Friday, January 1, 2021

Olanzapine FTW for Nausea Outside of CINV

by Drew Rosielle (@drosielle)

A few months ago an interesting olanzapine study was published which I have been meaning to write a post about. It's important because while olanzapine has really established itself in the last decade as a highly effective antiemetic for chemotherapy induced nausea and vomiting, and is now in multiple CINV guidelines (eg Antiemetics: ASCO Guideline), etc, we don't have a lot of data for its efficacy for nausea outside of CINV, and so a well-done RCT is welcome.

The study is a multi-center, US, adult, randomized, placebo-controlled, double-blind trial of olanzapine for nausea in advanced cancer patients who are not receiving chemo. (Small note: the abstract says 'double-line' instead of 'double-blind,' and as someone who does my best to edit typos from my and others' work all the time, it is just interesting and kind of quaint to see such a typo in a JAMA journal. I actually tried to figure out if 'double-line' is some novel trial design I had missed but I'm pretty sure it is not.) While well-done, it is a small study and is described as a pilot study by the investigators.

Patients (n=30, ~45% Black American and the rest mostly white, mean age ~60 years, broad spectrum of solid tumors represented, most were on either/both metoclopramide/ondansetron at baseline) had to have chronic nausea for at least a week rated >3 on a 0-10 scale, not be on chemo for at least 2 weeks (for the most part CINV is defined as chemo on days 0-5 of chemotherapy), and not be on 'antipsychotics' otherwise (to be clear, they allowed use of common neuroleptic antiemetics like prochlorperazine and metoclopramide but presumably these folks weren't on quetiapine, risperidone, etc & if you were wondering none of them were on haloperidol at baseline).

Patients were randomized to placebo or 5mg olanzapine orally, daily, for 7 days. Patients filled out simple, daily, self-reported 0-10 symptom scales looking at nausea, but also appetite, fatigue, sedation, and pain; as well as vomiting episodes and global well-being.

Primary outcome was change in nausea scores from baseline to day 7.

The results were ridiculous, as you can see by the Figures. The authors couldn't say that in print of course, so instead they noted, 'No other drug studied in this situation has been reported to decrease nausea/vomiting more than what was observed in this study.'



Nausea went from a baseline of 9/10 to 1/10 in the olanzapine arm and was unchanged in placebo arm. Emesis episodes went from 2 a day to zero in the active group, 3 to 2 a day in the placebo arm. Self-reported appetite improved from 1/10 to 7/10 for olanzapine, 1/10 to 2/10 for placebo. Given all this it won't be surprising to hear that global well-being improved in the olanzapine group as well, more than placebo.

My biggest challenge with olanzapine is its sedating/fatiguing effects and at least in this group on this relatively low dose of olanzapine, those toxicities weren't evident in their findings, and in fact self-reported fatigue improved in the olanzapine group vs placebo.

They noted that after the 7 days the patients could enter open label observation and all the olanzapine patients chose to stick with it.

So, wow. My guess is most who prescirbe olanzapine regularly aren't surprised that it is effective outside of CINV. Like many other antiemetics, it seems to have broad antiemetic efficacy. The magnitude of the effects though are what's really impressive and while I have zero doubt olanzapine is more effective than placebo for nausea in these patients, I think we'll need larger studies before we can make firmer conclusions about the 'actual' magnitude of benefit. That is, it may see get attenuated with larger trials, but I'd be surprised if it's more than a modest attenuation.

This is not the final word on olanzapine of course, like with everything else in medicine we would greatly benefit from comparative efficacy studies. Given how my clinical practice works, in that I don't prescribe more than one dopamine blocker at a time (eg both olanzapine + prochlorperazine or metoclopramide), comparative studies between those agents would be particularly welcomed (with metoclopramide we have comparative data for CINV with olanzapine, but not elsewhere). Especially given the relative expense, it would be helpful to know whether we should even be using prochlorperazine as a first-line agent anymore.

Basically what I'm saying is olanzapine is arguably in the running to become of our first-line dopamine antagonist antiemetic in palliative care, I think that's a reasonable possibility, and one that could be answered with additional investigation which I hope trickles out in the coming years. Please don't send me angry @'s on Twitter, I'm not saying olanzapine *is* currently first-line, more that at this point I wouldn't be surprised if we landed there in the coming decade.

A global aside about olanzapine. Why is it so good? My theory around olanzapine's efficacy, which I don't think is a profound one, but one I'll state publicly anyway, is that besides stopping a lot of patients from puking, it has significant, welcome, 'additional' effects which make many of our patients globally feel better, effects that many of our other common antiemetics eg ondansetron/prochlorperazine don't really have. By additional effects I'm talking about mood effects, anxiolysis, maybe a little mood elevation, etc. Olanzapine's impacts on those in addition its chemoreceptor trigger zone action is why it helps our patients so profoundly in a way many other of its peers just don't.

A final digression about appetite. This is not proof that olanzapine is an effective treatment for cancer related weight loss/cachexia syndrome. Nothing that I know of has been clearly demonstrated to be effective for that (apart from effectively controlling the underlying cancer). However I've long wondered whether we've missed the boat on drug investigation for cancer cachexia (which is super-complicated, with multiple interacting causes in any patient, and just not something that's amenable to being 'fixed' with a pill, or any other monotherapy like vaporizing high THC cannabis, etc), by ignoring the opportunity to study orexigens as essentially palliative therapies for the 'distress of low appetite'. Eg, I have a lot of patients who take orexigens and 'like them,' say they feel better on them, appreciate the fact that they feel hungrier, participate more in the social aspects of eating, etc, but who's actual weight loss/cachexia is not improved by them. Ie, I think there is a relatively understudied potential for some of these drugs as palliative agents for anorexia, as opposed to disease-modifying agents for cachexia.
For more Pallimed posts about nausea.
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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