This month we’re highlighting research published by Daniel Remillard (former NAPM medical assistant and current medical student at the University of Washington) and Dr. McAnally and published in the journal Current Pain and Headache Reports.

Not all opioids are created equal

The graph above shows survey data from nearly 90 patients with a formal diagnosis of opioid use disorder; 40% were active heroin users at the time of engagement with our practice. In case the resolution's a bit hazy, the bottom line is that the overwhelming majority of survey respondents chose oxycodone as their drug of choice (60%), the one they deemed most addictive (59%, and not necessarily the same phenomenon); and for those addicted to heroin, their 'gateway drug' to heroin (78%.)

This was no surprise, and actually formed our a priori hypothesis going into the study. We’ve known since the 1950s - long before the advent of OxyContin - that oxycodone is disproportionately addictive. (A systematic review of the literature is provided in the article.)

Anyone involved in pain management at any level, or addiction medicine knows that no other prescription opioid wields the same degree of destructive power over lives in terms of inducing singular and reckless pursuit of the drug, with 'fiending' driven by both desire for its euphorigenic and often stimulating effect, and also its severe withdrawal scourge.



Many theories over the years have tried to account for this unparalleled hook, and undoubtedly there is some truth to most of them. Our most recent understanding however of the unique neurobiology and pharmacokinetics of this drug likely hold the key to understanding its supreme addictive potential, and it has to do with both “positive” and “negative” subjective experiences.

oxycodone mat-su valley

From McAnally H, Freeman L, Darnall B. Preoperative Optimization
of the Chronic Pain Patient. Oxford University Press, 2019 (In press.)

There are two sides to oxycodone's supreme desirability and feverish pursuit, and they parallel roughly the co-phenomena of 'want' and 'need' - which are not the same thing. We all know that we can want what we don't need, and need what we don't want, and Robinson and Berridge (Robinson TE, Berridge KC. The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Rev. 1993; 18:247-91) taught us that from an addiction standpoint over a quarter century ago now.

From a desirability standpoint, the hedonic reward of oxycodone is unequaled (so say the majority of opioid-addicted persons) and we can explain that by unique pharmacokinetics that include extraordinarily efficient and rapid transport across the blood-brain barrier. All opioids exert their euphoric effect via mu-opioid receptors (MOR) in the brain; oxycodone does it better. We've known for half a century that the quicker a substance exerts its effect the more desirable it is (with dopamine activity in the mesolimbic system as a marker) - in other words, you can get across the country in a covered wagon or a Ferrari but the Ferrari is a lot more fun. But wait - there's more : oxycodone sticks around longer too, exerting sustained phasic dopaminergism in the nucleus accumbens and ventral tegmental area.

From the standpoint of all-else-be-damned demand, we can explain that (and addicted individuals concur) by the unparalleled kappa-opioid receptor (KOR) effects of oxycodone: the 'teeth' of the drug. KOR medites withdrawal, and oxycodone is the strongest KOR agonist we have in clinical practice (interestingly, there are stronger recreational KOR agonists like salvia, seemingly devoid of addictive potential. How does that work? It seems that in the absence of MOR-mediated reward, the depressant/aversive effects of KOR are enough to keep folks from getting hooked on salvia or similar compounds.)


Danger, Will Robinson

Dr. John Bonica, the father of pain medicine wrote in the 1970s:

“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.” [Halpern IM, Bonica JJ. Analgesics. In Modell W (Ed.) Drugs of Choice 1976-1977. St. Louis: Mosby; 1976 : pg. 213]

This giant upon whose shoulders we all stand made the point two decades before the onset of the American opioid epidemic that this drug is extremely high-risk. Increasingly folks (e.g., Ontario) are heeding his warning, and we've taken his advice to heart in our practice for the past 6 years; outside the context of terminal abdominal malignancy (where the KOR effect seems to be beneficial) we do not prescribe oxycodone. There are alternatives in the case of both analgesics and also medication-assisted treatment of opioid dependence; see Remillard D, Kaye AD, McAnally H. Oxycodone's Unparalleled Addictive Potential: Is it Time for a Moratorium? Curr Pain Headache Rep. 2019 Feb 28;23(2):15. doi: 10.1007/s11916-019-0751-7 [] for more in-depth coverage.