Journal of Pharmacology and Clinical Toxicology

Tizanidine Toxicity Requiring High Dose Naloxone Infusion: A Case Report and Review of the Current Literature

Case Report | Open Access | Volume 11 | Issue 1

  • 1. Northwell Department of Emergency Medicine, North Shore University Hospital, USA
  • 2. Northwell Department of Medical Toxicology, North Shore University Hospital, USA
+ Show More - Show Less
Corresponding Authors
Heuser William, Northwell Department of Emergency Medicine, North Shore University Hospital, USA

Tizanidine is a centrally acting imidazoline derivative with a novel mechanism of action, closely resembling clonidine in its structure and pharmacological mechanism. Tizanidine has Federal Drug Agency (FDA) approval for the use of muscle spasticity and/or musculoskeletal pain, however, sometimes used off label in the treatment of trigeminal neuralgia and tension headaches. Although clonidine and associated structurally similar compounds (e.g., brimonidine, guanfacine, and tetrahydrozoline) exposures are more reported, unintentional and intentional exposures of tizanidine are sparsely found in the literature, and many of these case reports and treatment are an extrapolation of clonidine overdose given their structural and pharmacologic resemblance.


Tizanidine, Clonidine,  Muscle spasticity


Heuser W, Rizvi K, Nogar J (2023) Tizanidine Toxicity Requiring High Dose Naloxone Infusion: A Case Report and Review of the Current Literature. J Pharmacol Clin Toxicol 11(1):1173.


Tizanidine is a centrally acting imidazoline derivative with a novel mechanism of action, closely resembling clonidine in its structure and pharmacological mechanism. Tizanidine has Federal Drug Agency (FDA) approval for the use of muscle spasticity and/or musculoskeletal pain, however, sometimes used off-label in the treatment of trigeminal neuralgia and tension headaches. Although clonidine and associated structurally similar compounds (e.g., brimonidine, guanfacine, and tetrahydrozoline) exposures are more reported, unintentional and intentional exposures of tizanidine are sparsely found in the literature, and many of these case reports and treatment are an extrapolation of clonidine overdose given their structural and pharmacologic resemblance. Presentation of previous case reports regarding alpha-2 and imidazoline receptor agonists were similar to ours with the most common effects reported to be hypotension, miosis, somnolence, lethargy, and bradycardia [1,2]. Furthermore, symptomatic imidazoline exposure are oftentimes managed medically with naloxone, however there is a paucity of literature on high dose or continuous naloxone infusion, specifically in the setting of tizanidine toxicity. We describe a case report of a large tizanidine successfully treated with the use of high dose naloxone followed by a naloxone continuous infusion.


A Thirty-year-old female with a past medical history of depression (not on any medications) was brought in by EMS after an intentional ingestion of approximately 12 tablets of 4mg tizanidine two hours prior to arrival. Patient was brought to the Emergency Department (ED), where patient was noted to be lethargic and unresponsive, with a Glasgow coma score (GCS) of 10 (E2, V4, M4). Patient was slurring her words on interview and continued to fall asleep and was unable to answer questions appropriately. Aside for mental status changes and miosis, the physical exam was unremarkable. Initial vital signs were: heart rate (HR) 93 bpm, blood pressure (BP) 136/112 mmHg, respiratory rate (RR) 16 breaths per minute, oxygen saturation of 98% on room air, and Temperature 97.2°F. ECG revealed sinus bradycardia with a rate of 46 bpm, QT 462 milliseconds, and QRS of 82 milliseconds. Initial laboratory values drawn on presentation were notable for: glucose 138, pH (venous) 7.36, pO2 43 mmHg, pCO2 43 mmHg, and bicarbonate (HCO3) 23 meQ/L, with a measured oxygen saturation (venous) of 74.6. A clean catch urine drug screen and serum drug screen was negative with undetectable levels of acetaminophen, ethanol, or salicylates.

On reassessment (2 hours after presentation), the patient became bradycardic to 39 bpm and systolic BP (SBP) dropped to 90 mmHg with continued lethargy. Given altered mental status and lethargy, activated charcoal was held due to the risk of potential aspiration. Naloxone 4mg was administered intravenously, in which the patient immediately became more alert and no longer required physical stimulation for arousal. Hemodynamics remained bradycardic and hypotensive. Forty five minutes following naloxone (4mg) administration, the patient again became lethargic and an additional 4mg of intravenous naloxone was administered with appreciable response in mental status. Patient woke up to voice, however, intermittently became somnolent. Patient’s HR increased to 80 bpm, and SBPs to 100. Ninety minutes following naloxone IV patient became increasingly lethargic, bradycardic to 35 bpm, SBP to 105 mmHg, however, she was adequately maintaining her airway (oxygen saturation 98%, with equal chest rise). Given continued lethargy and altered hemodynamics, patient was admitted to the medical intensive care unit (MICU) and a naloxone continuous infusion was started at 2mg/hour for 6 hours and then increased to 3 mg/hour for an additional 5 hours (total of 11 hours) [Figure 1].

Naloxone continuous infusion with ass.

Figure 1: Naloxone continuous infusion with ass.

Patient remained in the MICU for hourly neurologic assessment, respiratory monitoring, and cardiac monitoring. The patient was discharged from the MICU following discontinuation of naloxone continuous infusion after patient regained baseline neurological mental status and HR changed from sinus bradycardia to normal sinus rhythm with a mean arterial pressure (MAP) >65.


As a central alpha-2 receptor and imidazoline receptor agonist, our patient presented in an expected fashion with altered mental status, bradycardia, and hypotension as a result of tizanidine toxicity. This toxidrome is consistent with its pharmacological properties as an alpha-2 receptor adrenergic receptor agonist which leads to inhibition of excitatory neurotransmitters (e.g., norepinephrine), via a negative feedback mechanism. The signs and symptoms of toxicity from alpha-2 agonist and imidazoline compounds are nearly identical to that of opiate intoxication with decreased mental status, hemodynamic compromise and miosis, prompting the use of naloxone as a reversal agent for this toxidrome. Previous case reports of tizanidine overdose treatments are an extrapolation of other imidazoline compounds (e.g., clonidine) that are well reported in the literature, and include the use of intravenous fluids, atropine, naloxone, and vasopressors [3,4]. Although these treatments are transiently effective, there is no one specific treatment that is highly effective. Naloxone is postulated to competitively inhibit the endogenous opioid receptor agonists (e.g., endorphins) that is released following imidazoline/alpha-2 agonist administration, thereby reversing the underlying central nervous system depression (CNS) and possibly improving hemodynamics through an increase in sympathetic tone [5-7]. Naloxone in high doses, however, has been well described, with no current reported cases utilizing a continuous infusion naloxone infusion for tizanidine which has been reported with structurally similar compounds like clonidine, with varying degrees of success. Although mechanistically novel, the use of naloxone to is not an antidote and high-quality supportive care should be performed when resuscitating these patients as there are notable case reports that describe naloxone’s inefficacy in reversing the myriad of symptoms associated with this toxidrome [8,9].The minimal and short-lived response to lower doses of naloxone (<10mg) utilized in our patient and subsequent improved response with higher or repeated dosages of naloxone is consistent with previous reports of naloxone non-responders in the setting of alpha-2/imidazoline overdose [10,11]. However, the response of imidazoline exposure to continuous naloxone infusion has been variable in previous literature, with even more limited evidence for tizanidine exposure describing only high dose naloxone with subsequent continuous infusion [Table 1].

Table 1: Case reports of Tizanidine overdose including intervention and subsequent response/disposition.

Case Report Intervention Response/Disposition
27-year-old male; 48mg ingestion of tizanidine13 10mg IV bolus of naloxone Unremarkable ICU course followed by discharge at 38 hours post ingestion
3-year-old male; unknown quantity of tizanidine ingestion14 0.05mg/kg of naloxone IV, followed by 0.1 mg/kg of naloxone within 40 minutes of initial dose Monitored in the ICU and discharged home at 18 hours post ingestion

Unlike previous case reports of tizanidine overdose, our patient had improvements in both neurological status as well as hemodynamics following naloxone administration. Improvements in level of consciousness, without significant improvements in hemodynamics are well reported in the literature for clonidine and other structurally similar imidazoline compounds. It is therefore reasonable, based on the success of our case as well previous case reports, that early high dose administration followed by continuous infusion should be considered in the setting of tizanidine overdose with neurological and hemodynamic alterations.

It should be noted that tizanidine, in contrast to clonidine, has a 20-fold greater affinity for the imidazoline receptor over the alpha-2 receptor [12].The implications of this greater affinity at the imidazoline receptor are not known but may cause a different, possibly more severe, clinical toxidrome than that of the alpha-2 agonist clonidine. The half-life elimination of tizanidine is short lived and reported to be around 2 hours, however, alterations in the pharmacokinetic/toxicokinetic profile were undeniably seen in our patient.

As noted in the aforementioned case description, our patient required multiple doses of naloxone in addition to a prolonged continuous infusion to maintain an appropriate mental status and perfusion status. At the time of our case report, there are no documented cases of tizanidine toxicity being successfully managed with naloxone infusion, despite the structural similarities to an imidazoline compound such as clonidine. Although this is one limited case report, utilization of naloxone infusion for tizanidine toxicity needs further investigation. This case report is an important example of the success of naloxone in the treatment of tizanidine poisoning and we feel that consideration for high dose of naloxone (e.g., 10mg) with a low threshold to start a continuous infusion, soon thereafter is an appropriate consideration in tizanidine toxicity. Although this case is the first reported successful case of the use of naloxone infusion to reverse the toxidrome of tizanidine, further studies are needed to confirm the role of naloxone continuous infusion in both the adult and pediatric population.


1. Isbister G, Heppell S, page C, Ryan N. Adult clonidine overdose: prolonged bradycardia and central nervous system depression, but no severe toxicity. Clin Tox. 2017; 55: 187092.

2. Ahmad SA, Scolnik D, Snehal V, Glatstein M. Use of naloxone for clonidine intoxication in the pediatric age group: case report and review of the literature. Am J Ther. 2015; 22: e14-e16.

3. Spiller HA, Klein-Schwartz W, Colvin JM, Villalobos D, Johnson PB, Anderson DL. Toxic clonidine ingestion in children. J Pediatr. 2005; 146: 263-266.

4. Kappagoda C, Schell DN, Hanson RM, Hutchins P. Clonidine overdose in childhood: Implications of increased prescribing. J Paediatr Child Health. 1998; 34: 508-512.

5. Kunos G, Farsang C, Ramirez-Gonzales M. Beta-endorphin: possible involvement in the anti-hypertensive effect of central alphareceptor activation. Science. 1981; 211: 82-84.

6. Ramirez-gonzalez M, Tchakarov L, Garcia R, Kunos G. beta-endorphin acting on the brainsem is involved in the antihypertensive action of clonidine and a-methyldopa in rats. Circ Res. 1983; 53: 150-157

7. Farsang C, Kapocsi J, Juhasz I, Kunos G. Possible involvement of an endogenous opioid in the antihypertensive effect of clonidine in patients with essential hypertension. Circulation. 1982; 66: 1268-1272.

8. Lowry JA, Brown JT. Significance of the imidazoline receptors in toxicology. Clin Toxicol (Phila). 2014; 52: 454-469

9. Banner W, Lund ME, Clawson L. Failure of naloxone to reverse clonidine toxic effect. Am J Dis Child. 1983; 137: 1170-1171.

10. North DS, Wieland MJ, Peterson CD. Naloxone administration in clonidine overdosage. Ann Emerg Med. 1981; 10: 397

11. Cook P. Clonidine-induced unconsciousness: reversal with naloxone. Anaesth Intensive Care. 1987; 15: 470-471

12. Piletz JE, Zhu H, Chikkala DN. Comparison of ligand binding affinities at human I1-imidazoline binding sites and the high affinity state of alpha-2 adrenoceptor subtypes. J Pharmacol Exp Ther. 1996; 279: 694-702.

13. Amber Adams & Colton Copley. High dose naloxone for acute tizanidine overdose in the emergency department: a case report. Clin Toxicol. 2021; 59: 764-765

14. Bader D, Adam A, Shaban M, Alyahya B. Pediatric tizanidine toxicity reversed with naloxone: a case report. Int J Emerg Med. 2021; 14: 73.

Heuser W, Rizvi K, Nogar J (2023) Tizanidine Toxicity Requiring High Dose Naloxone Infusion: A Case Report and Review of the Current Literature. J Pharmacol Clin Toxicol 11(1):1173

Received : 03 Jun 2023
Accepted : 02 Aug 2023
Published : 05 Aug 2023
Annals of Otolaryngology and Rhinology
ISSN : 2379-948X
Launched : 2014
JSM Schizophrenia
Launched : 2016
Journal of Nausea
Launched : 2020
JSM Internal Medicine
Launched : 2016
JSM Hepatitis
Launched : 2016
JSM Oro Facial Surgeries
ISSN : 2578-3211
Launched : 2016
Journal of Human Nutrition and Food Science
ISSN : 2333-6706
Launched : 2013
JSM Regenerative Medicine and Bioengineering
ISSN : 2379-0490
Launched : 2013
JSM Spine
ISSN : 2578-3181
Launched : 2016
Archives of Palliative Care
ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
Author Information X