Stratified analyses of genome wide association study data reveal haplotypes for a candidate gene on chromosome 2 (KIAA1211L) is associated with opioid use in patients of Arabian descent.

BACKGROUND: Genome Wide Association Studies (GWAS) have been conducted to identify genes and pathways involved in development of opioid use disorder. This study extends the first GWAS of substance use disorder (SUD) patients from the United Arab Emirates (UAE) by stratifying the study group based on opioid use, which is the most common substance of use in this cohort. METHODS: The GWAS cohort consisted of 512 (262 case, 250 controls) male participants from the UAE. The samples were genotyped using the Illumina Omni5 Exome system. Data was stratified according to opioid use using PLINK. Haplotype analysis was conducted using Haploview 4.2. RESULTS: Two main associations were identified in this study. Firstly, two SNPs on chromosome 7 were associated with opioid use disorder, rs118129027 (p-value = 1.23 × 10 - 8) and rs74477937 (p-value = 1.48 × 10 - 8). This has been reported in Alblooshi et al. (Am J Med Genet B Neuropsychiatr Genet 180(1):68-79, 2019). Secondly, haplotypes on chromosome 2 which mapped to the KIAA1211L locus were identified in association with opioid use. Five SNPs in high linkage disequilibrium (LD) (rs2280142, rs6542837, rs12712037, rs10175560, rs11900524) were arranged into haplotypes. Two haplotypes GAGCG and AGTTA were associated with opioid use disorders (p-value 3.26 × 10- 8 and 7.16 × 10- 7, respectively). CONCLUSION: This is the first GWAS to identify candidate genes associated with opioid use disorder in participants from the UAE. The lack of other genetic data of Arabian descent opioid use patients has hindered replication of the findings. Nevertheless, the outcomes implicate new pathways in opioid use disorder that requires further research to assess the role of the identified genes in the development of opioid use disorder.

A case-control genome wide association study of substance use disorder (SUD) identifies novel variants on chromosome 7p14.1 in patients from the United Arab Emirates (UAE).

Genome wide association studies (GWASs) have provided insights into the molecular basis of the disorder in different population. This study presents the first GWAS of substance use disorder (SUD) in patients from the United Arab Emirates (UAE). The aim was to identify genetic association(s) that may provide insights into the molecular basis of the disorder. The GWAS discovery cohort consisted of 512 (250 cases and 262 controls) male participants from the UAE. Controls with no prior history of SUD were available from the Emirates family registry. The replication cohort consisted of 520 (415 cases and 105 controls) Australian male Caucasian participants. The GWAS discovery samples were genotyped for 4.6 million single nucleotide polymorphism (SNP). The replication cohort was genotyped using TaqMan assay. The GWAS association analysis identified three potential SNPs rs118129027 (p-value = 6.24 × 10-8 ), rs74477937 (p-value = 8.56 × 10-8 ) and rs78707086 (p-value = 8.55 × 10-8 ) on ch7p14.1, that did not meet the GWAS significance threshold but were highly suggestive. In the replication cohort, the association of the three top SNPs did not reach statistical significance. In a meta-analysis of the discovery and the replication cohorts, there were no strengthen evidence for association of the three SNPs. The top identified rs118129027 overlaps with a regulatory factor (enhancer) region that targets three neighboring genes LOC105375237, LOC105375240, and YAE1D1. The YAE1D1, which represents a potential locus that is involved in regulating translation initiation pathway. Novel associations that require further confirmation were identified, suggesting a new insight to the genetic basis of SUD.

Characterization of serotonin transporter gene (SLC6A4) polymorphisms and its association with drug dependence in a Jordanian Arab population.

Drug dependence is a pattern of repeated self-administration of a drug, which can result in tolerance, withdrawal and compulsive drug-taking behaviour. It has been recently suggested that 5-HTTLPR (LL/LS/SS) variants and rs25531 (A/G) polymorphism in the serotonin transporter gene (SLC6A4) may play a role in drug dependence. The current study aimed to (1) identify allelic, haplotypic and genotypic frequencies of the 5-HTTLPR variants and rs25531 polymorphisms of SLC6A4 gene in drug and nondrug-dependent Jordanian Arab population and (2) determine whether there is an association of these variants in a drug-dependent population from the same area. Jordanian drug male addicts of Arab descent (n = 192) meeting the Diagnostic and Statistical Manual of Mental Disorders - Fourth edition criteria for drug dependence and 230 healthy male controls from an ethnically homogenous Jordanian Arab population were examined. Genotyping was performed using the restriction fragment length polymorphism-polymerase chain reaction-based method to genotype the 5-HTTLPR variants and detect the A/G polymorphism at position rs25531. The biallelic analysis revealed that the frequency of 5-HTTLPR (LL/LS/SS) genotypes was statistically significant different between drug-dependent individuals and controls (χ (2) (2, N = 422), p = 0.04). Drug-dependent subjects had a higher frequency of 'L' allele. However, using the triallelic approach, the estimated frequency of haplotypes (SA , SG , LA and LG ) and phased genotypes (LA /LA , LA /SA , LA /LG , SA /SA and SA /SG) did not show significant association with drug dependence (χ (2) (3, N = 422), p = 0.53 and χ (2) (4, N = 422), p = 0.06, respectively). This study suggests a putative role of the 5-HTTLPR for drug dependence in the Jordanian Nationals of Arab ancestry.

Improving clinical outcomes for naltrexone as a management of problem alcohol use.

Despite being a relatively effective and safe treatment, the clinical management of alcohol abuse/dependence by oral naltrexone can be compromised due to the patient's non-compliance with daily use of this medication. Over the past decade an increasing body of research has suggested that the use of sustained release depot naltrexone preparations can overcome this issue and deliver improved clinical outcomes. However, at the same time, research findings from diverse areas of pharmacogenetics, neurobiology and behavioural psychology have also been converging to identify variables including genetic markers, patient psychosocial characteristics and drug use history differences, or clusters of these variables that play a major role in mediating the response of alcohol abuse/dependent persons to treatment by naltrexone. While this article does not attempt to review all available data pertaining to an individual alcohol dependent patient's response to treatment by naltrexone, it does identify relevant research areas and highlights the importance of data arising from them. The characterization of clinical markers, to identify those patients who are most likely to benefit from naltrexone and to tailor a more individual naltrexone treatment, will ultimately provide significant benefit to both patients and clinicians by optimizing treatment outcome.

The role of flumazenil in generalised anxiety disorder: a pilot naturalistic open-label study with a focus on treatment resistance.

Background: Anxiety disorders are highly prevalent and chronic disorders with treatment resistance to current pharmacotherapies occurring in approximately one in three patients. It has been postulated that flumazenil (FMZ) is efficacious in the management of anxiety disorders via the removal of α4ß2δ gamma-aminobutyric acid A receptors. Objective: To assess the safety and feasibility of continuous low-dose FMZ infusions for the management of generalised anxiety disorder (GAD) and collect preliminary efficacy data. Design: Uncontrolled, open-label pilot study. Method: Participants had a primary diagnosis of generalised anxiety disorder (GAD) and received two consecutive subcutaneous continuous low-dose FMZ infusions. Each infusion contained 16 mg of FMZ and was delivered over 96 ± 19.2 h. The total dose of FMZ delivered was 32 mg over approximately 8 days. Sodium valproate was given to participants at risk of seizure. The primary outcome was the change in stress and anxiety subscale scores on the Depression Anxiety Stress Scale-21 between baseline, day 8, and day 28. Results: Nine participants with a primary diagnosis of GAD were treated with subcutaneous continuous low-dose FMZ infusions; seven participants met the criteria for treatment resistance. There was a significant decrease in anxiety and stress between baseline and day 8 and baseline and day 28. There was also a significant improvement in subjective sleep quality from baseline to day 28 measured by the Jenkins Sleep Scale. No serious adverse events occurred. Conclusion: This study presents preliminary results for subcutaneous continuous low-dose FMZ's effectiveness and safety in GAD. The findings suggest that it is a safe, well-tolerated, and feasible treatment option in this group of patients. Future randomised control trials are needed in this field to determine the efficacy of this treatment.

A theory of the anxiolytic action of flumazenil in anxiety disorders.

BACKGROUND: Anxiety disorders are highly prevalent affecting up to 33.7% of people over a lifetime. Although many treatment options are available, they are often associated with unacceptable side-effect profiles and approximately one in three patients are treatment resistant. Allopregnanolone, a neuroactive steroid acting as a positive allosteric modulator at the GABAA receptor, is synthesised in response to stress and acts to negatively modulate the hypothalamic-pituitary-adrenal axis. FINDINGS: After chronic exposure to and withdrawal from allopregnanolone, an increase in α4ß2δ GABAA receptors results in a reduced inhibitory effect of allopregnanolone, resulting in decreased inhibition and, therefore, increased neuronal excitability. The relationship between allopregnanolone and increased α4ß2δ GABAA receptors has been demonstrated in animal models during methamphetamine withdrawal and puberty, events both associated with stress. The effect of allopregnanolone during these events is anxiogenic, a paradoxical action to its usual anxiolytic effects. Flumazenil, the GABAA receptor antagonist, has been shown to cause receptor internalisation of α4ß2δ GABAA receptors, which may results in anxiolysis. CONCLUSION: We propose that chronic stress and chronic exposure to and withdrawal from allopregnanolone in anxiety disorders result in alterations in GABAA receptor function, which can be corrected by flumazenil. As such, flumazenil may exhibit anxiolytic properties in patients with increased α4ß2δ GABAA receptor expression.

Long-Term Management of Generalised Anxiety Disorder with Low-Dose Continuous Infusions of Flumazenil: A Case Series.

BACKGROUND: Generalised anxiety disorder (GAD) is a common anxiety disorder associated with social and occupational impairment. Recently, a theory was postulated that dysfunctional gamma aminobutyric acid type A receptors (GABAA) are implicated in anxiety symptomology, which could be corrected by flumazenil, an antagonist at the benzodiazepine binding site on the GABAA receptor. METHOD: Participants had a primary diagnosis of GAD and were treated initially with an eight-day continuous low-dose flumazenil infusion (total 32 mg at a rate of 4 mg/24 h). Some participants were re-treated with a further four- or eight-day infusion. Treatment response was measured as a 50% reduction in anxiety or stress scores on the Depression Anxiety Stress Scale-21 (DASS-21). Remission was measured as scores ≤3 or ≤7 on the anxiety and stress subscales of the DASS-21, respectively. RESULTS: Eight cases are reported. All cases met the criteria for treatment response on the anxiety and stress subscale of the DASS-21. Remission was achieved in seven participants on the anxiety subscale and in five on the stress subscale. No changes in hepatic, renal, or haematological function were likely attributed to flumazenil. CONCLUSION: Data suggest that low-dose continuous flumazenil infusion manages GAD symptoms and is safe. Although these results are promising, future randomised control trials are required to confirm these results.

Motivation to quit smoking among hospitalised individuals with and without mental health disorders.

BACKGROUND: Persons with mental health disorders (MHD) have higher rates of smoking and poorer cessation of smoking outcomes than those without MHD. A decreased level of motivation may partially explain lower cessation rates, but there is little information on motivation among inpatients with MHD. OBJECTIVES: Primary aims were to compare (1) motivation to cease smoking among those hospitalised with MHD or non-MHD, (2) the proportion that attempted smoking cessation, and (3) use of aids to cessation. A secondary aim was to assess cessation up to six months post-discharge. METHODS: Smokers were recruited at a tertiary hospital in Perth, Western Australia. Surveys were administered upon admission and at 5 and 14 days and 6 months post-discharge. RESULTS: We recruited 64 MHD inpatients and 43 non-MHD inpatients. At baseline there were no significant differences between the groups on any measures of the five measures of motivation. Significantly more of the MHD sample attempted smoking cessation than those in the non-MHD sample (34 versus 13: chi(2)(1)=5.472, P=0.028). Nicotine replacement therapy (NRT) alone was used by 70% of those attempting to quit but was only provided as part of discharge medication to two people and few persons (<21%) in either group used NRT post-discharge. By 14 days, three (4.7%) of the MHD group and none (0%) of the non-MHD group reported abstinence, at 6-months one from each group reported continuous abstinence since discharge from hospital. CONCLUSIONS: Motivation to cease smoking among inpatients with MHD was similar to those without MHD, as was use of NRT while hospitalised. The low provision of post-discharge NRT may contribute to the poor cessation of smoking outcomes and does not fulfil evidence based guidelines.

Association of CamK2A genetic variants with transition time from occasional to regular heroin use in a sample of heroin-dependent individuals.

OBJECTIVES: Susceptibility to heroin dependence is strongly influenced by genetic factors with heritability estimates as high as 0.7. A number of genes, as well as environmental factors, are likely to contribute to its etiology. Not all individuals who have ever tried heroin at some stage during their lifetime become dependent on heroin. It has been suggested that genetic factors might be more important in the transition stage to heroin dependence rather than in environmental exposures and experimenting with heroin. As the features of substance dependence and memory formation have been found to be strikingly similar, we have focused on a key enzyme involved in long-term potentiation and synaptic plasticity, namely the calcium-dependent/calmodulin-dependent protein kinase IIα (CAMKIIa). We hypothesized, that CamK2A genetic variation may play a role in the transition from occasional to regular heroin use. MATERIALS AND METHODS: Using quantitative trait association analysis, we addressed this hypothesis by correlating the self-reported time interval between occasional and regular heroin use with the frequency of 12 single nucleotide polymorphisms located within the genomic region of the CamK2A gene. A sample of 570 Caucasian patients was available for analysis. RESULTS: Single marker association analysis (rs10066581, P=0.007), as well as haplotype analysis (global P=0.005), suggested an association with the quantitative trait 'time interval from occasional to regular heroin use.' CONCLUSION: Our results propose that genetic variants located in the genomic region of the CamK2A gene may be involved in transition time from occasional to regular heroin use.

Biodegradability of naltrexone-poly(DL) lactide implants in vivo assessed under ultrasound in humans.

Ultrasound was used to assess the in vivo biodegradability of a sustained release poly(DL)lactide naltrexone implant in 71 persons previously treated for heroin dependence. We assessed 139 implant sites ranging from 2 to 1808 days post implant. Ultrasound assessment showed that implant tablets were initially well demarcated from each other and from the surrounding tissues. Biodegradation resulted in less demarcated tablets followed by clumping into a single mass-like structure. This mass subsequently dispersed by approximately 1201 days post implant with no implant material visualized by ultrasound. The biodegradation was also assessed by visual clinical examination and palpation of the implant site as well as patient self-report. These measures were generally well correlated with ultrasound results. Clinical assessment of the biodegradation process concluded that the implant changed from 'firm' to 'less firm' and from 'initial square edge' to 'rounded edge' tablets. Collectively, these data provide direct evidence of the in vivo absorption of the Go Medical implant over time, and its biodegradability in humans.

Mental health outcomes following naltrexone implant treatment for heroin-dependence.

BACKGROUND: Oral naltrexone is an approved treatment for opioid dependence. However, the impact of sustained release naltrexone on the mental health of treated opioid users has not been studied. AIMS: To assess if naltrexone via implant treatment was associated with any change in (i) risk, (ii) rate, and (iii) duration for hospital morbidity related to several categories of mental disorders among treated heroin users. METHOD: A cohort of 359 heroin users treated with sustained release naltrexone via implants in Western Australia was retrospectively followed up for mental health related outcomes via a health record linkage system over an average period of 1.78 years post-treatment. RESULTS: Individual patient's risk for hospital mental diagnoses was not altered after naltrexone implant. On a population cohort level, hospital admission rates related to all mental health problems, except mood disorders, declined significantly post-treatment; however, length of hospital stay did not improve. Overall, young, female patients or those with pre-existing mental illness were more likely than other patients to require hospital care for mental health issues following treatment. Longer period of heroin use was associated with poorer mood outcomes. CONCLUSIONS: Naltrexone implants were not associated with an increased risk for hospitalisation due to mental illness, and in most cases, were associated with a decrease in mental related hospital admission rate.

Effectiveness of a smoking cessation intervention in older adults.

AIMS: To: (a) identify characteristics of older smokers considering cessation of smoking; (b) evaluate a cessation intervention plus access to nicotine replacement therapy (NRT); (c) identify predictors of those who successfully quit; and (d) evaluate the effectiveness of the intervention in those AGED >or = 75 years. DESIGN: Self-selection of: (a) a cessation of smoking programme; or (b) ongoing smoking. SETTING: Teaching hospital, Perth, Western Australia. PARTICIPANTS: A larger study recruited smokers and never smokers: from this the 215 community-dwelling smokers (>or= 5 cigarettes/day) aged >or= 68 years (171 males) were enrolled. INTERVENTION: Brief intervention with telephone support and access to NRT versus no intervention. MEASUREMENTS: (a) Profile of older adults planning to quit smoking compared with continuing smokers; (b) cessation at 6 months defined as 30-day point prevalence validated via expired carbon monoxide; and (c) factors predictive of successful cessation. FINDINGS: There were 165 intervention participants. Compared with the 50 continuing smokers, participants in the intervention were younger and had significantly less years of regular smoking, more previous quit attempts and greater nicotine dependence scores. At 6 months, the point prevalence of ex-smokers was 25% (n = 42) with 20% (n = 33) being abstinent throughout the study. No continuing smoker had ceased smoking. Among the intervention group, logistic regression showed that those who used NRT (OR 4.36), were male (OR 3.17), had higher anxiety (OR 1.67) or rejected 'more colds and coughs' as a reason for quitting (OR 2.91) were more likely to be successful quitters. Of those aged >or= 75 years (n = 77), 25% matched cessation criteria. CONCLUSIONS: Older smokers can be engaged successfully in a brief intervention plus NRT as aids to cessation of smoking. The intervention was also effective in the older subgroup of participants. Social factors may provide an additional means of motivating older smokers to quit.

Emergency department based intervention with adolescent substance users: 10year economic and health outcomes.

BACKGROUND: Alcohol and other drug (AOD) use are significant cause of disease burden and costs among adolescents. METHODS: We conducted a randomized trial in hospital emergency departments (ED) following an AOD-related presentation, comparing usual care with brief advice and referral to link adolescents aged 12-19 years with external AOD services. Subsequently, we used health data linkage to assemble data on mortality, hospital admissions, ED attendances, out-patient mental health and use of opiate pharmacotherapies in the next 10 years. From these, treatment costs and rates of events were estimated and compared using generalized linear models. RESULTS: Those who received the intervention had lower costs ($22 versus $227: z=3.16, p=0.002) and rates (0.03 versus 0.25: z=2.57, p=0.010) of ED mental health AOD presentations. However, the intervention did not significantly reduce overall mean health costs per patient (intervention $58746 versus control $64833, p=0.800). Similarly, there was no significant difference in the costs associated with hospitalizations ($48920 versus $50911 p=0.924), overall ED presentations ($4266 versus $4150, p=0.916), out-patient mental health services ($4494 versus $7717, p=0.282), or opiate pharmacotherapies ($1013 versus $2054, p=0.209). Injecting drug use was a significant baseline predictor of subsequent costs in the cohort (z=2.64, p=0.008). CONCLUSIONS: An ED delivered intervention may reduce direct ED costs and subsequent ED AOD attendances. There was also some indication that overall costs may be impacted, with economically large but non-significant differences between the groups. The high costs and morbidity incurred by some of this cohort illustrate the importance of targeting high-risk adolescents.

The pattern of substance use disorder in the United Arab Emirates in 2015: results of a National Rehabilitation Centre cohort study.

BACKGROUND: Substance use disorder (SUD) is a global problem with no boundaries, which also afflicts individuals from countries of the Arabian Peninsula. Data from this region is limited. In an effort to develop targeted prevention and intervention initiatives in the United Arab Emirates (UAE), it was necessary to identify the nature of substance use by describing the characteristics of those using different substances. Consequently, this study in the UAE was conceived to describe the pattern of SUD in a first-ever cohort that was systematically recruited from the country's National Rehabilitation Centre (NRC) in Abu Dhabi. METHODS: Two hundred and fifty male patients were recruited from the NRC. Information on substance use was collected using a questionnaire that was completed at an interview with patients who consented to participate. The questionnaire was based on information that the study was designed to capture. It was reviewed by members of institutional ethics committees and approved prior to use. Two hundred and fifty male subjects from the Emirates Family Registry (EFR) were used as a comparison group. RESULTS: In the cohort studied, SUD correlated with smoking and marital status. Poly-substance users formed the majority of the cohort (84.4 %) with various combinations of substances identified across different age groups. Opioid and alcohol were the most common substances used. The use of pharmaceutical opioids, primarily Tramadol (67.2 % of opioid users), was higher among the youngest age group studied (<30 years old), while older opioid users (≥30 years old) commonly used illicit opioids (Heroin). The use of prescribed medication for non-medical use also included Pregabalin (mean of 8.3 capsules ± 0.5 per day), Procyclidin (6.1 tablets + 0.6 per day) and Carisoprodol (4.2 tablets ± 0.4 per day) and was again highest in the age group below 30 years. CONCLUSION: This 2015 study highlights the importance of examining the pattern of poly-substance use in a population in order to develop targeted prevention programs to arrest the prevailing trends. It has drawn attention to the rise in use of prescription medication in the UAE, in particular among younger patients (<30 years), and continuing use of illicit opioid amongst males above 30 years. Specific prevention and intervention strategies, targeting differences between these distinct demographic profiles will capture a large subset of sufferers.

Adolescent substance use and hospital presentations: a record linkage assessment of 12-month outcomes.

AIMS: To examine the prevalence of different substances used by adolescents admitted to hospital emergency departments (ED); to evaluate the impact of an ED based brief intervention (BI) on hospital events; to compare outcomes for those using "alcohol alone", "alcohol plus illicit+/-licit drugs" ("alcohol plus"), or "other drugs" excluding alcohol, and investigate the relationship between hazardous alcohol consumption patterns and hospital events. DESIGN: We used hospital record linkage to follow-up a randomised control trial cohort. PARTICIPANTS: Adolescents (12-19 years) recruited in ED with presentations involving alcohol or other drugs (AOD): 67 received usual care and 60 a BI that facilitated attendance at community drug agencies. MEASUREMENTS: Drug-use categories were assigned from the substances used at the baseline presentation. Outcomes were assessed as hospital admissions plus ED presentations in the 12-month post-intervention. "Hazardous" alcohol use was categorised via the AUDIT-3. RESULTS: The drug-use categories were "alcohol alone" (n=67, 53%), "alcohol plus" (n=31, 24%) and "other drugs" (n=28, 22%). In the 12-month post-intervention, the randomisation groups had similar numbers of AOD hospital events. A Cox regression showed that in the usual care but not the BI group, for "other drugs" there was a 8-fold increased hazard ("risk") of an AOD hospital event compared with "alcohol alone" and a 10-fold increase compared to 'alcohol plus'. Each pre-recruitment AOD event doubled the hazard of an AOD event. For the BI group, these were not significant predictors. The "other drugs" group had more AOD events than either of the other groups. "Hazardous" (77%) alcohol use was common but was not a predictor of AOD hospital events. CONCLUSIONS: BI can be delivered in ED and reduce hospital AOD morbidity associated with the use of drugs other than alcohol. Interventions should focus on those with prior AOD events and "other drugs" presentations.

Emergency department-based intervention with adolescent substance users: 12-month outcomes.

We evaluated the 12-month outcomes of a brief intervention, enhanced by a consistent support person, which aimed to facilitate referral attendance for substance use treatment following a hospital alcohol or other drug (AOD) presentation. Outcomes were assessed as: attendance for substance use treatment; the number of hospital AOD ED presentations; change in AOD consumption and psychological wellbeing (GHQ-12). We recruited 127 adolescents, with 60 randomised to the intervention and 67 receiving usual care. At 12 months, 87 (69%) were re-interviewed. Significantly more of the intervention than the usual care group (12 versus 4) had attended a treatment agency. Excluding the index presentations, there were 66 AOD hospital presentations post intervention, with the proportion of AOD events falling for the intervention group, whilst no change occurred for the usual care group. Irrespective of randomisation, those who attended for substance use treatment had a greater decline in total self-reported drug use than the remainder. Both intervention and usual care groups had improved GHQ-12 scores by 12 months, with reduction in GHQ scores correlated with reduced drug use. In conclusion, while brief intervention in ED only has limited success in facilitating adolescents to attend for subsequent AOD treatment, it can significantly reduce the number of AOD related ED presentations.

Reducing hospital presentations for opioid overdose in patients treated with sustained release naltrexone implants.

BACKGROUND: Non-fatal overdoses represent a significant morbidity for regular heroin users. Naltrexone is an opioid antagonist capable of blocking the effects of heroin, thereby preventing accidental overdose. However, treatment with oral naltrexone is often associated with non-compliance. An alternative is the use of a sustained release preparation of naltrexone. The aim of this study was to assess the change in number of opioid and other drug overdoses in a large cohort of heroin dependent persons (n=361; 218 males) before and after treatment with a sustained release naltrexone implant. A sub-group of this cohort (n=146; 83 males) had previously received treatment with oral naltrexone, which also allowed a comparison of overdoses pre- and post-oral and also post-implant treatments. METHOD: We used a pre-post design, with data prospectively collected via the West Australian Health Services Research Linked Database, and the Emergency Department Information System. Participants were treated under the Australian Therapeutic Goods Administration's special access guidelines. RESULTS: Most (336, 93%) of the cohort was in one or both databases. We identified 21 opioid overdoses involving 20 persons in the 6 months pre-treatment that required emergency department presentation or hospital admission: none were observed in the 6 months post-treatment. This is consistent with the existing pharmacokinetic data on this implant, which indicates maintenance of blood naltrexone levels at or above 2 ng/ml for approximately 6 months. A reduced number of opioid overdoses were also observed 7-12 months post-implant. The study found a significant increase in sedative "overdoses", some of which occurred in the 10 days following implant treatment and were likely associated with opioid withdrawal and/or implant treatment. For those previously treated with oral naltrexone, more opioid overdoses occurred in both the 6-months prior to and after oral compared to the 6-months post-implant treatment. CONCLUSIONS: The findings support the clinical efficacy of this sustained release naltrexone implant in preventing opioid overdose. However, given the high prevalence of poly-substance use among dependent heroin users, programs offering this type of treatment should also focus on preventing, detecting and managing poly-substance use.

Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRM1.

BACKGROUND: No opioid receptor, mu 1 (OPRM1) gene polymorphisms, including the functional single nucleotide polymorphism (SNP) rs1799971, have been conclusively associated with heroin/other opioid addiction, despite their biological plausibility. We used evidence of polymorphisms altering OPRM1 expression in normal human brain tissue to nominate and then test associations with heroin addiction. METHODS: We tested 103 OPRM1 SNPs for association with OPRM1 messenger RNA expression in prefrontal cortex from 224 European Americans and African Americans of the BrainCloud cohort. We then tested the 16 putative cis-expression quantitative trait loci (cis-eQTL) SNPs for association with heroin addiction in the Urban Health Study and two replication cohorts, totaling 16,729 European Americans, African Americans, and Australians of European ancestry. RESULTS: Four putative cis-eQTL SNPs were significantly associated with heroin addiction in the Urban Health Study (smallest p = 8.9 × 10(-5)): rs9478495, rs3778150, rs9384169, and rs562859. Rs3778150, located in OPRM1 intron 1, was significantly replicated (p = 6.3 × 10(-5)). Meta-analysis across all case-control cohorts resulted in p = 4.3 × 10(-8): the rs3778150-C allele (frequency = 16%-19%) being associated with increased heroin addiction risk. Importantly, the functional SNP allele rs1799971-A was associated with heroin addiction only in the presence of rs3778150-C (p = 1.48 × 10(-6) for rs1799971-A/rs3778150-C and p = .79 for rs1799971-A/rs3778150-T haplotypes). Lastly, replication was observed for six other intron 1 SNPs that had prior suggestive associations with heroin addiction (smallest p = 2.7 × 10(-8) for rs3823010). CONCLUSIONS: Our findings show that common OPRM1 intron 1 SNPs have replicable associations with heroin addiction. The haplotype structure of rs3778150 and nearby SNPs may underlie the inconsistent associations between rs1799971 and heroin addiction.

Five-year outcomes of a brief alcohol intervention for adult in-patients with psychiatric disorders.

AIMS: To compare 5 year outcomes (general hospital and mental health morbidity and mortality) among general hospital psychiatric in-patients randomized to receive either an alcohol reduction motivational interview (MI) or information pack (IP), and compare these to matched controls. DESIGN: We recruited 120 patients aged 18-64 years who scored >/=8 on the Alcohol Use Disorders Identification Test (AUDIT). We selected matched controls from in-patients not recruited but who reached the same AUDIT threshold. At 5 years, follow-up data were collected via a state-wide hospital record system. FINDINGS: There were no significant differences between the MI and IP groups in terms of 'survival' to their first alcohol-related, other general hospital or mental health admission over 5 years. Matched controls had significantly more mental health in-patient episodes (F[1,226] 4.4, P < 0.05) and greater length of hospital stay (F[1,226] 4.8, P < 0.05) than the combined MI-IP group. Furthermore, the MI-IP group had longer 'survival' times to both first general hospital (mean 583 versus 392 days) and mental health in-patient (mean 788 versus 580 days) events. Collapsed across groups, dependent and harmful consumers had shorter 'survival' times than hazardous consumers (AUDIT classifications). CONCLUSIONS: Alcohol interventions have medium-term health benefits for those with mental health and alcohol use problems. Importantly, there were no differences in outcome between the intervention groups. The low cost of providing an IP makes it attractive as an alcohol intervention. The AUDIT provided an effective means of identifying those who are at risk of subsequent alcohol-related admissions and may benefit from intervention.