Methadone-induced mortality in the treatment of chronic pain: Role of QT prolongation

Methadone is increasingly prescribed for chronic pain, yet the associated mortality appears to be rising disproportionately relative to other opioid analgesics. We review the available evidence on methadone-associated mortality, and explore potential pharmacokinetic and pharmacodynamic explanations for its greater apparent lethality. While methadone shares properties of central nervous system and respiratory depression with other opioids, methadone is unique as a potent blocker of the delayed rectifier potassium ion channel (IKr). This results in QT-prolongation and torsade de pointes (TdP) in susceptible individuals. In some individuals with low serum protein binding of methadone, the extent of blockade is roughly comparable to that of sotalol, a potent QT-prolonging drug. Predicting an individual’s propensity for methadone-induced TdP is difficult at present given the inherent limitations of the QT interval as a risk-stratifier combined with the multifactorial nature of the arrhythmia. Consensus recommendations have recently been published to mitigate the risk of TdP until further studies better define the arrhythmia risk factors for methadone. Studies are needed to provide insights into the clinical covariates most likely to result in methadone-associated arrhythmia and to assess the feasibility of current risk mitigation strategies

Abstract 13376: Sleep-Disordered Breathing is Associated With Larger Ventricular Repolarization Instability

Byline: Soroosh Solhjoo, Johns Hopkins Univ Sch of Medicine, Baltimore, MD; Mark C Haigney, F. Edward HȨbert Sch of Medicine, Bethesda, MD; Trishul Siddharthan, Univ of Miami Miller Sch of Medicine, Miami, FL; Abigail L Koch, Univ of Miami Miller Sch of Medicine, Miami, FL; Ciprian M Crainiceanu, Johns Hopkins Bloomberg Sch of Public Health, Baltimore, MD; Naresh M Punjabi, Univ of Miami Miller Sch of Medicine, Miami, FL Introduction: Sleep-disordered breathing (SDB) is a common disorder in the general population that is associated with adverse cardiovascular events, such as sudden cardiac death, but the underlying mechanisms are unclear. Hypothesis: Ventricular repolarization instability is greater in those with severe SDB than those without SDB, independent of other risk factors. Methods: Among the participants of the Sleep Heart Health Study (SHHS), we identified those with SDB who had no diagnosed cardiovascular disease or other factors that could affect cardiac repolarization. Severe SDB was defined as having a respiratory disturbance index (RDI) > 33 events/hour (top 95%ile of the SHHS cohort). We also identified a group of participants matched to the severe SDB group on age, sex, BMI, and race and had RDI < 1.33 events/hour (bottom 25%ile; without SDB). Each group consisted of 61 (45 M and 16 F) participants. Oxygen saturation levels (SpO2) were used to measure hypoxemia burden as the percentage of sleep time with SpO2 < 90% (T90). Heart rate (HR), heart rate variability (SDNN), and QT variability index (QTVI, a measure of ventricular repolarization instability) were calculated from one-lead ECG recordings. Student's t-test was used to assess statistical associations. Results: The SDB group had a larger T90 than those without SDB (11.39 Ø 1.42% vs 1.32 Ø 0.61%, P < 0.001). Participants with SDB also had greater mean HR (P = 0.028), SDNN (P = 0.017), and QTVI (P = 0.027) than those without SDB. Based on a multivariable linear model that included hypoxemia burden, age, BMI, and smoking status, T90 was the only independent predictor of QTVI (P = 0.022). Conclusion: SDB is associated with higher HR, HRV, and QTVI, an indicator of increased instability in ventricular repolarization leading to increased risk for cardiac arrhythmias and sudden cardiac death. The severity of the destabilizing effect of SDB on ventricular repolarization appears to be modified by hypoxemia burden.Professiona

QT variability during rest and exercise in patients with implantable cardioverter defibrillators and healthy controls

Background: Increased QT Variability (QTVI) is predictive of life threatening arrhythmias in vulnerable patients. The predictive value of QTVI is based on resting ECGs, and little is known about the effect of acute exercise on QTVI. The relation between QTVI and arrhythmic vulnerability markers such as T-wave alternans (TWA) has also not been studied. This study examined the effects of exercise on QTVI and TWA in patients with arrhythmic vulnerability. Methods: Digitized ECGs were obtained from 47 ICD patients (43 males; age 60.9 ± 10.1) and 23 healthy controls (18 males; age 59.7 ± 9.5) during rest and bicycle exercise. QTVI was assessed using a previously validated algorithm and TWA was measured as both a continuous and a categorical variable based on a priori diagnostic criteria. Results: QTVI increased with exercise in ICD patients (-0.79 ± 0.11 to 0.36 ± 0.08, P \u3c 0.001) and controls (-1.50 ± 0.07 to -0.19 ± 0.12, P \u3c 0.001), and QTVI levels were consistently higher in ICD patients than controls during rest and exercise (P \u3c 0.001). The magnitude of QTVI increase from baseline levels was not larger among ICD patients versus controls (P \u3e 0.20). Among ICD patients, elevated exercise QTVI was related to lower LV ejection fraction and inducibility of ischemia (P \u3c 0.05). QTVI at rest correlated with exercise TWA (r = 0.54, P = 0.0004). Conclusions: QT variability increases significantly with exercise, and exercise QTVI is related to other well-documented markers of arrhythmic vulnerability, including low ejection fraction, inducible ischemia, and TWA. Resting QTVI may be useful in the risk stratification of individuals incapable of performing standard exercise protocols. ©2009, Wiley Periodicals, Inc

Psychological factors and cardiac repolarization instability during anger in implantable cardioverter defibrillator patients

Background  Evidence indicates that emotions such as anger are associated with increased incidence of sudden cardiac death, but the biological mechanisms remain unclear. We tested the hypothesis that, in patients with sudden death vulnerability, anger would be associated with arrhythmic vulnerability, indexed by cardiac repolarization instability. Methods  Patients with coronary artery disease (CAD) and an implantable cardioverter defibrillator (ICD; n = 41) and healthy controls (n = 26) gave an anger-inducing speech (anger recall), rated their current (state) anger, and completed measures of trait (chronic) levels of Anger and Hostility. Repolarization instability was measured using QT Variability Index (QTVI) at resting baseline and during anger recall using continuous ECG. Results  ICD patients had significantly higher QTVI at baseline and during anger recall compared with controls, indicating greater arrhythmic vulnerability overall. QTVI increased from baseline to anger recall to a similar extent in both groups. In ICD patients but not controls, during anger recall, self-rated anger was related to QTVI (r = .44, p = .007). Trait (chronic) Anger Expression (r = .26, p = .04), Anger Control (r = -.26, p = .04), and Hostility (r = .25, p = .05) were each associated with the change in QTVI from baseline to anger recall (Delta QTVI). Moderation analyses evaluated whether psychological trait associations with Delta QTVI were specific to the ICD group. Results indicated that Hostility scores predicted Delta QTVI from baseline to anger recall in ICD patients (beta = 0.07, p = .01), but not in controls. Conclusions  Anger increases repolarization lability, but in patients with CAD and arrhythmic vulnerability, chronic and acute anger interact to trigger cardiac repolarization lability associated with susceptibility to malignant arrhythmias