The follow-up to this article's prelude was initially intended to be an exposition of the clinical pharmacology and real-world outcomes data for tapentadol (Nucynta), which for numerous reasons has become our Schedule II opioid of choice for the treatment of chronic non-cancer pain severe and refractory enough to warrant consideration of such. That will have to wait another month or two though, as the lead-in article generated so much spirited feedback – much of it demanding response (and rebuttal) – that I've decided to present a tour of the pre-clinical, clinical, epidemiologic, and historical evidence indicting oxycodone as the most addictive of the prescription opioids.
Pre-clinical data
The current neurobiologic framework for understanding addiction rests upon the nearly ubiquitous manifestation of dopamine surges within the mesolimbic system of the brain, including nucleus accumbens and the ventral tegmental area. In short, if the organism really enjoys or likes a substance or activity, the brain will emphatically punctuate the experience and memory with an exclamation point comprising phasic (vs tonic) dopaminergic activity in this so-called "hedonic highway" circuitry. It's the beginning of a craving, but so much more than that.
What's unique about oxycodone relative to other opioids is the speed at which it's presented to the brain. There's a long-venerated addictionology axiom that basically says the more rapid (or dynamic) the pleasure, the more addictive. And in that regard, oxycodone reigns supreme (), likely having to do with the fact that oxycodone's transport across the blood-brain barrier is considerably faster and more efficient than that of other opioids – up to seven-fold greater in some species.
Oxycodone (and many other substances) addiction doesn't end though at striking a balance between desire and satisfaction; hardcore addiction occurs in the context of a subtle shift (with not so subtle teeth) such that now the issue is one of withdrawal avoidance. Much of the scourge of opioid withdrawal has to do with activation of the dynorphin/kappa-receptor (KOR) system, and oxycodone exhibits supranormal KOR activity compared to other in-class agents.
Clinical data
A question I asked several years ago during the height of the OxyContin epidemic was, "If all opioids are created equal, why aren't equipotent doses of MS Contin in equal demand? Or given the availability of substantially cheaper morphine generics, why not in greater demand?"
A common response pairing for nearly three decades now has been something along the lines of "oxycodone works better (ostensibly as an analgesic) and has fewer side effects." The data are mixed on both issues, but it's worth mentioning again that in the blinded head-to-head that generated the lead-in article here, there were no real differences in either category (what did differ was likability). What we do see empirically is that there are differences in side effect profile: morphine's histaminergic proclivity does tend to yield more pruritis for example, but oxycodone's KOR proclivity yields markedly worse withdrawal (and hyperalgesia). And its disproportionately effective CNS mu-receptor activity yields unparalleled hedonic reward and conditioning.
Along those lines, many respondents to the initial article vocalized umbrage at the allegation that oxycodone results in a "high." Almost certainly not everyone experiences this (and furthermore given adaptation and tolerance, such hedonic feedback declines). Nonetheless, there are plenty of studies out there over the decades – see the historical review included in our pain management/addiction medicine-based – specifically investigating whether euphoria and the experience of getting "high" occur more with oxycodone than other opioids; , as well as empiric observation and testimony from innumerable patients in recovery, overwhelmingly indict oxycodone as the of the prescription opioids.
There's another clinical question worth answering here, brought up by at least one respondent: what about pharmacogenomics? Basically the argument goes something like this: some people by virtue of P450 variability (either CYP2D6, responsible for generating oxymorphone, or CYP3A4, responsible for the essentially non-active noroxycodone) are more prone to become addicted to oxycodone. The issue has been looked into in some depth, with numerous studies examining whether poor or ultrarapid metabolizer status at either locus are more or less likely to misuse and abuse oxycodone. , however, have been anything but consistent and with population-level frequencies of allelic variation on the order of 1%-4%, this issue couldn't possibly explain the disproportionate (consistently on the order of 80%) drug-of-choice-status oxycodone enjoys.
Epidemiologic data
Data from the show that oxycodone is associated with more ED visits than any other individual drug (any guesses as to number two? That's right – alprazolam). Is the drug that much more dangerous? (If so, that alone would argue for serious re-thinking of its place in any formulary or practice). No and yes: there exists no evidence for increased cardiopulmonary toxicity with oxycodone compared to its cousins (unlike methadone, for example), but greater misuse and abuse yields greater incidence of adverse events.
Not surprisingly, per , oxycodone is also the drug most frequently encountered by law enforcement officers when responding to crises and crimes.
OxyContin of course has been tried and found guilty (literally) of generating the current American crisis, at least in Appalachia. But it's not just our country that has experienced widespread societal damage from the agent; Canada has fared similarly, and in 2012 Ontario became the first province to remove the drug from its public benefit program.
Historical evidence
Finally, it should be noted that observations of oxycodone's unparalleled addictive potential predated the advent of OxyContin by decades. Some of the most telling data come from a large from the 1970s and 1980s singling out oxycodone as the most treacherous prescription opioid in terms of dependence and functional compromise; similar reports however date back to the 1950s.
In closing, I'd like to quote John Bonica, MD, the father of pain medicine. "We find the risk of addiction [to oxycodone] greater than that attributed to morphine ... We do not recommend the use of oxycodone continued past the initial phases of treatment for pain." That statement was published in 1976; tragically his wisdom and experience have been largely ignored both within the discipline he founded as well as Western medicine in general. Perhaps we're ready to listen now?
, is a board-certified anesthesiologist, pain physician, and addictionologist practicing in Alaska (the military sent him there and he decided to stay). If he wasn't trying to guide people in improving their own lives, teaching medical students to do the same, or writing about it, he'd probably be outdoors right now slogging up a mountain with a good friend or two.