Table 1.
Case report risk factors for QTc interval prolongation and torsade de pointes (TdP) Cases in red formed the 21 patients allowing a correlation between QTc interval prolongation and methadone dose. Based on current evidence reviewed in this paper, risk factors in addition to methadone are tabulated and include (1) female sex [n=12], (2) heart disease [n=11], (3) electrolyte imbalance [hypokalemia (n=7) and hypomagnesemia (n=4)], (4) metabolic drug interactions [CYP inhibitors (CYP) [n=19], (5) concurrent use of medications associated with QTc interval prolongation [QTc prolonging (QTP) [n=14], (6) hepatic impairment [n=6] and (7) other risk factors: bradycardia [n=8][Brachmann et al. 1983] and cocaine [n=6][Magnano et al. 2006].
| Case & Citation | QTc msec | Methadone mg/day |
TdP | Age Years | Sex M/F | Heart disease |
Electrolytes imbalance ↓K, ↓Mg |
Interacting drugs CYP inhibitors (CYP) QTc prolonging (QTP) |
Hepatic impairment | Other risk factors | Total # |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1[Deamer et al. 2001] | 710 | 120 | Yes | 41 | F | ↓Mg | Cannabinoids (CYP3A4), Fluoxetine (CYP2D6, CYP2C19, CYP3A4, QTP) | 5 | |||
| 2[Walker et al. 2003] | Prolonged | 660 | Yes | 41 | F | ↓K | Fluoxetine (CYP2D6, CYP2C19, CYP3A4, QTP) | 4 | |||
| 3[Walker et al. 2003] | Prolonged | 650 | Yes | 52 | F | Yes | 2 | ||||
| 4[Walker et al. 2003] | Prolonged | 700 | Yes | 61 | F | Yes | Sertraline (CYP2B6, CYP2C19) | 3 | |||
| 5[Vodoz et al. 2003] | Prolonged | 200 | Yes | 25 | M | Yes | 1 | ||||
| 6[Gil et al. 2003] | 600 | 275 | Yes | 36 | M | Yes | Cotrimoxazole (CYP3A4, QTP) | 3 | |||
| 7[Gil et al. 2003] | 640 | 300 | Yes | 39 | M | Yes | Clarithromycin (CYP3A4, QTP) | Sinus bradycardia | 4 | ||
| 8[Gil et al. 2003] | 640 | 385 | ? | 34 | M | Sinus bradycardia | 1 | ||||
| 9[Gil et al. 2003] | 510 | 700 | Yes | 31 | M | Yes | Cotrimoxazole (CYP3A4, QTP), Foscarnet (QTP) | 4 | |||
| 10[Almehmi et al. 2004] | 549 | 700 | Yes | 51 | M | ↓K ↓Mg |
2 | ||||
| 11[Krantz et al. 2005] | 582 | 450 | Yes | 42 | M | Fluvoxamine (CYP3A4) | 1 | ||||
| 12[Krantz et al. 2005] | 635 | 80 | Yes | 46 | F | Yes | ↓K | Cocaine | 4 | ||
| 13[Lüthi et al. 2007] | 654 | 150 | Yes | 53 | F | ↓K ↓Mg |
Yes | 4 | |||
| 14[Routhier et al. 2007] | 517 | 145 | Yes | 52 | F | Yes | ↓K | Yes | Cocaine | 5 | |
| 15[Hussain et al. 2007] | 510 | In utero exposure | No | 0 | F* | Sinus bradycardia | 1* | ||||
| 16[Sekine et al. 2007] | 591 | 240 | No | 59 | M | 0 | |||||
| 17[Wong et al. 2007] | 516 | 375 | No | 22 | M | Sinus bradycardia, cocaine | 2 | ||||
| 18[Falconer et al. 2007] | 555 | 105 | Yes | 34 | M | Protease Inhibitors: Atazanavir (CYP3A4) and Ritonavir (CYP3A4, CYP2B6) | Yes | Sinus bradycardia | 4 | ||
| 19[Iskandar et al. 2007] | 605 | 160 | Yes | 43 | F | Yes | 2 | ||||
| 20[Abramson et al. 2008] | 600 | 230 | Yes | 47 | F | Amiodarone (QTP) | Yes | 3 | |||
| 21[Pimentel et al. 2008] | 577 | 135 | Yes | 40 | F | 1 | |||||
| 22[Esses et al. 2008] | 580 | 100 | Yes | 56 | M | 0 | |||||
| 23[Prosser et al. 2008] | 690 | 125 | Yes | 57 | M | Yes | Voriconazole (CYP3A4, QTP), Cannabinoids (CYP3A4) | Sinus bradycardia, cocaine | 6 | ||
| 24[Nair et al. 2008] | 538 | 120 | Yes | 56 | M | ↓K | Ciprofloxacin (CYP3A4, QTP) | Yes | 4 | ||
| 25[Reinhold et al. 2009] | 600 | 125 | Yes | 57 | M | Yes | Voriconazole(CYP3A4, QTP), Cannabinoids (CYP3A4), Amiodarone (QTP) | Sinus bradycardia, cocaine | 7 | ||
| 26[Noorzurani et al. 2009] | 520 | 120 | Yes | 44 | F | Itraconazole (CYP3A4) | 2 | ||||
| 27[Puri et al. 2009] | 540 | 70 | Yes | 36 | F | 1 | |||||
| 28[John et al. 2010] | 550 | 40 | Yes | 50 | M | Cotrimoxazole (CYP3A4, QTP), Protease Inhibitor: Atazanavir (CYP3A4) | 3 | ||||
| 29[De Jong et al. 2011] | 600 | Unknown | Yes | 52 | M | Yes | Cocaine | 2 | |||
| 30[Nordt et al. 2011] | 569 | Unknown | Yes | 55 | M | Amiodarone (QTP), Doxepin (QTP) |
2 | ||||
| 31[Thanavaro et al. 2011] | 626 | 110 | Yes | 61 | M | ↓K ↓Mg |
2 | ||||
| 32[Calver et al. 2012] | 480 | 120 | No | 27 | M | Cannabinoids (CYP3A4) | Sinus bradycardia | 2 |
Female sex not a risk as patient was an infant.