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Abstract: The aim of this secondary analysis of CTN-0048 was to identify prodynorphin (PDYN) genetic markers moderating the therapeutic response to treatment of cocaine dependence with buprenorphine/naloxone (Suboxone®; BUP). 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. 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 x 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. Conclusions: 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. Related protocols: CTN-0048

Abstract:

This is the outcomes paper for CTN-0051-A-1.

Sublingual buprenorphine-naloxone (BUP-NX), an FDA-approved treatment for opioid use disorder (OUD), combines buprenorphine (a partial mu/kappa agonist) with naloxone (a mu/kappa antagonist). Extended-release injection naltrexone (XR-NTX; a mu receptor antagonist and kappa receptor partial agonist) is also an FDA-approved treatment for OUD. However, while some patients respond well to these medications, many others leave treatment and relapse.

This study aimed to determine whether gene variants in the opioid gene system are associated with better or worse treatment response.

In a 24-week, multisite, randomized, comparative effectiveness trial of daily, sublingual self-administration of BUP-NX versus monthly injection of XR-NTX conducted in the NIDA Clinical Trials Network (X:BOT protocol, CTN-0051), DNA was collected and four opioid gene variants were evaluated: (1) mu opioid receptor 118A>G; (2) 68-bp repeat in prodynorphin; (3) prodynorphin SNP rs910080; and (4) kappa opioid receptor SNP rs6473797. In non-Hispanic Caucasians (N = 334), two outcomes measures were assessed: received first dose (yes/no) and received last dose (yes/no). Separate logistic regressions were used to each model outcome measure as a function of treatment (XR-NTX vs BUP-NX), each gene variant, and their interaction.

Analysis found no significant main effects of gene variant on receiving first dose or last dose. There were also no significant gene variant by treatment interactions.

Conclusions: The outcome of treatment of OUD with medications is likely a complex function of multiple factors, including environmental, psychosocial, and possibly genetic, such that major effects of genetic variants may be unlikely.

Related protocols: CTN-0051, CTN-0051-A-1

Abstract:

Opioid use disorders (OUD) and hepatitis C or B co-infection (HEP) are common among people living with HIV (PLHIV). The impact of OUD on innate and adaptive immunity among PLHIV with and without HEP is unknown.

This study, part of CTN-0055 (CHOICES), investigated the impact of OUD on monocyte and T-cell phenotypes, cytokine responses to lipopolysaccharide (LPS) and phytohemagglutinin (PHA), and plasma inflammatory markers, among PLHIV with and without HEP. It was a cross-sectional study enrolling PLHIV receiving ART with and without OUD. Flow cytometry determined monocyte and T-cell phenotypes; LPS and PHA-induced cytokine production was assessed following LPS and PHA stimulation by multiplex cytokine array; plasma IL-6, soluble CD163, and soluble CD14 were measured by ELISA.

Twenty-two PLHIV with OUD and 37 PLHIV without OUD were included. PLHIV with OUD exhibited higher frequencies of intermediate and neoclassical monocytes when compared with PLHIV without OUD (P=0.0025; P=0.0001, respectively), regardless of HEP co-infection. Soluble CD163 and monocyte cell surface CD163 expression was increased among PLHIV with OUD and HEP, specifically. Regardless of HEP co-infection, PLHIV with OUD exhibited reduced production of IL-10, IL-8, IL-6, IL-1alpha, and TNF-alpha in response to LPS when compared with PLHIV without OUD; PHA-induced production of IL-10, IL-1alpha, IL-1beta, IL-6, and TNF-alpha were also reduced among individual with OUD.

Conclusions: OUD among PLHIV are associated with altered monocyte phenotypes and a dysregulated innate cytokine response. Defining underlying mechanisms of opioid-associated innate immune dysregulation among PLHIV should be prioritized to identify optimal OUD treatment strategies.

Related protocols: CTN-0055

Abstract:

There is a reciprocal relationship between the circadian and the reward systems. Polymorphisms in several circadian rhythm-related (clock) genes were associated with drug addiction. This study aimed to search for associations between 895 variants in 39 circadian rhythm-related genes and opioid use disorder (OUD), using samples from CTN-0051 (X:BOT). Genotyping was performed with the Smokescreen® array.

Ancestry was verified by principal/MDS component analysis and the sample was limited to European Americans (EA) (OUD; n = 435, controls; n = 138). Nominally significant associations (p < 0.01) were detected for several variants in genes encoding vasoactive intestinal peptide receptor 2 (VIPR2), period circadian regulator 2 (PER2), casein kinase 1 epsilon (CSNK1E), and activator of transcription and developmental regulator (AUTS2), but no signal survived correction for multiple testing. There was intriguing association signal for the untranslated region (3’ UTR) variant rs885863 in VIPR2, (p = .0065; OR = 0.51; 95% CI 0.31–0.51). The result was corroborated in an independent EA OUD sample (n = 398, p = 0.0036; for the combined samples). Notably, this SNP is an expression quantitative trait locus (cis-eQTL) for VIPR2 and a long intergenic non-coding RNA, lincRNA 689, in a tissue-specific manner, based on the Genotype-Tissue Expression (GTEx) project. Vasoactive intestinal peptide (VIP) is an important peptide of light-activated suprachiasmatic nucleus cells. It regulates diverse physiological processes including circadian rhythms, learning and memory, and stress response.

Conclusions: This is the first report of an association of a VIPR2 variant and OUD. Additionally, analysis of combinations of single nucleotide polymorphisms (SNPs) genotypes revealed an association of PER2 SNP rs80136044, and SNP rs4128839, located 41.6 kb downstream of neuropeptide Y receptor type 1 gene, NPY1R (p = 3.4 × 10-6, OR = 11.4, 95% CI 2.7–48.2). The study provides preliminary insight into the relationship between genetic variants in circadian rhythm genes and long non-coding RNA (lncRNAs) in their vicinity, and opioid addiction.

Related protocols: CTN-0051, CTN-0051-A-1

Abstract:

Dysregulation of the stress response is implicated in drug addiction; therefore, polymorphisms in stress-related genes may be involved in this disease. Using samples from CTN-0051 (X:BOT), an analysis was performed to identify associations between variants in 11 stress-related genes, selected a priori, and heroin addiction. Two discovery samples of American subjects of European descent (EA, n = 601) and of African Americans (AA, n = 400) were analyzed separately. Ancestry was verified by principal component analysis. Final sets of 414 (EA) and 562 (AA) variants were analyzed after filtering of 846 high-quality variants. The main result was an association of a non-coding SNP rs255105 in the CRH (CRF) receptor 2 gene (CRHR2), in the discovery EA sample (Pnominal = .00006; OR = 2.1; 95% CI 1.4–3.1). The association signal remained significant after permutation-based multiple testing correction. The result was corroborated by an independent EA case sample (n = 364). Bioinformatics analysis revealed that SNP rs255105 is associated with the expression of a downstream long intergenic non-coding RNA (lincRNA) gene AC005154.6. AC005154.6 is highly expressed in the pituitary but its functions are unknown. LincRNAs have been previously associated with adaptive behavior, PTSD, and alcohol addiction.

Conclusions: Hypothesis-driven study of variants in stress-related genes and heroin addiction identified an association with non-coding SNP in the CRHR2 gene. A downstream lincRNA gene is a ciseQTL of this SNP and additional SNPs in the region. This result is intriguing since lincRNAs play a role in adaptive behavior and neurological diseases and are potential drug targets for stress-related disorders. Further studies are warranted to corroborate the association results and to assess the potential relevance of this lincRNA to addiction and other stress-related disorders.

Related protocols: CTN-0051, CTN-0051-A-1

Abstract:

Currently, no pharmacogenetic tests for selecting an opioid-dependence pharmacotherapy have been approved by the U.S. Food and Drug Administration. This study aimed to determine the effects of variants in 11 genes on dropout rate and dose in patients receiving methadone or buprenorphine/naloxone. Variants in 6 pharmacokinetic genes (CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4) and 5 pharmacodynamic genes (HTR2A, OPRM1, ADRA2A, COMT, SLC6A4) were genotyped in samples from a 24-week, randomized, open-label trial of methadone and buprenorphine/naloxone for the treatment of opioid dependence (n=764; 68.7% male). Genotypes were then used to determine the metabolism phenotype for each pharmacokinetic gene. Phenotypes or genotypes for each gene were analyzed for association with dropout rate and mean dose.

Results found that the genotype for 5-HTTLPR in the SLC6A4 gene was nominally associated with dropout rate when the methadone and buprenorphine/naloxone groups were combined. When the most significant variants associated with dropout rate were analyzed using pairwise analyses, SLC6A54 (5-HTTLPR) and COMT (Val158Met; rs4860) had nominally significant associations with dropout rate in methadone patients. None of the genes analyzed in the study were associated with mean dose of methadone or buprenorphine/naloxone.

Conclusions: This study suggests that functional polymorphisms related to synaptic dopamine or serotonin levels may predict dropout rates during methadone treatment. Patients with the S/S genotype at 5-HTTLPR in SLC6A4 or the Val/Val genotype at Val158Met in COMT may require additional treatment to improve their chances of completing addiction treatment. Replication in other methadone patient populations will be necessary to ensure the validity of these findings.

Related protocols: CTN-0027, CTN-0027-A-1

Abstract:

The mu-opioid receptor (MOR) is the primary target of methadone and buprenorphine. The primary neuronal transcript of the OPRM1 gene, MOR-1, contains a ~13kb 3′ untranslated region with five common haplotypes in European-Americans. We analyzed the effects of these haplotypes on the percentage of opioid positive urine tests in European-Americans (n=582) during a 24-week, randomized, open-label trial of methadone or buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. A single haplotype, tagged by rs10485058, was significantly associated with patient urinalysis data in the methadone treatment group. Methadone patients with the A/A genotype at rs10485058 were less likely to have opioid-positive urine drug screens than those in the combined A/G and G/G genotypes group (relative risk = 0.76, 95% confidence intervals = 0.73-0.80, P=0.0064). Genotype at rs10485058 also predicted self-reported relapse rates in an independent population of Australian patients of European descent (n=1215) who were receiving opioid substitution therapy (P=0.003). In silico analysis predicted that miR-95-3p would interact with the G, but not the A allele of rs10485058, suggesting a potential mechanism for the observed pharmacogenetic effect.

Conclusions: These findings suggest that selection of a medication for opioid dependence based on rs10485058 genotype might improve outcomes in this ethnic group.

Related protocols: CTN-0027, CTN-0027-A-1

Abstract:

The results of some studies suggest that the serotonin transporter-linked polymorphic region (5-HTTLPR) short (S) allele, relative to the long (L) allele, is associated with risk for Major Depressive Disorder (MDD), and thus serves as a biomarker for MDD, while results from other studies do not support that conclusion. Persons with an S allele demonstrate a 2- to 2.5 fold decrease in serotonin transcription rate compared to the L-allele, which may increase their risk for MDD. Differences in study populations may help explain the differences in findings between those meta-analyses. To date, there have been no published reports which have addressed the possible association between the S allele and MDD among military veterans.

This study, funded in part by NIDA’s National Drug Abuse Treatment Clinical Trials Network (CTN), assessed the possible association of the S allele with MDD among a study population of veterans in treatment for substance use disorder. It was hypothesized that the S allele would be associated with MDD in the study sample. Subjects signing informed consent were 101 veterans recruited from VA behavioral health and substance use treatment clinics in the VA Pittsburgh Healthcare System, and 91 of those subjects were genotyped for 5-HTTLPR polymorphisms. The study sample from whom genetic material was collected included 82 males and 9 females, of whom 53 were white, 38 were black, and one was “other.” Fifty-four members of the study sample (59%) met DSM-IV criteria for an MDD on the SCID. Forty-five of the subjects demonstrated one or two S alleles, while 46 did not do so.

Conclusions: The presence of the S allele of the serotonin transporter was not found to be significantly associated with the diagnosis of MDD in the sample. This finding, in combination with other recent negative findings from other researchers involving non-veteran populations raises questions regarding the clinical utility of using genetics tests involving the assessment of the alleles of the serotonin transporter as a possible biomarker for Major Depressive Disorder.

Abstract:

This is the Results Article for CTN-0027-A-1.

Two commonly prescribed treatments for opioid addiction are methadone and buprenorphine. Although these drugs show some efficacy in treating opioid dependence, treatment response varies among individuals. It is likely that genetic factors have a role in determine treatment outcome. This study analyses the pharmacogenetic association of six polymorphisms in OPRD1, the gene encoding the delta-opioid receptor, on treatment outcome in 582 opioid addicted European Americans randomized to either methadone or buprenorphine/naloxone (Suboxone) over the course of a 24-week open-label clinical trial. Treatment outcome was assessed as the number of missed or opioid-positive urine drug screens over the 24 weeks. In the total sample, no single-nucleotide polymorphisms (SNPs) in OPRD1 were significantly associated with treatment outcome in either treatment arm. However, sex-specific analyses revealed two intronic SNPs (rs581111 and rs529520) that predicted treatment outcomes in females treated with buprenorphine. Females with the AA or AG genotypes at rs581111 had significantly worse outcomes than those with the GG genotype when treated with buprenorphine. For rs529520, females with the AA genotype had a significantly worse outcome than those with the CC genotype. No significant associations were detected in males.

Conclusions: These findings suggest that rs581111 and rs52920 may be useful when considering treatment options for female opioid addicts; however, confirmation in an independent sample is warranted.

Related protocols: CTN-0027, CTN-0027-A-1

Abstract:

To date, the National Drug Abuse Clinical Trials Network Starting Treatment with Agonist Replacement Treatment Study (START) includes the largest database of patients (n=1269) entering opioid agonist treatment programs at community methadone centers around the United States (U.S.). Participants in the study were randomized to either Methadone (MET) treatment or Buprenorphine/Naloxone (BUP/Nx) treatment, and closely monitored during induction as well as throughout active treatment and follow-up. Pharmacotherapy was provided for 24 weeks with taper or continuation possible through week 32. Primary outcomes showed low rates of liver injury and no differences in liver functions between MET and BUP/Nx groups. Secondary findings present a multitude of interesting and clinically relevant outcomes. This Blending Initiative workshop presented several of those secondary outcomes from both a U.S. and international perspective.

Session One: United States Perspective

This segment of the session presented several important secondary outcomes from the START study including: From a comparison of the impact of MET vs. BUP/Nx treatment on HIV risk behaviors; a description of six different BUP/Nx and three different MET induction trajectories and their outcomes; and an association between genotype and treatment outcome in African-American participants receiving BUP/Nx or MET.

Session Two: International Perspective

To complement the findings and dissemination strategies from the U.S. perspective, a panel of international collaborators presented findings from studies conducted abroad and implementation strategies that have been successful. Presentations included outcomes from a collaborative project between NIDA and treatment providers in Indonesia, data from epidemiological studies showing the association between the length of MET treatment and mortality rates and dissemination and implementation strategies, and the use of incentive-based interventions in reducing drug use and associated consequences. The session also described the N-ALIVE (NALoxone InVEstigation) study–a large, prison-based, trial that assesses the number of lives that could be saved by providing Naloxone-on-release to adult prisoners with a history of heroin injection. The discussion after session two focused on on how the knowledge gained from these analyses and findings can be translated for the implementation of relevant MET or BUP/Nx treatment in clinical settings treating opioid dependent patients in the U.S. as well as internationally

Related protocols: CTN-0027

Abstract:

Individuals with addictive disorders often make rash decisions and behave impulsively, which can impact their treatment. This 1 hour, 45 minute webinar critically examines different ways to measure impulsivity and how performance on these measures can predict changes in addictive behaviors. The discussion highlights the important ways clinical research and basic science research can inform each other, including research from the Clinical Trials Network. It also examines various factors that impact impulsivity, including genetics, environmental history of adversity and stress, emotional state including distress due to substance withdrawal symptoms, and other psychosocial factors. The final part of this webinar outlines studies that show how these factors alter the neural functions that govern impulsivity.

Abstract:

Although buprenorphine and methadone are both effective treatments for opioid dependence, their efficacy can vary significantly among patients. Genetic differences may explain some of the variability in treatment outcome. Understanding the interactions between genetic background and pharmacotherapy may result in more informed treatment decisions. This study is a pharmacogenetic analysis of the effects of genetic variants in OPRD1, the gene encoding the mu-opioid receptor, on the prevalence of opioid-positive urine tests in African Americans (n=77) or European Americans (n=566) undergoing treatment for opioid dependence (as part of National Drug Abuse Treatment Clinical Trial CTN-0027, “Starting Treatment with Agonist Replacement Therapies (START)”). Patients were randomly assigned to treatment with either methadone or buprenorphine/naloxone (Suboxone) over a 24-week open-label clinical trial, in which illicit opioid use was measured by weekly urinalysis. In African Americans, the intronic SNP rs678849 predicted treatment outcome for both medications. Methadone patients with the CC genotype were less likely to have opioid-positive urine tests than those in the combined CT and TT genotypes group. In the buprenorphine treatment group, however, individuals with the CC genotype were more likely to have positive opioid drug screens than individuals in the combined CT and TT genotypes group.

Conclusions: These findings indicate that the genotype at rs678849 predicts African American patient response to two common treatments for opioid dependence, suggesting that matching patients to treatment type based on the genotype at this locus may improve overall treatment efficacy. This observation requires confirmation in an independent population.

Related protocols: CTN-0027-A-1

Abstract:

The addition of genetics research to pharmacotherapy trials is becoming more and more common. However, there has been some concern among community treatment providers that genetics research would be unacceptable to their clients. The CTN is currently conducting an add-on genetics substudy to a pharmacotherapy trial comparing the effects of long-term methadone and buprenorphine on liver function (CTN-0027, “Starting Treatment with Agonist Replacement Therapies (START)). The genetics substudy (CTN-0027-A-1) is exploratory in nature, with three main goals: 1) To better understand the potential genetic influence on opioid addiction; 2) To better understand how opioid dependent individuals metabolize buprenorphine and methadone; and 3) To evaluate feasibility of conducting a genetics sub-study within the CTN.

Although data are still being collected to accomplish the first two goals, there is good evidence to support the feasibility of collecting genetic samples for analysis through the CTN. To date, all 8 of the START research sites have submitted samples for this substudy. The genetics substudy has 4 different levels of consent so that participants can choose how their samples may be used in the future. Most participants (79%) have agreed to the most liberal use of their samples. Taken together, these data suggest that individuals in community treatment settings are willing to participate in genetic studies on addiction.

Related protocols: CTN-0027-A-1

Abstract:

This session of the 2008 NIDA Blending Conference featured three presentations about the role of genetics in addiction treatment. The first, by Mary Jeanne Kreek, provides a detailed description of how addiction develops and the hypothesis that it is driven by an atypical responsivity to stressors that may be genetic in nature. An overview of the way genetics have been studied in the addiction field is also provided.

The second and third presentations, by Louise Haynes and Allan Cohen respectively, introduce a new CTN protocol, CTN-0027a (an adjunct to CTN-0027, “Starting Treatment with Agonist Replacement Therapies (START)”) called “START Pharmacogenetics: Exploratory Genetic Studies in Starting Treatment with Agonist Replacement Therapies.” This study will ask for volunteers participating in START to provide blood samples that will be examined for the frequency of gene variants that have primarily been associated with addiction. The “START Genetics” protocol is the first, but hopefully not the last, genetics study conducted within the CTN. Details of the study’s objectives and methods are included in Cohen’s presentation.

Related protocols: CTN-0027, CTN-0027-A-1