Thursday, June 18, 2009

More on the cardiotoxic effects of methadone

There has been some controversy about methadone’s cardiac risk along with vigorous objections to the ACP guidelines for cardiac safety monitoring, coming mostly from advocates for methadone maintenance treatment for opiate addiction. My last post on the subject drew a blistering reply. The commenter is the author of this blog. She wrote:

Your broad assumption about methadone's cardio toxicity has yet to be proven and your talking about it like it's a given? It never fails to surprise me how easily even DOCTORS can leave their rationality and objectiveness behind, when they hear the word "methadone".

YOur writing this entry as if your assumptions about methadone are a "known fact" and it's simply not true.

Although there is widespread ignorance concerning methadone’s cardiac toxicity no informed person on either side of the debate, that I know of, denies the toxicity. What is in dispute is the degree of risk as well as whether, and how, the evidence of this risk should change practice. The evidence spans multiple levels from molecular mechanisms to clinical observations.

It’s been a while since I’ve compiled the evidence in one place so here’s a summary:

Methadone blocks the potassium channel.

An early report of torsade associated with very high doses of methadone.

Torsade and QT prolongation were common in hospitalized patients receiving methadone.

Sudden cardiac death was attributable to methadone in patients who had therapeutic (non-toxic) blood levels.

She went on to say:

The first study you mention was very poorly done, only has 17 participants and everyone in it had a dose of 400mg or more. Hardly what most people reading your blog are going to think of when they read "ordinary therapuetic dose".

That particular study (the second one linked above), a paper in the Annals of Internal Medicine, was not the basis for my comment about methadone causing cardiac problems in ordinary therapeutic doses. That comment was linked to this study (the last one linked above) showing that patients who experienced sudden cardiac death had therapeutic levels of methadone.

And this:

The recent rise in "body count" due to methadone has to do with OVERDOSES, not sudden cardiac death--and is usually in pain patients who took too much or in addicts who are not in a methadone program and they are almost ALWAYS poly bringing up the rise in methadone RELATED deaths is a poor choice. People will read your entry and believe that we have thousands of people dying because they took a small dose of methadone and their heart exploded. This is simply not the case.

Here’s a graphic from the CDC on the rise of deaths attributable to methadone as opposed to other drug poisonings.

Data from that same CDC report suggest that overdose is not the primary cause of rising deaths:

Since 1999, between 73 and 79 percent of poisoning deaths mentioning methadone have been classified as unintentional (3,202 such deaths in 2004), with an additional 11-13 percent being of undetermined intent, 5-7 percent as suicides, less than 1 percent as homicides, and about 1 percent were injuries other than poisoning.

73%-79% were classified as unintentional, not attributable to suicide or homicide. It could be argued that those deaths involved excessive use (and the CDC does refer to them as poisonings) but absent suicide or homicide what’s an overdose? Any death attributable to a drug is, in a sense, an example of excessive use. For opiates, overdose is judged by individual circumstances, there being no generalizable quantitative definition.

The commenter went on:

Posting the comment from another site about a doctor knowing methadone is to blame immediately by looking at the EKG. First, the symptoms you mention (pinpoint pupils and lethargy) happen in any overdose situation.

She was referring to my quotation from the article by James R. Roberts, MD:

The prescient clinician faced with a lethargic patient with pinpoint pupils can glance at the EKG and immediately pronounce methadone overdose.

First of all, pinpoint pupils do not “happen in any overdose situation.” If that were true pupillary examination would be of no value in identifying specific toxidromes. As it happens, some poisonings are associated with dilated pupils, such as TCA overdose. Pinpoint pupils do not prove methadone overdose, to be sure, but the electrocardiogram can be of added value. In a lethargic or comatose patient the combination of pinpoint pupils and long QT does strongly implicate methadone. Other factors that prolong the QT can be readily excluded (check the patient’s K+, Mg++ and look at their med list). TCA overdose, for example, is suggested by dilated pupils, a widened QRS and AVR pointing to the sky! There are in fact several electrocardiographic toxidromes. The whole point is that when presented with a comatose patient a rapid low tech assessment can provide powerful diagnostic information.

There is some truth in this point:

To date there has been no proof that routine EKG's, for anyone on methadone, will even HELP--and it may actually hurt many patients because of the cost. Especially considering that there is no proof that RANDOM ekg's will diagnose or help prevent this phenomenon.

True except for the cost, which is miniscule. The guidelines call for zero risk interventions. They are nothing more than drug safety monitoring recommendations. Drug safety monitoring is supported by post marketing reports, physiologic rationale and clinical judgment. Few if any drug safety monitoring recommendations are validated by RCTs that prove the benefit of the monitoring. If such high level evidence were required most FDA safety recommendations would have to be retracted.

Several letter writers expressed concern that the guidelines would produce barriers to appropriate use of methadone for patients in need of treatment for opiate addiction. But the guidelines only recommend precautions. They do not prohibit methadone use in any circumstance. In fact, failure to observe safety recommendations for methadone could result in it being yanked by the FDA---maybe not for the critically important niche of opiate addiction treatment, but a ban of use for chronic pain could occur as more reports trickle in. (That’s exactly what happened to cisapride, a drug known to cause torsade but which might still be on the market today had docs followed the warnings).

By the way, the guideline writers at the ACP aren’t the only ones concerned about methadone’s cardiac risks. The FDA issued this warning and the Center for Education and Research on Therapeutics, the leading repository of QT prolonging drugs, has placed methadone in the highest risk category.


Anonymous said...

Why not print my entire LETTER? If these guidelines are merely guidelines and can't hurt people-then why not publish the "other side of the story"? I gave you the links!

Why not post the link to the considerable comments AGAINST these guidelines from NUMEROUS well published, well educated doctors and organizations who actually work in methadone treatment? I guess it's a better idea to listen to a cardiologist who has never worked in methadone treatment!

Why not post the fact that two of the authors of the guidelines actually backed out? Or the fact that CSAT made the ANNALS take their name off the guidelines? At least two of the authors involved have a FINANCIAL incentive in showing methadone in a poor light?

These may just be guidelines to YOU...but right now we are facing the huge backlash of these poorly researched, poorly written scared doctors either quit their clinic jobs or slash patients doses (sending them back to the streets when they are sick)or patients are being forced out of treatment for any assessment of "risk", and as malpractice lawyers gun up to make money off any patient willing to believe that their (or their loved ones) cardiac arrest had NOTHING to do with the years of smoking crack and shooting dope--but is instead because of a rare side effect of methadone!

I find it infinitely profound that you believe the costs associated with routinely ekg'g are miniscule. It shows how very little you know about these patients and methadone treatment in general.
It's obvious that I am not a doctor and that I don't know what you know about ekg's or drug was great of you to pull out the pieces of my letter that you could mock, rather than to pull out the pieces that just MIGHT have some valid points or at least my links would have shown another side of the coin from people WHO ARE EDUCATED.

Please just sit with this thought--if I can ask one more thing?

How often do we see media headlines, published research and "experts" (who aren't really experts) talking about the "huge" risk people take by admitting themselves to the ER or hospital? The research is scary when looked at out of the context that most people who don't get treatment at a hospital would be DEAD without it or scarier still to look at the great big number of mistakes hospitals make--when you aren't looking at how many people they treat withOUT making a mistake.

Now think about the work you do and how you would feel if someone who does....oh lets say...addiction treatment!.....came to your ER and said "hey I just read a couple of studies that say you aren't doing your job correctly!" (even though the research wasn't done in YOUR hospital and instead was done in a very small ER with a small patient population that was older and sicker than most) this guy comes in and says to you "I just made up these guidelines for you to follow and if you don't I will make sure that patients stop coming here and I will make sure you get sued for not doing your job!"

Now how would you feel? Would it not be a giant slap in the face to the work you do to have someone that has never even done your job or even talked to you about your job tell you how to do it>? And more importantly how much damage would it do to your patients who are suddenly scared to come to the ER or who don't get treated because they are a liability.

R. W. Donnell said...


Although I moderate comments and could have chosen not to, I published yours in its entirety. Also, I linked to all the rapid responses to the guidelines published in the Annals. I don't know what more you expected me to do.

Yes, I should have pointed out that two of the guideline authors backed out and one professional society wanted their name removed, as you have noted.

I don't know why you think the guidelines would harm patients unless you think following the guidelines would somehow scare them away from treatment. I don't know if that's your objection, but if it is it would follow that doctors should just not inform patients at all about the cardiac risk. That's not something you would advocate, is it?

An EKG costs around $40. The guidelines recommend two tracings the first year and, for most patients, one a year thereafter. That's really pretty cheap.

I have a different view in that I think the more doctors ignore safety warnings the less likely the drug is to stay on the market. Failure of doctors to follow safety warnings has caused many good medications to be yanked from the market or withdrawn by the manufacturer.

Anonymous said...

i apologize, I didn't realize my entire comment was published on the first post.

This is my favorite link on the subject:

40$ is a lot of money for someone who is already paying 50-100$ per week for treatment as well as travel costs to the clinic daily.

Nothing with methadone treatment is as easy as "they are just guidelines" because methadone treatment is a medical ghetto that is heavily regulated, scrutinized and already demonized in this country.

Good luck

Anonymous said...

I have been off and on Methadone
for 40 years. I never heard off
anyone taking 400 mg. of Meth,unless of course they want to
Die in 30 to 40 min.
This is why Meth. addicts are afraid to tell Doctors about thier
Meth.addiction,because they don't
know anything about it.(the Doctors)
If anyone whats to know about
Methadone ask a Meth.addict.
I have wacthed Methadone dispensing
become a huge $ Industry. At first
they wanted you off in one year now
getting off is never mentioned,
addicts are told Methadone has no serious side effects,I can think of about 50. Thank You

Anonymous said...

I am a new to Methadone and use it for chronic pain management. I have to say that I am grateful for any and all literature on the possible cardiotoxic effects since I do have a heart condition already that includes syncope and tachycardia.

The intense reaction to the article from Dr. Donnell surprises me and seems to come from only one perspective, which ironically armme was accusing the Dr. of. The reason why physicians, in my humble opinion, want to abandon their authorship or participation in a published guideline is for legal reasons. It is a shame we have come to a point in this society where Doctors are more fearful of being sued than warning the public of possible dangers that include death, no matter WHAT the low percentage of occurance is.

The bottom line is that there are great benefits and risks with methadone. As a chronic pain sufferer I appreciate the relief. However, as a patient with serious heart issues I appreciate the danger and want to be aware of all the risks. If an EKG could save my life, I say "Bill me" as $40.00 is a small price to pay for living.

Thank you Dr. Donnell for your work, and also the risk you take by revealing possible dangers associated with this drug.