by David Juurlink

We need to talk about dependence—specifically, what it is, what it isn’t, and why it matters.

Dependence isn’t the same as addiction

Dependence is a special type of drug-related harm. It’s an adaptive phenomenon resulting from exposure to a centrally-active drug and defined by the development of withdrawal symptoms when the drug is removed or the dose lowered too quickly. It can happen with benzos, alcohol, opioids, SSRIs, baclofen, cannabis, pregabalin and many other drugs. Withdrawal symptoms vary by drug, dose and patient, but the gist of dependence is this: when billions of neurons have become accustomed to the presence of a drug, they don’t work properly when it’s suddenly taken away.

Addiction is different. The term generally implies a chronic, relapsing condition in which drug use continues despite harmful consequences. I don’t want to get into the weeds about evolving nomenclature¹ or the many subtleties², except to say that there’s merit in not conflating the two terms. To me, the guy smoking his fentanyl patch suffers from addiction (and most likely dependence, too), but the guy using it as prescribed for back pain, and who suffers withdrawal symptoms without it, is simply dependent.

But another reason to distinguish the two is that there’s a tendency to normalize dependence. I see this most often in the setting of chronic opioid therapy, with the implication being that dependence is just a thing that happens, and it’s no big deal as long as the medication is helping and the patient shows no signs of addiction.

This way of thinking is simplistic and dangerous.

Why dependence on medications is a problem

There are two ways in which dependence can create trouble for patients:

It can make stopping drugs hard

The most obvious problem occurs when the time has come to stop a drug, but withdrawal symptoms make doing so difficult. This doesn’t happen to everyone, but it happens, and you’ll have a hard time finding a more vivid description than that provided by Dr. Travis Rieder, an Assistant Professor of Bioethics at Johns Hopkins. For those without access to the Washington Post, he also has a TED talk, but here’s the summary: A young man is seriously injured in a motorcycle accident. Over the course of three hospitalizations, his mangled foot is saved by a series of operations. Two months after the accident, his surgeon tells him (regrettably, with a hint of tsk tsk) that he’s on a high dose (about 115 milligrams of oxycodone per day) and that it’s time to come off. Lacking further guidance, he decides to taper by 25% per week. He soon becomes miserable: crippling insomnia, inability to function, low mood with bouts of spontaneous crying, and—within a matter of weeks—thoughts of suicide.

This story should be required reading for any clinician who prescribes opioids. Seriously, spend the five minutes. You owe it to yourself and your patients. You can read about dependence all you want in textbooks and articles and blog posts hastily written by pointy-headed academics, but it takes an account like this to hammer home just how malignant dependence can be. I mean, here’s a smart young professional with a promising career, a family and a very good indication for opioid analgesia who literally contemplated ending his life because of what two months of opioids had done to his neural circuitry. Just imagine if he’d been less resilient, had fewer supports, or more in the way of life’s other challenges.

Travis’s experience offers clinicians a brutal lesson on why dependence matters, and why we shouldn’t lower doses too quickly or cut patients off altogether. Any clinician who doesn’t appreciate this has no business looking after patients with chronic pain. And since I’m feeling blunt, if you’re one of those doctors or nurses or pharmacists who gives the side-eye to chronic pain patients just because they’re dependent on opioids, hopefully reading this story will help you stop doing that.

But there’s another, more insidious way dependence can harm patients. And it’s related.

It can make a drug seem like it’s helping when it’s really causing harm

Yeah, this comment doesn’t tend to go over well. But think about it for a minute. The guy who gets irritable and sleeps poorly without his daily weed might insist that, for him, cannabis relieves these symptoms. Maybe it does, as I’ve argued before.³ But maybe—just maybe—his brain has become accustomed to THC and, to a certain extent, needs it to feel normal. In other words, maybe the “benefit” he perceives is, in whole or in part, is the avoidance of cannabinoid withdrawal.⁴

The stakes are a lot higher when the drug involved is inherently more dangerous and the withdrawal more severe. I’m thinking here about opioids, and high-dose opioids in particular, as I’ve written about previously.⁵ Since that article is paywalled (although the associated podcast is not) I’ll unpack the argument here. But before people get all up in my grill about how “opioids DO work for some people”, two things:

1. I agree, and I sometimes prescribe opioids for chronic pain, and
2. I’m not talking about you; I’m making comments of a general nature.

That said, consider a hypothetical patient who’s been taking opioids for years for back pain. He’s now on upwards of 200 milligrams of morphine per day (Travis Rieder doses), exhibits no features of aberrant use, and is adamant that it helps. From that commentary:

Anecdotes like this, delivered honestly and with conviction, can be powerful, especially to those of us who’ve written the prescriptions. Let’s be honest: doctors like it when our treatments work and when our reasoning is validated.

So, what should we do with this anecdote? We could just accept it at face value. He says it’s helping. He’s not addicted. Leave well enough alone. This line of thinking is central to the #patientsnotaddicts movement.

Alternatively, we could give some thought to the pharmacology behind the anecdote. We might acknowledge, for example, that an element of dependence is likely present, as in Travis Rieder’s case. We might ask ourselves whether being “unable to get out of bed without opioids” reflects, in part, the loss of function that can accompany withdrawal. And we might reflect on the fact that although withdrawal affects people differently, pain can be a feature⁶, even, weirdly, pain at the site of an old injury.⁷ In short, we might reasonably ask: How much of this man’s “benefit” is a genuinely beneficial drug effect, and how much is the avoidance of withdrawal?

(I want to be clear about something: We won’t be asking whether this hypothetical patient needs morphine. Of course he needs it. The question is why.)

Two additional observations:

The dose

He’s on ~200 milligrams morphine per day. Not stratospheric, but on the high side. How did he get there? Like most patients, gradually. Why was the dose escalated? Because of the progressive failure of lower doses. And why did that happen? Hard to say, but tolerance (a rightward shift in the dose-response curve over time), opioid-induced hyperalgesia, and progression of disease might all play some role.

A quick comment on the waning of analgesia over time. We’ve all seen this, but take a look at this figure from a 1996 study of opioids for chronic pain.⁸

Initially, morphine affords more pain relief than placebo. No surprise there. But after a few months, the mean pain relief in patients taking morphine (at an average of 83 milligrams per day) wasn’t much different from placebo.

If you practiced in the 2000s, you remember how we were taught to respond to the attenuation of pain relief over time: more opioids. After all, OxyContin 80 and Fentanyl 100 exist for a reason, right? And they’re approved for chronic pain, right? So increase the dose we did, until we began to realize just how simplistic and dangerous a maneuver it was. In doing so, we created a vast population of what some now refer to as “legacy patients”—people escalated over time to the equivalent of 300, 500, 1000 milligrams of morphine or more each day, largely because of the failure of lower doses.

This matters because the harms of opioids are dose-related, including dependence. In other words, the intensity of withdrawal (e.g. pain, reduced function, insomnia, low mood, etc.) will be greater at higher doses than lower ones, all other factors being equal.

Not buying it? Ask yourself if Travis Rieder would have had an easier time tapering if he’d been on only 20 milligrams of oxycodone per day instead of 115.

Hidden harms

Some opioid harms are obvious. You don’t need to be Sir William Osler to diagnose constipation and sedation as opioid-related problems. But like dependence, some opioid-related harms can be hard to appreciate. These include falls, fractures, motor vehicle collisions, infections, osteoporosis, sleep apnea, low libido, depression, or even pain itself. Are these always drug-related in a patient on opioids? Of course not. But sometimes they are, and we sometimes have a tendency to overlook that possibility.

The big picture

At the risk of stating the obvious, the goal of prescribing pain medication isn’t simply pain relief. Of course we’re trying to relieve pain, but that’s only part of the goal. If you accept that all medicines have the potential to help (as they do) and the potential to harm (as they do), the real goal is to afford the patient more benefit than harm. This is the overarching goal of all drug therapy.

Dependence (on opioids, cannabis, benzos, etc.) makes this assessment difficult by obfuscating the assessment of benefit. When “benefit” becomes, in whole or in part, the avoidance of withdrawal, the drug isn’t really doing what we intended. It’s preventing a harm caused by the drug.

And as we chase pain relief with higher and higher doses over time, dependence intensifies and other harms accumulate. In the case of chronic opioid therapy, it’s not hard to see how we might end up here:

In other words, we can find ourselves in a situation where the harms of treatment exceed the benefits, even if it seems the other way around. When this happens, the primary goal of drug therapy has been upended. The higher the dose, the more likely this becomes. Full stop.

This is why we owe it to patients on high-dose opioids to talk about the merits of a slow taper. This has nothing to do with addiction, and everything to do with optimizing the balance of benefits vs. harms. To do that, we have to acknowledge that dependence IS a harm, and it’s one that can masquerade as benefit.

Release the hounds . . .

Marc Schäfer

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