View source for Tizanidine

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{{SummarySheet}}
{{SubstanceBox/Tizanidine}}

'''Tizanidine''' (known by the trade names '''Zanaflex''' and '''Trinex''' among others) is a [[depressant]] substance of the [[chemical class::arylaminoimidazoline]] class closely related to [[clonidine]]. Tizanidine is primarily used primarily as an antispasmodic drug. Tizanidine's effectivness is similar to that of [[baclofen]] or [[diazepam]] <ref> 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;53(3):435-52. doi: 10.2165/00003495-199753030-00007. PMID: 9074844. </ref>.

Tizanidine is a central α<sub>2</sub> adrenergic agonist. The relationship between the α<sub>2</sub> receptor agonism and the spasmolytic function of tizanidine is not fully understood <ref> Katzung, Bertram G. (30 November 2017). Basic & clinical pharmacology. Katzung, Bertram G. (Fourteenth ed.). New York. p. 487. ISBN 9781259641152. OCLC 1015240036 </ref> .

While recreational use is extremely rare, some users take tizanidine for its standalone sedative effects or to potentiate the effects of [[opiates]] <ref> FDA. (2013, October 4) Highlights of Prescribing Information. ZANAFLEX. Retrieved https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/021447s011_020397s026lbl.pdf  </ref> <ref> DrugsDetails. (n.d.). Tizanidine recreational use. from https://drugsdetails.com/tizanidine-recreational-use/ </ref> <ref> Healthline. (n.d.). Tizanidine: Side Effects, Dosage, Uses, and More. from https://www.healthline.com/health/tizanidine-oral-tablet </ref> <ref> MedlinePlus.gov. (n.d.). Tizanidine: MedlinePlus Drug Information. from https://medlineplus.gov/druginfo/meds/a601121.html </ref> <ref> WebMD. (n.d.). MS Muscle Spasticity: How To Manage Muscle Spasms & Tightness. from https://www.webmd.com/multiple-sclerosis/controlling-muscle-spasms-multiple-sclerosis#1 </ref> <ref> National Institute on Drug Abuse. (2020, June 16). The Science of Drug Use: Discussion Points. from https://www.drugabuse.gov/drug-topics/criminal-justice/science-drug-use-discussion-points </ref> . In higher doses, tizanidine is capable of inducing [[hallucinations]], [[psychosis]], and [[delirium]] <ref>  pmhdev. [https://web.archive.org/web/20121111213511/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000106/ Tizanidine]. PubMed Health. Archived from [https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000106/ the original] on 11 November 2012. </ref> <ref> Suárez-Lledó A, Padullés A, Lozano T, Cobo-Sacristán S, Colls M, Jódar R. Management of Tizanidine Withdrawal Syndrome: A Case Report. Clin Med Insights Case Rep. 2018;11:1179547618758022. Published 2018 Feb 13. doi:10.1177/1179547618758022 </ref> <ref> Karol DE, Muzyk AJ, Preud'homme XA. A case of delirium, motor disturbances, and autonomic dysfunction due to baclofen and tizanidine withdrawal: a review of the literature. Gen Hosp Psychiatry. 2011 Jan-Feb;33(1):84.e1-2. doi: 10.1016/j.genhosppsych.2010.10.003. Epub 2010 Nov 13. PMID: 21353141. </ref> <ref> Fick, Donna, et al. "American Geriatrics Society updated Beers Criteria for potentially inappropriate medication use in older adults."
Journal of the American Geriatrics Society 60.4 (2012): 616-631. </ref>.

==Chemistry==
Tizanidine is 2,1,3-Benzothiadiazole substituted at C-4 by a Delta(1)-imidazolin-2-ylamino group and at C-4 by a chloro group. It is an agonist at α<sub>2</sub>-adrenergic receptor sites. It is a benzothiadiazole and a member of imidazoles<ref>National Center for Biotechnology Information. "PubChem Compound Summary for CID 5487, Tizanidine" PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/Tizanidine. </ref>.

==Pharmacology==
Tizanidine is an [[imidazoline]] derivative and centrally acting α<sub>2</sub> [[adrenergic]] [[agonist]] closely related to Clonidine. Tizanidine inhibits the release of excitatory amino acids from spinal interneurons. As a result, Tizanidine enhances the presynaptic inhibition of motor neurons <ref> Ghanavatian S, Derian A. Tizanidine. [Updated 2021 Aug 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519505/ </ref>. 

Tizanidine also has some affinity for the α<sub>1</sub> receptors, but to a lesser than Clonidine, which may explain why its cardiovascular effects are so much milder than that of Clonidine<ref> Ghanavatian S, Derian A. Tizanidine. [Updated 2021 Aug 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519505/ </ref>. Tizanidine has approximately one tenth to one fifteenth of the blood pressure lowering effect of clonidine <ref> Katzung, Bertram G. (30 November 2017). Basic & clinical pharmacology. Katzung, Bertram G. (Fourteenth ed.). New York. p. 487. ISBN 9781259641152. OCLC 1015240036 </ref> .

Tizanidine has also been found to have [[anticonvulsant]] effects against strychnine-induced seizures but not against [[GABA]]-induced seizures. The α<sub>2</sub> receptor mediated inhibition of inter-neuronal activity appears to be the cause of Tizanidine's anti-convulsant properties <ref> Denizbaşi A, Berkman K, Ozyazgan S, Eşkazan E. The effect of tizanidine on maximal electroshock seizures (MES) in mice. Gen Pharmacol. 1999 Apr;32(4):513-6. doi: 10.1016/s0306-3623(98)00249-3. Erratum in: Gen Pharmacol 2000 Jun;34(6):443. PMID: 10323494. </ref> <ref> Amabeoku G, Chandomba R. Strychnine-induced seizures in mice: the role of noradrenaline. Prog Neuropsychopharmacol Biol Psychiatry. 1994 Jul;18(4):753-63. doi: 10.1016/0278-5846(94)90082-5. PMID: 7938564. </ref>.

Tizanidine has an oral bioavailability of 20-34% and an elimination half-life of 2.5 hours. It attains steady-state concentration within 24-48 hours after administration <ref>Ghanavatian S, Derian A. Tizanidine. [Updated 2021 Aug 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519505/ </ref>

The table below compares the selectivity of Tizanidine and other drugs to the imidzaoline-receptor and the α<sub>2</sub> receptors in rats. Tizanidine has a significantly greater selectivity to the imidazoline receptor than clonidine. The imidazoline receptor selectivity of tizanidine may be responsible for its unique pharmacological profile<ref>Muramatsu I, Kigoshi S. Tizanidine may discriminate between imidazoline-receptors and alpha 2-adrenoceptors. Jpn J Pharmacol. 1992 Aug;59(4):457-9. doi: 10.1254/jjp.59.457. PMID: 1331591.. Retrieved from https://pubmed.ncbi.nlm.nih.gov/1331591/ </ref>.

{| class="wikitable"
|-
! Drug
! Imidazoline receptors Ki (nM)
! α<sub>2</sub> Receptors Ki (nM)
|-
| Tizanidine
| 4.17 ± 1.81
| 91.5 ± 9.1
|-
| Clonidine
| 9.20 ± 1.23
| 9.20 ± 1.23
|-
| Oxymethazoline
| 2.28 ± 0.36
| 25.9 ± 5.5
|-
| Naphazoline
| 309 ± 26
| 25.9 ± 5.5
|-
| Adrenaline
| > 10000
| 3.18 ± 0.41
|-
|}

==Subjective effects==
{{Preamble/SubjectiveEffects}}
{{effects/base

|{{effects/physical|


*'''[[Effect::Seizure suppression]]''' - Tizanidine has been found to suppress strycnine induced seizures, but not GABA induced seizures.
*'''[[Effect::Sedation]]''' - Tizanidine can produce a strong sedative effect. Users can become very tired and sleep through stimuli that would otherwise wake them.
*'''[[Effect::Pain relief]]'''
*'''[[Effect::Muscle relaxation]]'''
*'''[[Effect::Physical euphoria]]''' - This effect is very mild and may not be pronounced at all in some users.
*'''[[Effect::Spontaneous bodily sensations]]''' - It only occurs at higher doses as a result of low blood pressure and mostly at lips. 
*'''[[Effect::Perception of bodily heaviness]]'''
*'''[[Effect::Decreased blood pressure]]''' 
*'''[[Effect::Decreased heart rate]]'''
*'''[[Effect::Abnormal heartbeat]]'''
*'''[[Effect::Dizziness]]''' - Because of the cardiovascular effects of Tizanidine, users can become dizzy or lightheaded.
*'''[[Effect::Headache]]''' - When taking excessive doses, headaches are a common side effect.
*'''[[Effect::Watery eyes]]'''
*'''[[Effect::Physical fatigue]]'''
*'''[[Effect::Pupil constriction]]'''
*'''[[Effect::Dry mouth]]'''
}}

{{effects/visual|
*'''[[Effect::Acuity suppression]]''' - This effect typically presents itself at higher doses.

====Distortions====
*'''[[Effect::Environmental patterning]]'''
*'''[[Effect::Visual haze]]'''
*'''[[Effect::Drifting]]'''

====[[Effect::Geometry]]====
At high doses, geometry can be observed likely due to experiencing low blood pressure and circulation to the brain. The geometry is distinct from psychedelic and dissociative drugs. It can be described as intricate in complexity, abstract in form, synthetic in feel, unstructured in organization, dimly lit, multicolored in scheme, flat in shading, soft in edges, smooth in motion, slow in speed, small in size, angular in corners, non-immersive in depth, and consistent in intensity.

The geometry of Tizanidine never exceeds level 4. The doses required to observe such geometries can induce dangerously low blood pressures and cause one to lose consciousness <ref> Miyakawa T, Shikai I. Hallucinatory and delusional states in connection with blood pressure and EEG. Folia Psychiatr Neurol Jpn. 1979;33(1):9-13. doi: 10.1111/j.1440-1819.1979.tb00168.x. PMID: 456959. </ref>. Users should exercise caution when taking hallucinogenic doses, as the threshold for hallucinations is not far from the threshold for psychosis in many users <ref> Ghanavatian S, Derian A. Tizanidine. [Updated 2021 Aug 13]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519505/ </ref>.

====Hallucinatory states====
In higher doses, Tizanidine is capable of inducing a delirious state.

*'''[[Effect::Scenarios and plots]]'''
}}

|{{effects/cognitive|
*'''[[Effect::Cognitive fatigue]]'''
*'''[[Effect::Dream potentiation]]''' - Some users of tizanidine notice strange or increasingly vivid dreams after continuous use of tizanidine.
*'''[[Effect::Focus suppression]]''' 
*'''[[Effect::Anxiety suppression]]''' 
*'''[[Effect::Memory suppression]]''' - This effect occurs at higher doses
*'''[[Effect::Thought deceleration]]'''
*'''[[Effect::Delirium]]''' - At extremely high doses, delirium can be induced.
*'''[[Effect::Sleepiness]]''' - This is the most prevalent cognitive effect of Tizanidine
}}

{{effects/aftereffects|
*'''[[Effect::Increased heart rate]]''' - This occurs as a rebound effect to tizanidine's cardiovascular effects and typically presents itself after prolonged use.
*'''[[Effect::Increased blood pressure]]''' - This occurs as a rebound effect to tizanidine's cardiovascular effects and typically presents itself after prolonged use.
*'''[[Effect::Irritability]]'''
*'''[[Effect::Soreness]]''' - After the effects of tizanidine wear off, muscles that weren't sore before using the drug can become sore with more ease. For most users, this first presents itself as an increased soreness in the neck.
}}

}}
===Experience reports===
There are currently {{#ask:[[Category:SUBSTANCE]][[Category:Experience]] | format=count}} experience reports which describe the effects of this substance in our [[experience index]].
{{#ask: [[Category:SUBSTANCE]][[Category:Experience]]|format=ul|Columns=1}}
Additional experience reports can be found here:
* [https://erowid.org/experiences/subs/exp_Tizanidine.shtml Erowid Experience Vaults: Tizanidine] <!-- Check the link to see if it exists -->

==Toxicity and harm potential==
{{toxicity}}
It is strongly recommended that one use [[responsible use|harm reduction practices]] when using this substance.

While no long term studies of tizanidine use in humans have been done, studies done in animals indicate no signs of long term carcinogenicity. However, tizanidine has been shown to have a developmental effect on young rats<ref> https://www.drugbank.ca/drugs/DB00697 </ref>.

Some long term tizanidine use has been attributed to liver problems and in extreme cases, liver failure and death<ref> Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Tizanidine. [Updated 2017 Jan 30]. Available from: https://www.ncbi.nlm.nih.gov/books/NBK548048/ </ref>. 
===Lethal dosage===
The [[LD50]] of oral tizanidine in rats was found to be 414mg/kg in rats and 235 mg/kg in mice<ref> https://www.drugbank.ca/drugs/DB00697 </ref>.

In some cases, Tizanidine overdose can be reversed with naloxone; however, this is not the case with everyone <ref> Bader D, Adam A, Shaban M, Alyahya B. Pediatric tizanidine toxicity reversed with naloxone: a case report. Int J Emerg Med. 2021 Dec 14;14(1):73. doi: 10.1186/s12245-021-00397-y. PMID: 34906071; PMCID: PMC8903539. </ref> <ref> Spiller HA, Bosse GM, Adamson LA. Retrospective review of Tizanidine (Zanaflex) overdose. J Toxicol Clin Toxicol. 2004;42(5):593-6. doi: 10.1081/clt-200026978. PMID: 15462150. </ref>.

===Tolerance and addiction potential===
While dependence is rare, use of Tizanidine exceeding 36mg daily over an extended period of time can lead to hypertensive withdrawals. In cases where dependence has been built, a user should taper to avoid a hypertensive crisis<ref> "Tizanidine Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019. </ref>.
===Dangerous interactions===
{{DangerousInteractions/Intro}}
{{DangerousInteractions/Depressants}}

==Legal status==
{{LegalStub}}
* '''Austria:''' Tizanidine is available by prescription only.
* '''Turkey:''' Tizanidine is available in pharmacies without prescription.
* '''United States:''' Tizanidine is available by prescription only.
* '''United Kingdom:''' Tizanidine is available by prescription only.

==See also==
*[[Responsible use]]
*[[Depressant]]
*[[Baclofen]]
*[[Clonidine]]
*[[Adrenaline]]

==External links==
*[https://en.wikipedia.org/wiki/Tizanidine Tizanidine (Wikipedia)]
*[https://isomerdesign.com/pihkal/explore/15021 Tizanidine (IsomerDesign)]
*[https://erowid.org/experiences/subs/exp_Tizanidine.shtml Tizanidine (Erowid Vault)]
*[https://go.drugbank.com/drugs/DB00697 Tizanidine (DrugBank)]

==References==
<references />

[[Category:Psychoactive substance]]
[[Category:Arylaminoimidazoline]]
[[Category:Depressant]]