Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene.

Nielsen DA, Walker R, Graham DP, Nielsen EM, Hamon SC, Hillhouse M, Shmueli-Blumberg D, Lawson WB, Shores-Wilson K, Settles-Reaves BD, Rotrosen J, Trivedi MH, Saxon AJ, Ling W, Kosten TR. Moderation of buprenorphine therapy for cocaine dependence efficacy by variation of the Prodynorphin gene. European journal of clinical pharmacology. 2022 Jun 1; 78(6):965-973.

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Abstract:

PURPOSE: The aim of this secondary analysis was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). METHODS: Cocaine-dependent participants (N? = 302) were randomly assigned to a platform of injectable, extended-release naltrexone (XR-NTX) and one of three daily medication arms: 4 mg BUP (BUP4), 16 mg BUP (BUP16), or placebo (PLB) for 8 weeks (Parent Trial Registration: Protocol ID: NIDA-CTN-0048, Clinical Trials.gov ID: NCT01402492). DNA was obtained from 277 participants. Treatment response was determined from weeks 3 to 7 over each 1-week period by the number of cocaine-positive urines per total possible urines. RESULTS: In the cross-ancestry group, the PLB group had more cocaine-positive urines than the BUP16 group (P? = 0.0021). The interactions of genetic variant?×?treatment were observed in the rs1022563 A-allele carrier group where the BUP16 group (N? = 35) had fewer cocaine-positive urines (P? = 0.0006) than did the PLB group (N? = 26) and in the rs1997794 A-allele carrier group where the BUP16 group (N? = 49) had fewer cocaine-positive urines (P? = 0.0003) than did the PLB group (N? = 58). No difference was observed in the rs1022563 GG or rs1997794 GG genotype groups between the BUP16 and PLB groups. In the African American-ancestry subgroup, only the rs1022563 A-allele carrier group was associated with treatment response. CONCLUSION: These results suggest that PDYN variants may identify patients who are best suited to treatment with XR-NTX plus buprenorphine for cocaine use disorder pharmacotherapy.