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Addiction treatment forum - does methadone maintenance treatment affect heart health?

A D D I C T I O N
T R E A T M E N T
Does Methadone
Maintenance Treatment
Affect Heart Health?
Overview
Many factors can upset normal heart rhythm, provoking distur- bances known as cardiac arrhythmias. Recent warnings aboutLAAM in that regard also raised questions about whethermethadone might influence cardiac adverse events.
Persons coming into methadone maintenance treatment (MMT) programs typically have multiple risk factors for heart ill-ness, starting with their abuses of potentially cardiotoxic substances, such as heroin, cocaine, alcohol, and tobacco. Manypatients also have physical illness that may contribute to heartproblems. And, the variety of medications often prescribed forthese patients, in addition to methadone, may interact to producecertain cardiac electrical conduction disturbances.
Medical researchers continue to explore factors that may alter cardiac electrical conduction processes to cause arrhythmias.
Laboratory studies have demonstrated an effect of methadone oncardiac electrical conduction, but such approaches have limitationsand their relevance for patients in MMT programs is questionable.
Assessing risks of potential heart problems in MMT patients musttake into account diverse factors.
At present, based on more than 35 years of accumulated scien- tific research and its safety record in millions of patients,methadone itself does not appear to have clinically harmful effectson heart health. This report summarizes the conclusions of evidence-based research and the published commentary of expertsin the field to provide a current and balanced perspective. Somesuggested action steps for MMT clinics are provided.
Heightened Concern
women generally have longer QTc intervals than men.10-12 This Is oral methadone, as used in methadone maintenance treat- diversity of factors can make it difficult to interpret the signifi- ment (MMT) for opioid addiction, possibly associated with distur- cance of suspected QTc lengthening in individual patients.
bances of heart rhythm, called cardiac arrhythmias? This questionwas prompted by several events.
Defining "Prolonged" QT
In Spring 2001, the European Agency for the Evaluation of How long can the QT interval become before there is a risk Medicinal Products (EMEA) withdrew LAAM (levacetylmethadol or Orlaam®) from the market due to reported adverse cardiac The EMEA1,13 and others5,6,11,14-17 have suggested that QTc-inter- events.1 At the same time, the United States Food and Drug val values of 500 msec or more, or increases of greater than 601,13 Administration strengthened warnings about potential cardiac to 7511,16 msec from baseline, could be considered abnormal and problems associated with LAAM and highlighted them in a black box on product labeling.2 These directives were based on a rela- It has been suggested that the upper limits of normal QTc- tively small number of patients who were taking LAAM and interval values are greater than usually acknowledged8,15 and experienced serious cardiac electrical conduction disturbances might range from 420 to 500 msec.17 Yet, many studies have used known as Long QT Syndrome and Torsade de Pointes.
that range to indicate abnormal QTc lengthening, reporting 8% Although LAAM differs from methadone by its longer-term to 23% of patients at risk for arrhythmia.8 Thus, premature action and metabolites, there was speculation that methadone alarms may have been sounded in many cases.
also might influence such heart problems.1 Further interest wasstimulated by laboratory research from a team at Georgetown Long QT Syndrome (LQTS)
University, reporting methadone effects on certain electrical cur- A consistent, persistent, and abnormally prolonged QTc interval is referred to as Long QT Syndrome or LQTS. It can be an Is methadone harmful, helpful, or neutral when it comes to inherited condition, called congenital LQTS, involving defects heart health? This question must be considered in the light of sci- in genes that control electrical conduction channels in heart entific evidence and also take into account the special population LQTS also may be caused by certain drugs or toxins, abnormal levels of electrolytes (e.g., potassium, calcium, or magnesium), or certain physical ailments. This is known as Heart Rhythm & Arrhythmia
As a syndrome, there may be multiple aspects of LQTS. If the Electrical currents regulate heart rhythm in an orderly and heart muscle recharging process (repolarization) is extremely time-sensitive fashion. Disruption of electrical conduction delayed, such as by drugs that block electrical currents, it can processes can lead to life-threatening arrhythmias.
greatly slow normal heartbeat, which may influence arrhythmia.
Or, the ventricles may fire before they are fully recharged, ECGs Tell The Tale
An electrocardiograph (ECG) measures electrical current moving through the heart during each heartbeat, and an impor- A Lethal Twist: Torsade de Pointes (TdP)
tant portion of the characteristic waveform is the QT interval.
When the QTc becomes prolonged, there also is the risk of a See figure. It represents the time period from when the heart
rapid, abnormal heart rhythm called ventricular tachycardia
occurring. The particular ventricular tachycardia most frequently
associated with LQTS displays an ECG waveform that becomes
distorted in a series of undulating peaks twisting about a central
axis. See figure. This is called Torsade de Pointes (TdP), a French
phrase meaning "twisting of the points."15,19-21
ventricles discharge electrical energy and contract (called depo-
larization
) to when the ventricles become recharged and ready
again to pump blood through the body (repolarization). These
processes are controlled by electrically-charged calcium, sodium,
and potassium ions.4-7 (See sidebar for further details.)
The QT interval, measured in fractions of a second or mil- liseconds (msec), is a vital indicator of healthy heart function.
Prolongation of the QT interval to greater than normal lengthhas been considered a sign of potential arrhythmia.6-8 During a TdP episode, often brought on by exercise or sudden stress, the person may experience palpitations, dizziness, Measuring QT
or lightheadedness. In more extreme cases, the person may faint Heart rate affects QT length; for example, it becomes short- (called syncope) or have what appears as a seizure due to er as the heart speeds up. Therefore, the QT interval is usually insufficient blood flow to the brain.15,21 corrected for heart rate and expressed as QTc (QT-corrected),9 TdP can resolve on its own, with a return to more regular so comparisons can be made independent of heart rate. heart rhythm and the person recovering. However, further TdP (Also see sidebar.)
episodes may quickly follow and possibly degenerate into There are several obstacles to accurately and reliably mea- ventricular fibrillation (convulsive twitching), causing death if suring QTc intervals, and there are numerous individual factors that may influence a particular person’s QTc length. For example, arrhythmia.4,21 An estimated 7000 to 8000 of those deaths are in A Closer Look at Arrhythmia
young persons, with LQTS accounting for roughly half ofthem.4,21,29 After accumulated electrical energy reaches a sufficient LQTS occurs in all races and ethnic groups, and may be more level in the ventricles, calcium (Ca) and sodium (Na) ions flow common than presently imagined. An investigation in one med- into muscle cells, serving as a discharging "trigger" mechanism.
ical center found a 7% prevalence of LQTS in more than 34,000 This depolarization process reaches a peak at the R position of patients undergoing ECG screening during a 6-month period.30 the ECG waveform, causing the ventricles to contract.6,7 A genetic tendency for LQTS may exist in about 1 in 5000 See figure.
persons, or roughly 50,000 in the U.S. and more than 200,000worldwide.4,21,29 The death rate for patients with inherited LQTShas been estimated at 1% to 2% per year.20 An important indicator of inherited risk for persons coming into MMT programs would be a history of blood relatives whoexperienced sudden cardiac death.
Substance Abuse
Besides opioid dependency, a high prevalence of other substance abuse would be expected in persons entering MMT,including: cocaine, alcohol, tobacco, and marijuana.31 Cocaine has long been recognized as toxic to the heart, slow- ing sodium channels and depressing heart rhythm,7 and possiblycausing heart attack.32 The QTc may be prolonged in 17%33 to19%34 of patients who abuse alcohol and a third of those may Ventricular recharging primarily involves a flow of potassi- experience rapid heartbeat.33 Tobacco smoking has long been um ions (K) out of heart muscle cells. At least 7 different types known as a heart attack risk, and a recent report also has of potassium ion channels have been identified, and the channel most often involved in acquired LQTS is called the In a long-term study of heroin addicts, the death rate due to rapid component of the delayed rectifier potassium current.
cardiovascular diseases was 12%.31 Early studies found that 61%36 This repolarization process extends to the end of the recoveryT wave.6,7,22 to 84%37 of heroin addicts had adverse changes in their ECG The QT interval is most commonly corrected for heart rate waveforms. One study of persons entering an MMT program using Bazett’s formula: QTc = QT interval divided by the square noted that 31% exhibited QTc prolongation.36 root of the preceding RR interval. However, accurate measure- Taken together, the findings suggest that a significant ment of QT on the ECG rhythm strip is complicated by a lack of proportion of patients entering MMT might be expected to have standardization in ECG recorders, subtle changes in waveforms, irregularities in their ECG waveforms. These might consist and differences in interpreting readings.10,11,13-15 predominantly of longer QTc intervals than would be found in Furthermore, individual patient differences may affect QT length: e.g., abnormal electrolyte levels, physical illness, anddrug or alcohol consumption,6,23 shift work or time of day the Physical Illness
ECG reading is taken,24,25 postural changes during ECG record- A number of physical illnesses are associated with prolonga- ing,26 and even a full stomach.27 Calculated QTc intervals may be tion of the QTc interval, including: anorexia, cardiovascular 10% longer in women until age 50, when the QTc in men disease, endocrine abnormalities, central nervous system It should be noted that several authors have proposed that disorders, diabetes, electrolyte disturbances, HIV, liver disease, there actually is no "cutoff" level for QTc prolongation that obesity, and others.8,17 Thus, many patients in MMT programs clearly predicts the induction of cardiac arrhythmia or TdP. Also, could be at risk due to these conditions.
the relationship between QTc and TdP in general is poorlydefined, although women, with longer QTc intervals, are most Medications
prone to developing TdP. Many risk factors for developing Medications account for most cases of acquired LQTS that heart rhythm disturbances other than the QTc interval may be can induce TdP.17,38 Many patients in MMT programs are treated with multiple drugs that may alter electrical conduction in heartmuscle tissues.7,10,19,21,22 Patients with preexisting heart conditions may be receiving Risk Factors in MMT Patients
cardiovascular drugs. Many of these, especially those with antiar- Although there can be a strong hereditary influence in rhythmic properties, affect ion channels and electrical conduction developing life-threatening LQTS and/or TdP, it is believed that currents, and their misuse or combination with interacting acquired forms due to physical illness or drugs are much more medications can result in adverse events.7 common. Many risk factors for cardiac arrhythmia are typically Most conventional and some newer atypical antipsychotic agents have been associated with drug-induced QTc lengtheningand potential arrhythmias.8,17,39 Also, the tetra- and tricyclic, and LQTS Prevalence
some SSRI, antidepressants may provoke adverse cardiac In general, cardiac arrhythmias may account for more than reactions.8,17,21 Experience over the years has demonstrated that 10% of all natural deaths.4 There are 300,000 to 400,000 sudden many other noncardiac drugs sometimes used in MMT patients cardiac deaths each year in the U.S., with most due to ventricular also may influence LQTS and/or TdP.21,40 See chart.
Laboratory Investigations
Some* Noncardiac Drugs
A team at Georgetown University recently reported that Influencing LQTS and/or TdP7,8,10,17,21,39,40
methadone diminished potassium ion flow and reduced repolar- ization currents by half their maximal strength in human heart- cell cultures.3 However, it is not known what this might mean clin- ically and the effect was seen at methadone blood concentra- tions nearly 9 times greater than usual therapeutic levels recom- Earlier laboratory research had demonstrated similar effects.
In sheep heart cells, methadone at very high concentrations delayed electrical conduction.45 In squid and chick cells, methadone slowed potassium and, to a lesser degree, sodium *Partial list based on selections from the most prescribed drugs in the U.S.,Sigler & Flanders, Inc., 2000. and calcium electrical currents across cell membranes.46 This effect **Potentially minor effects at recommended therapeutic doses. also was demonstrated by reduced swimming speed in proto- [Brand names are registered trademarks of the respective manufacturers.] zoa,47 and the slowing was more than doubled by the addition ofalcohol.48 Lengthening of the QT interval can be an important precur- In guinea-pig45 and cat49 heart muscle, methadone strength- sor to TdP; however, not all drugs that prolong the QT also cause ened contractile force (called inotropic effect), which might be TdP. Furthermore, TdP may be caused by drugs having no prior beneficial in some patients. However, at very high doses, 10 times peak toxic concentrations in humans, methadone produced anapparent reduction in electrical excitability in cat heart-muscle Drug Interactions
cells accompanied by a negative inotropic effect – that is, it weak- Interactions during administration of multiple drugs can be ened contractility.50 This effect also was observed in rat tissues51 a critical risk factor for LQTS and TdP.3,5,19,22 It has been observed and appears related to methadone’s ability to retard inward cal- that nearly three-quarters of all adverse events associated with methadone, including those affecting cardiac function, involve It should be noted that laboratory research in cell cultures or animals does not necessarily translate into clinical significance in Simultaneous use of drugs that compete for or inhibit liver patients. Laboratory investigations allow studying pure drug enzymes needed for metabolism may result in elevated concen- effects at known concentrations;5 however, they do not take into trations of agents that could induce arrhythmia.3,5,19,22,39 account the idiosyncrasies of metabolism and cardiac function in Methadone, being variously metabolized by up to 5 liver humans.5,10,54 Differences in animal metabolism and response, and enzymes, may interact with many other medications and result in the experimental methods employed, have resulted in inconsis- tent reports of methadone’s effects on electrical conduction.50,55 One study found that roughly 38% of 206 psychiatric Furthermore, methadone was usually applied directly to patients with a prolonged QTc (defined conservatively as greater heart tissues on a single-dose basis and at high concentrations, than 420 msec) were on methadone. However, virtually all of the rather than simulating daily doses achieving steady-state blood methadone patients also received one or more antipsychotic serum levels that typify MMT.54 Also, methadone concentrations medicines that might have affected cardiac electrical conduc- in human heart muscle are unknown and may be lower than Furthermore, it has been proposed that some persons, per- haps more than commonly assumed, may be silent gene carriers Cardiac Advantages?
for LQTS. Such persons are at genetically increased risk from cer- Effects on cardiac electrical conduction do not automatically tain medications and are more prone to develop drug-induced imply harmful consequences, and actually may be a sign of a arrhythmias than patients who receive the same drug(s) safely.44 drug’s usefulness as a heart medication.19 Over the years, certain However, it has been suggested that use of drugs known to opioids, including methadone, have demonstrated cardioprotec- prolong QTc is not necessarily harmful, unless: a) the drug is tive effects and have been important adjuncts in treating heart administered rapidly and directly into the system (e.g., IV injec- attacks and coronary artery disease.32,50 tion), b) concomitant metabolic inhibitors are used, and/or c) Also, as noted above, methadone appears to reduce calcium other risk factors exist. Even in these circumstances, it is difficult flow into heart tissues. It has been suggested that decreases in to determine an upper threshold for prolongation of the QTc intracellular calcium may protect the heart from calcium overload interval that predicts development of TdP or other arrhythmia.10 during stress reactions. Furthermore, research in rats demon- There is an ongoing need to assess risk-benefit relationships strated that cocaine-related myocardial infarction could be pre- of multidrug administration in MMT patients. As one researcher vented by blocking calcium channels, and experiments in mice noted, "disparate factors ranging from inappropriate multidrug found that opioids helped protect the heart from adverse therapy to a glass of grapefruit juice can render the heart of any patient susceptible to ventricular arrhythmias." Physicians should The calcium-slowing effects of methadone may be analo- become more knowledgeable regarding drug interactions and gous to the actions of certain heart medications that suppress cardiac risk factors so they might prevent adverse situations some forms of arrhythmia.57 One author commented on similari- ties of methadone and verapamil (e.g., Calan®, Verelan®),52 a cal-cium-channel-blocking agent indicated for the treatment of Research Observations
hypertension and angina, and to prevent arrhythmia related to Results of laboratory investigations into methadone’s influ- rapid heartbeat. It has not appeared on any lists of agents known ence on cardiac electrical conduction have been conflicting, and to prolong QTc or induce TdP and, in fact, calcium-blocking some might be interpreted as implying cardiac benefits of methadone. Clinical studies in MMT patients specifically focusingon cardiac issues have been limited. Thus, while laboratory research suggests that methadone MMT Practice Implications
may influence certain ion channels and cardiac electrical conduc- There currently does not appear to be conclusive research tion, those effects have not been proved harmful in humans.
evidence suggesting that oral methadone itself is clinically harm- Some of methadone’s actions demonstrated in the laboratory ful to heart health.1 This is supported by methadone’s successful actually may provide a degree of cardiac protection in certain use for the treatment of opioid dependency in millions of MMT patients, although this still needs to be demonstrated in Long History of Safety
Clinical Explorations
Long-term clinical studies in large populations of methadone In one small study of MMT patients,36 66% had ECG alter- patients have found the medication to be safe and generally ations during their early tenure in the program, primarily QTc without toxic effects,58-60 even though risks for cardiac complica- prolongations (of undefined length) in 34%, which were likely tions were numerous in many patients. In one of the studies, 15% preexisting conditions. However, after 4 or more months in MMT, of deaths were due to tobacco-smoking-related heart disease, and abstinence from all illicit drugs and alcohol, the QTc irregu- 20% were due to HCV, 15% were AIDS-related, and 5% were larities vanished in 54% of those patients retested. Whereas, 4 associated with morbid obesity.61 In another study, 40% of deaths patients who continued sporadic drug abuse while in MMT devel- were drug-abuse-related, primarily alcohol.62 oped QTc prolongations that were not initially present.
Investigations of drug-related fatalities worldwide consis- Recently, there have been questions about whether tently have found few if any deaths directly related to methadone doses higher than those typically used in many MMT methadone.61,62 Toxicity due to multidrug abuse has been the programs might engender added cardiac risks and justify extra precautions.1,42 A case series from one large MMT clinic28 exam- The methadone induction phase is sometimes problemat- ined 12 patients receiving 500 mg or more of daily methadone ic,41,42 although 80% of deaths during this period have been (average 812 mg/d; range 500-1400 mg/d). See graph. All
attributed to mixed-drug overdose.41 This period prior to patients were taking comedications and many had physical methadone stabilization could be a time of increased cardiac risk, illness, such as HIV, hepatitis, liver cirrhosis, hypertension, and since there might be unexpected surges in blood levels of car- diabetes; although none of the patients had signs or symptoms dioactive comedications and/or abused substances due to meta- Steps To Consider
Sound medical practice dictates a need for continued vigi- lance to identify individual patient risk factors for cardiac illness.
Added to these are risks that may be imposed by treatment reg-imens involving multiple medications – iatrogenic risk factors.
The goal is to provide individualized treatment plans that preserve heart health. To help achieve this, clinics may want toadopt certain practices: • Patients entering MMT should be screened for cardiac risk factors and medical records for all patients should be period-ically updated in this regard.
• Records should note prior heart problems and current heart health status, family history of heart conditions, past and cur-rent substances abused (including tobacco), and current med-ications (including OTC and herbal products).
• Patients with prior heart problems or significant current risk As might be expected, females exhibited higher average QTc factors should be more closely monitored during MMT.
values than males: 460 vs 422 msec. The overall average QTc • These patients should be educated on symptoms to watch for interval of 435 msec was within normal limits.
– e.g., "racing" heartbeat, dizziness, or fainting spells – and Only one patient had a QTc greater than the 500 msec encouraged to contact the clinic immediately. Staff should be "abnormal threshold" – 512 msec. This was a 43-year-old woman trained in handling such calls from patients.
with hepatitis C, taking several medications, and receiving 1000 • In some cases, it may be useful to perform baseline ECGs in mg/d of methadone. She had never experienced symptoms of patients with significant cardiac risk factors upon entering heart distress and, in fact, was very athletic – an avid runner. An treatment or when they are prescribed medications with ECG ten years earlier, when she was receiving only 100 mg/d of known cardiac effects. An ECG should be repeated within methadone, had exhibited an identical QTc interval.
two weeks to detect any significant changes.
As the graph demonstrates, there was only a moderate • In patients taking comedications that have demonstrated correlation between methadone dose and QTc interval in these harmful cardiac effects or interactions with other drugs, it patients (r = 0.53). Methadone blood serum levels were not might be advisable to adjust therapy (e.g., change in dose or tested, and it is likely that any potential influence on QTc might medication) and/or to monitor those patients for adverse relate more to methadone blood concentrations rather The early identification and ongoing monitoring of factors As this study seems to confirm, it has been proposed that predisposing to QTc prolongation and/or TdP or other arrhyth- patients at higher methadone doses do not necessarily present mias can be vital for heart health in MMT patients. Even if some greater risks of cardiotoxicity induced by methadone. However, factors, such as female gender or genetics cannot be modified, those patients with known abnormal QTc prolongation and/or others such as electrolyte imbalances or potentially interacting multiple cardiac risk factors might merit extra precautions.42 medications might be easily remedied once identified.
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38. Drici M-D, Barhanin J. Cardiac K+ channels and drug-acquired long QT syndrome.
manufacturer of methadone. All facts and opinions are those of the sources cited. The publishers Therapie. 2000;55(1):185-193.
are not responsible for reporting errors, omissions or comments of those interviewed.
39. Gury C, Canceil O, Iaria P. Antipsychotic drugs and cardiovascular safety: current

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