2003]] are among these risk factors [Arbel et al. 2007; Hanon et al. 2010]. Bednar et al. [2001] in their Table 2 identified 16 factors prolonging the QTc interval. Those risk factors included (1) congenital, (2) increasing age, (3) female sex, (4) meals, (5) sleep, (6) drugs, (7) obesity/weight gain, (8) liquid protein diet, (9) alcoholism, (10) electrolyte disturbances (hypokalemia, hypomagnesemia, hypocalcemia), (11) hypoglycemia/diabetes mellitus, (12) myocardial ischemia and infarction, cardiomyopathy, (13) hypertension, (14) hypothyroidism/pituitary insufficiency, (15) central nervous system insult: stroke, subarachnoid

Inhibitors,research,lifescience,medical hemorrhage, trauma, infection, tumor and (16) cirrhosis. Viskin et al. [2003] in their review (Figure 3 derived Inhibitors,research,lifescience,medical from 229 published cases) of the long QT syndrome caused by noncardiac drugs identified seven major risk factors in order of greatest to least as follows: (1) female sex, (2) heart disease, (3) hypokalemia, (4) toxic drug CI1040 levels, (5) drug interactions involving the QT interval, (6) metabolic drug interactions Inhibitors,research,lifescience,medical and (7) familial history of long QT syndrome. The authors found that 96% of their study subjects had one or more risk factors, 72% had two or more risk factors and 39.5% had three or more

risk factors. In our Table 1, we slightly modified this list to include (1) female sex, (2) heart disease, (3) hypokalemia/hypomagnesemia, (4) drug interactions involving the QT interval and metabolic drug interactions, (5) hepatic impairment and (6) others including sinus Inhibitors,research,lifescience,medical bradycardia and cocaine. High-dose methadone (120 mg/day and above) The United Kingdom methadone treatment guidelines [Department of Health (England) and the Devolved Administrations, 2007] recommend obtaining an EKG in persons taking greater than 100 mg of methadone per day. Anchersen et al Inhibitors,research,lifescience,medical found an association with dosages ≥120 mg and QTc interval > 500 msec [Anchersen et al. 2009]. Twenty-three of our 31

adults (74.2%) were exposed to daily methadone doses of 120 mg or greater (Table 1). In the Hanon et al. [2010] series, seven of 12 subjects (daily dose range 35 to 250 mg) received daily doses of methadone 140 mg or greater. In contrast to daily methadone doses of up to 700 mg daily very (our Table 1), these patients were exposed to no more than 250 mg of methadone/day. In our sample, seven cases (25.8%) experienced QTc interval prolongation at doses less than 120 mg per day, with the lowest dosage reported being only 40 mg of methadone. Even though a methadone dose effect on QTc interval lengthening may appear [Krantz et al. 2003; Chang et al. 2011], its clinical utility is highly questionable [Cruciani, 2008].