Severe muscle cramps after intravenous administration of amiodarone - a novel, potentially dose-dependent adverse effect

Abstract

Amiodarone is a widely available anti-arrhythmic agent used to treat both ventricular and refractory supra-ventricular tachyarrhythmias. The most widely recognized adverse effects of amiodarone include those affecting the eyes, lungs, liver, heart, skin and thyroid. Amiodarone also causes a spectrum of neuromuscular adverse effects, but these usually develop after long-term administration. This report describes a case of acute onset severe muscle cramps in a young man, which developed after initiation of intravenous amiodarone therapy. A 32-year-old Caucasian man was admitted to the cardiac electrophysiology service for ongoing management of recurrent intra-atrial tachycardia. He had a history of congenital heart disease, and had several cardiac electrophysiology studies which showed re-entrant intra-atrial tachycardia, which had recurred in spite of treatment with various anti-arrhythmic agents, multiple electrical cardioversions, radiofrequency catheter ablation and a Cox maze IV procedure. His medication regimen included digoxin, sotalol, furosemide, lisinopril and coumadin. Laboratory tests on admission revealed normal serum electrolytes, hepatic and renal function, normal thyroid-stimulating hormone concentration and an international normalized ratio (INR) of 2.9. After being aggressively diuresed with intravenous furosemide, he received two 250 mg doses of intravenous amiodarone and was then started on a continuous infusion of 900 mg over the next 24 h. About 12 h after initiation of intravenous amiodarone, the patient started complaining of episodic, severe muscle cramps affecting his neck, back, thighs and calves. He described these episodes as involuntary, sustained, painful contractions of the muscles, about 6–8 episodes every hour, each lasting up to 2 min in duration, and not associated with tremors or paresthesiae. A detailed neurological examination revealed no cranial nerve deficits, no focal motor or sensory deficits, normal gait and co-ordination, symmetric deep tendon reflexes and no muscle fasciculations. The only relevant positive finding on physical examination was mild tenderness over the affected muscle groups in his calves. Repeat laboratory tests showed a normal serum chemistry profile (including ionized and total calcium, magnesium and phosphorus concentrations), normal serum creatinine and creatine phosphokinase (CK), normal free T4 concentrations and a normal urinalysis without myoglobinuria. No relevant drug–drug interactions were identified to explain his muscle cramps. He was started on low dose cyclobenzaprine (2.5 mg three times a day) with partial improvement in his symptoms, and amiodarone was continued orally at a dose of 400 mg three times a day. The following day, he underwent direct current cardioversion with 50 joules, and his cardiac rhythm converted to a normal sinus rhythm alternating with an atrial-paced rhythm. His muscle cramps continued unabated, and follow-up neurological examination and laboratory tests remained normal, except for mild elevation of total serum CK (348 units per litre). The oral maintenance dose of amiodarone was reduced to 200 mg once daily, and over the next 12 h or so, the patient's cramps completely resolved. A battery of screening tests for an inherited metabolic myopathy, including serum ketones, lactate, pyruvate, lactate dehydrogenase, uric acid, free and total serum carnitine concentrations, a quantitative serum acylcarnitine profile and serum free fatty acid profile, were within normal limits. Using the Naranjo probability scale for adverse drug effects [1], this case of acute onset severe muscle cramps scored 7 points. This score places this adverse event in the ‘probable’ category for causal association with amiodarone treatment. The patient was continued on the lower maintenance dose of oral amiodarone, and has not had recurrence of muscle cramps after 6 weeks' follow-up. This case has been reported to the United States Food and Drug Administration (FDA) through its Safety Information and Adverse Event Reporting (MedWatch) Program [2]. The prevalence of amiodarone-induced neurotoxicity ranges from 27.5% to 74% [3–5]. The most commonly reported neurologic adverse effects of amiodarone include tremors, ataxia and peripheral neuropathy, but cases of encephalopathy, parkinsonism, optic neuropathy and myopathy have also been reported. Most reports of amiodarone-induced neurotoxicity are in patients on long-term oral maintenance therapy. However, in the literature there are no reports of acute neurotoxicity or myopathy after the use of intravenous amiodarone. A recent consensus guideline recommends monitoring for neurologic adverse effects such as weakness, paresthesiae, tremors and gait abnormalities during follow-up of patients on long-term amiodarone therapy [6]. However, many widely used adverse event monitoring guidelines [7, 8] do not include specific recommendations for monitoring neurologic symptoms. Clinicians need to be cognizant of the known neurotoxic effects of amiodarone therapy. A baseline neurologic examination should be performed in all patients being started on amiodarone therapy, and published recommendations for pharmacovigilance of amiodarone induced adverse effects should include baseline assessment and monitoring for neurologic adverse effects. In conclusion, this is a case of acute, severe muscle cramps associated with the use of intravenous amiodarone in a young man with congenital heart disease, which resolved spontaneously after conversion to oral amiodarone and dose reduction.