Death of Michael Jackson: How could Demerol (meperidine) cause cardiac arrest?

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.

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.