Vol. 5 Low-dose buprenorphine and other matters
Getting lost will help you find yourself. And other Instagrammable guff.
I wanted to go for a solid clinical topic this week and one editorial caught my eye. The wrinkles between buprenorphine and methadone are fascinating. The editorial was published in Addiction, fits easily on two pages, and offers good insight into low- and very low-dose buprenorphine induction.
Methadone vs buprenorphine
We know that people on methadone tend to be retained in treatment slightly better than buprenorphine — the systematic review in PLOS One in 2020 is perhaps now the definitive paper on retention. The key numbers were as follows:
Methadone at 6 months: 67.0%
Methadone at 12 months: 60.7%
Buprenorphine at 6 months: 56.8%
Buprenorphine at 12 months 45.8%
Now, we've got to be careful. These are numbers taken from a lot of studies with some wide ranges, all smushed together, and averaged out. (There is a fascinating book on the more general problems of using averages that I highly recommend: The End of Average by Todd Rose.)
We all know there is a long-term challenge with retention. That, of course, is the come-hither wink offered by extended-release buprenorphine and I await longer term data with interest. One study, a case series, published last year in the Journal of Substance Abuse Treatment showed a retention rate of 65% at the "end of data collection". I am actually having enormous difficulty determining how long they were in treatment from the paper and the methods section doesn't give enough information.
It could, potentially, be just a few weeks if people were recruited towards the end of the study period from Feb to July 2019. At the most, it would seem to be up to six months, which makes the retention damn fine when compared against sublingual buprenorphine averages, but no better than methadone. It could be a lot worse if these are retention percentages from a much shorter period.
That case series was only 40 people but it does have to be pointed out that they were a high-risk low threshold group and they got a high percentage of negative urines suggesting real promise. Counter-balancing that I'd add that these were people who had chosen to have extended-release buprenorphine, presumably guided by clinicians who thought it could work, and you'd expect them to have better outcomes. It’s messy. See what I mean about the problem with averages?
Anyhow, I have digressed slightly. All the people in the case series had to be on sub-lingual buprenorphine before getting extended-release buprenorphine. Which leads me back to the editorial on induction where I started.
Low-dose buprenorphine initiation
We know it can be tough to get onto buprenorphine. The high affinity means it will kick out any other full agonist opioids and because it is only a partial agonist it can precipitate withdrawal symptoms. Yet, you can get someone up to a good going dose of buprenorphine within days — not to be sneezed at and a major advantage. I do think the buprenorphine induction is a significant barrier for many reasons. Many people are understandably wary, may have had bad experiences in the past, and induction failures happen even with careful preparation.
I agree with the authors, Melissa Weimer and David Fiellin, that 'low-dose buprenorphine initiation' is a good phrase to describe this process of starting with very low doses. It is often described as ‘micro-dosing’ but this is lousy for several reasons.1
They start by presenting a case vignette of a woman admitted to hospital needing cardiac surgery. She was given methadone but ended up with torsade de pointes — an abnormal heart rhythm related to methadone's prolonging effect on the QT interval.
So, normally when starting buprenorphine, we go with 2-4mg on day 1; then assuming no precipitated withdrawal we can give 8mg on day 2 and we have lift off. The problem is that on day 1 people have to have stopped full agonist opioids like heroin or methadone for long enough that they are withdrawing. That's not much fun and in some circumstances — like being in hospital after cardiac surgery — it’s a terrible idea.
The aim with low-dose buprenorphine initiation is to start with very low doses, bring them up gradually, and allow the buprenorphine to gradually displace the other opioids loitering around the receptors. The hospital setting is the classic place for this and there are several papers looking at series of patients where it has happened. In the woman in hospital described by Weimer and Fiellin they went with a 7-day transition from 225 micrograms daily buccal buprenorphine to 450 micrograms twice daily over 3 days. This is equivalent to 2mg sublingual buprenorphine and they were up and running.
Mind the gaps…
The editorial spends some time lingering on what we don't know.
There is a potential publication bias problem with low-dose buprenorphine initiation in the academic literature. Weimer and Fiellin describe how the first case-series was published in 2010 and 26 case reports/series have since followed. They add: "most published cases describe successful initiations..." and that should certainly raise concerns that all the cases where it went pear-shaped were never written up or never got accepted for publication.
We need to be careful about the potential harmful effects. One of the potential reasons for a bump in risk when starting methadone, other than its inherent pharmacological profile, is that there is a period when people are on methadone and they are still using illicit drugs. When we start dragging out the induction for buprenorphine we could lose that key advantage over methadone and we may increase the risk of death in that time.
For my part, I am going to keep my eye out for people who may be worth considering for a low-dose initiation. Certainly people in hospital are an obvious group. It will be a harder sell in the community but it could be an option for people who prefer to be on buprenorphine but keep falling off the induction. Or those who have had a bad experience with a precipitated withdrawal and now refuse to consider it as an option.
There are gaps in our knowledge but it’s certainly worth having in mind.
Having written a little about stigma a couple of weeks ago in Vol.3 This is Water one of the things I had been mulling over to investigate was the evidence on interventions to address stigma. I was a little surprised to see this advert on the TV last night:
Goodness knows the impact but one can’t do anything but applaud the effort. Well done Scotland. 🏴
I wrote a thread on a recent editorial in Drug and Alcohol Review on the Australian plans to introduce a new drugs consumption room in Canberra. Do check it out. I’m planning to do a lot more threads as my main effort on Twitter.
It is always a challenge finding photos with the appropriate licensing… I do enjoy a bit of photography so each week I’m aiming to use a photo of my own. The one at the top was taken by me in a Bob & Berts this week. It is a little bit of an Instagram-type bullshit inspirational quote but I can stand them in, ahem, microdoses 😀.
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Thanks folks. 🙏
Micro-dosing is currently super-trendy having leached out from the frat boy venture capital type wankers from Silicon Valley. Micro-dosing isn’t particularly accurate for what it is going on here with buprenorphine. And that trendiness for micro-dosing is kind of obscuring the fact the current evidence is somewhat preliminary and promising rather than nailed on. The use of hallucinogens should be fully explored for therapeutic benefit and pst restrictions on those investigations have been lamentable. Another casualty and collateral damage in the war on drugs. Not good. However, that doesn’t necessarily mean they are going to work how we hope either… it would just be better if people could do the research.