George O'Neil

Blood naltrexone and 6-β-naltrexol levels following naltrexone implant: Comparing two naltrexone implants

The aim of this study was to profile and compare blood naltrexone and 6‐ β‐ naltrexol levels with time following treatment with two sustained‐release naltrexone preparations produced by GoMedical Industries, Australia at a community heroin treatment clinic in Perth, Western Australia. A sample of 10 patients who each received a 1.7 g naltrexone implant were compared to 24 patients who each received a 3.4 g naltrexone implant as treatment for heroin dependence. Blood naltrexone levels following treatment with the 1.7 g naltrexone implant remained above 2 and 1 ng/ml for approximately 90 and 136 days, respectively. Use of the 3.4 g naltrexone implant extended the period of coverage to approximately 297 (1 ng/ml) or 188 (2 ng/ml) days. Blood 6‐ β ‐naltrexol levels remained above 10 ng/ml for approximately 18 and 83 days, respectively, following use of the 1.7 g and 3.4 g naltrexone implants. The current study data indicate that blood naltrexone and 6 ‐β‐ naltrexol levels following treatment with either the 1.7 g or 3.4 g naltrexone implant are greater than those reported in other published data on other sustained‐release naltrexone preparations. Furthermore, duration of blood naltrexone and 6 ‐β‐ naltrexol levels achieved following use of the 3.4 g implant were superior to those achieved with the 1.7 g naltrexone implant, with naltrexone blood levels maintained above 2 ng/ml for a period of approximately 6.3 months compared to 3 months, respectively. The implications of this in managing the heroin‐dependent patient, especially those who find it difficult to shift away from dependent use patterns, are discussed.

Hepatitis C virus eradication in intravenous drug users maintained with subcutaneous naltrexone implants

The effectiveness of HCV antiviral therapy in patients who have undergone recent drug dependency treatment and continue to inject drugs sporadically is presently not clear. Patients attending a community‐based drug rehabilitation and naltrexone implant clinic from October 2002 until March 2005 were screened for HCV infection and if positive offered further assessment and treatment with interferon and ribavirin therapy. The first 50 patients to commence HCV therapy and complete at least 6 months follow‐up were prospectively studied. ETR response (HCV PCR negative) was 34/50 (68%) and SVR 6 months post‐treatment was 31/50 (62%). Viral eradication was maintained in those 22 patients that have had 12 months or more post‐treatment follow‐up. Eleven (22%) patients stopped therapy early due to side effects or poor compliance. Only two patients with an ETR likely reinfected due to unsafe injection practices. One was re‐treated and achieved an SVR. Of the patients achieving a 6‐month SVR, 17 of 31 patients reported no further IDU and 13 of 31 patients occasional IDU during treatment and this was maintained after HCV treatment cessation. 46% of patients received antidepressant and/or antipsychotic medication during treatment. Conclusion: This study of HCV treatment in a community‐based subcutaneous naltrexone implant clinic found antiviral therapy resulted in a 62% SVR. This result is comparable to that reported in hospital‐based clinics in non‐IDU patients. The side effect profile and compliance was also similar. HCV antiviral therapy should be offered to this large and currently under treated group. (HEPATOLOGY 2007;45:111–117.)

Using naltrexone implants in the management of the pregnant heroin user

To describe the case history and associated obstetric and neonatal outcomes of eight women who had their heroin dependency managed over pregnancy by naltrexone implant (two × 1.8 g of naltrexone embedded in poly‐DL‐lactide acid) treatment.

Achieving long-term continuous blood naltrexone and 6-β-naltrexol coverage following sequential naltrexone implants

The aim of this study was to assess blood free naltrexone and 6‐β‐naltrexol levels with time following treatment with sequential sustained‐release naltrexone preparations. Data were collected from blood samples analysed independently for naltrexone and 6‐β‐naltrexol and from clinical record review at a community heroin treatment clinic in Perth, Western Australia. Five patients received sequential 3.4 g (3.49 ? 0.01 g and 3.36 ? 0.05 g, respectively) naltrexone implants. The second implant was received on average within 131.2 ? 15.67 days of the first implant. The mean length of follow‐up was 307.2 ? 18.28 days of the first implant. Blood naltrexone levels have the potential to remain above 2 and 1 ng/ml for a total of 390 and 524 days, respectively, and blood 6‐β‐naltrexol was maintained above 10 ng/ml for a total of 222 days following insertion of these implants. No patient relapsed to dependent heroin use during the implant coverage period while blood naltrexone concentrations were above 2 ng/ml. Results indicate that blood naltrexone and 6‐β‐naltrexol levels can be maintained above therapeutic levels for prolonged periods following use of sequential 3.4 g naltrexone implants. These extended periods of coverage will offer significant benefits for managing the heroin‐dependent patient.

The role of flumazenil in the treatment of benzodiazepine dependence: physiological and psychological profiles.

Abstract Two-related studies are presented here, detailing our early experience with benzodiazepine-dependent patients treated with a four-day flumazenil infusion using a novel delivery technique. Patients with long-term benzodiazepine dependence who attended the Australian Medical Procedures Research Foundation (AMPRF, Perth, Australia) for treatment were recruited for these studies. Self-reported psychological and physical symptoms, as well as objective vital signs data were collected at intervals before, during and 2 weeks postinfusion. Study A is a case series with cardiovascular measures; study B is an open trial that tracks the psychological profiles of 13 subjects. Withdrawal symptoms were tracked, however, the nature and severity of these symptoms differed between patients. No major complications or discomfort prompting study dropout was observed. Significant benzodiazepine abstinence occurred with this flumazenil infusion method despite high levels of initial dependence, comorbid substance use and comorbid psychiatric illness. Low-dose flumazenil infusion appears to be a safe and effective treatment resulting in withdrawal symptoms of lesser severity than any other cessation method currently available. Recommendations for future research are discussed.

Naltrexone implant and blood naltrexone levels over pregnancy

Approximately 80–90% of all women using intravenous heroin are of reproductive age. Although heroin use can cause menstrual irregularities such as amenorrhoea, oligomenorrhea and suppression of ovulation, pregnancy is not uncommon. Maternal heroin use during pregnancy is associated with an increased risk of a number of adverse maternal and neonatal outcomes, including low birthweight (LBW) and reduced birthweight neonates, ante-partum haemorrhage and increased neonatal mortality. The currently accepted management of the pregnant heroin user involves methadone maintenance treatment (MMT). Importantly, no serious foetal toxicity has been associated with methadone. Naltrexone, a long-acting opiate antagonist that can be administered to persons who have detoxified completely from heroin and which is effective in completely blocking the effects of heroin, has also been used in a depot preparation in the management of the heroin dependent pregnant women. In this form of maintenance, naltrexone is delivered by a surgically inserted sustained release preparation. Recently, a number of case studies have described positive obstetric and neonatal outcomes associated with the management of pregnant women with implant naltrexone; however, no data on blood naltrexone concentration with time has been provided to date. The present case study provides profiles of blood concentrations of naltrexone and 6-beta naltrexol following naltrexone implant over pregnancy. It uses data from blood samples collected over pregnancy by the treating clinic (Australian Medical Research Procedures Foundation (AMPRF), Perth, Western Australia) as part of routine clinical management to investigate the length of time naltrexone blood levels are sustained above 2 ng/mL following implant. Bloods were analysed for naltrexone by the Forensic Science Laboratory, Chemistry Centre (WA) by liquid chromatography and mass spectrophotometry using an adaptation of the method described by Bugge et al. These methods are able to quantify naltrexone and its active metabolite 6-beta-naltrexol in human blood with a limit of detection of 0.5 ng/mL for both compounds.

Blood morphine levels in naltrexone-exposed compared to non-naltrexone-exposed fatal heroin overdoses

The aim of this study was to investigate the association between prior exposure to naltrexone and increased risk of fatal heroin overdose using a review of toxicology reports for heroin‐related fatalities between July 1997 to August 1999 for two groups: those treated with oral naltrexone and those who were not treated. Additional information for the oral naltrexone group was obtained from clinic files. Naltrexone‐treated deaths were identified from the patient database at the Australian Medical Procedures Research Foundation (AMPRF), Perth, Western Australia (WA) through the Western Australian Department of Health, Data Linkage Project. Non‐treated cases were identified from the database at the Forensic Science Laboratory, State Chemistry Centre (WA). We identified and investigated blood morphine concentrations following 21 fatal heroin overdoses with prior exposure to naltrexone and in 71 non‐naltrexone‐exposed cases over the same time period. The proportion of deaths where heroin use was a major contributing factor was little different in the non‐naltrexone compared to the naltrexone‐exposed group. Furthermore, in ‘acute opiate toxicity’ deaths, blood morphine levels were lower in non‐naltrexone‐exposed compared with naltrexone‐exposed cases. Although there was a higher number of deaths designated as rapid (i.e. occurring within 20 minutes) in the naltrexone‐exposed (89%) compared with the non‐exposed group (72%) this was not statistically significant. Other drug use in relation to heroin‐related fatalities is discussed. Findings do not support the hypothesis that prior exposure to naltrexone increases sensitivity to heroin toxicity.

Withdrawal and psychological sequelae, and patient satisfaction associated with subcutaneous flumazenil infusion for the management of benzodiazepine withdrawal: a case series

Our group and others internationally have previously reported data on the use of low-dose flumazenil administered intravenously for the management of benzodiazepine withdrawal. This paper describes the first reported use of subcutaneous flumazenil infusion in the management of acute benzodiazepine withdrawal. Self-reported withdrawal symptoms and psychological state and anxiety sequelae were collected at baseline and then at intervals to 5 days following initiation of subcutaneous flumazenil infusion. Data indicate that patient subjective benzodiazepine withdrawal symptoms were well managed, with significant reduction in psychological distress seen over the duration of treatment. Perceived difficulty in performing everyday functions was positively correlated with withdrawal severity and improved over treatment. Patients reported high treatment comfort, willingness to undertake a future subsequent treatment using this technique, and willingness to recommend this treatment to a friend. This small proof-of-concept study indicates that subcutaneous flumazenil infusion has excellent tolerability, efficacy and improvement on measures of psychological distress. Given this technique is less invasive and requires fewer staff resources compared with intravenous administration, it may prove a significant asset in the management of benzodiazepine withdrawal.

Management of an opioid‐impaired anaesthetist by implantable naltrexone

Compared with the general population, physicians are at increased risk for abuse of prescription opioids. This use can interfere with work function and has potential negative implications for patient safety. The case example in this brief communication describes an opioid‐dependent anaesthetist who, following 10 years of opioid abuse/dependency and a number of unsuccessful treatments, including oral naltrexone, and relapses, received a number of sequential naltrexone implants as part of his management. The case involved a close collaboration between the treating doctor, employer and the General Medical Council (GMC), with ongoing monitoring and follow‐up, a GMC requirement of return to medical employment. This case study is used to illustrate that by sequential implant treatment blood levels of naltrexone can be maintained at levels required for antagonism of opioid‐based drugs for significant periods of time. The GMC, employer and treating physician were able to monitor blood naltrexone levels, with the treating physician able to palpate the implant and thereby confirm that the previously opioid‐dependent physician had remained on treatment. The authors conclude that with implantable naltrexone, opioid abstinence can virtually be guaranteed. Naltrexone implants therefore offer a level of protection not achieved with any previous treatment.