I'll leave my neuropharmacology and neuroscience colleagues to comment in greater detail on this story (see earlier DrugMonkey post), but this report is just in from AP on Heath Ledger's toxicology report:
The cause of death was "acute intoxication by the combined effects of oxycodone, hydrocodone, diazepam, temazepam, alprazolam and doxylamine," spokeswoman Ellen Borakove said in a statement.
I haven't seen a copy of the report itself (maybe Smoking Gun will have it soon) but plasma concentrations of each were not noted. However, this was the statement from the family:
In a statement released through Ledger's publicist, the actor's father, Kim, said Wednesday: "While no medications were taken in excess, we learned today the combination of doctor-prescribed drugs proved lethal for our boy. Heath's accidental death serves as a caution to the hidden dangers of combining prescription medication, even at low dosage."
Is it me or would the redundant use of two opioids and three benzodiazepines (plus an antihistamine with good anticholinergic activity) seem to indicate an intentional rather than accidental overdose? Not that it matters and this has already been painful enough for the family but I'm just thinking out loud.
A very sad conclusion to a very sad story.
I'm with you on accidental versus intentional. No sane physician prescribes three benzos for one patient, especially when diazepam is one of them; that stuff has a ridiculously long-half life and sticks around in the body for quite some time. The doxylamine is also a giveaway, if you ask me. The only commercially available source I can think of for doxylamine is Unisom Sleep-Tabs. You don't load up on Oxycontin and Valium and then "have trouble sleeping." It sounds like he was cleaning the CNS depressants out of his medicine cabinet in one fell swoop.
However, sadly enough, I have seen patients prescribed similar cocktails, especially with benzodiazepines; it isn't necessarily common, but you get the folks who are on clonazepam chronically with alprazolam as a shorter-acting drug (for "breakthrough anxiety?") and a side of temazepam or triazolam or maybe zolpidem "for those nights when they have trouble sleeping." And I'm not talking about doctor shoppers. I'm talking about one physician prescribing the whole lot. I always make a point to ask people whose profiles look like that if they take all those drugs together.
I heard this on the news literally about one minute before coming across your post, and my reaction was the same. You shouldn't need a doctor to tell you that a mix of drugs like that is something to approach with, at the very least, extreme caution. Do we know what supposed conditions all of those prescriptions were written for, and whether they all came from the same doctor?
While I agree with both of the above comments, don't forget that celebrities inhabit a different realm from The Rest of Us when it comes to pharmacology. It is painfully easy for anyone with a modicum of public recognition to find an MD who's loose with the prescription pad - just look at the laundry list of celebs who've been given enough drugs to start their own pharmacies. I don't absolve Heath Ledger of his responsibility to know what he was ingesting, but at the same time I know there's always the chance that he was never warned of the true dangers of combining drugs.
Good find Abel. I hadn't run across anything mentioning the opiates as one of the meds that was found up to this point.
It raises some questions. There was some tabloid-ish mention of a possible heroin problem but it was so scant and infrequently reported that I didn't know whether to credit it or not. If true or if he was really abusing OxyContin and this got misreported as "heroin" addiction...well that puts us back on that particular trail.
I really like that family statement. Good thing to have generally known whether it is strictly the main causal factor in this case or not. Certainly we can assume at least two semi-independent respiratory suppressant effects. Know anything about the metabolism? Same hepatic enzyme by any chance?
I actually did a tv interview last week, and a radio interview today about this.
Most doctors, I hope, don't prescribe multiple benzos to patients, however, many patients have multiple doctors. Also, the oxycontin is a funny one. I kinda doubt that was one of the more legit parts of the mix.
Either way, I certainly believe in the "accidental" OD. Someone who is anxious and depressed may keep taking one pill after another, hoping to finally feel better, or at least fall asleep. It is a common scenario.
People who take ODs with the intention of killing themselves often fail. If they don't use tylenol, then they often use a single med.
The synergistic effects of multiple medications are...bad.
Diazepam is a major substrate of CYP 3A4 and 2C19; none of the other drugs on the list are major inhibitors of those enzymes. The ultimate effect was most likely a pharmacodynamic interaction, not a kinetic interaction. We're looking at additive CNS depression--nothing more complicated than that.
It might've been accidental, but that's not where I'd put my money at the moment. Perhaps a thorough police investigation--and a tox screen complete with precise serum levels--will shed some light on the matter.
Do we know if they were all prescribed by the same doctor? If not, it is minimally plausible that he had multiple doctors and was not keeping their various treatments coordinated.
As someone already mentioned, the rich and famous go about things differently. But in the real world, electronic medical records and e-prescribing go a long way to cutting out accidents.
Patients can always find ways to circumvent this, however.
I believe that press reports immediately after Ledger's death noted that he had Rxs from multiple physicians, no surprise given that he was filming all over the world then living in NYC.
The metabolism questions from DM and N.B. deserve a whole post and are rather complicated. While there is no CYP overlap between benzodiazepines (3A4) and the benzomorphan opioids (2D6), people vary quite a bit in CYP2D6 activity and can fall into poor or rapid metabolizers. The counterintuitive factor to consider is that 2D6 converts oxycodone and hydrocodone into the more active oxymorphone and hydromorphone, respectively. So, if Ledger had a CYP2D6 rapid metabolizer phenotype, that would be a bad thing.
As N.B. points out neither benzodiazepines nor opiates are particularly noted for induction of Phase I or Phase II drug metabolizing enzymes.
The common thread between benzodiazepines and benzomorphans is that both classes undergo glucuronide conjugation via UGT2B7 activity. This is primarily an inactivation pathway (although some opioids are more active as glucuronide conjugates, flying in the face of the pharmacology I learned). So, you essentially got five drugs where some could act as competitive inhibitors of the inactivation of one or more of the others. That would be consistent with the mixture being worse than the sum of the parts pharmacokinetically. However, even just the additive CNS depressant effects of all the drugs would be enough for pharmacodynamic additivity or synergy without invoking metabolic arguments.
Finally, doxylamine is also the antihistamine in NyQuil, well-known to knock the hell out of people far more than Benadryl/diphenhydramine. Moreover, it is sold as a sleep aid in Australia in dosage forms (50 mg) larger than those in the US (6.25-25 mg).
If you're confused by now, you should be. My feeling is that this drug combination could be lethal even at recommended doses of each without invoking drug metabolism interactions. However, adding in the competition for glucuronidation makes this combination even worse.
Abel's kinetics and metabolism knowledge no doubt exceed my own; it's true that whether any of the drugs in question were inhibitors or not that they were probably saturating the guy's liver enzymes just through sheer dose overload. Impaired metabolic clearance of the drugs probably didn't help, but we're in agreement that it likely wasn't necessary.
Somehow it had slipped my mind that doxylamine is present in NyQuil, but the report didn't mention alcohol at all--and NyQuil is about 10% alcohol by volume, not to mention the acetaminophen and dextromethorphan, hence my immediate conclusion that tablets were the dosage form.
Of course, this is all conjecture barring a more detailed report on serum concentrations of the drugs. I'm sure the tabloids are going to have a field day with this. Whether we'll get the real truth--and whether it really matters, because it certainly isn't going to console the family any--is another issue altogether.
"The only commercially available source I can think of for doxylamine is Unisom Sleep-Tabs."
I noticed that he had been filming in London for a few weeks just prior to his death-- doxylamine is in more things in Britain in tablet form than in America, such as Tylenol... or at least it was a few years ago when I lived there. Many things which are prescription here are over-the-counter there.
I don't think signs point to it being intentional-- many people think that if drugs are prescription, approved by the FDA, they're completely safe. I've seen many people take multiple things at once that are dangerous even when taken alone, people not informing their doctors they're on another medication... people are crazy.
"But in the real world, electronic medical records and e-prescribing go a long way to cutting out accidents."
Not when you have doctors in different countries, which movie stars often do, filming for a few months at a time in different places around the world. In the past few years he'd been to at least three continents promoting and filming movies. That gives a lot of opportunity to see disparate doctors.
Movie studios have often gone to great lengths to keep the star of the show on set and able to perform. It's not totally out of the realm of possibility that he was given the prescriptions by an on-set doctor and was therefore not aware of the effects.
I can belive that a doctor can prescribe things that are whacko - a relative was on an SSRI, a narcotic, an anti seizure drug, and a tricyclic antidepressant at the same time. Yeah. When i checked on the drug interaction checker there were 7 cautions- one really big no and 6 little ones, that all added up to a wee bit of a problem. On top of that there was something for breakthrough pain. Now, understand that this regimen was on a checklist through worker's comp - so they essentially had a bunch of drugs that were thrown at people and the doc was encouraged to try them- apparently all at once.
That summer I seriously thought this person was going to die. That was the summer I started looking up stuff on the internet and educating myself. The time that the nurse at WCB suggested tramadol as a pain management drug, I was able to say no forcefully enough that the person involved did not take it. Apparently that has some lovely effect when paired with the SSRI....
The problem is often not the patient asking for drugs, it is a protocol driven system that says try this and this and this, often at the same time. Often the person is not involved with anything other than the thought of getting rid of god awful pain, and they do what they are told in hopes that the expertise of health care practiotioners will help.
Lucky for me I didn't have to deal with a funeral, but I know how close we were and I still get mad. And not at the doctor even- these things are on a stupid protocol and are mandated by the workers insurance and the government. You should see the pain guidelines where I live- they have not been updated since 1992 or 93 and are archaic.
So, I can see how it would happen and I am so sorry that it did happen to another young person.
A question---- Is there any responsibility that the pharmacist takes on if you go to the same pharmacy and fill all your prescriptions if things go badly?
I know I've come close to doing myself serious damage before by mixing (a) a medication I was prescribed, (b) an OTC medication for the same condition that a doctor friend suggested, and (c) a fairly powerful painkiller that I was fairly used to taking routinely. Neither doctor involved thought to warn me of the dangers, because neither had any inkling of the other stuff I was taking - and I had no real idea of what I was knocking back, and anyway assumed that at such small doses there could be no real harm. Never underestimate ignorance!
I suppose that he might have decided to commit suicide by swallowing everything he had in the house, but otherwise I would tend to expect him to take a bunch of one drug rather than a bit of several.
I am more inclined to suspect multiple doctors with incomplete information, and an unsophisticated patient who doesn't really understand that drugs prescribed to treat different conditions are not necessarily really different when it comes down to the risk of overdose. A lot of people think in terms of the indication rather than the class of drug.