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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.

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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 $509033 prior to treatment to $270001 following treatment. Costs associated with hospital admission showed the most significant reduction, falling from $424605 (82 admissions/36 patients) before treatment to $203462 (43 admission/24 patients) after. While costs associated with ED attendances also fell ($74885 to $54712), costs associated with mental health out-patient attendances increased ($9543 to $11827). The use of implant naltrexone was associated with a reduction health events and costs in patients with problematic alcohol use in the first 6 months following treatment.

Of particular interest in the psychosocial treatment of addictions is determining how much therapy is required to bring about behaviour change. Stepped care approaches, where non-responders to a less intensive therapy receive a more intensive intervention, aim to only provide intensive assistance to those who need it, thereby allocating therapeutic resources more efficiently. This paper provides a systematic review of stepped care models involving different levels of psychosocial intervention for the treatment of alcohol use disorders and smoking cessation. Five publications on alcohol and three on smoking were included in the review. Due to the heterogeneity of outcome measures, participant characteristics and interventions, a narrative review format was employed. Overall, little evidence was found to suggest that stepping up non-responders to more intensive therapy improved outcomes, a finding that could partially be attributed to a lack of power to find significant effects. In one study, the application of a stepped care approach was found to reduce treatment costs compared with usual care. There was some evidence that the greater differentiation between the intensity of the interventions offered at each step, the better the outcome. Further research is needed to evaluate the efficacy of stepped care approaches to providing psychosocial treatment, employing larger samples and/or consistent definitions of the nature of the interventions offered at each step, and assessing treatment response in a timely manner.

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.

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.

Background: Observational studies investigating the association between smoking, cognitive decline and dementia have produced conflicting results. We completed this trial to determine if smoking cessation decreases the progression of cognitive decline in later life. Methods: We recruited older smokers (n. =229) and never smokers (n. =98) and invited smokers to join a smoking cessation trial. The primary outcome of interest was change in Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog) scores over 24. months. Secondary measures included the Logical Memory test and changes in gray matter density. Successful smoking cessation was defined as a minimum of 547 smoking free days during follow up. Results: The ADAS-cog scores of unsuccessful quitters (UQ) increased (i.e., became worse) 1.1 ± 0.3 and 1.2 ± 0.4 points more than the scores of never smokers (NS) (p. =0.001) and successful quitters (SQ) (p. =0.006) respectively over the 24. months of follow up. Similarly, the scores of UQ declined (i.e., became worse) relative to NS on measures of immediate (p. =0.004) and delayed recall (p. =0.029). All analyses were adjusted for age, years of education, baseline cognitive performance, alcohol use, depression scores, and the presence of chronic respiratory disease. Thirty-six NS, 18 SQ and 48 UQ completed the imaging substudy. Compared with NS, UQ showed a disproportional loss of gray matter density in the right thalamus, right and left inferior semi-lunar lobule, as well as left superior and inferior parietal lobule over 24. months. SQ showed loss of gray matter compared with NS in the right middle and inferior occipital gyri, right and left culmen, and the left superior frontal gyrus. We did not find any brain regions in which UQ had lost more gray matter than SQ over 2. years. Conclusion: These results are consistent with the hypothesis that smoking causes cognitive decline and loss of gray matter tissue in the brain over time. © 2011 Elsevier Inc.

Our objectives were to (i) estimate lifetime prevalence of psychiatric comorbidity in heroin users and (ii) evaluate psychiatric comorbidity as a predictor of drug-related hospitalization following either (a) methadone maintenance or (b) naltrexone implant treatment.Our method consisted of retrospective, longitudinal follow-up using prospectively collected, state-wide hospital data on two cohorts of heroin-dependent persons (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition), first time treated with naltrexone implant (n = 317) or methadone (n = 521) between January 2001 and December 2002. Outcome measures were: (i) prevalence of comorbidity and (ii) changes in risk for drug-related hospitalization-categorized as 'opioid drugs', 'non-opioid drugs', and 'any drug'-to 3.5 years post-treatment.Nearly 32% had psychiatric comorbidity. In both cohorts, comorbid patients generally had significantly greater odds of drug-related hospitalization pre-treatment compared with non-comorbid counterparts. These differences generally reduced in magnitude post-treatment. Comorbid naltrexone-treated patients had less 'opioid' and 'any drug' related hospitalizations post-treatment. Similarly, comorbid methadone-treated patients had reduced hospitalization risk for 'non-opioid' and 'any drug' related hospitalization post-treatment. Treatment of persons without depression, anxiety, or personality disorder with naltrexone implant was associated with increased risk of 'non-opioid' drug-related hospitalization, while methadone treatment was associated with increased risk of 'opioid' drug-related hospitalization.Although comorbid heroin users entered treatment with significantly higher risk of drug-related hospitalization than non-comorbid users, substantial reductions in drug-related hospitalization were generally observed post-treatment. This challenges the view that comorbidity predicts poor drug treatment outcomes. Differences in research methodology were noted; recom

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: ?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. © 2010 The Royal Australian and New Zealand College of Psychiatrists.

Background: Oral naltrexone effectively antagonizes heroin, but patient noncompliance limits its utility; sustained-release preparations may overcome this. Few data are available on optimal blood naltrexone levels for preventing craving and/or return to heroin use. This study assesses various risk factors, including blood naltrexone level, for heroin craving and relapse to illicit opioids. Methods: Heroin-dependent persons from a randomized controlled trial of oral versus implant naltrexone were followed up for 6 months. Thirty-four participants received 50 mg oral naltrexone daily, plus placebo implant; thirty-five participants received a single dose of 2.3 g naltrexone implant, plus daily oral placebo tablets. Results: Compared to oral naltrexone patients, implant naltrexone patients were significantly less likely to use any opioids and had one-fifth the risk of using heroin = weekly. Risk of = weekly heroin use increased by 2.5 times at blood naltrexone concentration < .5 ng/mL compared with < .5 ng/mL, with 3 ng/mL associated with very low risk of use. Craving remained near "floor" levels for implant patients but rebounded to higher levels among oral patients. Lower craving scores (= 20/70) predicted lower relapse risk. Noncompliance with daily oral formula, higher baseline craving, longer history of use, and being younger predicted higher craving at follow-up. Conclusions: Implant naltrexone was better associated with reduced heroin craving and relapse than oral naltrexone. Effective treatment was achieved at blood naltrexone levels of 1 ng/mL to 3 ng/mL, with higher levels associated with greater efficacy. Craving assessment may be valuable in predicting relapse risk allowing timely intervention. © 2010 Society of Biological Psychiatry.

Oral naltrexone is used to treat alcohol and heroin dependence but is associated with poor patient compliance. Sustained-release preparations have been developed to overcome noncompliance. Many sustained-release preparations are composed of polymers combined with naltrexone. Limited data indicate that polymers induce variable levels of tissue reactivity and that naltrexone may increase this effect. A slow-release subcutaneous naltrexone-poly (DL-lactide) implant is currently being trialed to treat heroin dependence in Western Australia. A minority of women fall pregnant and, although tissue reactivity in nonpregnant humans is relatively minor, detailed chronological data during pregnancy are lacking. Histological changes in pregnant rats were assessed; a single active tablet containing poly[trans-3,6-dimethyl-1,4-dioxyane-2,5-dione] (DL-lactide) loaded with 25 mg of naltrexone was implanted subcutaneously, and tissue response was compared with inactive polymer implantation. Rats were timed mated at 13-26 days postimplant. Tissue assessment up to 75 days by a pathologist showed that naltrexone induced chronic inflammatory response in a dose-dependent manner, although still at a low level. Furthermore, for inactive implants, minimal foreign body reaction and fibrosis, together with low-level inflammation, suggested good longterm biocompatibility. We conclude that the Australian naltrexone-poly(DL-lactide) implant is tolerated in pregnant rats, reinforcing its potential role for managing alcohol and heroin dependence in pregnant humans. © 2008 Wiley Periodicals, Inc.

CONTEXT: Oral naltrexone hydrochloride effectively antagonizes heroin, but its utility is limited by patient noncompliance. Sustained-release preparations may overcome this limitation.OBJECTIVE: To compare the safety and efficacy of a single-treatment sustained-release naltrexone implant with daily oral naltrexone treatment.DESIGN: Seventy heroin-dependent volunteers entered a randomized, double-blind, double-placebo controlled trial with a 6-month follow-up period.PATIENTS: Eligibility criteria were DSM-IV opioid (heroin) dependence; age 18 years or older; willingness to be randomized; residing in the Perth, Western Australia, metropolitan area; and completion of preclinical screening and written consent. A total of 129 eligible participants were identified, and 70 (54%) provided informed consent and were randomized as per the study design.INTERVENTION: Participants received oral naltrexone, 50 mg/d, for 6 months (plus placebo implants) or a single dose of 2.3 g of naltrexone implant (plus placebo tablets).MAIN OUTCOME MEASURES: (1) Maintaining therapeutic naltrexone levels above 2 ng/mL; (2) return to regular heroin use (>or=4 d/wk); (3) other heroin use and abstinence; (4) use of illicit nonopioid drugs; (5) number of opiate overdoses requiring hospitalization; (6) treatment-related unexpected and expected adverse events; and (7) blood naltrexone levels (ie, pharmacokinetic profile) for recipients of active naltrexone implants.RESULTS: More participants in the oral vs the implant group had blood naltrexone levels below 2 ng/mL in months 1 (P < .001) and 2 (P = .01); in addition, more oral group participants had returned to regular heroin use by 6 months (P = .003) and at an earlier stage (median [SE], 115 [12.0] days vs 158 [9.4] days). There were 10 trial-related, unexpected adverse events. One serious adverse event, a wound hematoma, was associated with surgical implantation. Naltrexone blood levels in implant recipients were maintained above 1 and 2 ng/m

Background People with mental health (MH) disorders smoke at higher rates, are more nicotine-dependent and suffer greater morbidity and mortality from smoking-related illnesses than the general population. Helping these people to quit smoking is a public health priority; however, many MH professionals assume that those with mental illness are not motivated to quit. Objectives To use predetermined criteria to identify, review critically and evaluate empirically all English language, peer-reviewed data on motivation to quit smoking in MH populations. Methods A systematic search was conducted and key data on subject characteristics, measures of motivation and other variables abstracted. ?2 analyses were used to compare motivation between MH and general populations, between in-patients and out-patients and between people with depression and people with psychotic disorders. Results Evidence suggests that people with MH disorders are as motivated to quit smoking as the general population, although those with psychotic disorders may be less motivated than individuals with depression. Although readiness to cease smoking was assessed in 14 studies, only two evaluated motivation to quit smoking in in-patient populations. Conclusions People with MH disorders are motivated to quit smoking, although more research is needed looking at in-patient populations. The commonly held false belief that people with MH disorders are not motivated to cease smoking means that opportunities to encourage smoking cessation among this disenfranchised group are being missed. © 2009 Society for the Study of Addiction.

Aims: Oral naltrexone is used in the management of both heroin and alcohol dependence. However, poor compliance has limited its clinical utility. The study's objective was to determine the period of therapeutic coverage (= 2 ng/ml) provided by a 3.3 g naltrexone subcutaneous implant compared with existing data on 1.1 g and 2.2 g implants. Methods: We assessed free blood naltrexone levels following treatment with a 3.3 g naltrexone implant in heroin dependent patients (n = 50) in Perth, Western Australia. Results were compared with previously collated data for patients treated with either a 1.1 g (n = 10) or 2.2 g (n = 24) implant. Results: Following 3.3 g naltrexone implant treatment, free blood naltrexone levels remained above 2 ng/ml for 145 days (95% CI 125-167). In comparison, 1.1 g or 2.2 g implant treatment resulted in 95 days (95% CI 69-121) and 136 days (95% CI 114-158) coverage, respectively. Conclusions: The 3.3 g implant provides longer therapeutic coverage than the 1.1 g implant but not significantly longer than the 2.2 g implant. © 2007 Elsevier Inc. All rights reserved.

Most women using heroin are of reproductive age with major risks for their infants. We review clinical and experimental data on fetal, neonatal and postnatal complications associated with methadone, the current "gold standard", and compare these with more recent, but limited, data on developmental effects of buprenorphine, and naltrexone. Methadone is a µ-opioid receptor agonist and is commonly recommended for treatment of opioid dependence during pregnancy. However, it has undesired outcomes including neonatal abstinence syndrome (NAS). Animal studies also indicate detrimental effects on growth, behaviour, neuroanatomy and biochemistry, and increased perinatal mortality. Buprenorphine is a partial µ-opioid receptor agonist and a ?-opioid receptor antagonist. Clinical observations suggest that buprenorphine during pregnancy is similar to methadone on developmental measures but is potentially superior in reducing the incidence and prognosis of NAS. However, small animal studies demonstrate that low doses of buprenorphine during pregnancy and lactation lead to changes in offspring behaviour, neuroanatomy and biochemistry. Naltrexone is a non-selective opioid receptor antagonist. Although data are limited, humans treated with oral or sustained-release implantable naltrexone suggest outcomes potentially superior to those with methadone or buprenorphine. However, animal studies using oral or injectable naltrexone have shown developmental changes following exposure during pregnancy and lactation, raising concerns about its use in humans. Animal studies using chronic exposure, equivalent to clinical depot formulations, are required to evaluate safety. While each treatment is likely to have maternal advantages and disadvantages, studies are urgently required to determine which is optimal for offspring in the short and long term. © 2008 Bentham Science Publishers Ltd.

Context: Most research on heroin dependence treatments assesses short-term changes in patients' self-reported drug use. To our knowledge, long-term sustainability of changes in patients' drug use and associated hospital morbidity posttreatment have not been studied. Objectives: To evaluate drug-related hospital morbidity in heroin users at 6 months and 31/2 years after receiving naltrexone implant treatment and to compare these results with outcomes from a similar cohort treated with methadone maintenance treatment. Design: Retrospective longitudinal follow-up, using data prospectively collected via a state hospital (public and private) reporting system. Setting: Perth, Western Australia. Methadone maintenance dosage was generally dispensed daily by registered community pharmacies. Naltrexone implant treatment was performed as a day procedure at a community clinic. Participants: A total of 522 and 314 heroin-dependent persons (according to DSM-IV), first time treated with methadone maintenance or a naltrexone implant, respectively, between January 1, 2001, and December 30, 2002, were identified, using health record linkage. Main Outcome Measures: Planned outcomes included crude hospital admission rates, adjusted changes in risks (odds ratio [OR]), and rates (rate ratio) of "overdose-related" and "non-overdose-related" hospital morbidity associated with opioid vs nonopioid drugs 6 months and 31/2 years posttreatment. Results: Following naltrexone implant treatment, opioid-related risk decreased for overdose (OR, 0.23; 95% confidence interval [CI], 0.11-0.48) and nonoverdose (OR, 0.64; 95% CI, 0.46-0.89) conditions at 31/2 years. Such reductions were not observed after methadone treatment. Overdose on nonopioid drugs increased in older patients to 6 months: OR of 16.31 (95% CI, 3.07-86.53) for naltrexone and OR of 5.03 (95%CI, 1.18-21.54) for methadone. Nonoverdose (eg, dependence and withdrawal) associated with nonopioid drugs also increased for patients receiving th

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. © 2007 The Authors.

Concerns that treatment for heroin dependence using naltrexone may increase suicide rates during treatment and fatal overdoses posttreatment have been expressed. There is also disquiet about mortality during induction onto methadone. We assessed mortality during specific periods following treatment with naltrexone implants or methadone. Data were assembled using the Western Australian Data Linkage System. The methadone cohort comprised all those who started methadone in Western Australia during 2001-2002: The naltrexone cohort comprised all Western Australian heroin-dependent persons who received their first implant in 2001-2002. There were 15 (2.7%) deaths in the methadone cohort (n = 553) and 6 (1.8%) deaths in the naltrexone cohort (n = 341). Mortality rates for the "initial 14-day period," "stable treatment," and "overall" were 94.47, 0.0, and 5.83 deaths/1,000 person-years for the methadone group. In the naltrexone group, the rates "during first treatment (0-6 months)," "post first treatment," and overall were 0.0, 4.21, and 3.76 deaths/1,000 person-years. The age-standardized mortality rate ratio for naltrexone compared to methadone was 0.645 (95% confidence interval = 0.123-1.17). Increased mortality during induction onto methadone was confirmed. Evidence relating naltrexone to either increased suicide or overdose was not found. Overall mortality rates for naltrexone implant were similar to those for methadone, but increased mortality during methadone induction was avoided. © 2008 Elsevier Inc. All rights reserved.