Is methadone plus haloperidol ready for prime time?

Methadone: A pharmacologically unusual drug, that inspires great passion.

I've prescribed more and more of it over the years, and I guess I'm in the Methadone: It's a Good Thing, But Probably Not Liquid Jesus camp of thought. While I think most of the patients I place on methadone are helped, a significant minority are not, and a few are clearly harmed (increased side effects, etc). I had a oncology PA I work with today, when we were chatting about whether or not to rotate a patient to methadone, note something along the lines of "I've been seeing more and more people on it, and many of them just seem to be zoned out...flattened." A single, anecdotal observation to be sure, but I wasn't shocked to hear her say it as I'd seen it a few times as well.

So I've been paying attention to the rumblings in our literature, which have been around for a while, around using very low-dose methadone as a co-analgesic, as well as the emergence of a discussion in Journal of Palliative Medicine of using scheduled low-dose methadone plus scheduled low-dose haloperidol (+/- use of other short-acting opioids prn if needed).

The proponents of this practice seem to argue that it prevents opioid-induced hyperalgesia (they even put it in the title); that it's a very effective and tolerated analgesic strategy: see here for their publication laying this out. This was a retrospective case series of hospice patients with no comparison group: needless to say it proved nothing and prompted this terse and I think entirely justified letter saying, essentially, Nice idea but you should back off on the over-reaching claims until you have data.

One of my passionate, pro-methadone colleagues carries the case-series around and has been gung-ho about trying it. I've told him I think we should wait for more data and that this is practice should be treated as extremely hypothetical. While we're prescribing methadone anyway, in particular I'm worried about committing our patients to scheduled haloperidol, especially as many of our patients are not dying and may live for a long time and I worry about long-term extrapyramidal side effects. I've also remained extremely skeptical neuroleptics have any real analgesic properties, but one has to acknowledge that one can be wrong, and can be convinced otherwise by good data, and I'll note that in pinging this question off Cochrane it seems like there is a smidge of data that neuroleptics are analgesic. A smidge.

Which brings us to today, and the reasons I'm writing this.

The methadone+haloperidol group has published their 2nd foray. This time a hospital-based case series, again uncontrolled. It's from a single hospital, and looks at patients who were started on, or rotated to methadone after receiving a palliative care consultation (n=43). They're not entirely clear but my sense is that this team's practice was to routinely rotate (they don't say under what circumstances they actually do the rotations, if not automatically) all their patients to methadone+haloperidol.

They used low doses, and were not rotating patients off of very high doses of other opioids (median morphine equivalent daily dose was 78mg before rotation): most patients ended up on 5-10mg of methadone a day and 1-2mg of haloperidol a day. Small doses. Key to their strategy as they present it  is that they really try to minimize patients' exposure to other opioids, I believe because they consider the hyperalgesic effects of them to have a significant clinical impact, and stopped them completely in many of them (some of them they didn't and continued a prn short-acting non-methadone opioid).

Basically by week 1 and 2 after rotation, median pain scores went from 5/10 to 0/10 in the groups. Yup. And this:

"There was a significantly greater reduction in severe pain scores by week 1 for full conversion, using haloperidol for breakthrough pain, compared with tapered conversion, using short-acting opiates (Fig. 2; p=0.02 for difference). Similar reductions in scores were seen in patients with cancer and noncancer diagnoses (Table 4; p=0.06 for difference). Significant improvements in pain scores were seen for those with an initial MEDD of ≥250 mg (median, 415 mg) and for those with a MEDD of 30 mg to 80 mg (median, 37.8 mg), but there was a significantly greater improvement associated with highest-dose opiate group (p less than 0.001 for difference). The patient with the highest initial MEDD (1600 mg) had full conversion to methadone 7.5 mg/day, for a conversion ratio of 213."

To be clear, these are  uncontrolled data. We don't know what other interventions were tried, we don't know what would have happened if they left the patients alone (regression to the mean and all that good stuff), we have no organized collection of data on side effects and toxicities, etc etc.

But, I have to say that after reading the most recent study, I am officially intrigued, and no longer willing to discard this idea on the without further consideration. 

So, to the authors of this line of investigation, I implore you - keep it up, but please move onto to higher quality investigational methods. Yes a double-blinded RCT would be great, but even a prospectively planned and implemented observational study of a clearly defined protocol (including patient inclusion criteria) which collects prospective safety data (not just efficacy) would be a big move in the right direction.

Also, if anyone out there is doing this - I think it's been an idea that's been floating around in various forms for years (?decades) - please comment and share your experience.



Salpeter SR, Buckley JS, Buckley NS, Bruera E (2014). The Use of Very-Low-Dose Methadone and Haloperidol for Pain Control in the Hospital Setting: A Preliminary Report. Journal of Palliative Medicine PMID: 25494475