Saturday, January 16, 2016

Prescription Opioids and Benzodiazepines, and a Failed Opportunity to Meaningfully Inform the Public

As I said in a previous post, I am extremely skeptical of the CDC’s reports on rising prescription painkiller overdose deaths. More pointedly, I think their scare-mongering is irresponsible and their proposed policy responses are mistaken. My best guess is that the recent increase in “drug poisoning” deaths is partially real, but most of the increase is attributable to drug *interactions*, not overdoses per se. I think they have missed an opportunity to meaningfully inform the public about a real hazard. They could be saying “Don’t take opioids with benzodiazepines or alcohol. It will kill you!” Instead they are saying things like, “Let’s crack down on doctors who prescribe too much and patients who use too much. Let’s restrict the supply.” A patient taking prescription painkillers could read one of these CDC reports without actually being informed of the risks and how to avoid them. (See here and here . In the both links, the CDC actually manages to say that drug interactions between opioid painkillers and benzodiazepines are common, but it fails to emphasize the importance of this phenomenon.)

Here is something interesting I’ve found in the CDC's mortality data:

Data for the above chart comes from the CDC's Multiple Cause of Death mortality database. The "Other Opioids" category includes most of the prescription painkiller deaths. Look at how closely the Benzodiazepine trend line follows the Other Opiods trend line (the thick lines, in blue and green). Both show a rise over the period from 1999 to 2011. They even show the same dip in 2012 and 2013, and a fairly significant bump in 2014. It’s unlikely to be a coincidence. The linear correlation is 0.995. If you look at the raw death counts, they match up reasonably well. Between 1999 and 2000 there were 184 additional other opioid deaths and 183 additional Benzodiazepines deaths. In 2002 to 2003 the numbers are 455 and 249. In 2004 to 2005 the numbers are 544 to 455. In 2011 to 2012 the numbers are both negative; they drop by 575 for other opioids and 321 for benzodiazepines. It’s not exactly a 1-to-1 matching, but the correlation is very strong. The linear correlation between these numbers (change in other opioid deaths and change in benzodiazepines deaths) is 0.83. Not perfect, but strong.

One can make a similar observation state-by-state. I pulled MCD data from the CDC’s Wonder database. For every state with any volume of deaths, the correlation between benzodiazepine deaths and Other Opioid deaths is in the high 80s or 90s. So every state with a significant amount of data is seeing the countrywide pattern. See how the scatter plots show a linear pattern for each of several states. 

Combine this with the fact that just about *every single* category of drug is on the rise. (See chart above and in previous post.) Most of these aren’t overdoses. Most of these categories of drugs are hard to actually “overdose” on. Painkillers aren’t enslaving their users and forcing them to compulsively swallow pill after pill until they drop dead, nor is this happening with other pharmaceuticals or street drugs. Rather, uninformed users are taking bad combinations of drugs, the interaction of which is fatal. So the increase in prescription opioid deaths is showing up in other categories of drugs.

The impression you might get from reading some of the CDC’s public service warnings (like this one) is that irresponsible and recreational use of prescription drugs is on the rise. This is a problematic story, in that it appears to be contradicted by government surveys on drug use. According to those surveys (SAMSHA  and Monitoring the Future), rates of *illicit* use of pharmaceuticals are flat, or even declining. One could surmise that there’s a bias in the surveys, whereby someone who misuses a legal drug doesn’t report the use as illicit. Perhaps the number of abusers is growing, but they aren’t reporting their use as “illicit use” because they have a legal prescription. But the survey wording is pretty clear; it asks the respondent to count as “illicit” any use that’s recreational or other than recommended by the doctor. See page 30 and page 32 of the Monitoring the Future report, where a change in wording of the question caused a sudden jump in self-reporting; clearly the respondents are *somewhat* following the survey instructions or this wouldn’t have happened. Supposing there *is* a reporting bias, it’s very hard to claim that such a bias explains the survey results. If respondents are less likely to report illicit use because they are getting more and more legitimate prescriptions, there should be a *downward* trend in the use rates from ~2000 to 2011, when legal prescriptions for opioids were steadily increasing. And responses admitting to illicit use should have increased after 2011, when legal prescriptions leveled off (and recreational users presumably resorted more often to illegal supplies of these drugs). In fact, illicit use of pharmaceuticals decreased after 2011, in both surveys and for all age groups. One would also have to argue that the same reporting bias exists for two different surveys, and for every age category of respondents. If you *do* think that a trend-inducing reporting bias is possible, consider that it might be a factor in the “drug poisoning” figures put out by the CDC, and that it likely overstates an existing trend, or creates one out of nothing. Several CDC reports assume that “diversion” is a huge and growing problem, but apparently that’s not the case. We should see that in the “illicit use” numbers.  We simply do not. From years 2002 to 2014, the correlation between death rates and illicit use rates is actually slightly negative, although the correlation between deaths and opioid sales (in kg per 100k) is in the high 90s. More people have been using legal prescription opioids, probably mostly as directed. If illicit use of prescription painkillers is a problem, it’s no more so than it was 11 years ago, and it’s not the driver of the recent surge in poisoning deaths.

There are more legitimate prescriptions than there were 15 years ago, but properly administered narcotics almost never turnspatients into addicts 
“Although there were 11,882 patients who received at least one narcotic preparation, there were only four cases of reasonably well documented addiction in patients who had no history of addiction. The addiction was considered major in only one instance. The drugs implicated were meperidine in two patients, Percodan in one, and hydromorphone in one. We conclude that despite widespread use of narcotic drugs in hospitals, the development of addiction is rare in medical patients with no history of addiction.” This is consistent with the survey results. We are prescribing more opioid painkillers, but we aren’t getting hordes of zombified addicts as a result."

If the recent surge in drug-related poisonings is real, the most likely explanation is that these are drug interactions. Even the CDC appears to know that this is an important drug interaction. From the link: 
“Benzodiazepines were involved in 31% of the opioid-analgesic poisoning deaths in 2011, up from 13% of the opioid-analgesic poisoning deaths in 1999.” 

It’s quite plausible this is an understatement, as thorough toxicology screenings aren’t always done in all localities. This report, also from the CDC, indicates that a high percentage of both opioid and benzodiazepine poisoning deaths involve alcohol as well. 

“The analyses showed alcohol was involved in 18.5% of OPR and 27.2% of benzodiazepine drug abuse-related ED visits and 22.1% of OPR and 21.4% of benzodiazepine drug-related deaths.” 

In previous hysterical scare-stories related to OxyContin, it was revealed that 1) the number of poisoning deaths was vastly overstated and 2) actual poisoning deaths were most often from combinations of drugs, not from a single drug. See here
“…overdose victims tend to have multiple drugs in their bodies. Approximately 40 percent of the autopsy reports of OxyContin related deaths showed the presence of Valiumlike drugs. Another 40 percent contained a second opiate such as Vicodan, Lortab, or Lorcet, in addition to oxycodone. Thirty percent showed an antidepressant such as Prozac, 15 percent showed cocaine, and 14 percent indicated the presence of over-the-counter antihistamines or cold medications. Deaths like those could be the result of any of the drugs present, drugs working in combination, or one or more drugs plus the effects of other conditions, such as illness or disease. Indeed, the March 2003 issue of the Journal of Analytical Toxicology found that of the 919 deaths related to oxycodone in 23 states over a three-year period, only 12 showed confirmed evidence of the presence of oxycodone alone in the system of the deceased. About 70 percent of the deaths were due to “multiple drug poisoning” of other oxycodone-containing drugs in combination with Valium-type tranquilizers, alcohol, cocaine, marijuana, and/or other narcotics and anti-depressants.” 

Benzodiazepines by themselves are also very unlikely to cause an overdose

“Taken alone, they rarely cause severe complications in overdose; statistics in England showed that benzodiazepines were responsible for 3.8% of all deaths by poisoning from a single drug.”

And here
“Taking benzodiazepines with alcohol, opioids and other central nervous system depressants potentiates their action. This often results in increased sedation, impaired motor coordination, suppressed breathing, and other adverse effects that have potential to be lethal.”

So it’s probably hard to literally “overdose,” as in “take such a large dose as to be fatal”, on any single one of these drugs, but it’s easy to accidentally take a fatal combination of drugs.

So what’s the point?, you might ask. Am I just hair-splitting here? Am I pedantically correcting the imprecise language of a government agency, who insists on saying “overdose” when it should be saying “multi-drug interaction”? Isn’t 15,000 deaths per year a big problem, by whatever name you call it?  No, I think this is an important point. If you don’t properly specify what the problem is, people will miss the point. Governments will enact the wrong policy responses. A patient who is taking painkillers should be meaningfully informed by the CDC's news briefs and public service announcements. Someone taking a therapeutic dose of prescription opioids should not be worried that s/he will turn into an addict, or drop dead of an overdose. Both outcomes are exceedingly rare for a properly administered round of painkillers. But such patients *should* be concerned about potential drug interactions. They should be alerted to talk with their doctors about their current medications and drinking habits. A properly educated patient should be able to read these CDC news briefs and say, “Ah, I can do something *myself* to make sure *I* don’t fall victim to this growing problem.” Take another look at this somewhat hysterical brief; the section titled “Solutions” is entirely about what *other* people can do to solve the problem. If I’m a random guy reading this brief, there’s very little I can actually do to effect government policy. I might be convinced (wrongly) that opioids are inherently dangerous and that the recent rise in prescription rates is inherently problematic. I might also be convinced (again, wrongly) that the solution is to stop *other people* from prescribing and using painkillers so often. The link vaguely hints at talking to your doctor, but that’s not at all the thrust of the message. I don’t think I’m just picking on one bad PSA, either. The link is typical of what comes up in my Google searches on this topic. I consider it irresponsible fear-mongering. It misses the point, badly. It fails to meaningfully inform the reader of the problem. Indeed it *misinforms* the reader. 

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