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Studies
of Analgesic Combinations Single analgesics often fail
to relieve more than a portion of the patient’s pain. For
example, meta-analyses of randomized trials in neuropathic
pain (Sindrup
and Jensen, 1999) show that after correction for placebo
effects, even the most effective treatments (opioids, tricyclic
antidepressants, and gabapentin) only reduce pain by 50%
or more in one of every three patients treated. Similar
limits encountered treating hypertension, congestive heart
failure, cancer, and infectious diseases have been overcome
by the use of drug combinations. However, apart from combinations
of NSAIDs and acetaminophen with opioids, there have been
few clinical trials of analgesic combinations, so this is
a major research need.
For
basic researchers, studies of drug combinations have become
an active topic. Debate on the methodology for analgesic
drug combination studies in animals has focused on whether
the combination produces synergy for analgesia, defined
as an effect that exceeds the sum of the analgesia expected
from the components (Berenbaum,
1989). However, from the clinician’s point of view,
the emphasis on synergy is misplaced. The key issue regarding
clinical usefulness is whether the combination has a better
therapeutic ratio (ratio of analgesia to side effects) than
either component, or produces a higher maximal analgesic
efficacy at tolerable doses. Treatment groups must be chosen
to ensure that a comparison of side effects at equianalgesic
doses will be possible (Max,
1994). In order to be certain of the ability to compare
equal levels of analgesia, at least by interpolation, one
needs to study more than one dose of at least one, and optimally
each, of the treatment regimens (Carter
and Carchman, 1988; Lavigne
et al., 1989; Plummer
and Short, 1990; Eisenach
et al., 1994; Max, 1994;
Sethna
et al., 1998; Levine
et al., 1988). An example of such a design is the relative
potency bioassay discussed above (Figure
6.3.1). In order to be clinically useful, the components
need not be synergistic for analgesia; they may be merely
additive or even subadditive, as long as side effects show
even less additivity in the combination.
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