Erin Kelty

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.

Examination of mortality rates in a retrospective cohort of patients treated with oral or implant naltrexone for problematic opiate use

AIMS To examine and compare mortality rates in patients treated with oral and implant naltrexone. DESIGN A retrospective cohort study. SETTING A community not-for-profit drug treatment clinic. PARTICIPANTS Patients treated with oral naltrexone (n = 2155, 17 207 patient-years) and implant naltrexone (n = 2389, 11 678 patient-years) for problematic opiate use between August 1997 and December 2009. MEASUREMENTS Crude gender, age, treatment period and cause-specific mortality rates were calculated using data obtained from the National Death Index. FINDINGS Crude mortality rates for patients treated with oral naltrexone [8.78 deaths per 1000 patient-years (ptpy), 95% confidence interval (CI): 7.38-10.17] were significantly different to those treated with implant naltrexone (6.59 ptpy, 95% CI: 5.13-8.06) (P = 0.0339). During the first 4 months following treatment, differences in the two groups were particularly apparent, with a mortality rate of 26.28 ptpy in patients treated with oral naltrexone compared to 7.34 ptpy in patients treated with implant naltrexone (P = 0.0003). Differences in initial mortality rates following treatment were associated predominantly with high rates of opiate overdoses in oral naltrexone patients during the first 4 months following treatment (17.22 ptpy compared with 0.67 ptpy in implant naltrexone patients) (P < 0.0001). CONCLUSIONS The use of implant naltrexone can reduce all-cause mortality and opiate overdose during the first 4 months following treatment compared with patients treated with oral naltrexone.

Use of subcutaneous flumazenil preparations for the treatment of idiopathic hypersomnia: A case report.

Idiopathic hypersomnia (IH) is a rare sleep disorder, recently hypothesized to be related to the production of a molecule that facilitates the binding of gamma-aminobutyric acid (GABA) to the GABA receptor. This paper reports on the treatment of a patient with IH who was treated with a 96-hour continuous low dose (4 mg/day) infusion of a benzodiazepine antagonist, flumazenil, followed by a slow-release flumazenil implant. The use of flumazenil mitigated the patient’s IH symptoms including excessive daytime sleepiness, sleep drunkenness and self-reported cognitive problems. The case both provides a possible treatment and system for short (subcutaneous (SC) administration) and longer term (implant) flumazenil delivery. Current data supports the need for further research into the use of flumazenil for the treatment of IH and to develop long term flumazenil delivery systems.

Fatal and non-fatal opioid overdose in opioid dependent patients treated with methadone, buprenorphine or implant naltrexone

BACKGROUND Illicit opioid use is associated with high rates of fatal and non-fatal opioid overdose. This study aims to compare rates of fatal and serious but non-fatal opioid overdose in opioid dependent patients treated with methadone, buprenorphine or implant naltrexone, and to identify risk factors for fatal opioid overdose. METHODS Opioid dependent patients treated with methadone (n=3515), buprenorphine (n=3250) or implant naltrexone (n=1461) in Western Australia for the first time between 2001 and 2010, were matched against state mortality and hospital data. Rates of fatal and non-fatal serious opioid overdoses were calculated and compared for the three treatments. Risk factors associated with fatal opioid overdose were examined using multivariate cox proportional hazard models. RESULTS No significant difference was observed between the three groups in terms of crude rates of fatal or non-fatal opioid overdoses. During the first 28days of treatment, rates of non-fatal opioid overdose were high in all three groups, as were fatal opioid overdoses in patients treated with methadone. However, no fatal opioid overdoses were observed in buprenorphine or naltrexone patients during this period. Following the first 28 days, buprenorphine was shown to be protective, particularly in terms of non-fatal opioid overdoses. After the cessation of treatment, rates of fatal and non-fatal opioid overdoses were similar between the groups, with the exception of lower rates of non-fatal opioid overdose in the naltrexone treated patients compared with the methadone treated patients. After the commencement of treatment, gender, and hospitalisations with a diagnosis of opioid poisoning, cardiovascular or mental health problems were significant predictors of subsequent fatal opioid overdose. CONCLUSIONS Rates of fatal and non-fatal opioid overdose were not significantly different in patients treated with methadone, buprenorphine or implant naltrexone. Gender and prior cause-specific hospitalisations can be used to identify patients at a high risk of fatal opioid overdose.

Barriers to accessing methamphetamine treatment: A systematic review and meta-analysis

BACKGROUND Methamphetamine use is associated with a range of poor health, social and justice outcomes. In many parts of the world increased methamphetamine use has been identified as a major public health concern. Methamphetamine treatment programmes have been effective in reducing and ceasing use, however a range of barriers have prevented these programmes being widely adopted by methamphetamine users. This review examines the barriers to accessing meth/amphetamine treatment identified in the literature. METHODS Databases were systematically searched using relevant terms for peer-reviewed articles describing original research exploring the barriers to accessing treatment for meth/amphetamine use. Reviews and grey literature were excluded. Eleven studies conducted in 5 countries were included in data synthesis; this involved a systematic review of all 11 studies, and meta-analysis of the prevalence of barriers reported in 6 studies that published sufficient quantitative data. RESULTS Psychosocial/internal barriers to accessing methamphetamine treatment were most prevalent across studies (10/11 studies). Meta-analysis confirmed the four most commonly endorsed barriers to treatment access across studies all psychosocial barriers were embarrassment or stigma (60%, 95% CI: 54-67%); belief that treatment was unnecessary (59%, 95% CI:54-65%); preferring to withdraw alone without assistance (55%, 95% CI:45-65); and privacy concerns (51%, 95% CI:44-59%). CONCLUSIONS The primary barriers to accessing methamphetamine treatment are psychosocial/internal. Services and treatment models that address these barriers are urgently required. There is a growing need for methamphetamine-appropriate treatment services. Further research evaluating treatment engagement and effectiveness for methamphetamine and polysubstance use, including the development of effective pharmacotherapies is warranted.

Assessing the usefulness of health data linkage in obtaining adverse event data in a randomised controlled trial of oral and implant naltrexone in the treatment of heroin dependence

Background The completeness of self-reported serious adverse events (SAEs) in clinical trials can be reduced by inaccuracies in subject reporting and lost to follow-up. Purpose This study assesses the usefulness of a health data linkage system in obtaining SAE data in a randomised controlled study of oral and implant naltrexone. Methods SAEs were collected from 68 heroin-dependent subjects during a randomised controlled trial of oral and implant naltrexone with follow-up to 26 weeks. Patient self-report data were cross-matched against hospital and emergency department (ED) attendances for the same period using a health data linkage system. Results A total of 29 hospital admissions and 74 ED attendances were identified using health data linkage. Of these, 12 (41.4%) hospital admissions and 50 (67.7%) of ED attendances had not been reported as SAE in the randomised controlled trial. In subjects participating in the trial at the time of the event, there was a 1.25-fold increase in the number of hospital admissions and a 2.25-fold increase in the number of ED attendances recorded using data linkage. Overall (including withdrawn subjects or those lost to follow-up), there was a 1.71-fold increase in hospital admission and a 3.09-fold increase in ED attendance recorded. Limitations The use of data linkage should not be used as a replacement for thorough follow-up, as the datasets can take substantial periods to update, making them a poor substitute for real-time follow-up. Additionally, some SAEs such as life-threatening events that do not involve ED or hospital attendance may be overlooked as would SAEs that occurred outside the dataset’s range, for example, interstate or overseas. Conclusions Health data linkage can be used to effectively reduce the extent of missing health data in a clinical trial.

The occurrence of spontaneous lymphomas but not adenomas or sarcomas in rats treated with sustained release naltrexone

Naltrexone has been observed to have both a stimulatory and inhibitory effect on the development of tumours in rodents, potentially mediated by changes to the neuroendocrine system as a result of blockade of the opiate receptors, with the period of blockade and the tumour type thought to be influential. This study examined the occurrence of spontaneous tumours in rats treated with a sustained release naltrexone preparation. Materials and methods: 27 male and 27 female rats were randomized into three equal treatment groups (A, B and C). Rats in group A were implanted with a single naltrexone implant tablet, rats in group B were implanted with a single polymer implant tablet (placebo) and rats in group C underwent a sham procedure (control). Three different groups of spontaneous tumours were observed; lymphomas, adenomas and sarcomas. Lymphomas (4 tumours/3 rats) were observed solely in naltrexone treated rats, while adenomas (9 tumours/5 rats) and sarcomas (4 tumours/3 rats) were only observed in the placebo and the control groups. The data suggests that the association of naltrexone on the development of tumours maybe dependent on tumour type. Long term exposure to naltrexone appears to have both a stimulatory and inhibitory effect on tumours in rats, dependent on tumour type.

Rates of Hospital and Emergency Department Attendances in Opiate-dependent Patients Treated With Implant Naltrexone, Methadone, or Buprenorphine

Objective:To compare rates of hospital and emergency department (ED) attendance in opiate-dependent patients treated implant naltrexone, with patients treated with methadone and buprenorphine. Materials and Methods:Treatment records for opiate-dependent patients treated with implant naltrexone, methadone, or buprenorphine were linked with routine, prospectively collected health data sets. Rates of hospital and ED attendances were calculated for each cohort and compared using generalized estimating equations. Results:Following the commencement of treatment, rates of hospitalizations was significantly higher in patients treated with implant naltrexone compared with both methadone [risk ratio (RR), 0.83, confidence interval (CI), 0.77-0.89] and buprenorphine (RR, 0.92, CI, 0.85-0.99), as were rates of ED attendances in methadone-treated patients (RR, 0.85, CI, 0.78-0.92), whereas rates of ED attendances in buprenorphine patients were comparable (RR, 0.92, CI, 0.85-1.01). The difference was largely attributable to the induction period (0 to 28 d), where rates of hospital and ED attendances in naltrexone-treated patients were almost double that of both methadone and buprenorphine. However, after the initial period and following the cessation of treatment, rates of hospital and ED attendances in naltrexone-treated patients were less than or equivalent to methadone or buprenorphine patients. Conclusions:Rates of morbidity in opiate-dependent patients treated with implant naltrexone were significantly elevated compared with methadone and buprenorphine in the first 28 days of treatment, however, are comparable after this initial period.

Changes in hospital and out-patient events and costs following implant naltrexone treatment for problematic alcohol use

The harmful use of alcohol places a considerable burden on the community, both socially and financially. The aim of this study was to determine if the use of implant naltrexone is associated with a reduction in health care events and costs in patients treated for problematic alcohol use. Ninety four patients (60.6% male) treated between 2002 and 2007 were matched against state hospital, emergency department (ED), mental health out-patients and mortality data sets for 6 months prior to and 6 months post treatment. The number of patients, events, and costs associated with each health event were compared before and after treatment. Overall health care events and costs were reduced from

A retrospective cohort study of the health of children prenatally exposed to methadone, buprenorphine or naltrexone compared with non‐exposed control children

509033 prior to treatment to