HIV, High Dose Methadone, and the Treatment Conundrum 5/8/2014. Frederick L. Altice, MD, MA

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1 EXPERT PANEL Managing HIV in Special Circumstances: Patients on High-Dose Methadone Frederick L. Altice, MD, MA Professor of Medicine, Epidemiology, and Public Health Yale University HIV, High Dose Methadone, and the Treatment Conundrum 1

2 Integrating Methadone Into HIV Treatment Is an Evidence Based Practice Recommendation 27: Offering methadone or buprenorphine to opioid dependent patients is recommended (II A). Methadone Related Mortality Methadone: 250K on maintenance and 720K for pain. Mortality increased from 1999 (N~500) to 2007 (~5,500), but decreased thereafter. Most mortality due to chronic pain prescription. Accounts for 1 in 3 opioid related deaths. Most methadone related deaths do not occur in the patient for whom it was prescribed. Recent systematic review of the literature and Delphi grading system were used by the American Pain Association and the College on Problems of Drug Dependence to rate the evidence and provide guidance. Systematic Review of Impact of MMT and Cardiac Arrhythmias Delayed cardiac repolarization (QTc) from MMT is dose dependent (case reports, cross sectional studies, and prospective studies). Increased QTc prolongation is associated with structural heart disease, family history, or drug interactions that affect cytochrome P450 or methadone. Pretreatment QTc prolongation risk threshold is 450 ms for both genders, despite notable differences. Methadone dose is just one consideration to limit arrhythmia risk. Arrhythmias were reported at doses as low as 29 mg/day, creating a safety efficacy paradox. 2

3 Mostly related to human herg (ether ago go related gene) K + Factors associated: female sex, hypokalemia, ESLD or ESRD, and medications Some genetic predispositions Methadone, especially the S enantiomer, binds to the herg channel QTc Prolongation and Torsade de Pointes Patient Assessment and Selection Individualize treatment decisions Maintenance vs pain management MMT vs buprenorphine vs XR NTX Drug interactions Baseline risks for or presence of QTc prolongation Clinical and social factors Patient education and provision of complete informed consent of risks and benefits Medication and Drug Interactions Drugs that increase the levels of methadone, such as inhibitors of CYP3A4, CYP2B6, and CYP2D6 Macrolides, fluoroquinolones, grapefruit juice, azoles, benzos, SSRIs, verapamil, PPIs CYP2B6 increases S enantiomer formation Drugs that are associated with prolonged QTc and torsade de pointes Some antiarrhythmics, antipsychotics, citalopram, tricyclic antidepressants, macrolides, fluoroquinolones, and cisapride 3

4 Baseline Electrocardiograms and Recommendations Baseline ECG recommended for any patient with increased risk for QTc prolongation (prior QTc > 450 ms or prior arrhythmia ECG within 3 months with QTc < 450 ms MMT should not be used if QTC > 500 ms Consider alternative treatment options if QTc is 450 to 500 ms (buprenorphine or XR NTX) Follow up Electrocardiograms Follow up ECG 2 to 4 weeks after MMT initiation, and following significant dose increases, for patients with risk factors for prolonged QTc, any prior ECG demonstrating a QTc > 450 ms, or a history of syncope. Repeat ECG when MMT dose is 100 mg, or if new risk factors (or medications) for prolonged QTc should emerge. Monitoring for and Management of Adverse Side Effects If QTc 500 ms, address other reversible causes and switch from MMT to alternative therapy. Follow ECG to ensure reduction in QTc. If QTc , consider switch to alternative treatment or reduce MMT dose, address reversible QTc prolongation causes, and monitor ECG with changes. 4

5 Clinical Management of Torsade de Pointes Discontinue methadone immediately Consider reversal with naloxone Consider restoration of opioids with buprenorphine IV magnesium Replete K + Temporary cardiac pacing or ICD placement in extreme or refractory cases Summary An anticipated 5K (2%) of 250K patients in OTPs will exceed the 500 ms prolongation threshold and constitute a principal target for risk reduction interventions. Prolonged QTc and arrhythmias are associated with increased methadone levels. Automated ECG screening with QTc interpretation is a feasible screening tool for risk stratification. MMT can be safely administered as long as the potential for QTc interval prolongation is recognized through ECG screening, and appropriate action is taken for QTc interval prolongation. 5