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