Background-Pathophysiological models of Attention-Deficit/Hyperactivity Disorder (ADHD) have focused on frontal-striatal circuitry with alternative hypotheses relatively unexplored. Based on evidence that negative interactions between frontal foci involved in cognitive control and the nongoal directed 'default-mode' network prevent attentional lapses, we hypothesized abnormalities in functional connectivity of these circuits in ADHD.

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Summary Background Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX. Methods We initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433. Findings Between Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0·0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10–1·68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0·44). Opioid-negative urine samples (p<0·0001) and opioid-abstinent days (p<0·0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0·0012), then converged by week 24 (p=0·20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group). Interpretation In this population it is more difficult to initiate patients to XR-NTX than BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future wo...

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Heroin addiction is a chronic complex disease with a substantial genetic contribution. This study was designed to identify genetic variants that are associated with susceptibility to develop heroin addiction by analyzing 1350 variants in 130 candidate genes. All subjects had Caucasian ancestry. The sample consisted of 412 former severe heroin addicts in methadone treatment, and 184 healthy controls with no history of drug abuse. Nine variants, in six genes, showed the lowest nominal P values in the association tests (P < 0.01). These variants were in noncoding regions of the genes encoding the mu (OPRM1; rs510769 and rs3778151), kappa (OPRK1; rs6473797) and delta (OPRD1; rs2236861, rs2236857 and rs3766951) opioid receptors; the neuropeptide galanin (GAL; rs694066); the serotonin receptor subtype 3B (HTR3B; rs3758987) and the casein kinase 1 isoform epsilon (CSNK1E; rs1534891). Several haplotypes and multilocus genotype patterns showed nominally significant associations (e.g. OPRM1; P 5 0.0006 and CSNK1E; P 5 0.0007). Analysis of a combined effect of OPRM1 and OPRD1 showed that rs510769 and rs2236861 increase the risk of heroin addiction (P 5 0.0005). None of these associations remained significant after adjustment for multiple testing. This study suggests the involvement of several genes and variants in heroin addiction, which is worthy of future study. Heroin addiction is a chronic relapsing disease characterized by compulsive drug seeking, drug abuse, tolerance and physical dependence. It is treated by methadone, buprenorphine and behavioral therapy. Heroin addiction is part of group of addictions (e.g. cocaine, alcohol and nicotine) that constitute a worldwide public health crisis. The genetic contribution to vulnerability to develop heroin addiction is 40-60%, suggesting a complex inheritance mode in which multiple genes exert a small effect, along with the environment (Kendler et al. 2003;Tsuang et al. 1996Tsuang et al. , 1998. ). These include variants in the genes encoding the mu and kappa opioid receptors, dopamine receptors D2 and D4, serotonin receptor 1B, gamma-aminobutryic acid (GABA) receptor subunit gamma 2, catechol-O-methyltransferase, period circadian protein (PER3), proenkephalin, proopiomelanocortin, tryptophan hydroxylase 2 and brain-derived neurotrophic factor.To identify genetic variants that underlie heroin addiction, we performed a candidate gene case-control association study using a single nucleotide polymorphism (SNP) array that was designed by the group of D. Goldman at the National Institute of Alcohol Abuse and Alcoholism (NIAAA). This approach is based on physiological hypotheses and the genes were selected based on their function (e.g. drug receptors, neurotransmitters, transporters and drug metabolism enzymes) and related pathways (e.g. reward modulation, behavioral control, cognitive function, signal transduction and stress response). In order to maximize the power of the study, the cases were selected from the extreme margin of the specific phenotype range (e.g. severe heroin a...

BACKGROUND Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited. METHODS In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78. RESULTS A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P = 0.91). The rates of other prespecified secondary outcome measures — self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration — were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P = 0.02). CONCLUSIONS In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation.

Background Models of cocaine addiction emphasize the role of disrupted frontal circuitry supporting cognitive control processes. Yet, addiction-related alterations in functional interactions among brain regions, especially between the cerebral hemispheres, are rarely examined directly. Resting state fMRI approaches, which reveal patterns of coherent spontaneous fluctuations in the fMRI signal, offer a means to directly quantify functional interactions between the hemispheres. We examined interhemispheric resting state functional connectivity (RSFC) in cocaine dependence using a recently validated approach named “voxel-mirrored homotopic connectivity.” Methods We compared interhemispheric RSFC between 25 adults (aged 35.0±8.8) meeting DSM-IV criteria for cocaine dependence within the past 12 months, but currently abstaining (>2 weeks) from cocaine, and 24 healthy comparisons (35.1±7.5), group-matched on age, sex, education and employment status. Results We observed reduced prefrontal interhemispheric RSFC in cocaine dependent participants relative to controls. Further analyses demonstrated a striking cocaine-dependence-related reduction in interhemispheric RSFC among nodes of the dorsal attention network (DAN), comprising bilateral lateral frontal, medial premotor and posterior parietal areas. Further, within the cocaine-dependent group, RSFC within the DAN was associated with self-reported lapses of attention. Conclusions Our findings provide further evidence of an association between chronic exposure to cocaine and disruptions within large-scale brain circuitry supporting cognitive control. We did not detect group differences in DTI measures, suggesting that alterations in the brain’s functional architecture associated with cocaine exposure can be observed in the absence of detectable abnormalities in the white matter microstructure supporting that architecture.

Background Alcohol and drug use are leading causes of morbidity and mortality that frequently go unidentified in medical settings. As part of a multi-phase study to implement electronic health record-integrated substance use screening in primary care clinics, we interviewed key clinical stakeholders to identify current substance use screening practices, barriers to screening, and recommendations for its implementation.MethodsFocus groups and individual interviews were conducted with 67 stakeholders, including patients, primary care providers (faculty and resident physicians), nurses, and medical assistants, in two urban academic health systems. Themes were identified using an inductive approach, revised through an iterative process, and mapped to the Knowledge to Action (KTA) framework, which guides the implementation of new clinical practices (Graham et al. in J Contin Educ Health Prof 26(1):13–24, 2006).ResultsFactors affecting implementation based on KTA elements were identified from participant narratives. Identifying the problem: Participants consistently agreed that having knowledge of a patient’s substance use is important because of its impacts on health and medical care, that substance use is not properly identified in medical settings currently, and that universal screening is the best approach. Assessing barriers: Patients expressed concerns about consequences of disclosing substance use, confidentiality, and the individual’s own reluctance to acknowledge a substance use problem. Barriers identified by providers included individual-level factors such as lack of clinical knowledge and training, as well as systems-level factors including time pressure, resources, lack of space, and difficulty accessing addiction treatment. Adapting to the local context: Most patients and providers stated that the primary care provider should play a key role in substance use screening and interventions. Opinions diverged regarding the optimal approach to delivering screening, although most preferred a patient self-administered approach. Many providers reported that taking effective action once unhealthy substance use is identified is crucial. ConclusionsParticipants expressed support for substance use screening as a valuable part of medical care, and identified individual-level as well as systems-level barriers to its implementation. These findings suggest that screening programs should clearly communicate the goals of screening to patients and proactively counteract stigma, address staff concerns regarding time and workflow, and provide education as well as treatment resources to primary care providers.Electronic supplementary materialThe online version of this article (10.1186/s13722-018-0110-8) contains supplementary material, which is available to authorized users.