Terra Sigillata

AOL’s celebrity gossip page TMZ.com was first yesterday to report Michael Jackson’s death, in part due to their direct line to one or more Jackson family members.

They appear to have had another scoop today in referencing a family member who reported that Mr Jackson had received an injection of the opioid analgesic, Demerol (meperidine), at 11:30 am yesterday. It is not clear whether this shot was administered by Dr Conrad Murray, the physician who was present when the 911 call was made to L.A. dispatchers. (Non-US readers may also refer to meperidine as pethidine or the trade name, Pethadol.)

[Note: See also this post from DrugMonkey that he put up while I was composing this one]

But how might Demerol/meperidine have caused cardiac arrest, the cause of death reported universally in the press?

First, and as a commenter has pointed out, the most obvious cause of death was simple respiratory depression and pulmonary edema which is characteristic of overdose with any number of opioid drugs. However, press reports lead us to believe that Mr Jackson had been given medications, including Demerol injections, by his personal physician. It seems unlikely that a dosing error would’ve caused such acute onset of death, so let us consider other possibilities.

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Meperidine (muh-PAIR-ih-deen) is an unusual compound that has been known since 1951 to have cardiotoxic properties. Unlike morphine and codeine, opioid drugs that occur naturally, meperidine was the product of a chemical synthesis by Eisleb and Schaumann in 1939. It is a member of a chemical family called phenylpiperidines, similar to the analgesics methadone and fentanyl, and was made originally to resemble atropine, a naturally-occurring anticholinergic drug (antimuscarinic, more precisely). However, meperidine was later discovered to have analgesic properties that could be blocked by the non-selective opioid analgesic antagonist, naloxone.

So, while meperidine is widely considered a morphine-like analgesic, it is often overlooked that it has other properties not shared by morphine. Most relevant is that meperidine is metabolized (N-demethylation by CYP2D6) to an active compound, normeperidine, which has been associated with paradoxical stimulation (not depression) of the central nervous system. This CNS stimulation has been linked to known reports of meperidine-induced seizures and is correlated directly with blood concentrations of the normeperidine metabolite.

As far back as my 1980 edition of my classic pharmacology text, Goodman & Gilman’s The Pharmacological Basis of Therapeutics, meperidine-specific effects on the cardiovascular system are noted: while intramuscular (IM) injection of meperidine has no effect on heart rate, “intravenous administration frequently produces an increased heart rate that is sometimes alarming.” Dramatic increases in heart rate can cause ventricular fibrillation or pulseless ventricular tachycardia, both rhythmic conditions that can lead to cardiac arrest.

Although Jackson apparently received IM meperidine injections, the TMZ report quoting a family member suggests they were given daily, a point that may be very telling: while meperidine itself has a relatively short half-life of 3 hr, the active CNS-stimulating metabolite normeperidine has a half-life of 15 to 20 hours. Therefore, daily IM injections over time might have caused normeperidine concentrations to accumulate to toxic levels relative to the parent drug. (Note to the toxicology laboratory testing Jackson’s blood: pay very close attention to the concentrations of normeperidine and its ratio to the parent, meperidine.).

PharmGirl MD, who alerted me to this story earlier today, also dug out some information for you and me from a subscription-only site. This particular passage, from a MD Consult entry prepared by Gold Standard, Inc., notes that meperidine should be used extremely carefully with any CNS depressant. Concomitant use of other CNS depressants by Mr Jackson might be likely and these combination effects might also lead to the same end result of cardiac arrest:

Hypotension, respiratory and/or CNS depression (e.g., profound sedation or coma) may occur if meperidine is used concomitantly with CNS depressants.[7760] Examples of CNS depressants include amitriptyline; amoxapine; anxiolytics, sedatives, and hypnotics [5610]; carisoprodol; clomipramine; clozapine; dimenhydrinate; doxepin; dronabinol, THC; droperidol; entacapone; ethanol [6341]; general anesthetics [5610]; sedating H1-blockers; haloperidol; imipramine; maprotiline; methocarbamol; mirtazapine; molindone; nabilone [9044]; nefazodone; nortriptyline; olanzapine; other opiate agonists [5610]; phenothiazines [5610]; pimozide; pramipexole; pregabalin [7523], quetiapine; risperidone; ropinirole; skeletal muscle relaxants; trimipramine; tolcapone; tramadol [5043]; and trazodone. Meperidine should be used with great caution and at a reduced dosage if used concurrently with a CNS depressant.[7760] [emphasis mine -APB]

[. . .]

Meperidine and related compounds can cause cardiovascular adverse reactions. These reactions include sinus bradycardia, sinus tachycardia, palpitations, hypertension, hypotension, orthostatic hypotension, diaphoresis, and syncope. Orthostatic hypotension may arise as a secondary effect from peripheral vasodilatation. In cases of severe respiratory and/or circulatory depression, shock and cardiac arrest may occur.

As an aside, meperidine was associated with the 1984 hospital death of New York City college student, Libby Zion. Her death received great attention because she had been on a monoamine oxidase inhibitory antidepressant, phenelzine (Nardil) – MAO inhibitors were common antidepressants before the introduction of SSRI antidepressants such as Prozac (fluoxetine) in the early 1990s. While in the hospital, Zion was given meperidine by a medical resident and she experienced a severe case of serotonin syndrome that led to her death. Her death was attributed to overworked, inexperienced medical residents and interns and the case led to a change in New York law limiting medical residents from working more than 80 hours per week. The reality, though, was this was a drug interaction that would have been overlooked by many physicians at the time, regardless of experience. (For further reading on this case, see these 2007 and 2009 NYTimes articles.)

However, MAO inhibitors such as phenelzine are rarely used today as antidepressants. In the case of Mr Jackson’s death, however, the possibilities right now appear to be cardiac arrest due to accumulation of normeperidine or a litany of drug interactions that could have led to fatal CNS depression.

There is no evidence to suggest that meperidine provides any greater analgesia or less risk of dependence than any other opioid analgesic. With its unusual toxicity profile, I see little reason for why it continues to be used when there are over a dozen other options. Perhaps the death of Michael Jackson will further raise awareness of the risks of meperidine use.

Comments

  1. #1 zuse
    June 27, 2009

    Sorry, but from my point of view there is no need for sohisticated pharmacological explanations like the one given here.

    Every anesthesiologist in the world can tell you how demerol/meperidine (like any other morphine-like agent, called “opiods”) can cause a cardiac arrest: Just by it’s most prominent side-effect: the power to induce severe respiratory depression (especially in combination with oher drugs or perhaps alcohol) which induces hypoxemia that inevitably leads to a cardia arrest in minutes.

  2. #2 zuse
    June 27, 2009

    Sorry, but from my point of view there is no need for sohisticated pharmacological explanations like the one given here.

    Every anesthesiologist in the world can tell you how demerol/meperidine (like any other morphine-like agent, called “opiods”) might have caused a cardiac arrest: Just by it’s most prominent side-effect: the power to induce severe respiratory depression (especially in combination with oher drugs or perhaps alcohol) which induces hypoxemia that inevitably leads to a cardiac arrest in minutes.

  3. #3 Abel Pharmboy
    June 27, 2009

    @zuse, you raise a good point that I have now addressed in the revised post above. The most obvious cause of death was simple respiratory depression and pulmonary edema which is characteristic of overdose with any number of opioid drugs. However, press reports lead us to believe that Mr Jackson had been given medications, including Demerol injections, by his personal physician. It seems unlikely that a dosing error would’ve caused such acute onset of death, so that’s why I sought to consider other possibilities.

  4. #4 David
    June 27, 2009

    If this had been a simple case of respiratory depression from an opioid, I would have thought the physician in attendance could have provided mechanical ventilation, either by bag or mouth, until help arrived. Also, if a physician was gauging his dose and he was taking the same meperidine dose regularly I would classify him as “opioid-tolerant” and a repeat dose of his habitual dose should not have produced respiratory depression.

    I agree with you, Abel, it’s a suspicious event. I’ll also add that Jack-o was 50 years old and Creatinine Clearance declines linearly with age; his normeperidine half-life may have been double the value you state.

  5. #5 drlynn
    June 27, 2009

    Dear Friends,

    My impression is this story is beyond opioid induced respiratory depression and dependence. If true, why in the world is a licensed physician giving IM demerol injections to a famous celebrity (?). Normeperidine is known for it’s toxicity (cardiac, renal, etc.) and drug interactions. It’s sad that such a famous man was surrounded by such enablers and inadequate medical care. However, there are 2 sides to the story, so more info is needed.

    Dr. Lynn

  6. #6 Angelo
    June 27, 2009

    Coming from an ex Demoral junkie you really can build a tolerance to the stuff very quickly. I’m positive MJ was abusing more then just Demerol. In the past he broke his leg a veterbrate in his back set his hair on fire and other things I can’t think of, that he was on many different pains meds and benzos at different times and even went into treatment once. Treatment hardly every works and unless you dedicate yourself to methadone or suboxone (my life saver) opiate addicts tend to never make it.

  7. Angelo: “opiate addicts tend never make it.” Another urban legend unsupported by empirical scientific data. I suggest you read the recent paper by Branconnier and Moncheski (2009) at http://www.addictioninfo.org/articles/3532/1/

  8. #8 Chris
    June 27, 2009

    How serious do you think anyone is going to take a non-reviewed paper published in a website?

  9. #9 zayıflama
    June 28, 2009

    It’s sad that such a famous man was surrounded by such enablers and inadequate medical care.

  10. #10 söve
    June 28, 2009

    In the past he söve broke his leg a veterbrate söve in his back set söve his hair on fire and other things I can’t think of, that he was on many different söve pains meds and benzos at söve different times and even went söve into treatment once. Treatment söve hardly every works and unless you dedicate yourself to methadone söve or suboxone (my life saver) söve opiate addicts tend to never make it.

  11. Chris, This is a classic fallacious argumentum ad hominem. Read the paper and then criticize its conclusions based on a reasoned and rational rebuttal of the data. Obviously, you have never been a journal referee, I have.

  12. #12 Pete goldman, MD
    July 1, 2009

    ? inadvertant injection intravascular instead of IM causing OD

  13. #13 John
    July 3, 2009

    quote Chris: “How serious do you think anyone is going to take a non-reviewed paper published in a website?”
    That’s a standard rebuttal. I don’t depend upon research having being reviewed by any society or cartel, to examine it’s worth. Particularly so, as some have been proved to be corrupt. And, the fact that it’s published on a website doesn’t reduce it’s worth. You should, in order to be honest, change ‘anyone’ to me.
    Independent researchers and reviewers exist, and do important work. It’s up to you to examine it’s worth, reviewed or not. Science is not the property of government or corporations..

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