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 |