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1.  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.
PMCID: PMC3853523  PMID: 22946873
alcoholism; clinical subtypes; naltrexone maintenance; oral naltrexone; pharmacogenetics; pharmacokinetics; predictors of treatment outcomes
2.  Lifetime opiate exposure as an independent and interactive cardiovascular risk factor in males: a cross-sectional clinical study 
While several studies have identified an increased incidence of cardiovascular disorders in opiate dependence, neither opiates as a cardiovascular risk factor nor their effect on central arterial function has been considered.
Pulse wave analysis (SphygmoCor, AtCorMedical Pty Limited, Sydney, NSW, Australia) was undertaken on a cohort of controls and opiate dependent patients and the results compared to their lifetime opiate exposure.
Controls (N = 401) were compared with 465 opiate dependent men. The mean (log) ages were different and were found to be 28.80 ± 0.49 years versus 35.02 ± 0.39 years (P < 0.0001), respectively. Of the opiate dependent group, 87.7% were treated with buprenorphine, 8.8% with methadone, and 3.4% with naltrexone. Multiple regression analysis was used to adjust for chronologic age (CA). At CA of 60 years, the modeled age in the controls was 66.40 years, and that in the addicted group was 73.11 years, an advancement of 6.71 years, or 10.10%. Exacerbations of age dependent changes in central arterial stiffness, central pressures, pulse rate, ejection duration, diastolic duration, and subendocardial perfusion ratio by opiate dependence were all noted (P < 0.05). Current heroin dose, heroin duration, and the dose duration interaction were all significantly related to the vascular (or “reference”) age (RA)/CA ratio (all P < 0.006). After multivariate adjustment, the opiate dose duration was independently predictive of RA (P < 0.02). Opiate dose and/or duration were included in a further 25 terms.
These data show that opiate use is not benign for the male cardiovascular system, but has a dose response relationship to central arterial stiffness and thus cardiovascular aging, acting independently and interactively with established cardiovascular risk factors. These findings imply accelerated organismal aging.
PMCID: PMC3794871  PMID: 24124373
arterial stiffness; heroin; opiate dependence; vascular aging; human aging; methadone
3.  Maternally Administered Sustained-Release Naltrexone in Rats Affects Offspring Neurochemistry and Behaviour in Adulthood 
PLoS ONE  2012;7(12):e52812.
Naltrexone is not recommended during pregnancy. However, sustained-release naltrexone implant use in humans has resulted in cases of inadvertent foetal exposure. Here, we used clinically relevant dosing to examine the effects of maternally administered sustained-release naltrexone on the rat brain by examining offspring at birth and in adulthood. Maternal treatment (naltrexone or placebo implant) started before conception and ceased during gestation, birth or weaning. Morphometry was assessed in offspring at birth and adulthood. Adult offspring were evaluated for differences in locomotor behaviour (basal and morphine-induced, 10 mg/kg, s.c.) and opioid neurochemistry, propensity to self-administer morphine and cue-induced drug-seeking after abstinence. Blood analysis confirmed offspring exposure to naltrexone during gestation, birth and weaning. Naltrexone exposure increased litter size and reduced offspring birth-weight but did not alter brain morphometry. Compared to placebo, basal motor activity of naltrexone-exposed adult offspring was lower, yet they showed enhanced development of psychomotor sensitization to morphine. Developmental naltrexone exposure was associated with resistance to morphine-induced down-regulation of striatal preproenkephalin mRNA expression in adulthood. Adult offspring also exhibited greater operant responding for morphine and, in addition, cue-induced drug-seeking was enhanced. Collectively, these data show pronounced effects of developmental naltrexone exposure, some of which persist into adulthood, highlighting the need for follow up of humans that were exposed to naltrexone in utero.
PMCID: PMC3530485  PMID: 23300784
4.  Custom genotyping for substance addiction susceptibility genes in Jordanians of Arab descent 
BMC Research Notes  2012;5:497.
Both environmental and genetic factors contribute to individual susceptibility to initiation of substance use and vulnerability to addiction. Determining genetic risk factors can make an important contribution to understanding the processes leading to addiction. In order to identify gene(s) and mechanisms associated with substance addiction, a custom platform array search for a genetic association in a case/control of homogenous Jordanian Arab population was undertaken. Patients meeting the DSM-VI criteria for substance dependence (n = 220) and entering eight week treatment program at two Jordanian Drug Rehabilitation Centres were genotyped. In addition, 240 healthy controls were also genotyped. The sequenom MassARRAY system (iPLEX GOLD) was used to genotype 49 single nucleotide polymorphisms (SNPs) within 8 genes (DRD1, DRD2, DRD3, DRD4, DRD5, BDNF, SLC6A3 and COMT).
This study revealed six new associations involving SNPs within DRD2 gene on chromosome 11. These six SNPs within the DRD2 were found to be most strongly associated with substance addiction in the Jordanian Arabic sample. The strongest statistical evidence for these new association signals were from rs1799732 in the C/−C promoter and rs1125394 in A/G intron 1 regions of DRD2, with the overall estimate of effects returning an odds ratio of 3.37 (χ2 (2, N = 460) = 21, p-value = 0.000026) and 1.78 (χ2 (2, N = 460) = 8, p-value = 0.001), respectively. It has been suggested that DRD2, dopamine receptor D2, plays an important role in dopamine secretion and the signal pathways of dopaminergic reward and drug addiction.
This study is the first to show a genetic link to substance addiction in a Jordanian population of Arab descent. These findings may contribute to our understanding of drug addiction mechanisms in Middle Eastern populations and how to manage or dictate therapy for individuals. Comparative analysis with different ethnic groups could assist further improving our understanding of these mechanisms.
PMCID: PMC3477049  PMID: 22963930
SNP; DRD2; Opiates; Cocaine; Association; Substance addiction; Jordan; Arab
5.  Mu opioid receptor (OPRM1) as a predictor of treatment outcome in opiate-dependent individuals of Arab descent 
A number of research studies on the genetics of opiate dependence have focused on the μ-opioid receptor (OPRM1), which is a primary target for opiates. This study aims to identify genetic polymorphisms within the OPRM1 gene involved in response to the biopsychosocial treatment in opiate-dependent individuals of Arab descent.
Unrelated Jordanian Nationals of Arab descent (N = 183) with opiate dependence were selected for this study. These individuals, all males, met the DSM-IV criteria for opiate dependence and were undergoing a voluntary 8-week treatment program at a Jordanian Drug Rehabilitation Centre. All individuals were genotyped for 22 single nucleotide polymorphisms (SNPs) within the OPRM1 gene using the Sequenom MassARRAY® system (iPLEX GOLD). Statistical analyses were carried out using the R package.
Patients receiving biopsychosocial treatment showed that there was a significant difference in their OPRM1 SNPs’ genotyping distribution between good, moderate, and poor responders to the treatment at two sites (rs6912029 [G-172T], and rs12205732 [G-1510A], P < 0.05, Fisher’s exact test).
This study is the first report of an association between the OPRM1 G-172T and G-1510A polymorphisms and treatment response for opiate dependence. Specifically, this study demonstrated that the OPRM1 GG-172 and GG-1510 genotypes were more frequent among patients who were nonresponders to the biopsychosocial treatment. However, further pharmacogenetic studies in a larger cohort of opiate-dependent patients of Arab descent are needed to confirm these findings and identify individuals with increased chance of relapse.
PMCID: PMC3513232  PMID: 23226066
OPRM1; association; opiates; dependence; treatment response; Arab
6.  Reducing hospital presentations for opioid overdose in patients treated with sustained release naltrexone implants 
Drug and alcohol dependence  2005;79(3):351-357.
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.
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.
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.
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.
PMCID: PMC1646626  PMID: 15899557
Opioid dependence; Naltrexone; Sustained release; Record linkage; Overdose; Heroin

Results 1-6 (6)