Saturday, October 5, 2019

Part 4 - Everything We Were Taught About High Doses Was Wrong, and the Same Hand-Crafted Graph

by Drew Rosielle (@drosielle)

A Series of Observations on Opioids By a Palliative Doc Who Prescribes A Lot of Opioids But Also Has Questions.

This is the 4th post in a series about opioids, with a focus on how my thinking about opioids has changed over the years. See also:

Part 1 – Introduction, General Disclaimers, Hand-Wringing, and a Hand-Crafted Graph.

Part 2 – We Were Wrong 20 years Ago, Our Current Response to the Opioid Crisis is Wrong, But We Should Still Be Helping Most of our Long-Term Patients Reduce Their Opioid Doses

Part 3 – Opioids Have Ceiling Effects, High-Doses are Rarely Therapeutic, and Another Hand-Crafted Graph


This is Part 4 – Everything We Were Taught About High Doses Was Wrong, And The Same Hand-Crafted Graph

I no longer consider opioid dosing and conversions as a linear matter. That is, my approach to both opioid dose adjustments and rotations changes markedly the higher the dose of opioid a patient is on.

Most of us have long been familiar with the idea that methadone’s ‘equianalgesic’ relationship to other opioids is non-linear. Ie, the higher the dose of another opioid you’re on, methadone becomes relatively more potent (you use relatively less methadone) – the equianalgesic ratio changes.

I now believe this is true of all opioids both with conversions and with titrations, and I imagine a lot of you believe this too.

To give you an example: if someone is on 4 mg of oral hydromorphone PRN and has severe uncontrolled pain, there’s a decent chance I’d increase them to 8 mg if they’re otherwise doing ok, and if I did I wouldn’t spend much time worrying about that decision. If someone is on 40 mg of oral hydromorphone PRN – while what I would end up doing is a highly individualized decision, let me tell you I would 100% think twice before increasing them to 80 mg. In fact, I’d be extraordinarily unlikely to do that, whereas I just wouldn’t hesitate to double a similar patient from 4 to 8 mg. Ie, despite all the textbooks saying we should increase opioids in percentile increments I don’t believe that once I’m working with high doses. It Is Not Linear.

And I bet a lot a lot of you reading this would agree – you’d, at least, hesitate. And I’ve been asking myself why, and again I think part of it is my recognition that very high doses are rarely effective, or at the very least changes at the very high range of opioid dosing are far less effective than in the low range (see my last post and its lovely hand-made graphic which I’m reproducing here), and that the benefit:hazard ratio of escalating at very high doses is far lower than with low dose opioids. (About that benefit: hazard ratio – for well monitored, highly opioid tolerant patients I’m not arguing that the risk of harmful overdose is very high for these patients, in my experience it isn’t and opioid tolerance is a truly remarkable thing. I’m more arguing that the benefit to patients from dose escalations for patients already in the very high range are very small, and much smaller for the typical patient when you, say, increase their morphine ER from 15 mg to 30 mg).



Regardless of the reasons underlying it, my point here is that I do, and I think most people do, think of these ratios, and these rules of dose titration, differently at high doses than at lower/moderate doses, although I’ve never yet read that anywhere, and I don’t really understand why because my impression is that this is common practice.

Same with drug rotation.

There’s been a lot of speculation with methadone – why it seems to be more potent the higher the baseline opioid someone is on and some of the speculation is that patients are hyperalgesic from the baseline opioid, and since methadone perhaps directly counteracts some of that hyperalgesia or at the very least doesn’t contribute to it much, it can be surprisingly potent. Eg, we can get away with such small doses of methadone sometimes because a patient’s baseline opioid dose was largely there just to overcome the hyperalgesia from that very baseline opioid. If that’s the case, then you could also imagine a scenario where the same phenomenon would obtain, at least to an extent, with rotating away from any opioid at a very high dose, not just methadone. To an extent: other commonly used opioids don’t theoretically counteract tolerance and hyperalgesia in the way we believe methadone does, but nonetheless it’s a sort of ‘partial-cross tolerance’ phenomenon. Ie, going from, say, high dose hydromorphone to morphine, perhaps you don’t have as much hyperalgesia initially from that morphine so you can get away with lower relative morphine dose. I need to stress this is speculation, I do not understand the mechanism here, but am more observing that the speculative explanation we have about why it seems to work for methadone could partially apply to any opioid rotation.

I don’t think any of this is extraordinary, however I’ll also add that I haven’t really seen any of this in a textbook, or as an asterix in opioid conversion tables (with the exception of methadone).

Consider this example: I remember every pretty early on in my career, having people on something like 10 mg/hr continuous hydromorphone infusions and needing to transition them off the IVs and doing the math and feeling the acid and bile rise to the back of my mouth. Eg 10 mg/hr = 240 mg/24 h = 4800 mg OME (by most equianalgesic tables). Even if you reduced ‘for incomplete cross tolerance’ by a whopping 75% (which, I’ll note, is more than most textbooks ever mention) that would still be putting someone on, eg, MSContin 600 mg twice a day. Like, whoa. Like, would any of you do that? Even if you use the so-called ‘new’ ratios based off the excellent MD Anderson study looking at IV hydromorphone to PO med ratios, that suggests a ratio of 1 mg hydromorphone : 10 mg PO morphine, which would be 2400 mg of morphine a day. And, note, that study calculated the ratio based on the final dose of what the patient actually ended up on, so if we use this as a conversion ratio the implication is you don’t need to account further for incomplete cross tolerance, which would suggest in fact we put this patient on 1200 mg of morphine ER bid.

LOL/puke.

(Now that I prescribe methadone…we didn’t prescribe it much where I started my career…I just put them on something like 10 mg tid of methadone and continue to be delighted that *most* of the time it goes just fine.)

But here’s the point: even before I routinely used methadone in these situations, I still ended up putting people on far lower doses than any textbook/consensus guidelines would recommend, maybe something like 120 mg tid of morphine ER and was surprised at how it went ok much of the time. Patients were ok (not perfect, adjustments were needed, but the rotation was not a catastrophe) with what is technically a massive dose reduction.

Why can we ‘get away’ with stuff like this? We can speculate all we want why but we don’t know, but I’m still going to make an empirical claim that the so-called equianalgesic ratios don’t apply at high doses.

They are worse than worthless, they are dangerous.

When I talk with people around the country about this, most people I talk with are doing just what I describe above. So, I don’t think I’m describing a particularly novel or extraordinary clinical approach.

What I’m more interested in is why we still talk about methadone’s non-linear conversion curve as something unique, when it isn’t (methadone’s curve is probably more pronounced than with other opioids, but the fact that it has a curve is not). By acting like methadone’s all fancy and unique, and by putting out equianalgesic charts and dose adjustment rules (eg the 25-50-100% rule) that don’t qualify that perhaps none of this applies to patients on very high doses, I think we are promoting unsafe practices. To an extent, most patients on very high doses are being cared for by specialists, and most of us know what we’re doing, so we have that safety buffer, but that doesn’t seem like enough

Most fellowship years, a few months into it, a fellow comes to me as they are figuring this out, and I have to break the news to them that most of us throw those tables out for patients on very high doses, and it’s kind of like breaking bad news to them, and I start telling them the truth, is that I sometimes don’t even bother doing the math when people are on really high doses, and half the time just ask myself Is there any reason not to put this patient on 10 mg of methadone tid? and nothing else.

Part 1 – Introduction, General Disclaimers, Hand-Wringing, and a Hand-Crafted Graph.
Part 2 – We Were Wrong 20 years Ago, Our Current Response to the Opioid Crisis is Wrong, But We Should Still Be Helping Most of our Long-Term Patients Reduce Their Opioid Doses
Part 3 – Opioids Have Ceiling Effects, High-Doses are Rarely Therapeutic, and Another Hand-Crafted Graph
Part 4 – Everything We Were Taught About High Doses Was Wrong, And The Same Hand-Crafted Graph
Part 5 – Why Do We Lump The Non-Cancer Pain Syndromes Together?
Part 6 - Why Is Cancer Pain So Special?

For more Pallimed posts about opioids.
For more Pallimed posts by Dr. Rosielle click here.

Drew Rosielle, MD is a palliative care physician at the University of Minnesota Health in Minnesota. He founded Pallimed in 2005. You can occasionally find him on Twitter at @drosielle.

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