The theory that
pruritus from
cholestasis is due to increased
opiate tone appears to have merit, based on the results of the clinical trials presented above. However, although
opioid antagonists relieve
itching to a large extent, the
itching usually is not abolished completely. Several factors may explain this lack of complete relief. The doses used in the clinical trials may have been insufficient, or
duration of therapy may have been short. It is also possible that nonopioid mechanisms contribute to
pruritus from
cholestasis. Although effective,
naloxone therapy has several limitations for long-term use, including a short half-life and large first-pass metabolism, which necessitates parenteral administration.
Intravenous administration is clearly not practical for a
chronic disease.
Nalmefene treatment has several advantages over
naloxone, with both prolonged duration of action and increased potency at the
opioid receptor level. However,
nalmefene is available only as a parenteral product in the US. The
nalmefene studies are limited by their small sample size and short follow-up periods. Additionally, two of the studies are available in abstract form only. Based on two clinical studies,
naltrexone therapy appears promising. Gradual dose titration from 25 mg/d up to a maximum of 50 mg/d may minimize withdrawal reactions. Further long-term clinical trials using objective measures that compare
opioid antagonists with other
therapies are needed to clearly establish the role of these agents. Potential tachyphylaxis from long-term use of
opioid antagonists requires further investigation. Combination
therapy may also be required, since monotherapy with either
opioid antagonists or other
therapies have failed to completely relieve the
pruritus caused by
cholestasis. Given the potential for severe withdrawal reactions,
opioid antagonists should be reserved for patients refractory to other treatments.