Another death in the tribe and this one is...close to home.

Sep 29 2009 Published by under Drug Fatality, Opiates, Tribe of Science

The initial news reporting from Baltimore led with "Post-Doctoral Fellow Charged After Girlfriend's Death". Oh Christ.

A post-doctoral fellow at the University of Maryland School of Medicine has been charged with illegal drug possession after his live-in girlfriend, also a fellow, died.

Not. Good. Not good in the least.


According to investigators, Dr. Carrie Elisabeth John injected herself Monday with a drug known as "bupe" in the house she and McCracken shared.
Bupe is intended to help addicts break their dependency on heroin.
Court documents said John stopped breathing and was pronounced dead in the university hospital emergency room.

"Bupe" or buprenorphine [Wikipedia] is an mu opioid receptor partial-agonist used as agonist therapy for opiate dependency under trade names such as Subutex® and Suboxone®.


Of course we will have to wait as more information develops on this story but dying of respiratory suppression is certainly consistent with opiate overdose. The partial agonist buprenorphine is supposed to provide some margin of safety relative to full opioid agonists...but Dr. John may have been using other opiate drugs as well:

Guglielmi says several drugs, including more than 25 marijuana plants, were found in her Baltimore home.
"Medications were that of buprenorphine, oxycontin, oxycodone, morphine -- very potent painkillers."

There's some interesting general stuff in this story, while we await additional detail, about opiate abuse and the general problems with agonist therapy. Buprenorphine is an opioid partial agonist which means, as with other agonist therapy, it is supposed to work as a weenie version of the preferred drug. The idea is that a weaker signal can alleviate the withdrawal effects while hopefully not accelerating the addiction. Combined with additional counseling and intervention, agonist therapy can be quite helpful in weaning people out of their addiction.
Of course, since it does have pharmacological activity similar to the preferred drug that means it comes with some level of abuse potential. Indeed, people inject buprenorphine to get high and the smart money assumes that that is why Dr. John was injecting the stuff.
The comment about Dr. McCracken obtaining the drug from an online source in the Phillipines could just be an access thing but it made me think about commercial formulations as well. Subutex, the sublingual oral commercial product with only buprenorphine was reformulated as Suboxone which has 4:1 buprenorphine to naloxone ratio. Naloxone is an opiate antagonist. The "bought from the Phillipines" quote made me wonder if perhaps they had found a source for Subutex instead of Suboxone- but that is pure speculation.
Why add an antagonist to an agonist therapeutic?
The idea is that naloxone taken sublingually doesn't make it into the brain in great amounts because of a high first-pass metabolism by the liver (monkeys, humans). If you try to inject the stuff, however, you end up with a good fraction being available to the brain which leads to a precipitated withdrawal effect. It is sort of like accelerating the drop-off in drug effect that would normally be occurring because of metabolism and excretion- introduce a sufficiently competing antagonist drug at the receptor level and you shut off the signal quickly.
alho09-streetpricesuboxone.jpg
Figure 1: Higher street price for buprenorphine than for the buprenorphine + naloxone combination. Respondents reported the prices they had paid for 8 mg of the two products. The graph shows the percentage of respondents willing to purchase the drug at a particular price. For example, 89% were willing to pay €25 for 8 mg of buprenorphine but only 3% would pay that much for 8 mg of the combination.
I'm trying to see how this theory is panning out- addicts are willing to put up with lots of stuff to get high and MSM reports quickly pointed to abuse patterns. You will find some mixed results in pubmed quite easily. In this example from Alho et al, 2007, Finnish opiate injecting drug users were willing to pay for the combined product, albeit they liked the pure buprenorphine product much better.
I have a few closing remarks for the tribe of science and particularly the drug abuse fields. These postdoctoral fellows worked in and around the addiction areas and I have little doubt that many of their colleagues, past and present, are beating themselves up. "How could we have missed this, we are supposed to be addiction specialists!??!". Please don't hold yourselves responsible for this tragic death and the likely disruption of Dr. McCracken's career. You could not have foreseen this coming to pass.
One clear factor that comes out time and again in cases of middle-class, so-called "functional" drug dependence is that people are fantastically good at concealing their drug use. Fantastically. And when it all comes out, people around the addicted person are AMAZED how much/often the person was using...and still nobody clued in. Addicts are good at concealing their actual drug administration and their state of being high. I have a thought for all of their colleagues who might be casting about for answers- it is not your fault for not noticing.
Dammit.

23 responses so far

  • The Isis family is keeping the people who knew and loved Dr. John in their thoughts.

  • Anonymous says:

    Thanks so much for an empathetic and well-informed post. Yours is the first post which does not malign either party and acknowledges the fickleness of addiction.
    Let's just say the media coverage of this tragedy has just started, and I'm already sick to death of it.
    My thoughts are with Dr. John's family and labmates.

  • leigh says:

    "How could we have missed this, we are supposed to be addiction specialists!??!". Please don't hold yourselves responsible

    this quote hit me square in the chest.
    i've been very heavily beating on myself for this very reason, in an even closer-to-home situation for me, for weeks now. i can vouch for how hard it is to not blame yourself, and to forgive yourself for your own perceived shortcomings.
    and i also thank you, DM, for putting this out there. i really needed to hear it myself... sometimes telling it to yourself is not enough.
    my sincerest sympathies go out to those affected by this tragedy.

  • Zetetic says:

    This does hit close to home, as I know several people at the University of Maryland, though in a very different department. My heart goes out to everyone affected by this loss.

  • HP says:

    When I was growing up, my small-town family doctor was a drug addict. I didn't figure out what was going on until I was maybe 15 or 16. After a routine visit, I told my Mom, "I don't want to see Dr. Bennett* anymore. He's a drug addict."
    Mom says, "What makes you say that?"
    I said, "He's pale and covered in sweat. He shakes and his eyes are the size of basketballs. He's a drug addict."
    Mom says, "Dr. Bennett's a good doctor. And besides, he always gives me exactly what I ask for."
    "Mom, that's not a sign of a good doctor."
    Anyway, long story short, I went off to college, and a couple of years later, while I was home on a visit, the big news in the local paper was that Dr. Bennett had fled the country, probably for Mexico, under indictment for criminal conspiracy along with a local pharmacist.
    "Hah! You see, Mom? I told you Dr. Bennett was a drug addict."
    "Now, now, HP. Just because Dr. Bennett was forging prescriptions for controlled substances and taking kickbacks from a pharmacist doesn't necessarily mean he was a drug addict."
    As far as I know, that bastard is still practicing medicine in Mexico, and I'm left with a deep mistrust of the medical professions, which has both contributed to my current health problems and my difficulties in getting timely treatment. (I'm now seeing a doctor I trust. Let's hope I don't get laid off from work.)
    Sorry to take up space on your comments with this rant. But it might nice to get some "buzz" going among the medical and pharmaceutical SciBlings about drug abuse among medical professionals.
    * Bennett is his real name. Sue me.

  • PalMD says:

    Very well said, DM

  • Ahh, this sucks. I haven't read the news today but I imagine the media is all 'blah, blah, scientists and medical people and drugs, blah, blah, up to no good'.
    I really appreciate the way you wrote this post. Really informative yet sympathetic to the people caught up in this tragedy. My heart goes out to those involved.

  • pinus says:

    This at once reminds me how small the science world is, and why I do the work that I do. My thoughts are with the families and friends.

  • Govt. Bureaucrat says:

    Once upon a time in the day before MTA's, I could write a letter to Roussel Uclaf and ask for a sample of RU486 and it showed right up in a plain white envelop--in a little plastic bag!)
    Then I did opiate research for awhile and resented the fact the the Dept. Chair made me come over to his office and sign small quantities out of the safe-- over and over.
    He was right and had his head on straight

  • David says:

    A tragic tale. And, DM, you're exactly right that addicts are very good at hiding their problem from their friends and family. I've seen anesthesiologists abuse IV fentanyl for years without being noticed.
    A couple of comments about Suboxone(R): the 4:1 ratio to naloxone is sufficient to reduce "drug liking" but probably not sufficient to prevent death from respiratory suppression. This is because the naloxone component has a very short half-life, whereas the terminal half-life of buprenorphine is long. As the naloxone wears off, the injection user becomes susceptible to respiratory depression. Second, the bioavailability of Suboxone and Subutex(R) varies with the dose, but is not high, possibly in the 50% range. This means that crushed and injected Suboxone delivers much more buprenorphine than it does when taking sublingually, as intended. Thus the low bioavailability contributes to the risk of death with IV injection. Finally, the tablets come in doses designed to treat opioid-tolerant addicts, and those doses are markedly higher than a non-habituated casual user might be able to tolerate. For instance, Subutex comes in 2 and 8 mg tablets whereas Temgesic (buprenorphine sublingual available in europe) comes in 0.2 and 0.1 mg doses for treatment of pain in opioid-naive patients.
    Another comment: FDA is moving to restrict prescription and dispensing of long-lasting and extended release schedule II opioids. A public hearing was early this summer. This would affect drugs like Oxycontin(R), but only when obtained via prescription. These victims were importing the drugs illegally, and the best efforts of FDA will not be able to alter this kind of abuse.
    disclosure: I work for a pharma company and conduct research on potentially competing products.

  • DRK says:

    "Ahh, this sucks. I haven't read the news today but I imagine the media is all 'blah, blah, scientists and medical people and drugs, blah, blah, up to no good'".
    Nope. Luckily for you, Candid Engineer, we are all obsessed with Roman Polanki.

  • Anonymous says:

    "Nope. Luckily for you, Candid Engineer, we are all obsessed with Roman Polanki."
    Try the local Baltimore news. . . all stations led with the story last night . . .

  • msphd says:

    DM, maybe you should write a post on how to spot the signs that someone is using/addicted? Or point me toward one you already wrote on the subject?
    I've dealt with mental health issues among my colleagues and advisors, as well as just plain old health issues. Both can affect behavior and it's not always clear, to those of us who are not trained in psychology, how to identify the cause or determine how serious it is.
    Very recently, one of my collaborators has undergone what appears to me to be a dramatic behavioral shift. I'm not sure, but as usual, I feel like I'm the only one who has noticed, so maybe I am just being hypersensitive, but I don't think so (especially since I have more experience with this than anyone I know).
    How do I know if it's a side-effect of a medication, a drug abuse problem, or some other health problem? And even if I could tell the difference, is there anything I can do about it? This person has tenure. At this point I'm walking a fine line of wanting to get the hell away from the fallout, needing to stay on good terms, and worrying for this person's well-being (and everyone else who depends on them).

  • DSKS says:

    "One clear factor that comes out time and again in cases of middle-class, so-called "functional" drug dependence is that people are fantastically good at concealing their drug use."
    With certain dependencies that's certainly true, but I think a sufficiently negative stigma attached to the addiction is an important prerequisite for that behaviour. But my limited experience with prescription opioid abusers so far is that they're not terribly subtle at all; shockingly blase would be a more appropriate description of that particular seeking behavior. Perhaps this is because they haven't yet, or don't believe that they have, got a "problem". But it seems to me that the prescription abuse problem tearing through the professional classes (and it is rampant in the US) is in part due to there being no real stigma attached to it*, and as a result, a reluctance on the behalf of wary peers to step in and express reservations at a time when those reservations still have the power to influence the outcome.
    * Well, there's arguably a small bit of stigma; just enough to facilitate a half-baked excuse about a persistent back pain or some abstract reference to insomnia, but the effort is minimal at best.

  • DrugMonkey says:

    DM, maybe you should write a post on how to spot the signs that someone is using/addicted? Or point me toward one you already wrote on the subject?
    I'm really not qualified to write such a post. I also suspect any attempt would be either frustratingly vague or misleadingly specific because of the nature of diagnosable dependence versus the many ways a drug problem might be expressed. This is the same for many of the behavioral disorders, I would argue.
    A change in behavior is pretty slim stuff to go on and what are you going to do, front them with "hey are you on drugs?". When it could be a pending divorce, sick kid, bad grant score, brain tumor, god-knows-what? I think if you are concerned about the person it is best to start with the behavioral changes and not assume a particular cause. And go more down the line of recommending they see someone rather than suggesting possible causes.

  • CP says:

    Given their expertise on drug effects and probably more than some clue about toxicology, it surprises me that they would even trust an online source for drugs. Is there any reason to think the drug would be any more pure than something you could obtain on the street? Of course, they wouldn't use intravenous drugs from any source if they were making sound decisions to begin with.

  • DrugMonkey says:

    Is there any reason to think the drug would be any more pure than something you could obtain on the street?
    Sure. If they are illicitly obtaining the real thing, i.e., pharmaceutical products designed for licit use, you would expect the tablets to contain the proper ingredients at the advertised dose of active agent(s).
    Of course, I know next to nothing as to whether shady internet sources which purport to have genuine pharmaceuticals for sale might substitute uncontrolled look-alike tablets...

  • Andy Nonymous says:

    Okay, I will take a somewhat unpopular view here. Why is any intake of a "controlled substance" defined as an addiction? I am dependent on caffeine as are a fair number of my colleagues but no one cares about it. However, a few of my colleagues also take marijuana occasionally (legal here), is that something that is necessarily a problem. If it not affecting the rest of their lives then they are doing fine and living life on their own terms so I do not see why people should all go trying to "help" them. In this case, if the drug's composition was different from what they expected why not treat it as a simple poisoning issue. Why do people have to be on a lookout for who is doing what in their private lives?

  • DrugMonkey says:

    Why is any intake of a "controlled substance" defined as an addiction?
    It isn't.
    is that something that is necessarily a problem. If it not affecting the rest of their lives then they are doing fine and living life on their own terms so I do not see why people should all go trying to "help" them.
    No, it is not necessarily a "problem". Read this and this.
    The reason *I* don't treat it as "a simple poisoning issue" is that frequently it is not. Actually, whenever illicit recreational drugs are involved it is not "simple".

  • David says:

    regarding definitions of abuse, dependence, and addiction:
    DSM-IV is the best touchstone. Abuse is "a maladaptive pattern of substance use leading to clinically significant impairment or distress" (with a bunch of specific examples following the definition). Dependence is a more complex definition, requiring 3 or more of: 1) tolerance, 2) withdrawal, 3) dose increase, 4) persistent desire, 5) time spent on drug-related activities, 6) reduction of time spent on other activities, or 7) pattern persisting despite awareness of harm. (I've simplified the details here). DSM doesn't define addiction. The Am. Acad of Pain Medicine gives "Addiction is a compulsive disorder in which an individual becomes preoccupied with obtaining and using a substance, the continued use of which results in a decreased quality of life."
    In the case at hand, the drug users were illegally importing drugs and hiding them in teddy bears, indicating distress at being caught. Their actions covered more than one drug, indicating a pattern. So it's abuse. I don't see enough information in the press reports I've read to tell if it was dependence or addiction.

  • anonymous says:

    We are natural born liars. But we can spot one another at a glance.

  • Meat Robot says:

    Drugs which are buccally absorbed do not undergo first past metabolism. That requires intestinal or gastric absorption, and then transport to the liver via the mesenteric venous drainage into the hepatic portal system. Veins draining the tongue drain into the jugular vein and then superior vena cava.
    Andy N, I'm sure we can all reasonably distinguish between drug use, drug misuse, drug abuse, and drug dependence. This unfortunate soul was at least misusing, as evidenced by crushing and injecting a tablet meant for oral use.

  • mat says:

    An obituary for Dr. John has been posted on the SFN website.
    http://sfn.org/index.aspx?pagename=memberObituaries_johnC

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