As I've written many times before (and you probably know anyway), opioid abuse, addiction, and overdoses are a big deal in the U.S. It's troubling any way you slice it, but the fact that many opioid-related problems can be traced to prescribed medications is a particular problem for the health system. For example, in 2013, about twice as many opioid overdose deaths (16,000) were attributable to pharmaceutical opioids than to heroin (8,000).

That's just one of the lessons about opioid addiction and overdose worth sharing from "Opioid Abuse in Chronic Pain — Misconceptions and Mitigation Strategies," by Nora Volkow and A. Thomas McLellan (NEJM, 2016). There are many more.

Opioid overdose or death is almost always the result of respiratory failure. Opioids slow down the central nervous system, including breathing. Slow it enough and the body starts to suffocate. What's helpful about the paper by Volkow and McLellan is that the authors tease apart this effect of opioids from others, explaining how prescription opioids can both help and harm.

In particular, tolerance to or physical dependence on opioids' different effects occur at different rates. For example, "tolerance to the analgesic and euphoric effects of opioids develops quickly, whereas tolerance to respiratory depression develops more slowly." Therefore, as doses are increased to maintain pain control (or euphoric reward), so does risk of overdose. If the body only tolerated opioid's effects differently — more rapid tolerance to respiratory depression than to the analgesic or euphoric effects — the drugs would be less problematic.

Tolerance or physical dependence, however, is not the same thing as addiction. Whereas one can be genetically predisposed to addiction — about one-third of the risk of addiction is genetic — one cannot be genetically predisposed to tolerance. Volkow and McLellen wrote,

[R]ecent studies have shown that the molecular mechanisms underlying addiction are distinct from those responsible for tolerance and physical dependence, in that they evolve much more slowly, last much longer, and disrupt multiple brain processes.

Take enough opioids and you will become physically dependent, but not necessarily addicted. Stop taking opioids and tolerance will dissipate within days or weeks, but signatures of addiction may last for years. Pronounced craving, compulsive drug taking, and other behavioral changes associated with addiction are simultaneous with structural and functional changes in the brain.

This heightens the risk of overdose among patients with addiction, after a period of abstinence, perhaps due to substance use disorder treatment. Cravings remain but tolerance has dissipated. This is precisely why controlling cravings with medication — even if one is physically dependent on them — is a component of the most effective forms of opioid use disorder therapy.

Peter Friedmann, Brown University Professor of Medicine and Professor of Health Services, Policy & Practice and an expert on substance use and addiction medicine put it this way:

People often confuse physical dependence (tolerance and withdrawal) with addiction. [...] The oral, long-acting opioid agonists currently FDA approved to treat opioid use disorders produce physical dependence, but by diminishing the reinforcing effects of short-acting opioids they function to extinguish addictive behavior. [...] The idea is that blocking the euphoria (positive reinforcement) and stopping the withdrawal symptoms (negative reinforcer for cessation) will extinguish the antisocial and dysfunctional behaviors.  Spending more time feeling normal also allows the patient to focus on the difficult process of self-exploration, life re-orientation and relationship re-building necessary for long-term remission and recovery.

I suspect I've conflated opioid dependence and addiction in my mind, if not some of my prior writing. I'm almost certainly not the only one. Thanks to Volkow and McLellan, the distinction is now much clearer to me, and it has relevance for health care delivery and health services research: dependence should be managed, to be sure. But addiction requires treatment, which is in short supply. Illuminating where treatment is underprovided and why is the job of health services research.

I recommend you read their paper in full.

Austin Frakt
Author, Committee Member, Member

Austin Frakt, Ph.D.

The Incidental Economist Chair, Translation and Dissemination Institute Advisory Committee

Austin is a health economist and researcher; the creator, co-manager, and a primary author of The Incidental E... Read Bio