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Treatment of methadone-induced torsades de pointes with lidocaine.

CASE REPORT

A 41-year-old woman who was on MMT for opioid dependence presented to an outside hospital emergency room for multiple episodes of lightheadedness and presyncope of one-day duration. She was taking methadone 150 mg daily and no other prescription or over the counter medications. The patient's past history was significant for gastric bypass surgery, alcohol abuse, and chronic back pain. On examination, she was not in distress, BP was 114/80 mmHg, and pulse rate was 60/minute with normal heart sounds and clear lung fields. The rest of her physical exam was unremarkable. Cardiac monitor showed runs of polymorphic ventricular tachycardia typical of Tdp for which the patient was given IV magnesium 2 grams with no effect. She was then started on IV amiodarone and subsequently transferred to our hospital several hours later and admitted to the intensive care unit. Soon after presentation, the patient had a similar episode of lightheadedness and was noted to have TdP that degenerated into ventricular fibrillation (Figure 1). The patient was defibrillated with a 300 J shock, which restored sinus rhythm. Amiodarone drip was continued. An EKG done at this time showed normal sinus rhythm with QTc of 529 milliseconds (Figure 2). Laboratory values revealed potassium of 3.1 mmol/L, magnesium of 1.7 mg/ dl, and calcium of 8.1 mg/dl. Potassium and magnesium replacement was started intravenously. The patient continued to have more episodes of TdP, two of which degenerated into VF within the next few hours and had to be defibrillated again. After cardiology consultation, amiodarone drip was discontinued, and the patient was given 75mg IV lidocaine bolus and started on lidocaine infusion at 1 mg/min. This prevented any further arrhythmias. Lidocaine drip was con tinued for 24 hours. The patient was treated with clonidine, lorazepam, and morphine for opioid withdrawal. Morphine was used as it is one of the more acceptable opiates in the presence of a prolonged QT. (1) The patient was then started on metoprolol and later discharged with arrangements made with her primary care physician to wean her off methadone. EKG at discharge showed normal sinus rhythm with a QTc of 493 milliseconds (Figure 3). At six-months follow-up, after she had been weaned off methadone, EKG QTc was 440 milliseconds (Figure 4), and she did not have any more arrhythmias.

DISCUSSION

Methadone inhibits hERG voltage gated potassium channel and prolongs action potential and QT interval. (2) In up to 80% of patients on MMT, some degree of QT prolongation is observed. (3) However, profound QT prolongation is less commonly reported in the literature, with an incidence varying from 2.4% to 16.7%.4 Methadone-induced TdP is quite rare and mostly reported in the literature as case reports. Higher dose of methadone; CYP450 inhibitors, which will inhibit metabolism of methadone; concomitant use of QT-prolonging substances, including alcohol and cocaine; and electrolyte abnormalities, such as hypokalemia, hypocalcemia, and existing conditions such as congenital long QT syndrome, have been associated with methadone-induced TdP. (4) In our case, amiodarone, a drug known to prolong QT, was used to treat VF and resulted in worsening of TdP. On the other hand, IV lidocaine resulted in resolution of TdP in our patient. It is not clear why our patient developed TdP three years after being on MMT and not sooner. Concomitant use of alcohol and low levels of serum potassium, calcium, and magnesium likely potentiated the effect of methadone on QT interval. However, the patient continued to have repeat episodes of TdP, even after the electrolytes were replaced and resolved completely when amiodarone was stopped and lidocaine infusion was started following a bolus administration. Amiodarone is well known to cause QT prolongation; however, there are conflicting studies regarding its role in causing TdP. In an animal study in a dog model, Opstall et al. showed that even though amiodarone therapy prolonged QT, it did not cause TdP. (5) In a case report on two patients, Lim et al. reported TdP shortly after administration of a low dose of oral amiodarone in the absence of predisposing factors. (6) Although amiodarone is an excellent antiaryrthmic drug, it should not be used for treatment of TdP, as it can actually worsen it. Lidocaine was successful in resolution of TdP in our patient.

Myocardial repolarization is primarily dependent on both slow ([I.sub.ks]) and rapid ([I.sub.kr]) outward potassium currents. Nearly all drugs that prolong QT interval do so by blocking rapid outward potassium ([I.sub.kr]), currently resulting in delayed phase 3 repolarization and prolongation of action potential duration.

Action potential duration lengthening and consequently prolonged repolarization cause early after depolarizations (EADs) due to activation or delayed inactivation of inward depolarizing sodium and L type calcium currents. EADs occur during phases 2 and 3 of the action potential as depolarization oscillations. EADs that reach threshold potential cause ventricular premature complexes that initiate runs of polymorphic ventricular tachycardia.

Drugs, including antiarrhythmic drugs that prolong repolarization, do not uniformly prolong repolarization in all three layers of myocardium and Purkinje fibers, resulting in heterogeneity of repolarization. Such heterogeneity can produce areas of unidirectional block and delayed conduction and lead to re-entry and TdP initiated by repetitive PVCs induced by triggered activity. (7-9)

Both Class IA (quinidine) and class III (sotalol) antiarrhythmic agents prolong action potential duration by blocking outward potassium current and cause TdP in a small percentage of patients who are on these drugs. In these patients, occurrence of TdP is facilitated by hypokalemia, hypomagnesemia, and drugs or agents that prolong myocardial action potential duration. Among class III antiarrhythmic drugs, amiodarone is least likely to produce TdP, even though it significantly prolongs QT interval because amiodarone prolongs action potential duration uniformly in all three layers of myocardium. Such uniform prolongation of APD results in less heterogeneous repolarization and refractoriness and thus, making the myocardium less susceptible to re-entry. Less commonly, amiodarone, by its non-competitive beta antagonism and blockade of inward L type calcium current, may actually reduce EADs and prevent TdP.

In the case reported here, amiodarone did not cause TdP but aggravated the arrhythmia caused by methadone. Also, low levels of potassium and magnesium likely potentiated the effect of methadone.

Lidocaine, a class IB antiarrhythmic agent, decreases APD in normal myocardial cells but prolongs it in ischemic, depolarized myocardial cells. Although the net effect of lidocaine in patients with myocardial disease is unpredictable, and it is not seen as an effective drug in treating TdP, there have been several case reports where IV lidocaine was successfully used in treatment of patients with TdP. (10,11) Lidocaine suppressed an episode of torsade, as well as prevented further episodes in a patient with Sotalol overdose. (12) Lidocaine may suppress the triggered potentials indirectly by preventing the development of EADs due to the shortening effect on the APD, (13) and by this way, could control TdP in these patients.

In conclusion, the treatment options that are considered most effective for TdP are removal of underlying cause (e.g. ischemia or medication), administration of Mg even when its level is normal, replacement of electrolytes with maintenance of potassium level at high normal, and modulation of heart rate by isoproterenol in presence of pause-dependent TdP or by atrial/external pacing to suppress EADs in presence of congenital or acquired QT prolongation. In patients with refractory TdP, lidocaine treatment can be considered, and amiodarone should be avoided.

REFERENCES

(1.) Hunter JD, Sharma P, Rathi S. Long QT syndrome. Contin Educ Anaesth Crit Care Pain 2008;8(2): 67-70. doi: 10.1093/bjaceaccp/ mkn003.

(2.) Kornick CA, Kilborn MJ, Santiago-Palma J, Schulman G, Thaler HT, Keefe DL, Katchman AN, Pezzullo JC, Ebert SN, Woosley RL, Payne R, Manfredi PL. QTc interval prolongation associated with intravenous methadone. Pain 105, 499-506.

(3.) Maremmani I, Pacini M, Cesaroni C, Lourecic M, Perugi G, Tagliamonte A. QT interval prolongation inpatients on long-term methadone maintenance therapy. Eur Addic Res 2005; 11:44-9.

(4.) Thanavaro KL, Thanavaro JL. Methadone-induced torsades de pointes: a twist of fate. Heart Lung. 2011 Sep-Oct; 40(5):448-53. Epub 2011 Mar 16.

(5.) Lim EH, Pak HN, Ahn JC, Song WH, Kim YH. Torsade de pointes induced by short-term oral amiodarone therapy. Europace (2006) 8(12): 1051-1053 doi:10.1093/europace/eul118

(6.) Opstal JM, Schoenmakers M, Verduyn SC, Marieke SH, de Groot M, Leunissen JDM, Van der Hulst FF, Mirella MC, Molenschot, Hein J.J. Wellens, and Marc A. Vos. Chronic Amiodarone Evokes No Torsade de Pointes Arrhythmias Despite QT Lengthening in an Animal Model of Acquired Long-QT Syndrome. Circulation. 2001; 104:2722-2727, doi:10.1161/hc4701.099579.

(7.) El-Sherif N, Craelius W, Boutjdir M, et al. Early after Depolarizations and Arrhymogensis. J Cardiovas Electrop 1990;1:45-60

(8.) Yap YG, Camm Aj. Drug Inducted QT Prolongation and Torsades de Pointe. Heart 2003;89:363-72.

(9.) Hohnloser SH, Klinghaben T, Singh BN. Amiodarone Associated Proarrhythmic effects - A Review with Special Reference to Torsades de Pointes Tachycardia. Ann Int Med 1994;126:529-35

(10.) O'Brien CE, Harik N, James LP, Seib PM, Stowe CD. Cesium-induced QT-interval prolongation in an adolescent. Pharmacotherapy. 2008 Aug;28(8):1059-65.

(11.) Tajiri O, Ito H, Yago Y, Masumori Y. Torsade de pointes (TdP) observed during general anesthesia for cerebral aneurysm clipping in a patient with QT prolongation. Masui. 2011 Sep;60(9):1090-3.

(12.) Assimes TL, Malcolm I. Torsade de pointes with sotalol overdose treated successfully with lidocaine. Can J Cardiol. 1998 May;14(5):753-6.

(13.) Takanaka C, Ogunyankin KO, Sarma JS, Singh BN. Antiarrhythmic and arrhythmogenic actions of varying levels of extracellular magnesium: possible cellular Basis for the Differences in the Efficacy of magnesium and Lidocaine in Torsade de Pointes. J Cardiovasc Pharmacol Ther. 1997 Apr;2(2):125-134.

Saurabh Rajpal, MBBS, MD; Amandeep S. Mundi, MD; Pratap C. Reddy, MD, FACC; Nuri I. Akkus, MD, FACC

Drs. Rajpal and Mundi are Cardiology Fellows at Louisiana State University Health Sciences Center in Shreveport. Dr. Reddy is the Joe E. Holoubek, MD Professor of Medicine, Director of the Cardiology Fellowship Program, and Chief of the Division of Cardiology at LSUHSC-Shreveport. Dr. Akkus is an Assistant Professor and Director of the Cardiac Catheterization Laboratory at LSUHSC-Shreveport.
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Author:Rajpal, Saurabh; Mundi, Amandeep S.; Reddy, Pratap C.; Akkus, Nuri I.
Publication:The Journal of the Louisiana State Medical Society
Article Type:Case study
Date:Nov 1, 2013
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