Abstract: 【Abstract】 Objective To investigate the efficacy of naloxone in improving health-related quality of life in patients with chronic arsenic exposure-related pruritus, and to explore the modification effect of gene polymorphisms associated with arsenic metabolism and endorphin receptors. Methods A randomized, double-blind, placebo-controlled trial was conducted between January and March 2019 in Changde City, Hunan Province, China. Eligible patients with moderate to severe chronic pruritus under arsenic exposure were recruited, and randomly assigned to the naloxone group and the control group to receive sublingual naloxone and placebo （0.4 mg/d） respectively for 7 consecutive days. Outcomes were assessed before treatment and on day 7 after treatment, including the primary outcome （the dermatology life quality index ［DLQI］） and secondary outcomes （depression symptoms, anxiety symptoms, and quality of sleep）. Genotyping of the arsenic （+3 oxidation state） methyltransferase and 3 opioid receptor genes was performed using ligase detection reaction. Data analysis was performed using t test for normally distributed continuous variables, non-parametric tests for skewed continuous variables, and chi-square test for categorical data. Linear regression analysis was carried out to evaluate the effect of naloxone on outcome measures, while the interactive effect of demographic factors, genotypes and treatment methods on changes in DLQI were assessed by the generalized linear model. Results A total of 126 patients with chronic arsenic exposure-related pruritus were enrolled, including 73 males and 53 females. They were randomly divided into the control group （64 cases） and the naloxone group （62 cases）, with the ages being 60.0 ± 9.1 years and 58.4 ± 8.6 years, respectively. There were no significant differences between the two groups in terms of age, gender, income, education levels, or hair arsenic concentrations （all P > 0.05）. After treatment, the decrease in DLQI scores was significantly higher in the naloxone group than in the control group （-8.79 ± 6.84 vs. -5.19 ± 8.10; P = 0.008）. However, there were no significant changes in depression symptoms, anxiety symptoms, or quality of sleep between the naloxone group and control group （all P > 0.05）. Linear regression analysis showed that naloxone significantly affected DLQI with a crude regression coefficient of -3.60 （95% CI: -6.25, -0.96; P = 0.008）. Stratification analysis revealed that patients with the κ-opioid receptor gene rs1051660 （wild-type, CC） responded better to the treatment than those with the mutated genotype （CA）, and there was a significant interaction between the rs1051660 genotype and therapeutic drugs in relation to DLQI changes （P = 0.014）. Conclusion Naloxone can effectively improve health-related quality of life in patients with chronic arsenic exposure-related pruritus, and its efficacy is modified by the gene polymorphism of the κ-opioid receptors.

Key words: Arsenic poisoning, Pruritus, Naloxone, Quality of life, Environmental exposure, Clinical trial, Arsenic exposure