Clinical Toxicity of Methadone

Learning Objectives: After reading this article, the physician should be able to:

1. Discuss the relevant issues of methadone-linked QTc prolongation.

2. Describe the concept of Torsades de Pointes (TdP) in relation to methadone.

3. Summarize the basic ED approach to the methadone-TdP connection.

Release Date: June 2009

As you can tell, I am fascinated with methadone and methadone maintenance treatment (MMT). Given the scope of opioid use in this country, emergency physicians will be increasingly exposed to methadone toxicity and to patients seeking MMT. Those in addiction treatment programs find their way to the ED with a plethora of problems. While EPs don't use usually prescribe methadone, it's becoming a popular analgesic for chronic pain, and diverted and abused methadone is a gargantuan street drug problem in many areas.

Methadone also has replaced heroin as the drug of choice for the opioid seekers, and the darker side of methadone abuse has not escaped the national news, the courts, or the scrutiny of the DEA. It is likely that the EP will be challenged by methadone-related issues in the ED, and basic familiarity with this drug and its side effects is a prerequisite for prudent ED care.

Anyone can administer naloxone for an even suspected opioid toxidrome, and deftly snatch the hapless opioid recipient from the jaws of death. The true ED aficionado, however, will contemplate the role of methadone toxicity in sudden death or near-sudden death by merely ordering an EKG, asking a few basic questions, and perusing the omnipresent medication reconciliation record (but only if the patient has been truthful).

Figure. All ventricu...

Torsades de Pointes Associated with Very High-Dose Methadone

Krantz M, et al

Ann Intern Med

2002;137[6]:501

This landmark article was one of the first in the medical literature to highlight the possibility of Torsades de Pointes (TdP) precipitated by high-dose methadone use. Generally considered effective and inexpensive therapy for chronic pain, methadone prescribing is accelerating in everyday clinical practice. Although methadone has been successfully used as a substitute for heroin addiction for more than 35 years and is prescribed liberally for MMT, most physicians know little about the drug's theoretical or reported arrhythmogenic potential. A derivative of methadone, levacetylmethadol (LAAM), previously approved therapy for opioid dependence, is no longer used because of its association with TdP. These authors reported similar cardiotoxic experience in 17 patients receiving what they described as very high doses of methadone.

Gleaning information from MMT and chronic pain centers from 1996 to 2001, a proposed possible connection between methadone and TdP was reported. Although actual patients or medical records were not reviewed, and much of the information appeared to be verbal, the authors voiced a concern about the potential for a methadone-TdP connection. They stressed the need for further investigation of their initial findings.

The definition of a significant prolonged QT interval was a QTc of at least 500 msec in polymorphic ventricular tachycardia, otherwise known as TdP. Patients manifesting these variables (methadone plus TdP) were assessed by echocardiogram or angiography for structural heart disease. Serum electrolytes, specifically potassium, were measured. Other medications or substances that could contribute to TdP were tabulated. Specific drugs of interest and those previously known to affect the QTc are antiarrhythmic agents, antihistamines, and tricyclic antidepressants. Many other drugs are known to cause an acquired prolonged QTc, and some individuals have a congenital or genetic predisposition. The daily dose of methadone in the MMT patients in this report averaged an amazing 400 mg/day. Fourteen of the 17 patients had other risk factors for arrhythmia, such as hypokalemia or the use of other drugs that could produce QTc prolongation.

The mean QTc on presentation was 615 (±77) msec, with a mean heart rate of 64 (±15) beats per minute. Importantly, 10 patients were bradycardic, a condition previously known to predispose to TdP. Following the identification of this phenomenon, 14 of 17 patients had a cardiac defibrillator or pacemaker implanted.

Despite the fact that 14 of 17 patients had at least one previously described risk factor for TdP other than methadone use, the authors claim that their data suggest but importantly do not prove that very high-dose methadone can cause TdP. The ability of methadone to produce bradycardia, a well known precipitant of TdP in the presence of prolonged QTc, was emphasized. Other common predispositions or risk factors were the use of medications known to interfere with the metabolism of methadone. The actual effect of this pharmacologic observation is somewhat theoretical, and the aberrant and unpredictable metabolism of methadone is so pronounced that it's difficult to categorize or stipulate the specifics of drug-drug interactions. Cocaine, for example, prolongs the QTc, and is commonly ingested with methadone. Because many methadone recipients also have psychiatric illness, the cardiac effects of tricyclic antidepressants or antipsychotics cannot be ignored. HIV medication also alters methadone kinetics, usually decreasing serum methadone clearance.

The authors acknowledge the limitations of their study, which include a small sample size, no control groups, and no true causal association. No genetic testing was conducted for the presence of congenital QTc prolongation. Most importantly, there were no baseline EKG data.

Comment: The actual methods of subject identification and associated clinical investigations in this frequently quoted report are a bit fuzzy to me. Apparently the cases were discovered fortuitously, and the actual prevalence could not be ascertained. The overall magnitude of this association must be very miniscule, but it is still an important topic. The association between methadone and TdP was termed plausible, but the authors do not conclude that even high-dose methadone use is inherently unsafe. Importantly, the mean dose of methadone was extremely high, much higher than would be seen in many patients benefiting from methadone analgesia. Data from chronic pain centers, however, have noted that if the average dose of methadone is 300 mg/day, this phenomenon was not observed. Of course, the magnitude of the QTc prolongation was prodigious, and certainly not subtle. The mean QTc was 615 msec!

Methadone is currently high on everyone's radar, including researchers, pain specialists, addiction specialists, the FDA, and the courts. Methadone is a powerful drug, and it should be well understood prior to prescribing. Methadone surely must be clinically respected. Overuse or misuse can be fatal.

It's common knowledge that the vast majority of patients suffering methadone-related fatalities experience respiratory failure. Severe pulmonary edema is a common postmortem observation. Decedents simply stop breathing because they took too much methadone or combined it with alcohol, benzodiazepines, or other narcotics. The prodigious doses of methadone used in pain management and MMT appear to be generally well tolerated the vast majority of the time, and previous columns have questioned reports of deaths during methadone maintenance as being less than pristine evidence for methadone's role. Patients have died, however, seemingly suddenly and unexpectedly, when taking methadone for decades, and an overt overdose is not always obvious or proven. Perhaps the QTc-TdP issue may explain this phenomenon, but the well known authors of this highly quoted paper are avid methadone researchers themselves, and are careful to make only vague suggestions, not conclusions. I admire their analysis, caution, and scientific honesty.

The influence of methadone on the conduction system of the heart, particularly cellular potassium flow during repolarization (encoded by the HERG gene) is a confusing but popular subject of interest for pharmacologists and researchers. It is apparent that methadone and other medications interfere with or influence normal cardiac repolarization via modification of myocardial cell potassium-dependent channels. It is not denied that methadone and a cornucopia of other QTc-manipulating substances block potassium currents, and this electrophysiological effect can increase the QT interval. Bench experimental work has been extrapolated to humans in an attempt to explain why methadone could cause TdP. In the lab, a number of cell and tissue experiments have demonstrated such adverse effects on cardiac electrophysiology from high concentrations of methadone, but hard evidence so far has been observed only in the Petri dish.

To date, the exact causative role, prevalence, and true clinical importance of the methadone-TdP phenomenon eludes medical science. Small clinical studies on pain control and MMT are contradictory, some supporting a true clinical effect, others not finding one. Of the scattered case reports in humans where QT prolongation was seen in conjunction with methadone, the waters are muddied by other issues, such as individual risk factors, concomitant medications, electrolyte disturbances, genetics, and underlying clandestine cardiac pathology. Alcohol use, for example, can cause cardiomyopathy and, of course, hypomagnesemia. Cocaine abuse is a relatively common cause of QTc prolongation in my ED. Nonetheless, the FDA in its wisdom decided to highlight methadone toxicity in general and this potential cardiac problem via a nationwide warning. (See table.) This is the same FDA that essentially banished droperidol from my ED for similar guilt by association based on questionable relevant science. In this case, however, that action seems prudent and justified.

In reality, there appears to be a modest effect of oral methadone on cardiac repolarization, but the data are sketchy, and the clinical specifics are vague, theoretical, variable, and not borne out on all investigations. In one prospective observational trial of 132 patients undergoing MMT, there was a small increase in QTc during the early stages of methadone induction. The mean increase was only 10.8 msec, the clinical significance was questionable, and no TdP was reported. Because a QTc of greater than 500 msec is of concern, even this study is questionable. Given the polydrug abuse of many MMT and other opioid-addicted subjects, the true significance of such a small QT increase solely from methadone remains uncertain.

Methadone is metabolized primarily by a number of cytochrome P450 liver enzymes (CYP 34A and others). This pathway is affected by other medications that inhibit or are metabolized these enzymes. There can be excess accumulations of methadone from drug-drug interactions, but again, clinical significance is largely theoretical. Hundreds of drugs modify the QTc, and there are entire web sites devoted to this issue. (See www.torsades.org.)

An excellent discussion of cardiac considerations during MMT as of 2003, with conclusions that likely can be extrapolated to methadone today, appears in the publication Addiction Treatment Forum. An erudite discussion by Leavitt and Krantz, authorities in this field, is extraordinarily complete and quite enlightening. (www.atforum.com/pdf/CardiacPaper)

It would be reasonable to conclude that methadone alone at very high doses, in combination with other drugs, or in the presence of cardiac risk factors and with correct genetics may prolong the QT interval and potentially influence the development of TdP in susceptible patients. Methadone doses during MMT or pain management do not necessarily have to be altered solely because of this concern. A screening EKG would be prudent if there are preexisting risk factors or if high doses are prescribed. As of now, a high dose has not been quantified. Concomitant medication use should be evaluated. No one appears to recommend routine EKG or continuing EKG follow-up in patients undergoing MMT or for those treated with methadone for chronic pain.

For the ED, identifying the combination of palpitations, syncope, dizziness, VT, and methadone use should conjure up the possibility of TdP.

Case Files of the Drexel University Medical Toxicology Fellowship: Methadone-Induced QTc Prolongation

Wong SC, Roberts JR

J Med Toxicol

2007;3(4):190

This is a single case report of a patient I saw who ingested methadone and exhibited significant QTc prolongation. The 22-year-old man was taking 125 mg of methadone per day for MMT, and somehow found another 250 mg to take in an overdose, apparently a simple task for the streetwise addict. He had respiratory depression, a decreased heart rate, and decreased blood pressure, and he was lethargic and mildly hypothermic. There was no syncope or palpitations. The pupils were pinpoint. This defines a classic opioid toxidrome.

Nothing was out of the ordinary until an EKG demonstrated a QTc of 516 msec. Careful questioning failed to elicit symptoms of TdP or syncope. The patient responded well to naloxone, and the urine drug screen was positive for methadone, benzodiazepines, and cocaine metabolites. The patient was admitted to a monitored bed, and the QTc gradually reverted to normal without intervention or consequence. In this case, a markedly prolonged QTc was an incidental finding but a curious one that prompted admission and cardiac monitoring.

Comment: This case report defines a common clinical scenario. A patient taking high-dose methadone scores more methadone or supplements with other medications, particularly cocaine and benzodiazepines, shows up in the ED. This individual was fortunate enough to avoid respiratory arrest, and demonstrated a gargantuan tolerance to massive doses of methadone. This case depicts the common scenario of bradycardia in opioid overdose, a known predisposition to TdP in the presence of a prolonged QTc. As with most cases, this subtle but respectable QTc prolongation may be just an interesting clinical finding, but it cannot be totally ignored. It would be prudent to check all the usual suspects (K, Mg, Ca), and admit this patient for cardiac monitoring if there were any compromising parameters found. But if he were otherwise squeaky clean, disposition would be variable.

The prescient clinician faced with a lethargic patient with pinpoint pupils can glance at the EKG and immediately pronounce methadone overdose. After that stellar diagnosis, the clinical course is relatively straightforward. Some clinicians may suggest prophylactic use of magnesium for prolonged QTc, a seemingly reasonable intervention, but one that is neither standard nor proven. Judicious replacement of potassium would be prudent if the patient were hypokalemic. Because methadone has a long half-life, it is almost impossible to discharge a patient quickly if he manifests serious symptoms. It's always a judgment call best made by an experienced clinician at the bedside, but any narcotics overdose patient should be monitored until it is clinically safe without residual naloxone. That's usually two to six hours, depending on the naloxone dose and other variables too long to list. Methadone overdose, however, requires a cautious approach indeed.

One can usually ferret out the details of overmedication in the cancer patient taking prescribed methadone. But the history of drug abuse on the street is often vague and commonly an outright lie, and the milieu to which this patient eventually returns can be hostile, if not inscrutable. The protective arms of the hospital are usually extended, if for no reason other than keeping the patient from harming himself or exposing him to the ravages of opioid dependence. Perhaps yet another attempt at MMT would be an option, but as demonstrated by this patient, MMT is not always successful.

There is nothing clandestine or tricky about managing a known narcotic overdose. Most immunoassay urine drug screens do not identify methadone or oxycodone, but such a qualitative test is readily available and should be added to one's routine urine test if you can find a cooperative laboratory director. The judicious use of naloxone, by either small boluses or with a modest naloxone infusion, will keep the patient out of respiratory distress. I have heard that some use nebulized naloxone for this titration, a pretty nifty concept that has escaped my clinical acumen till now.

If carefully titrated, minimal intervention with naloxone will minimize withdrawal symptoms. Slamming in 4 mg of naloxone usually precipitates a nasty narcotic withdrawal, a condition that can be counterproductive. Most patients can't handle it, making ED management more difficult, even confrontational, and engenders restraining a really annoying patient or outright elopement to ameliorate the symptoms with even more street drugs. According to the Joint Commission, a mentally competent individual cannot be physically restrained just because he likes heroin or methadone, even if he just had a life-threatening overdose. Go figure that bizarre logic, a rule likely penned by a well-intentioned bureaucrat or ACLU proponent who never worked in an ED.

Exactly how to approach the methadone patient with Torsades is an enigma. You don't see TdP often, and only case reports and small series address therapy; none specifically deals with methadone. The neophyte intern or the overwhelmed clinician might look at TdP and simply classify it as VT. Although the EKG manifestation is extant if you're smart enough to spot it, often the arrhythmia is transient and self-terminating. Manifestations of TdP (palpitations, dizziness, near-syncope) likely go unaddressed in the ED when more serious sounding pathology, such as coma-respiratory depression, is the clinician's focus. I have not seen any scientific investigation outlining a specific approach to this exact scenario. It seems reasonable to employ the classic intervention described for garden-variety TdP. No controlled studies exist, and therapy is empirical for the most part.

Cardioversion, or more correctly the nonsynchronized defibrillation mode, is the best option for sustained VT. Magnesium appears to be the drug of choice, even if serum magnesium levels are normal. The dose is 2 to 4 grams given IV over five to 15 minutes. A repeat dose may be used with proper attention to magnesium toxicity. Patients who are hypokalemic from diuretic use are usually also magnesium depleted; it's difficult to maintain serum potassium levels without supplementing magnesium. It is safe and reasonable to give magnesium and potassium to patients who are hypokalemic, particularly if they are on diuretics. Oral potassium is well absorbed, so giving 40-80 mEq orally a few times repletes serum potassium levels more quickly than the intravenous route. The maximum potassium that can be given per hour via a venous infusion is probably 40 mEq, and this is often given through a central line. At least 20 mEq per hour can be given peripherally, but concentrated solutions can cause pain and venous irritation. By the time the lab informs you of a significantly low potassium, the patient probably has a deficit of at least 100-150 mEq.

Some clinicians would try phenytoin and lidocaine for TdP. Their benefit is unknown, but they have little downsides. Sodium bicarbonate also is an attractive theoretical intervention. Of course, the first drug choice for VT is usually amiodarone, but it can prolong the QTc, and has not been listed as an intervention for TdP. I don't know whether it would help or hurt, but TdP is only rarely linked to amiodarone. Procainamide was a common treatment for VT in the old days (my residency), but would probably be a poor choice for TdP because it does prolong the QTc. Procainamide has been making a comeback for atrial fibrillation, so some might be tempted to use it. Resist that temptation. Remember also that QTc prolongation was the impetus for Haldol's infamous black box warning. Finally, for your next trivia session, arsenic trioxide (overdose or therapy for leukemia) will prolong the QTc.

Because TdP can be initiated by bradycardia or a ventricular pause, overdrive pacing is another common suggestion. As the heart slows, the QT interval lengthens. The use of isoproterenol to induce overdrive tachycardia is often suggested, and I have used this drug for asthma; it's a powerful cardiac stimulant. Isoproterenol is unknown to most modern-day clinicians, and it's probably too complicated for routine use. External transcutaneous pacing can be an option, but I have no experience with it for TdP. As a guide, you need the heart rate over 100-120 per minute to be effective.

I found it interesting that some patients were given an implantable cardioverter defibrillator (AICD) once TdP was demonstrated, and apparently could not be prevented by some intervention (like stopping methadone and cocaine?). In this report, an AICD was implanted so subjects could continue on their methadone or perhaps have prophylaxis against a host of other contributing effects. The technology is quite cool, and the AICD's first programmed response to a tachycardia is to initiate overdrive pacing so the AICD makes perfect sense for someone who has recurrent bouts of TdP.

To further complicate matters, it has recently been reported that atypical antipsychotic medication may increase the risk of sudden death via a similar TdP mechanism. (New Engl J Med 2009; 360[3]:225.) Methadone users are also great consumers of atypical antipsychotic medication, and opioid abuse in those with mental illness is ubiquitous. Many methadone users in MMT like the buzz they get with quetiapine (Seroquel), a drug they think is very safe. It likely is overall, but it is becoming a popular street drug in its own right.

FDA ALERT [11/2006]: Death, Narcotic Overdose, and Serious Cardiac Arrhythmias

FDA has reviewed reports of death and life-threatening side effects such as slowed or stopped breathing, and dangerous changes in heart beat in patients receiving methadone. These serious side effects may occur because methadone may build up in the body to a toxic level if it is taken too often, if the amount taken is too high, or if it is taken with certain other medicines or supplements. Methadone has specific toxic effects on the heart (QT prolongation and Torsades de Pointes). Physicians prescribing methadone should be familiar with methadone's toxicities and unique pharmacologic properties. Methadone's elimination half-life (8-59 hours) is longer than its duration of analgesic action (4-8 hours). Methadone doses for pain should be carefully selected and slowly titrated to analgesic effect, even in patients who are opioid-tolerant. Physicians should closely monitor patients when converting them from other opioids and changing the methadone dose, and thoroughly instruct patients how to take methadone. Health care professionals should tell patients to take no more methadone than has been prescribed without first talking to their physician.

Source: www.fda.gov/cder/drug/infopage/methadone/default.htm

Methadone and the Heart: Questions Remain

▪ Methadone has an overall favorable safety profile for cardiac issues. It is effective therapy for opioid addiction, and is a widely used analgesic for chronic pain.

▪ Respiratory depression, decreased mental status, bradycardia, hypotension, hypothermia, and pinpoint pupils are classic opioid effects associated with methadone, the opioid toxidrome.

▪ Bradycardia may be an important precipitating factor for TdP.

▪ In laboratory preparations, methadone blocks potassium currents, which in turn can lead to cardiac repolarization abnormalities.

▪ Methadone's cardiac effects appear to result in prolongation of the QT interval, altering cardiac repolarization that, if severe enough, may result in ventricular dysrhythmias, particularly Torsades de Pointes (TdP). The incidence is small, and the true clinical importance of this observation is still somewhat vague.

▪ Case reports and small series suggest methadone can influence the QTc and may cause TdP; however, this seems to be a high-dose issue, and additional factors complicate this analysis.

▪ Data are conflicting on QTc prolongation with standard MMT or oral methadone therapy, and the clinical significance of a minimal QTc increase is uncertain.

▪ Hereditary factors, cardiomyopathy, hypokalemia, hypomagnesemia, the use of other substances with cardiac effects (such as cocaine), and the cardiac effects of other prescription medications have been involved in almost all case reports implicating methadone as a cause of TdP.

▪ It is unclear whether methadone has a primary adverse effect or an added one.

▪ Drugs that affect the P450 liver enzyme system may increase methadone levels and potentiate the QTc phenomenon.

▪ Syncope in a patient taking methadone should prompt a concern for QTc-TdP issues.

▪ At the current time, there is no firm evidence necessitating a change in methadone-dosing practices, but a baseline and follow-up EKG is prudent in patients at risk.

▪ This issue is far from certain, but the FDA Alert on death, narcotic overdose, and serious cardiac arrhythmias from methadone should be familiar to clinicians.

Reader Feedback:

Readers are invited to ask specific questions and offer personal experiences, comments, or observations on InFocus topics. Literature references are appreciated. Pertinent responses will be published in a future issue. Please send comments to [e-mail].

Dr. Roberts: After reading the April 2009 edition of EMN, I have some questions for Dr. James Roberts about methadone clinics. (EMN 2009;31[4]: 8.) I attended a lecture by Dr. William James, who is a pain specialist in Toledo, OH, where he discussed the treatment of pain with different narcotics. He does not use methadone because of its toxicity and dangerous drug interactions. With these serious side effects, I wonder why we are using methadone.

As an emergency physician, I do not see the need for methadone clinics. They are just clinics where we are dispensing free, legalized narcotics. Many of these patients I see in the ED do not work and are not productive in society. Why are we condoning such a practice, especially when we have ways to treat narcotic withdrawal other than with methadone, especially when the government does not have the funds to spend for these clinics? - Marcus Ma, MD, Temperance, MI

Dr. Roberts responds: It is difficult to reconcile the significant controversy in medicine and society in general regarding the use of methadone as an analgesic and with the entire concept of methadone clinics. Methadone is a powerful opioid but no more toxic than any other opioid. It's just a matter of dosing and understanding kinetics and drug interactions. Fentanyl, for example, is much more potent and toxic than methadone, but the patches are omnipresent, and doled out daily for chronic pain, even from office practices by generalists. One simply has to know what one is doing when prescribing methadone.

The philosophy behind methadone clinics is also controversial, reminiscent of supplying needles to heroin addicts to decrease AIDS, free condoms to high school students to prevent STDs and pregnancy, legalizing abortion for reproductive missteps, or giving a liver transplant to an acetaminophen overdose or alcoholic, all at the taxpayers' expense, no less. What about keeping a vegetative patient alive for years with tube feedings, antibiotics, or ventilators?

Those who condone methadone maintenance view addiction as a disease, similar to alcoholism and diabetes. Those, like Dr. Ma, who question the concept perhaps don't see it that way. A teenage mother is also nonproductive and nonworking, and what about the octumom, all supported by our generous, yet insolvent, government? One can either take a head-in-the-sand approach to addiction or support at least an attempt to intervene with our current best effort (MMT), albeit imperfect or bordering on pathetic by some standards. Statistics, however, seem to bear out an overall benefit to society from MMT. Wouldn't it be nice if addiction and chronic pain would just leave us all alone?

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