[Anhedonia, depression, anxiety, and craving in opioid dependent patients stabilized on oral naltrexone or naltrexone implant]. / Angedoniia, depressiia, trevoga i vlechenie k upotrebleniiu narkotikov u patsientov s opioidnoi zavisimost'iu pri kursovom lechenii peroral'noi ili implantiruemoi formoi naltreksona.

AIM: To assess the relationship between long-term naltrexone treatment and anxiety, depression and craving in opioid dependent individuals. MATERIAL AND METHODS: Opioid dependent patients (n=306) were enrolled in a three cell (102ss/cell) randomized, double blind, double dummy, placebo-controlled 6-month trial comparing extended release implantable naltrexone with oral naltrexone and placebo (oral and implant). Monthly assessments of affective responses used a Visual Analog Scale for opioid craving, the Beck Depression Inventory, Spielberger Anxiety Inventory, and the Ferguson and Chapman Anhedonia Scales. Between-group outcomes were analyzed using mixed model analysis of variance (Mixed ANOVA) and repeated measures and the post hoc Tukey test. RESULTS AND CONCLUSION: Anhedonia, depression, anxiety, and craving for opiates were elevated at baseline but gradually reduced to normal within the first 1-2 months for patients who remained in treatment and did not relapse. There were no significant between-group differences prior to treatment dropout as well as between those who relapsed and who continued on naltrexone. CONCLUSION: These data do not support concerns that naltrexone treatment of opioid dependence precipitates anhedonia, depression, anxiety or craving for opiates.

[A pharmacogenetic analysis of dopaminergic and opioidergic genes in opioid addicts treated with the combination of naltrexone and guanfacine]. / Farmakogeneticheskii analiz vliyaniya genov dofaminovoi i opioidnoi sistem na effektivnost' kombinirovannoi terapii naltreksonom i guanfatsinom bol'nykh opioidnoi zavisimost'yu.

AIM: To evaluate an effect of opioid receptor and dopamine system gene polymorphisms on the efficacy of combined treatment with oral naltrexone and guanfacine in a randomized double blinded double dummy placebo controlled clinical trial. MATERIAL AND METHODS: Three hundred and one patients with opioid dependence were randomized into 4 treatment groups: naltrexone 50 mg/day + guanfacine 1 mg/day (N+G); naltrexone + placebo guanfacine (N+GP); placebo naltrexone + guanfacine (NP+G); double placebo (NP+GP). The primary outcome was treatment retention. All enrolled participants were genotyped for polymorphisms in the following genes: mu- (OPRM1), kappa-opioid receptors (OPRK1), catechol-O-methyltransferase (COMT), dopamine receptors types 2 (DRD2) and 4 (DRD4), dopamine-beta-hydroxylase, and dopamine transporter (SLC6A3, DAT1) and alpha-2-adrenoreceptor (ADRA2A) a pharmacological target of guanfacine. RESULTS: The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone monotherapy. Regardless of treatment, several gene polymorphisms were associated with higher chance to complete the treatment program: allele Т DRD4 - 521 С/Т (rs1800955) (р=0.039; OR (95% CI)=3.7 (1.1-12.7); log-rank test: р=0.01); allele С DRD2 С957Т (rs6277) (р=0.03; HR=0.6 (0.34-0.95); genotype combination: DRD4 VNTR (LL) + OPRM1 A118G (rs1799971) (AA), р=0.051; DRD2 C957T (ТТ) + OPRM1 (rs1074287) (СС), р=0.025; DRD2 - 141С (II) + OPRM1 (rs510769) (АА), р=0.035; DBH Fau(СС) + OPRM1 (rs1074287) (СС), р=0.0497. Regardless of treatment several polymorphisms were associated with high risk of relapse: allele Т (rs510769) OPRM1 (р=0.053), allele А (rs1799971, A118G) OPRM1 (р=0.056), allele S exon III 48 bp DRD4 VNTR (р=0.001; HR=3.1 (ДИ 95% 1.57-6.18); genotype combinations: DRD4 - 521 С/Т (ТТ) + DRD2 Nco I (TT), р=0.026; DRD4 -521 С/Т (ТТ) + DRD2 -141 С (II), р=0.011; DRD4 - 521 С/Т (ТТ) + OPRM1 A118G (rs1799971) (AA), р=0.011; DRD2 Nco I(ТТ) + ADRA2A (СС), р=0.012; DRD2 Nco I(ТТ) + OPRM1 A118G (AA), р=0.02. The effects dependent on the treatment group were as follows: 1) in the N+G group, patients with the DRD4 -521 С/Т TT genotype had higher probability of completion of treatment program in comparison with other genotypes (CC and CT) (log-rank test: p=0.002); 2) in NP + GP group, patients with the OPRM1 rs510769 T allele had higher risk of relapse compared to the genotype GG (p=0.008) (FDR p<0.0125). CONCLUSION: The additive effect of opioid receptor genes and dopaminergic system genes on outcomes of treatment opioid dependence with oral naltrexone and guanfacine was shown. Pharmacological effects of naltrexone and guanfacine were associated with genetic variants of the DRD4 - 521C/T polymorphism, since its effect was shown only in the N+G group. The effect of the OPRM1 rs510769 polymorphism was demonstrated in the double placebo group that was associated with personality traits (temperament, character) and determined compliance. Genetic analysis is useful for determining potential responders to treatment of opioid dependence; genotyping can increase the efficacy of pharmacotherapy.

[A double-blind randomized placebo-controlled study of the efficacy of the combined treatment with naltrexone and guanfacine for relapse prevention in opiate dependence].

OBJECTIVE: Authors studied the effect of α-2-adrenoreceptor agonist guanfacine on replace prevention in opiate addicts. MATERIAL AND METHODS: Three hundred and one recently detoxified opiate addicts were randomized under the double-blind double-dummy conditions into one of four treatment groups: naltrexone 50 mg/day+guanfacine 1 mg/day (N+G), naltrexone+guanfacine placebo (N+GP), naltrexone placebo+guanfacine (NP+G), and double placebo (NP+GP). The primary outcome was retention in treatment. The secondary outcomes were perceived stress (Perceived Stress Scale) and craving. RESULTS: At the end of six months, 20 (26.7%) patients in the N+G group and 15 (19.7%) (p=0.26 to N+G) in N+GP group were retained in treatment compared to 5 (6.7%) in the NP+G group (p=0.002 to N+G group and p=0.017 to N+GP group) and 8 (10.7%) in the double placebo group (p=0.013 to N+G group). There is no significant difference in retention between the N+G group and N+GP group at the end of treatment. CONCLUSION: Guanfacine had significant craving and stress reducing effect. Naltrexone was more effective than placebo for relapse prevention in opioid dependent patients. The efficacy of the combination of naltrexone and guanfacine was comparable to naltrexone alone. Guanfacine moderately reduced both stress and craving.

[Stabilization of remission in patients with opioid dependence with naltrexone implant: a pharmacogenetic approach]. / Stabilizatsiia remissii u bol'nykh opiinoi narkomaniei implantom naltreksona: farmakogeneticheskii aspekt.

AIM: To evaluate the effect of opioid receptor genes and dopamine system genes polymorphisms on treatment outcomes of opioid dependence with implantable and oral naltrexone. MATERIAL AND METHODS: Authors carried out a randomized double-blind, double-dummy, placebo-controlled clinical trial. Three hundred and six patients with opioid dependence were randomized into 3 equal treatment groups. The first group received implantation of 1000 mg naltrexone every 2 months during 6 months + oral naltrexone placebo; the second group - placebo implant every 2 months + oral naltrexone (50mg/day) and the third group - placebo implant + oral naltrexone placebo. It was genotyped polymorphisms in the 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 treatment several polymorphisms of these genes were associated with high risk of relapse: an allele L (2R) DRD4 120bp (p=0.05; OR (95% CI)=3.3(1.1-10.1)); an allele С DRD2 NcoI (р=0,051; OR (95% CI)=2,86 (1,09-7,52)); the genotype 9.9 DAT VNTR 40bp (р=0,04; OR (95% CI)=1,4 (1,3-1,5)); on the contrary, (СС+СТ)-(ТТ)) variants of OPRK1-DRD2Ncol increased a chance to complete 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 the carriers of these variants was higher in the oral naltrexone group (p=0.016), lower in the double placebo group (p=0.015), but did not influence on treatment outcomes in the naltrexone-implant group. CONCLUSION: Naltrexone-implant is a highly effective medication for treatment of opioid dependence and its effectiveness exceeds that of oral naltrexone and placebo. The study has shown the joint influence of opioid receptor genes and genes of dopaminergic system on treatment outcomes of opioid dependence. Genetic analysis is useful for determining potential responders to naltrexone treatment of opioid dependence.

[Naltrexone and fluoxetine for maintenance of remission in patients with heroin addiction: a double-blind randomized placebo-controlled trial].

Two hundreds and eighty patients with heroin addiction were randomized into 4 equal groups. Patients of the group 1 received naltrexone (N) in dosage 50 mg/day and fluoxetine (F) in dosage 20 mg/day during 6 months. Group 2 received N/F-placebo (FN), group 3--N-placebo (NP)/F and group 4--NP/FP. All patients underwent a session of individual psychotherapy for the maintenance of remission. Express urine drugs tests were used for remission control. Compliance was controlled by a riboflavin marker. Clinical state, psychiatric status and social functioning were assessed using quantified international scales and tests. To the end of the 6 month course, 43% of patients of group 1, 36% of group 2, 21% of group 3 and 10% of group 4 were in remission. Therefore, N/F was more effective than F/NP (p < 0.01) and FP/NP (p < 0.001); N/FP was more effective than F/NP (p < 0.05) and NP/FP (p < 0.001); F/NP did not differ significantly from NP/FP (p = 0.1); N/F did not differ from N/FP (p = 0.2). However N/F was more effective compared to N/FP only in women, probably, due to the higher baseline levels of depression, anxiety and anhedonia. Naltrexone was superior to placebo and fluoxetine in the efficacy of maintenance of remission and preventing relapse in patients with heroin addiction. The combination of naltrexone and fluoxetine was more effective compared to the monotherapy with naltrexone in women only.

Prevention of suicide by naltrexone in a recently detoxified heroin addict.

This case describes a heroin addict who was participating in a placebo-controlled randomized trial of naltrexone as an aid to relapse prevention. The patient tried to commit suicide by taking a heroin overdose after learning that he was HIV-positive. He was on naltrexone at the time and, as a result, survived what would probably have been a fatal overdose. This case demonstrates that naltrexone can have immediate as well as long-term positive effects in persons who are attempting to recover from heroin addiction.