Saturday, 11 February 2017

Should we give a lower dose of ketorolac for treating acute pain in the ED?

Ok, ketorolac is a little bit funny...

For some reason, it was never granted TGA approval in Australia for intravenous use although it is used all over the world in this manner. (Therefore it is perfectly fine for giving it IV off-label).

Second, it is probably the only drug where it is recommended to give a lower oral dose (10mg) than parenteral (30mg).

But now that 30mg IV dose is being challenged.

These authors from New York suggest the “ceiling dose” of ketorolac is probably 10mg and postulate that higher doses can cause more harm than good.

They performed a RCT of three different doses of IV ketorolac monotherapy; 10, 15 and 30mg. Inclusion criteria were adults with undifferentiated pain (most had acute flank, abdominal, musculoskeletal pain and headache). They had to have a numerical rating (NRS) of pain >5 not having had any previous pain medication.

The primary outcome was reduction in pain score at 30 minutes.

It was powered to find a 1.3 difference and as such 80 patients in each arm were enrolled.


The pain score dropped about 2.5 in both the 10 & 15mg doses of ketorolac. It dropped by 3.0 in the 30mg dose. This was not statistically significant.

The authors boldly conclude, “The results of our study provide a basis for changes in practice patterns and guidelines in ED care, supporting use of the 10mg intravenous ketorolac dose.

Unfortunately this conclusion is inappropriate.

Despite the decent design and blinding of this study, there were significant problems such that one cannot make any decent conclusions.

Any time one does not see a dose response with a particular drug then one must seriously consider if it is having any effect at all. This is pharmacology 101. I very much imagine that placebo (i.e. a ketorolac dose of zero) would have given similar results in this heterogeneous group of patients with these study methods.

I give ketorolac in patients in whom I think it will have a greater benefit. This is usually part of a cocktail of medications and not monotherapy. It works extremely well in patients with renal colic but less so in those with abdominal pain and headache. So extrapolating the results of this study to the individual patient is problematic.

A key foundation of this study is predicated on the theoretical harm with a higher dose of ketorolac. Otherwise this whole discussion is moot. I would seriously question if a single dose at the higher range would cause clinically important problems. In addition, we can pick and choose which patients get higher doses. An 85 year old 40kg woman with chronic renal failure would probably never get ketorolac in the first place.

In summary, we don’t know if a lower dose of ketorolac is appropriate at the moment. A single administration of ketorolac at the standard dose would be extremely unlikely to cause clinically significant problems.

It is always wise to be sceptical of small single centre studies. In the end they are often proven wrong. Nevertheless, this study could provide foundation for future study and clinical equipoise for inclusion of a placebo dose of ketorolac.

Watch this space but don’t change you dose of ketorolac just yet.

(Addendum: Please see lead authors reply to this post under the comments section)


Friday, 10 February 2017

Midazolam-Droperidol, Droperidol, or Olanzapine for Acute Agitation in the ED. An Australian RCT

What is the best drug for treatment of acute agitation in the ED?

Generally speaking we know the real answer to such questions is, “it depends...” And this is often followed by an emphatic explanation of the clinician’s beliefs based on eminence based medicine.

This study at least makes an attempt to enter some high quality evidence into the discussion.

This randomized, controlled, double blind, triple-dummy (who you callin’ dummy?) clinical trial enrolled adult patients requiring IV sedation for acute agitation in 2 ED’s. They randomized 349 patients to either:

·         Group 1: Midazolam 5mg + Droperidol 5mg or
·         Group 2: Droperidol 10mg or
·         Group 3: Olanzapine 10mg

If patients were not adequately sedated by five minutes they could get further pre-specified study drug.

The primary outcome was adequate sedation by 10 minutes.

If you have any knowledge of pharmacodynamics of the study drugs, you can probably guess the results.

Yes, the midazolam group did better. By the 10 minute mark, about 75% were adequately sedated vs. 50% in the groups that got monotherapy with droperidol or olanzapine.

Once again, the results of this study are not a surprise. Intravenous midazolam works within seconds of IV administration whereas the antipsychotics take several minutes.

I personally (eminence based medicine anyone?) rapidly titrate midazolam in combination with a single dose of antipsychotic. I have most of this done well before the 10 minute mark with the attendants already wiping the sweat off their brow.

Of course we have made no mention of safety. This study was not powered for safety outcomes. Nevertheless it is quite clear that drugs in combination require extra care; especially benzodiazepines.

What’s the take-home point?

Combination therapy with IV midazolam plus an antipsychotic is probably the best strategy if the goal is rapid sedation of the acutely agitated patient. But really, therapy should be tailored to the individual patient and adequate precautions taken.

This is a great triple dummy RCT... but whatever you do, “don’t call me stupid.”