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Problem
4.2
Positive
Controls in Repeated Dose Studies
The
principles of designing repeated dose studies are similar
to those applicable to single-dose studies in that:
- Provisions
must generally be made for a rescue analgesic; and
- The
protocol should allow for lowering doses of the test drug
or standard analgesic should the extra analgesic given
as the positive control prove to cause side effects.
Let us consider a study by Lehmann
et al.,(1989) as an example of repeated dose studies that
do not include a positive control. These investigators examined
the ability of the cholecystokinin (CCK) receptor antagonist
proglumide to augment opioid analgesia. They studied patients
in the first 18 hours after major abdominal surgery. All patients
could self-administer intravenous morphine by PCA machine.
Patients were randomized to four different treatment groups.
In these respective groups, each PCA bolus consisted of:
-
MORPHINE,
3 MG + NO ADDITIVE
-
MORPHINE, 3 MG + PROGLUMIDE, 50 mcg.
-
MORPHINE,
3 MG + PROGLUMIDE, 100 mcg.
-
MORPHINE,
3 MG + PROGLUMIDE, 50,000 mcg.
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Figure
4.3a: Value of Positive Control in a PCA Study
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Figure
4.3a (above) shows that none of the doses of proglumide reduced
the amount of PCA morphine that patients consumed. Pain intensity
levels (not shown) were also almost identical among the four
groups.
Question
4.2.1
If
we were to assume that the number of patient demands for PCA
morphine reflects their pain level (not a trivial assumption
as discussed above), how would we interpret the above results?
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