AUTHORS	JOURNAL	TYPE OF STUDY	NUMBER	STUDY POPULATION (MMTP OR PAIN)	OTHER MEDICATIONS EVALUATED OR PRESENT	OTHER DRUGS OF ABUSE EVALUATED	OTHER MEDICAL CONDITIONS EVALUATED	MAJOR FINDINGS	NOTES, INCLUDING LIMITATIONS
Chugh et al., 2008	American Journal of Medicine		22 cases compared with 106 controls	All deaths in Portland metropolitan area over 4 years with ‘therapeutic’ levels of methadone present, compared with non-methadone cases. 55% were taking methadone for pain control.	Yes	Persons with evidence of methadone overdose or other recreational drug use excluded	Structural heart disease only	Among methadone cases, evidence of structural heart disease in 23%, compared with 60% of controls	There is no single cut-off level at which methadone becomes toxic for all persons.
Cruciani et al., 2005	Journal of Pain and Symptom Management	Cross-sectional	104 total	Both MMTP and pain	Yes (not included in a multivariate analysis)	No	Excluded with congenital long QT syndrome, implanted pacemaker, atrial fibrillation, or wide QRS complex on prior ECG Serum electrolytes measured	33% had QTc prolongation (defined as QTc>430 ms for males and 450 ms for females) No patient had QTc>500ms Significant dose response was seen in men on methadone <12 months	No control group Small, exploratory study
Ehret et al., 2006	Archives of Internal Medicine	Case-control	167 methadone cases 80 control	Hospitalized IDU on methadone versus control IDU not on methadone	Yes, but not specified	Yes	HIV Hepatitis C Hepatitis B Structural heat disease	16.2% of methadone patients had QTC ≥ 500ms compared to 0% of controls. 3.6% of those in the methadone group had TdP. QTc was weakly but significantly correlated with methadone dose. In a multivariate regression analysis, QT prolongation was associated with higher methadone dose, lower potassium, lower prothrombin time, and co-medication with CYP3A4 inhibition.	No formal assessment of structural heart disease Other substance use was self-reported
Fanoe et al., 2007	Heart	Cross-sectional	450 (52%) of treatment population in Copenhagen	OTP (methadone versus buprenorphine)	No	Yes Cocaine, cannabis, illicit opioids, illicit benzodiazepines (but not included in the multivariate analysis)	Persons with atrial fibrillation or flutter, bundle branch block, bigeminy, or pacemaker were excluded -serum potassium was checked	Methadone dose was significantly correlated with QTc for both men and women. No association was found between buprenorphine dose and QT interval. In a multivariate analysis, methadone dose was associated with prolonged QT interval, and serum potassium was negatively associated with prolonged QT. Odds of self-reported syncope also were 1.2 times higher when methadone dose was increased by 50mg.	Buprenorphine group was younger and had shorter duration of therapy
Kornick et al., 2003	International Association for the Study of Pain	Prospective (chart review) over 20 months	N=47 (iv methadone) N=35 (morphine)	Cancer pain	Unknown if other medications were present. According to article, information was collected. Morphine.	Morphine	None	Methadone in combination with chlorobutanol is associated with QT interval prolongation.	IV methadone, which contains chlorobutanol, was evaluated. Chlorobutanol alone can affect QT interval. Small sample size.
Krantz et al., 2003	Pharmaco-therapy	Retrospective case series analysis	N=17	9 patients were receiving methadone for opioid dependency (6 were from Colorado); 8 patients were receiving methadone for chronic pain from one center. All patients had been hospitalized from 1996–2001 with torsades de pointes.	Olanzapine, fluoxetine, levacetylmethadol, nelfinavir, amitriptyline	Cocaine, alcohol	Structural heart disease	A relationship was found between daily methadone dose and the QT interval.	Small study population, retrospective study design, and inherent selection bias.
Maremmani et al., 2005	European Addiction Research	Cross-sectional	83	MMTP program in Italy. In MMTP for at least 6 months Stable dose for at least 4 months	No other medications known to prolong QT on board Reported all had normal electrolytes and nutritional status (values not provided)	At time of ECG, all negative for morphine, cocaine metabolites, and amphetamines All self reported “habitual” alcohol use (not defined)	Not reported Reported all had normal electrolytes and nutritional status (values not provided)	83.1% had QT more prolonged than age and sex matched controls Only 2 subjects (2.4%) had QT>500ms No relationship observed between QT and methadone dose	Small sample size No data on plasma levels
Martell et al., 2005	American Journal of Cardiology	Prospective	160	MMTP	Antidepressants; Ca+ Channel Blockers; Antiretrovirals; Diuretics; Phenytoin	Cocaine; ETOH; tobacco	Hepatitis C; HIV infection	Positive correlation between serum Methadone conc. and magnitude of QT prolongation	Effect of medical conditions or prescription medications on QT prolongation could not be totally excluded
Peles et al., 2006	Society for the Study of Addiction	Prospective. Patients’ medical charts were also reviewed retrospective-ly for prescribed medications in the period before the study was performed. Cross sectional.	N=138	MMT (must be in treatment for at least 100 days in addition to being on steady methadone doses for at least 14 days). Physicians encouraged patients receiving high methadone doses (over 120 mg/day) to participate.)	Benzodiazepines, opiates, amphetamines. Other medications present: ursodeoxycholic acid, spironolactone, colchicine, salbutamol, theotrime, ipratropium bromide, trazodone, metformin, thyroxin sodium, clonazepam, amoxicillin, fluoxetine, diazepam, fluvoxamine, insulin, penfluridol, enoxaparin, escitalopram, amitriptyline, melatonin, haloperidol, biperiden, propanolol, aspirin, mirtazapime sodium, valproate, acetylsalicylic acid, simvastatin, ramipril, isosorbide.	Benzodiaze-pines, opiates, cocaine, cannabis, amphetamines.	HCV, HIV	No correlation between QT interval and methadone doses and serum levels; however, significant correlation between methadone dose and QT interval were found in patients who were urine positive for cocaine.	Even though the study was cross-sectional, a greater proportion of “high-dose” patients (120 mg/day) were included, limiting the generalizability of the finding. Study population limited to one program in Tel Aviv, Israel; not multi-center. No baseline ECGs.
Wedam et al., 2007	Archives of Internal Medicine	Randomized controlled trial	220	MMTP	N/A	Alcohol; heroin; cocaine	N/A	Compared to levomethadyl and methadone, buprenorphine is associated with less QT prolongation	Absence of placebo arm to assess random incidence of QT prolongation