Exploring genetic predictors of naltrexone treatment response in opioid use disorder

Purpose: The present study was aimed to evaluate the effect of the opioid receptors genes and dopamine system genes polymorphisms on the treatment outcomes of opioid dependence with implantable and oral naltrexone in randomized double blinded double dummy placebo controlled clinical trial. Methods: 306 patients with opioid dependence were randomized in 3 treatment groups (102 ss in each). The first group received implantation of 1000 mg naltrexone every 2 months during the 6 months period + oral naltrexone placebo; the second group — placebo implant every 2 months + oral naltrexone (50mg/day), and the third group — placebo implant + oral naltrexone placebo. All enrolled participants provided blood sample at baseline for genetic analysis of polymorphisms in following genes: mu-opioid receptor (OPRM1), kappa-opioid receptor (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (DAT1). Results: Regardless of provided treatment several polymorphisms of tested genes were associated with high risk of relapse: allele L (2R) DRD4 120bp (p=0.05; OR(95% CI)=3.3(1.1-10.1) ); allele С DRD2 NcoI (р=0,051 OR(95% CI) = 2,86 (1,09 — 7,52); genotype 9.9 DAT VNTR40bp (р=0,04; RR(95% CI) = 1,4(1,3 — 1,5)); on the contrary variants of polymorphisms (СС+СТ)-(ТТ)) of genes (OPRK1- DRD2Ncol) increased the chance to complete the treatment program (р=0,004; OR(95% CI) = 7.4 (1.8 — 30.4)), Kaplan-Meier survival analysis, р=0,016). The probability of completing treatment program by carriers of all these above mentioned variants of polymorphisms (OPRK1DRD2Ncol) was higher for oral naltrexone group (p=0.016), lower for double placebo group (p=0.015), but did not influence treatment outcomes in naltrexone-implant group. Conclusion: Naltrexone-implant is an effective medication for treatment of opioid dependence and its effectiveness exceeds oral naltrexone and placebo. The study showed joint influence of opioid receptor genes and genes of dopaminergic system on the treatment outcomes of opioid dependence. Genetic analysis is useful for determining potential responders to naltrexone treatment of opioid dependence.

opiate dependence, naltrexone, pharmacogenetics, gene polymorphism, dopamine

1. Al-Eitan L.N., Jaradat S.A., Su S.Y., Tay G.K., Hulse G.K. Mu opioid receptor (OPRM1) as a predictor of treatment outcome in opiate-dependent individuals of Arab descent. Pharmgenomics Pers Med. 2012; 5: 99-111. doi: 10.2147/PGPM.S33351.

2. Kleber H., Kosten T., Gaspari J. Non-tolerance to opioid antagonism of naltrexone. Biological Psychiatry. 1985; 20: 66-72. doi: 10.1016/00063223(85)90136-2

3. Krupitsky E., Zvartau E., Blokhina E., Verbitskaya E., Tsoy M., Wahlgren V., Burakov A., Masalov D., Romanova T.N., Palatkin V., Tyurina A., Yaroslavtseva T., Sinha R., Kosten T.R. Naltrexone with or without guanfacine for preventing relapse to opiate addiction in St.-Petersburg, Russia. Drug Alcohol Depend. 2013; 132(3): 674-80. doi: 10.1016/j.drugalcdep.2013.04.021

4. Krupitsky E., Zvartau E., Blokhina E., Verbitskaya E., Wahlgren V., Tsoy-Podosenin V., Bushara N., Burakov A., Masalov D. Romanova T., Tyurina A., Palatkin V., Slavina T., Pecoraro A., Woody G.E. Randomized trial of long-acting sustained-release naltrexone implant vs oral naltrexone or placebo for preventing relapse to opioid dependence. Archives General Psychiatry, 2012, 69(9): 973-981. doi: 10.1001/archgenpsychiatry.2012.1a.

5. Krupitsky E.M., Zvartau E.E., Masalov D.V., Tsoi M.V., Burakov A.M., Egorova V.Y., Didenko T.Y., Romanova T.N., Ivanova E.B., Bespalov A.Y., Verbitskaya E.V., Neznanov N.G., Grinenko A.Y., O’Brien C.P., Woody G.E. Naltrexone for heroin dependence treatment in St. Petersburg. Russia. J Subst Abuse Treatment. 2004; 26: 285-294. doi: 10.1016/j.jsat.2004.02.002

6. Krupitsky E.M., Zvartau E.E., Masalov D.V., Tsoy M.V., Burakov A.M., Egorova V.Y., Didenko T.Y., Romanova T.N., Ivanova E.B., Bespalov A.Y., Verbitskaya E.V., Neznanov N.G., Grinenko A.Y., O’Brien C.P., Woody G.E. Naltrexone with or without fluoxetine for preventing relapse to heroin addiction in St. Petersburg. Russia. J Subst Abuse Treat. 2006; 31: 319-328. doi: 10.1016/j. jsat.2006.05.005

7. Oslin D.W., Berrettini W., Kranzler H.R., Pettinati H., Gelernter J., Volpicelli J.R., O’Brien C.P. A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology. 2003; 28(8): 15461552. doi: 10.1038/sj.npp.1300219

8. Pal R., Mendelson J.E., Flower K., Garrison K., Yount G., Coyle J.R., Galloway G.P. Impact of prospectively determined A118G polymorphism on treatment response to injectable naltrexone among methamphetamine-dependent patients: an openlabel, pilot study. J Addict Med. 2015; 9(2): 130135. doi: 10.1097/ADM.0000000000000107