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DOSE-RESPONSE
STUDIES
Once
analgesic efficacy has been suggested, a key second step
is to define the optimal dose for subsequent studies. To
get unbiased estimates of the optimal drug doses, one must
prospectively randomize patients to different dose levels--that
is, drug dose is the independent variable and pain intensity
is the dependent variable. Sometimes investigators try to
glean information about dose-response from the "sledgehammer"
study described above, in which drug dose is increased in
individual patients until a maximum level is reached or
until the patient reports complete pain relief or intolerable
side effects. However, this type of post hoc analysis has
several pitfalls, described in the following problem:
Problem
6.2
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Figure
6.2 Pain Reduction vs. Dose and Plasma Concentration
of Tricyclic Antidepressants in Post-Herpetic
Neuralgia
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Thirty-four
patients with post-herpetic neuralgia were individually
titrated to the highest dose of amitriptyline (AMI) they
could tolerate, or an absolute maximum dose of 150 mg/day.
Each square represents one patient. The decrease in pain
over the 6-week treatment period is plotted against the
daily dose of AMI (left) or the serum concentration of AMI
plus its metabolite nortriptyline (NOR). There were modest
but statistically significant correlations of decrease in
pain with AMI dose (r = 0.43) and serum AMI + NOR (r = 0.44).
From Max
et al., 1988.
Question
6.2.1
Does
this data suggest that amitriptyline doses approaching 150
mg are optimal for pain relief?
 
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