Tizanidine in postmortem forensic cases

Alpha-2 adrenergic receptor agonists are established therapeutic medications that are used for conditions such as hypertension, pain disorders, muscle relaxation, spasticity, opioid withdrawal, insomnia, and sedation. While forensic toxicologists may be familiar with more common alpha receptor agonists, tizanidine is a less frequently identified compound, with limited published data available regarding antemortem and postmortem concentrations. Tizanidine therapeutic concentrations found in plasma are reported in the range of 0.0025-0.025 mg/L, although CYP1A2 inhibitors can significantly raise tizanidine levels in the body, thereby increasing the risk of dose-related toxicity. Additionally, imidazoline receptor activity is an underappreciated contributor to the mechanism of action and potential for adverse effects of this drug. Due to its high potency, tizanidine may be missed by forensic laboratories that are not targeting this drug or carefully inspecting untargeted data for its presence. In this study, 18 postmortem cases involving tizanidine are reviewed to improve the understanding of its forensic toxicological profile. These cases have been divided into categories as ruled by the certifying pathologist of "Suicide" involving tizanidine (N = 8, mean 6.2 mg/L and median 0.77 mg/L) and "Accident" involving tizanidine (N = 4, mean 0.86 mg/L and median 0.89 mg/L), and additionally a category of "Incidental" (N = 6, mean 0.35 mg/L and median 0.035 mg/L). Comparison of tizanidine concentrations to those in example cases such as this dataset can assist postmortem forensic toxicologists and pathologists in distinguishing therapeutic postmortem concentrations from toxic/lethal concentrations. However, consideration of scene details and totality of case investigation is essential when determining cause and manner of death.