Journal of Addictive Diseases

ISSN: 1055-0887 (Print) 1545-0848 (Online) Journal homepage: https://www.tandfonline.com/loi/wjad20

Cocaine-Related Torsade de Pointes in a

Methadone Maintenance Patient

Mori J. Krantz MD , Shane B. Rowan MD & Philip S. Mehler MD

To cite this article: Mori J. Krantz MD , Shane B. Rowan MD & Philip S. Mehler MD (2005)
Cocaine-Related Torsade de Pointes in a Methadone Maintenance Patient, Journal of Addictive
Diseases, 24:1, 53-60, DOI: 10.1300/J069v24n01_05

To link to this article: https://doi.org/10.1300/J069v24n01_05

Published online: 17 Oct 2008.

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 Cocaine-Related Torsade de Pointes
in a Methadone Maintenance Patient
Mori J. Krantz, MD
Shane B. Rowan, MD
Philip S. Mehler, MD

ABSTRACT. A patient maintained on methadone for opioid-depend-

ency developed recurrent syncope. Episodes occurred within hours after
using cocaine, and were initially presumed secondary to seizure disorder.
However, the patient subsequently suffered a cardiac arrest, and poly-
morphic ventricular tachycardia (torsade de pointes) was documented.
Other than cocaine and methadone the patient was receiving no addi-
tional agents known to prolong the QT interval. Low serum methadone
concentrations and marked reversible left ventricular systolic dysfunc-
tion were noted during the hospitalization. These findings, in conjunc-
tion with a history of torsade de pointes temporally related to cocaine
abuse, suggest that cocaine was a major precipitant of arrhythmia. Re-
cent experimental studies have shown that cocaine and methadone pro-
long the QT interval through the same mechanism. We examine the
effects of cocaine and methadone on cardiac conduction in the context of
the opioid-dependent population. [Article copies available for a fee from
The Haworth Document Delivery Service: 1-800-HAWORTH. E-mail address:
<docdelivery@haworthpress.com> Website: <http://www.HaworthPress.com>
 2005 by The Haworth Press, Inc. All rights reserved.]

Mori J. Krantz, Shane B. Rowan, and Philip S. Mehler are affiliated with the De-
partment of Internal Medicine, Denver Health Medical Center and the University of
Colorado Health Sciences Center.
Address correspondence to: Mori J. Krantz, MD, Denver Health Medical Center,
Department of Medicine, Cardiology Division, Mail Code 0960, 777 Bannock Street,
Denver, CO 80204-4507 (E-mail: Mkrantz@dhha.org).
The authors wish to thank Marc N. Gourevitch, MD, MPH, for his conscientious
review of their manuscript.
Journal of Addictive Diseases, Vol. 24(1) 2005
http://www.haworthpress.com/web/JAD
 2005 by The Haworth Press, Inc. All rights reserved.
Digital Object Identifier: 10.1300/J069v24n01_05 53
54 JOURNAL OF ADDICTIVE DISEASES

KEYWORDS. Cocaine, torsade de pointes, methadone, drug-induced

arrhythmia

REPORT OF A CASE

A 46-year-old female with a history of heroin abuse had been suc-

cessfully maintained on 80-mg daily of methadone for over one year at
an opioid treatment program (OTP). She had no other significant medi-
cal history. Over the course of two months she began abusing cocaine
by inhalation and injection. She subsequently developed frequent epi-
sodes of self-limited syncope over the course of one month. These
syncopal events consistently occurred within an hour after cocaine use.
Episodes lasted approximately one to two minutes, occurred with a
prodrome of dizziness, and resolved without apparent sequelae. Family
members described the episodes as tonic-clonic seizures without subse-
quent confusion. Care providers at the OTP referred her for neurology
consultation, but a cardiovascular etiology for syncope was not pur-
sued.
On the day of hospital admission her family reported that the patient
experienced a transient syncopal episode, walked outside where she
collapsed and became unresponsive. Upon arrival, paramedics docu-
mented her cardiac rhythm to be polymorphic ventricular tachycardia,
consistent with torsade de pointes (Figure 1a). Cardioversion with 360
joules restored normal sinus rhythm with left bundle branch block (Fig-
ure 1b). Treatment with intravenous magnesium, epinephrine, and lido-
caine was initiated. The left bundle-branch block resolved after 24
hours and repeat electrocardiogram (ECG) demonstrated marked pro-
longation of the corrected QT interval (635 msec) with dramatic T-wave
inversion (Figure 1c).
The patient was admitted to the intensive care unit in a comatose
state. Cardiac auscultation revealed distant heart tones, and the remain-
der of her examination was normal. Urine toxicology screen confirmed
the presence of cocaine, but no tricyclic antidepressants or other QT
prolonging medications were detected. Admission laboratory studies
demonstrated mild hypokalemia and a serum methadone concentration
at the lower limit of normal (Table 1). Additional laboratory results
were within normal limits. A transthoracic echocardiogram demon-
strated severely reduced left ventricular systolic function, which im-
proved over the course of her hospitalization (Table 2). No further
episodes of arrhythmia were noted. She was felt to have irreversible
 Krantz, Rowan, and Mehler 55

FIGURE 1. ECG tracings

a)

b)

c)

a) Rhythm strip documenting torsade de pointes on initial presentation

b) Representative lead (V6) illustrating left bundle branch block morphology
c) Representative lead (V4) showing marked T-wave abnormality and QT prolongation

anoxic brain injury secondary to cardiac arrest and after a prolonged

hospitalization was discharged to a chronic care facility.

DISCUSSION

Torsade de pointes is a form of polymorphic ventricular tachycardia

characterized by a twisting of the mean electrical axis around an iso-
electric line and occurring in the setting of QT interval prolongation.1
Drug-induced (acquired) QT prolongation often results from delayed
cardiac repolarization secondary to blockade of potassium ion chan-
56 JOURNAL OF ADDICTIVE DISEASES

TABLE 1. Clinical and laboratory data

Admission Day 1 Day 3

Potassium (mmol/L)* 3.0 4.4 4.0
Magnesium (mEq/L)† 5.7‡ 1.9 2.0
QT interval corrected for heart rate (msec)¶ 604 635 590
Serum methadone level (ng/mL)§ 380 380 300
*Reference range 3.5-5.0 mmol/L.
† Reference range 1.5-3.5 MeEq/L.
‡ Level obtained immediately after intravenous magnesium administered in emergency department.
¶ Bazett’s formula (QT/square root of RR interval), Normal < 450 in men and < 470 in women.
§Therapeutic trough level > 200 ng/ml.

TABLE 2. Echocardiographic data showing improvement in cardiac size and

function

Time of study LV* ejection fraction LV diastolic dimension LV Diastolic volume

(%) (normal range (cm) (normal range (ml) (normal range
56-78%)† 3.6-5.4 cm)‡ 45-65 ml)‡
Presentation 25 6.08 156
One week 33 5.03 111
Three weeks 40 4.50 92
* LV denotes left ventricular.
† Kennedy JW, et al. Circulation 1966;34:272.
‡ Weyman AE. Principles and practice of echocardiography, 1994, Lea & Febiger, Philadelphia, 2nd edition.

nels.2 Delayed repolarization manifests as QT interval prolongation on

the surface 12-lead ECG. Torsade de pointes is frequently a self-termi-
nated arrhythmia that presents with syncope or presyncope, but may re-
sult in ventricular fibrillation and sudden death.
Patients receiving methadone maintenance therapy (MMT) for the
treatment of opioid dependency may be particularly vulnerable to tor-
sade de pointes. Nearly 40% of patients entering MMT have comorbid
psychiatric disease beyond substance abuse disorder.3 Many of the
medications used to treat these psychiatric disorders, particularly anti-
depressants and anti-psychotics, have QT prolonging effects. More-
over, recent data suggest that methadone itself is associated with QT
prolongation and torsade de pointes.4 As with many psychiatric medica-
tions, the proarrhythmic effects of methadone appear to be mediated
through blockade of HERG-potassium ion channels in cardiac myocytes.5
 Krantz, Rowan, and Mehler 57

Another critical risk factor for cardiac arrhythmia in the opioid-de-

pendent population is cocaine abuse, as entrants into MMT are often ad-
dicted to both heroin and cocaine.6 Cocaine is an increasingly common
drug of abuse among Americans; between 1994 and 1998, the number
of new cocaine users increased from 514,000 to 934,000 per year.7 This
epidemic is magnified in the MMT population where cocaine abuse has
been reported in more than half of patients.8,9 Cocaine is associated with
numerous cardiovascular complications (Table 3), most notably torsade
de pointes.10-12 Like many proarrhythmic drugs, cocaine leads to QT
prolongation through blockade of the HERG-potassium ion channel,
though it also inhibits cardiac depolarization by sodium-channel block-
ade.10
It may be very difficult to identify a single causative factor when tor-
sade de pointes occurs in the MMT population. Although recent atten-
tion has focused on the effects of methadone on QT prolongation and
torsade de pointes,4,14,15 it is important to recognize that methadone is
rarely the sole contributor to this arrhythmia. Electrolyte disturbances
(hypokalemia, hypomagnesemia), occult structural heart disease, and
concomitant administration of other QT prolonging medications are of-
ten implicated in cases of acquired torsade de pointes. In the case pre-
sented here, a number of factors may have predisposed our patient to
arrhythmia: hypokalemia, female gender, left ventricular dysfunction,
methadone therapy and active cocaine abuse.
Several factors suggest that methadone was not the primary causative
agent in the development of torsade de pointes in our patient. First, she
was on a stable, moderate dose (80-mg daily) of methadone for over a
year without cardiac sequelae. Syncopal episodes emerged only after
she began abusing cocaine. In addition, the temporal correlation between
cocaine use and syncope supports a causal role of cocaine in arrhythmia
development. Second, the patient’s serum methadone concentration
was within the therapeutic range throughout her hospitalization (Table 1).
In contrast, previously reported cases of methadone-related torsade de
pointes, have been associated with very high daily doses (mean ~ 400
mg) of methadone,4 which presumably led to high serum concentra-
tions. The effect of methadone on the QT interval in these patients was
also dose-dependent, which further supports the notion that metha-
done’s proarrhythmic effects are most likely to manifest with high-dose
therapy.16 Another potential contributor to our patient’s arrhythmia was
the presence of left-ventricular systolic dysfunction. This has never
been reported as an adverse effect of methadone, though it is a well-doc-
umented complication of cocaine use.17 Cocaine induced myocardial
58 JOURNAL OF ADDICTIVE DISEASES

TABLE 3. Adverse cardiac effects of cocaine.*

ISCHEMIC COMPLICATIONS
Increased coronary microvascular resistance†
Coronary artery vasospasm
Chest pain syndrome
Unstable angina
Myocardial infarction
Accelerated atherosclerosis
RHYTHM DISTURBANCES
Sinus tachycardia
Sinus bradycardia
Asystole
Complete heart block
Bundle branch block
Supraventricular tachycardia
Accelerated idioventricular rhythm
Ventricular tachycardia
Torsade de pointes
Brugada pattern‡
MISCELLANEOUS
Infective endocarditis (from intravenous use)
Chronic and malignant hypertension
Aortic dissection
Cardiomyopathy
*Adapted from Lang et al.10
† Kelly RF et al. Clin Cardiol. 2003;26:319-322.
‡ Right bundle branch block pattern and ST-segment elevation in right
precordial leads.

dysfunction probably results from excessive sympathetic activation

secondary to blockade of presynaptic catecholamine reuptake. Finally,
the occurrence of transient left bundle branch block merits consider-
ation; although a single case of QRS-interval prolongation has been de-
scribed with high-dose intravenous methadone,18 this is more likely to
result from cocaine given its aforementioned sodium-channel blocking
effects.
 Krantz, Rowan, and Mehler 59

In summary, we describe a methadone-treated patient with recurrent

syncope and resuscitated sudden death due to torsade de pointes. This
case illustrates the inherent challenge in defining an arrhythmic etiol-
ogy in the MMT population. Torsade de pointes frequently results from
a confluence of factors, making it difficult to identify a single cause. Al-
though a prospective cohort study of 132 entrants into MMT demon-
strated that methadone prolongs the QT interval,19 none of the study
participants developed torsade de pointes. It is instructive to note that in
a recently published series of torsade de pointes attributed to methadone
toxicity, traces of cocaine were present in each case.21 Observational
data suggest that higher doses of methadone are associated with a de-
crease in illicit drug use including cocaine.20 However, since higher-
dose methadone predisposes patients to QT prolongation, this creates a
potential substrate for arrhythmia in MMT patients actively abusing co-
caine. Currently, in the absence of prospective data, we believe that es-
calation of methadone dose should not be recommended as an adjunct to
treating cocaine abuse. OTP providers should have a high level of suspi-
cion for arrhythmia in MMT patients who complain of near-syncope
and seizures. Despite the fact that MMT patients tend to be relatively
young and lack structural heart disease they may be uniquely suscepti-
ble to arrhythmic syncope rather than primary seizure disorder.22 MMT
patients presenting with syncope or seizures should be referred promptly
for screening electrocardiography to assess for QT interval prolonga-
tion.

REFERENCES
1. Dessertenne F. [Ventricular tachycardia with 2 variable opposing foci]. Arch
Mal Coeur Vaiss. 1966;59:263-72.
2. Vincent MG. Long QT syndrome. Cardiol Clin. 2000;18:309-25.
3. Brooner RK, King VL, Kidorf M, Schmidt CW Jr, Bigelow GE. Psychiatric and
substance use comorbidity among treatment-seeking opioid abusers. Arch Gen Psychi-
atry. 1997 Jan;54(1):71-80.
4. Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS.
Torsade de pointes associated with very-high-dose methadone. Ann Intern Med.
2002;137:501-4.
5. Katchman AN, McGroary KA, Kilborn MJ, Kornick CA, Manfredi PL, Woosley
RL, Ebert SN. Influence of opioid agonists on cardiac human ether-a-go-go-related
gene K(+) currents. J Pharmacol Exp Ther. 2002;303:688-94.
60 JOURNAL OF ADDICTIVE DISEASES

6. Kosten TR, Gawin FH, Rounsaville BJ, Kleber HD. Cocaine abuse among
opioid addicts: Demographic and diagnostic factors in treatment. Am J Drug Alcohol
Abuse. 1986;12(1-2):1-16.
7. Idem. Summary of findings from the 1999 national household survey on drug
abuse. Rockville, MD: Substance abuse and mental health services administration, Au-
gust 2000. DHHS publication no. (SMA) 00-3466.
8. Borg L, Broe DM, Ho A, Kreek MJ. Cocaine abuse sharply reduced in an effec-
tive methadone maintenance program. J Addict Dis. 1999;18(4):63-75.
9. Joseph H, Stancliff S, Langrod J. Methadone maintenance treatment (MMT): A
review of historical and clinical issues. Mt Sinai J Med. 2000;67(5-6):347-64.
10. Lange RA, Hillis LD. Cardiovascular complications of cocaine use. N Engl J
Med. 2001;345:351-8.
11. Riaz K, McCullough PA. Fatal case of delayed repolarization due to cocaine
abuse and global ischemia. Rev Cardiovascular Med. 2003;4(1):47-53.
12. Khan IA, Win MT, Bali AJ, Vasavada BC, Sacchi TJ. Torsades de pointes: A
case with multiple variables. Am J Emerg Med. 1999;17:80-5.
13. Ferreira S, Crumb JR, Carlton CG, Clarkson CW. Effects of cocaine and its ma-
jor metabolites on the HERG-encoded potassium channel. J Pharmacol Exp Ther.
2001;299:220-6.
14. Bittar P, Piguet V, Kondo-Oestreicher J, et al. Methadone induced long QTc and
“torsade de pointe.” Swiss Medical Forum. 2002 (Apr 10, Suppl 8):36S.
15. Huber A, Ling W, Fradis J, et al. Comparison of the effects of methadone and
LAAM on the electrocardiogram [Abstract]. Drug Alcohol Depend. 2001;63:S70.
16. Krantz MJ, Kutinsky IB, Robertson AD, Mehler PS. Dose-related effects of
methadone on QT prolongation in a series of patients with torsade de pointes. Pharma-
cotherapy. 2003 Jun;23(6):802-5.
17. Missouris CG, Swift PA, Singer DR. Cocaine use and acute left ventricular dys-
function. Lancet. 2001;357(9268):1586.
18. Karir V. Bradycardia associated with intravenous methadone administered for
sedation in a patient with acute respiratory distress syndrome. Pharmacotherapy.
2002;22:1196-9.
19. Martell BA, Arnsten JH, Ray B, Gourevitch MN. The impact of methadone in-
duction on cardiac conduction in opiate users. Ann Int Med. 2003;139(2):154-5.
20. Maxwell S, Shinderman MS. Optimizing long-term response to methadone
maintenance treatment: A 152-week follow-up using higher-dose methadone. J Addict
Dis. 2002;21(3):1-12.
21. De Bels D, Staroukine M, Devriendt J. Torsade de pointes due to methadone.
Ann Int Med. 2003;139(2):E156.
22. Krantz MJ, Mehler PS. Synthetic opioids and QT prolongation. Arch Intern
Med 2003;163:1615 Comment on: Goldschlager et al. Etiologic considerations in the
patient with syncope and an apparently normal heart. Arch Int Med. 2003;163:151-62.