ultra-low-dose opioid antagonists increases the therapeutic index of the opiate. Since
opiate analgesic efficacy is very often limited by side effects, this augmented analgesic
efficacy may help to minimize the side effects of opiates, such as the problematic
gastrointestinal and respiratory depressive
effects. In addition, the reductions in
constipation, somnolence and pruritis observed in the Phase III clinical trial were of a
greater magnitude than would be expected fr
om an opioid sparing
effect. Second, an
alleviation of tolerance would preserve analgesia over time allowing more effective
long-term treatment, an aspect particularly important for the chronic pain population. A
lack of tolerance would also prevent the opioid-induced hyperalgesia that may occur
with chronic treatment. Third, a lack of physical dependence or withdrawal would
alleviate the need to carefully taper off the
drug. Finally, an atte
nuation in the addictive
potential of opiates by the addition of ultr
a-low-dose opioid antagonists is supported by
the reduction in their rewarding or euphoric effects as well as in drug craving during
abstinence in rat models of drug reward, dr
ug taking and drug seeking. While all these
properties of ultra-low-dose opioid antagonists are supported by preclinical data, so far
only enhanced and prolonged analgesia,
reduced physical dependence and certain
reductions in side effects have been demo
nstrated in randomized, controlled clinical
trials. Although the attenuation of a
ddictive potential by ultra-low-dose opioid
antagonists is well supported by rat data, this property will be the most difficult to
confirm in humans and may emerge only after fairly extensive clinical experience with
these combination therap
eutics.