and Breastfeeding Warnings". Drugs.com. Retrieved 3 March 2019.
  8. ↑ Kane SP. "Top 300 of 2023". ClinCalc. Archived from the original on 12 August 2025. Retrieved 12 August 2025.
  9. ↑ Kane SP. "Tizanidine Drug Usage Statistics, United States, 2014 - 2023". ClinCalc. Retrieved 18 August 2025.
  10. ↑ Ghanavatian S, Derian A (January 2026). "Tizanidine". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID 30137790. It is also prescribed off-label for migraine headaches, insomnia, and as an anticonvulsant. [...] Off-label Use [...] Refractory insomnia in spastic quadriplegic patients[7] [...] Tanaka H, Fukuda I, Miyamoto A, Oka R, Cho K, Fujieda K. [Effects of tizanidine for refractory sleep disturbance in disabled children with spastic quadriplegia]. No To Hattatsu. 2004 Nov;36(6):455-60. [PubMed]
  11. ↑ Broese M, Riemann D, Hein L, Nissen C (September 2012). "α-Adrenergic receptor function, arousal and sleep: mechanisms and therapeutic implications". Pharmacopsychiatry. 45 (6): 209–216. doi:10.1055/s-0031-1299728. PMID 22290201. Tizanidine is a centrally acting α2 -receptor agonist, structurally related to clonidine. [...] In a study by Tanaka et al. [ 75 ] tizanidine was used in children with spastic quadriplegia to treat refractory sleep disturbances. Tizanidine treatment improved sleep induction and/or maintenance in 61.9 % of the children.
  12. ↑ Tanaka H, Fukuda I, Miyamoto A, Oka R, Cho K, Fujieda K (November 2004). "[Effects of tizanidine for refractory sleep disturbance in disabled children with spastic quadriplegia]". No to Hattatsu = Brain and Development (in Japanese). 36 (6): 455–460. PMID 15560387.
  13. ↑ Smith HS, Barton AE (2000). "Tizanidine in the management of spasticity and musculoskeletal complaints in the palliative care population". The American Journal of Hospice & Palliative Care. 17 (1): 50–58. doi:10.1177/104990910001700111. PMID 11094920. Tizanidine can cause sedation, which is minimized by dose titration. When taken at night, patients report improvement in getting to sleep and little drowsiness or "hangover sensation" upon waking. Tizanidine is potentially helpful to many palliative care patients with chronic muscle pain and sleep disturbances.
  14. ↑ "Tizanidine". PubMed Health. Archived from the original on 11 November 2012. Retrieved 4 September 2017.
  15. ↑ Spiller HA, Bosse GM, Adamson LA (January 2004). "Retrospective review of Tizanidine (Zanaflex) overdose". Journal of Toxicology. Clinical Toxicology. 42 (5): 593–596. doi:10.1081/CLT-200026978. PMID 15462150. S2CID 38946270.
  16. ↑ "Tizanidine Uses, Dosage, Side Effects – Drugs.com". drugs.com. Retrieved 4 September 2017.
  17. ↑ NHS Wales (2011). "Tizanidine (Zanaflex) Gwent Primary Care Prescribing Guidance" (PDF). Aneurin Bevan University Health Board.
  18. ↑ "Tizanidine package leaflet: Information for the user" (PDF). Medicines and Healthcare products Regulatory Agency (UK). 2016. Archived from the original (PDF) on 16 September 2018. Retrieved 16 September 2018.
  19. ↑ "Zanaflex (tizanidine hydrochloride) dose, indications, adverse effects, interactions... from PDR.net". www.pdr.net. 13 April 2023. Retrieved 16 September 2018.
  20. 1 2 3 Blaxall HS, Murphy TJ, Baker JC, Ray C, Bylund DB (October 1991). "Characterization of the alpha-2C adrenergic receptor subtype in the opossum kidney and in the OK cell line". The Journal of Pharmacology and Experimental Therapeutics. 259 (1): 323–329. doi:10.1016/S0022-3565(25)20309-3. PMID 1656026.
  21. ↑ "Tizanidine: MedlinePlus Drug Information". medlineplus.gov. U.S. National Library of Medicine. Retrieved 29 October 2019.
  22. 1 2 US patent 3843668, Neumann P, "Certain 4-substituted amino-2,1,3-benzothiadiozoles", published 22 October 1974, issued 22 October 1974, assigned to Sandoz AG and Sandoz Wander Inc,us
  23. ↑ Pesin VG, Sergeev VA (1969). "Research on 2,1,3-thia- and selenadiazole". Chemistry of Heterocyclic Compounds. 3 (5): 662–666. doi:10.1007/BF00468340. S2CID 98830770.
  24. ↑ "Pharmaceutical Substances: Tizanidine". Thieme. Archived from the original on 16 February 2023. Retrieved 16 February 2023.
  25. 1 2 "Tizanidine". PubChem. Retrieved 10 August 2026.
  26. 1 2 Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. ISBN 978-1-4757-2085-3. Retrieved 10 August 2026.
  27. 1 2 3 Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. ISBN 978-3-88763-075-1. Retrieved 10 August 2026.
  28. 1 2 "Tizanidine". AdisInsight. 16 April 2026. Retrieved 10 August 2026.
  29. ↑ "Tizanidine trandermal patch". AdisInsight. 28 November 2019. Retrieved 10 August 2026.
  30. ↑ "Etoricoxib/tizanidine". AdisInsight. 16 July 2016. Retrieved 10 August 2026.
  31. ↑ "Tizanidine extended release". AdisInsight. 13 July 2022. Retrieved 10 August 2026.
  32. 1 2 "Tizanidine intranasal". AdisInsight. 5 September 2017. Retrieved 10 August 2026.
  33. ↑ "Tizanidine oral spray". AdisInsight. 2 October 2021. Retrieved 10 August 2026.
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