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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Tizanidine

Last Update: January 30, 2017.

OVERVIEW

Introduction

Tizanidine is a commonly used muscle relaxant that has been linked to rare instances of acute liver injury, a few of which have been fatal.

Background

Tizanidine (tye zan' i deen) is an imidazoline derivative and is a centrally acting muscle relaxant used for therapy of acute muscle spasms and chronic spasticity. The mechanism by which tizanidine causes skeletal muscle relaxation is not well known; it appears to act at the level of spinal cord pain reflexes, most likely through activity as a central alpha-adrenergic agonist which results in an decrease in activity of motor neurons. Tizanidine was approved for use in the United States in 1996 and currently several million prescriptions are filled yearly. The current indications are limited to short-term management of spasticity. Tizanidine is available in several generic forms as well as under the brand name of Zanaflex in tablets and capsules of 2, 4 or 6 mg. The recommended dose in adults is 2 to 6 mg orally three to four times daily. Common side effects include tiredness, drowsiness, dizziness, muscular weakness, dry mouth and occasionally hypotension.

Hepatotoxicity

Transient and asymptomatic elevations in serum ALT greater than 3 times the upper limit of normal occur in ~5% of patients taking tizanidine compared to 0.4% of subjects on placebo. Reports of severe hepatotoxicity, acute liver failure and death have been mentioned in review articles on tizanidine, but few case reports have been published. In these reports, the latency to onset of jaundice has ranged from 2 to 14 weeks and the enzyme elevations have been both cholestatic and hepatocellular (Case 1). Immunoallergic and autoimmune features have not been mentioned. Recovery was complete after 1 to 2 months.

Likelihood score: C (Probable rare cause of clinically apparent liver injury).

Mechanism of Injury

The cause of acute hepatic injury from tizanidine is unknown, but is probably idiosyncratic due to hypersensitivity.

Outcome and Management

The idiosyncratic liver injury due to tizanidine ranges from hepatitis with jaundice to acute liver failure leading to death. Chronic injury and vanishing bile duct syndrome have not been reported after tizanidine therapy. Recurrence on re-exposure has been reported and rechallenge should be avoided. No cross reactivity with other muscle relaxants has been identified.

Drug Class: Muscle Relaxants

CASE REPORT

Case 1. Acute hepatocellular injury with jaundice after tizanidine therapy.

[Modified from: de Graaf EM, Oosterveld M, Tjabbes T, Stricker BH. A case of tizanidine-induced hepatic injury. J Hepatol 1996; 25: 772-3. PubMed Citation]

A 55 year old woman with multiple sclerosis and lower limb muscle spasms developed jaundice 4 months after starting tizanidine therapy. The jaundice had been preceded by a 2 week period of progressive fatigue, nausea and poor appetite. She denied a history of liver disease or exposure to hepatitis and did not drink alcohol. Her other medications included baclofen, chlormezanone, diazepam, flurazepam, dexchlorpheniramine and diclofenac, all of which she had been taking chronically. On examination, she was deeply jaundiced and somnolent. She had no signs of chronic liver disease and did not have rash or fever. Laboratory testing showed a total bilirubin of 26.5 mg/dL and marked elevations in serum aminotransferase levels with minimal increase in alkaline phosphatase (Table). Tests for hepatitis A, B and C were negative as were autoantibodies (smooth muscle antibody was marginally positive). An abdominal ultrasound showed no evidence of biliary obstruction. Tizanidine had been discontinued 2 weeks before admission, but she worsened during the next several weeks, but then began a spontaneous recovery which was complete 2 months later. Several months later, the patient was inadvertently rechallenged with a single 4 mg dose of tizanidine and within 6 days the ALT levels had increased from 14 to 155 U/L. Tizanidine was discontinued again, and one week later serum ALT levels had returned to normal.

Key Points

Medication:Tizanidine 36 mg daily
Pattern:Hepatocellular (R=15)
Severity:4+ (jaundice, hospitalization, mild hepatic failure)
Latency:14 weeks to onset of symptoms
Recovery:Complete recovery 2 months after stopping
Other medications:Baclofen, diclofenac, chlormezanone, diazepam, flurazepam, dexchlorpheniramine

Laboratory Values

Time After StartingTime After StoppingALT (U/L)Alk P (U/L)Bilirubin* (mg/dL)Other
0Tizanidine started
2 days0NormalNormalNormal
16 days0Tizanidine stopped
18 days2 days83018726.5Admission. INR=1.6
22 days8 days27036.0
24 days10 days6030.0
26 days12 days304.0
30 days16 days141.0Single dose of tizanidine
31 (1)** days17 (1) days1551.0
32 (2) days18 (2) days301.0
Normal Values<30<100<1.2

* Bilirubin levels converted from μmol/L. Some values were estimated from Figure 1.

** Values in parentheses are the number of days after rechallenge

Comment

The onset of hepatic injury after 4 months of therapy, the improvement with stopping treatment, and the accelerated recurrence of hepatic injury with restarting tizanidine make it highly likely that the hepatitis was due to tizanidine induced liver injury. The pattern of injury was distinctly hepatocellular. Diclofenac can also cause similar hepatocellular injury, but the other features and particularly the rechallenge argue in support of tinazidine as the cause. The rapidity of recurrence on reexposure suggests that the hepatic injury was due to hypersensitivity. The muscle relaxants are a diverse group of medications and share little in structure or mechanisms of action, so that cross sensitivity to hepatic injury should not be a problem. This patient was restarted on baclofen and a benzodiazepam without complication.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Tizanidine – Generic, Zanaflex®

DRUG CLASS

Autonomic Agents: Muscle Relaxants, Central

COMPLETE LABELING

Product Labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NOMOLECULAR FORMULASTRUCTURE
Tizanidine51322-75-9C9-H8-Cl-N5-S
Tizanidine chemical structure

ANNOTATED BIBLIOGRAPHY

References updated: January 30, 2017

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    (Expert review of hepatotoxicity published in 1999; discusses dantrolene, chlorzoxazone and baclofen, but not tizanidine).
  • Hibbs RE, Zambon AC. Agents acting at the neuromuscular junction and autonomic ganglia. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s The pharmacological basis of therapeutics, 12th ed. New York: McGraw-Hill, 2011. p. 255-76. (Textbook of pharmacology and therapeutics).
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    (Among 112 patients in a placebo controlled trial [59 treated with tizanidine], no hepatic adverse events reported).
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    (Placebo controlled trial of tizanidine with ibuprofen for 7 days in patients with low back pain; no hepatic adverse events reported in 51 tizanidine treated patients).
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    (Randomized controlled trial of tizanidine versus diazepam for 8 weeks in 105 patients with spasticity; there were no changes in “biochemical parameters” during the study).
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    (55 year old woman developed jaundice 14 weeks after starting tizanidine [bilirubin 26.5 mg/dL, ALT 830 U/L, Alk P 187 U/L], resovling within 6 weeks; recurrence of ALT elevations after reexposure to a single tablet: Case 1).
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    (73 year old man received tizanidine for spasticity after ischemic stroke, developed malaise and jaundice 17 days later [bilirubin 7.2 mg/dL, ALT 616 U/L, Alk P 2810 U/L], resolving within 3 weeks of stopping).
  • Saper JR, Winner PK, Lake AE 3rd. An open-label dose-titration study of the efficacy and tolerability of tizanidine hydrochloride tablets in the prophylaxis of chronic daily headache. Headache 2001; 41: 357-68. [PubMed: 11318882]
    (Among 39 patients with frequent headaches treated for 12 weeks with tizanidine, one developed elevated ALT levels [320 U/L] without jaundice or symptoms, which resolved on stopping the drug).
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    (Among ~50,000 liver transplants done in the US between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, but none were attributed to tizanidine or other muscle relaxants).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, one was attributed to chlorzoxazone, but none to tizanidine or other muscle relaxants).
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    (Summary of tizanidine adverse events in children from off-label use with major focus on somnolence, enuresis and anxiety; ALT elevations mentioned, but they were mild and largely attributed to concurrent anticonvulsant therapy).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation . [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were due to tizanidine or other muscle relaxants).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver iInjury in the General population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to tizanidine or other muscle relaxants).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases; one case was attributed to verapamil, but none were linked to amlodipine or other calcium channel blockers).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-1352.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 5 [0.7%] were attributed to muscle relaxants, including one to trizanidine: 51 year old man developed jaundice 5 weeks after starting tizanidine [bilirubin peak 4.8 mg/dL, ALT 2387 U/L, Alk P 150 U/L, ANA 1:160] and recovered within 2 months of stopping).

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