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Effects of Naloxone Infusions in Patients with the Pruritus of Cholestasis: A Double-Blind, Randomized, Controlled Trial

Nora Valeria Bergasa; David W. Alling; Thomas L. Talbot; Mark G. Swain; Cihan Yurdaydin; Maria L. Turner; Joseph M. Schmitt; Elijah C. Walker; and E. Anthony Jones
[+] Article and Author Information

From the National Institutes of Health, Bethesda, Maryland. Requests for Reprints: Nora Valeria Bergasa, MD, Laboratory of the Biology of Addictive Diseases, Box 241, The Rockefeller University, 1230 York Avenue, New York, NY 10021. Acknowledgments: The authors thank Drs. Michael W. Fried and Tse- Ling Fong for their participation in the conduct of this study; the nursing staff of Patient Unit 9-D, under the direction of Head Nurse Joyce Harris, for their vigilance; and Mr. Robert Ennis of the Applied Clinical Engineering Section, Biomedical Engineering and Instrumentation Program, National Center for Research Resources, for his assistance in the operation of the Scratching Activity Monitoring System.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1995;123(3):161-167. doi:10.7326/0003-4819-123-3-199508010-00001
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Objective: To determine whether endogenous opioids contribute to the pruritus of cholestasis by studying the effect of the opiate antagonist naloxone on the perception of pruritus and on scratching activity in patients with this form of pruritus.

Design: Double-blind, placebo-controlled, crossover trial with four periods.

Setting: Clinical research referral center.

Patients: 29 pruritic patients with liver diseases of various causes.

Intervention: Each patient received as many as two naloxone and two placebo solution infusions consecutively in random order. Each infusion lasted 24 hours.

Measurements: During the infusions, visual analog scores of pruritus were recorded every 4 hours while patients were awake; scratching activity independent of limb movements was recorded continuously.

Results: One patient had a mild reaction consistent with a naloxone-precipitated syndrome similar to opiate withdrawal. A significant 24-hour rhythm of scratching activity was seen in 7 of 11 patients for whom complete 96-hour data were collected. The mean of a visual analog score of the perception of pruritus (maximum, 10.0) recorded during naloxone infusions was 0.582 lower than that recorded during placebo infusions (95% CI, 0.176 to 0.988; P < 0.01). Furthermore, the ratio of the geometric mean hourly scratching activity during naloxone infusions to that during placebo infusions was 0.727 (CI, 0.612 to 0.842; P < 0.001) and was greater than 1.0 in only five patients.

Conclusions: Naloxone administration is associated with amelioration of the perception of pruritus and reduction of scratching activity in cholestatic patients. Because of the opioid receptor specificity of the action of naloxone, these findings support the hypothesis that a mechanism underlying the pruritus of cholestasis is modulated by endogenous opioids and suggest that opiate antagonists may have a role in the management of this complication of cholestasis.

Figures

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Figure 1.
Distribution of differences between naloxone and placebo administration in visual analog scores (VAS).

The mean visual analog scores recorded by each patient during placebo infusions were subtracted from the corresponding mean visual analog scores during naloxone infusions. Inset: Mean visual analog score recorded during naloxone infusion plotted as a function of the mean visual analog score during placebo infusion. The therapeutic advantage of naloxone over placebo is indicated by negative values of the differences shown in the horizontal plot and by data points below the 45-degree line in the inset graph.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Distribution of naloxone-placebo ratios of hourly scratching activities (HSA).

The geometric mean hourly scratching activity recorded by each patient during naloxone infusions was divided by the corresponding mean hourly scratching activity during placebo infusions. Inset: Mean hourly scratching activity recorded during naloxone infusions plotted as a function of the mean hourly scratching activity during placebo infusions. The therapeutic advantage of naloxone over placebo is indicated by values of the ratio below 1.0 in the horizontal plot and data points below the 45-degree line in the inset graph.

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Grahic Jump Location
Figure 3.
Correlation between visual analog (VAS) score and log10 hourly scratching activity (log10HSA) recorded during placebo infusions (top) and during naloxone infusions (bottom). Top.10rPBottom.10rPrP

Mean visual analog score for each patient during placebo infusions plotted against corresponding mean log hourly scratching activity (Spearman = 0.34; = 0.07). Mean visual analog score for each patient during naloxone infusions compared with corresponding mean log hourly scratching activity ( = 1.0; < 0.01 for the left-hand group of five points and = 0.51; < 0.01 for the other points). No obvious clinical or serum biochemical features enabled the five patients in the left-hand group to be distinguished from the other patients.

Grahic Jump Location
Grahic Jump Location
Figure 4.
Mean hourly scratching activity during the 96-hour study period of a patient with benign recurrent cholestasis.P

The continuous line indicates the 24-hour rhythm that best fits the observations; this line has a significant downward linear trend (slope = −0.0081±0.0021) ( < 0.001), which is consistent with the sequence of treatments (placebo, placebo, naloxone, naloxone).

Grahic Jump Location

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