Clinically Significant Bradycardia From Tizanidine.

To the Editor: A 44-year-old woman presented to the hospital with severe dizziness, excessive fatigue, and recent occurrence of multiple syncopal episodes. She had a medical history of a known pituitary cyst, adrenal insufficiency, obstructive sleep apnea, degenerative joint disease, and a gastric bypass surgery. Her home medications included trazodone (50 mg PO nightly) and zolpidem (5 mg PO nightly as needed for insomnia). In addition, she had a motor vehicle accident a month ago, resulting in some back discomfort and spasms for which she was prescribed tizanidine (12 mg PO daily) and oxycodone/acetaminophen (5/325 mg PO q8 hours as needed for back pain). On presentation, her physical examination revealed nonorthostatic hypotension (BP 76/52) and sinus bradycardia [heart rate (HR) 35 bpm]. Rest of the physical examination was unremarkable. Her kidney, liver, and thyroid function tests were within normal limits. Electrocardiogram showed sinus bradycardia and QT/QTc interval 570/435 milliseconds (Figure 1). Echocardiography revealed normal heart structure and function. Further testing established a diagnosis of central adrenal insufficiency based on a positive ACTH stimulation test, normal mineralocorticoid function, and brain magnetic resonance imaging findings of an expanded sella containing cerebrospinal fluid signal intensity, consistent with an empty sella. She was treated with intravenous hydrocortisone for central adrenal insufficiency. However, sinus bradycardia (HR 30–40 s), fatigue, and dizziness persisted despite corticosteroid therapy. At this time, tizanidine was discontinued, and her symptoms improved dramatically. Repeat vital signs on 3 occasions after discharge showed improvement in the HR with a range of 70–96 bpm. This case is unique and challenging because it presents a patient with sinus bradycardia in the setting of adrenal insufficiency, which classically present with tachycardia. The temporal association of the discontinuation of the drug and resolution of bradycardia and symptoms signify tizanidine as the likely cause. Tizanidine is a centrally acting a2-adrenergic agonist that manifests its clonidinelike effects in the form of bradycardia and hypotension.1,2 Therefore, it is imperative to raise awareness among treating physicians and clinical pharmacists of the potential adverse events of this medication. Previous clinical trials of tizanidine did not report this significant complication as part of the safety profile. Literature review does reveal a few case reports but not in the setting of adrenal insufficiency (Table 1).3–6 Further research studies are warranted