A double-blind randomised crossover trial of low-dose flumazenil for benzodiazepine withdrawal: A proof of concept.

INTRODUCTION: Benzodiazepines (BZD) are a class of anxiolytics with varying uses, which primarily act on the GABAA receptor resulting in hyperpolarisation. BZDs are often a difficult drug class to cease once neuroadaptation has occurred; recommendations usually involve gradual dose reductions at variable rates. A growing body of evidence has suggested that low-dose flumazenil, a GABAA receptor antagonist, may be a useful agent to allow for rapid detoxification. AIM: To collect pilot data on the safety and efficacy of low-dose subcutaneous flumazenil to reduce BZD use, withdrawal symptoms, and craving in participants taking above and below the therapeutic maximum diazepam equivalent of 30 mg to inform on sample size for future trials. METHOD: In a randomised double-blinded crossover study design, participants received low-dose flumazenil first (4 mg/24 h for approximately eight days) or placebo first. Groups were divided into those taking < 30 mg diazepam equivalent and ≥ 30 mg diazepam equivalent at baseline. Main outcome measures were percentage reduction in daily diazepam use, withdrawal symptoms, and craving scores from baseline, difference in diazepam use across the placebo first group, and flumazenil related adverse events. RESULTS: Twenty-eight participants were recruited and randomised to flumazenil first (n = 14) and placebo first (n = 14). In participants taking ≥ 30 mg diazepam equivalent at baseline (n = 15), flumazenil significantly reduced diazepam use by 30.5% (p = 0.024) compared to placebo. CONCLUSION: Low-dose flumazenil may aid in BZD detoxification in participants taking daily diazepam equivalent doses greater than or equal to the therapeutic maximum (≥30 mg) by reducing the need for diazepam.

Outcomes of patients treated with low-dose flumazenil for benzodiazepine detoxification: A description of 26 participants.

INTRODUCTION: Benzodiazepines are commonly prescribed for a variety of indications and can be employed in the short- and long-term. While they are efficacious, issues arise from long-term use with the emergence of dependence and tolerance to doses within the therapeutic range and beyond. Discontinuation from benzodiazepines can be problematic for patients and may result in a withdrawal syndrome, which can be protracted and last months to years. METHODS: 26 participants received low-dose subcutaneous flumazenil infusions (4 mg/24 h for approximately eight days) as part of a randomised control crossover trial. Return to benzodiazepine use was assessed monthly for three months based on the benzodiazepine use in the previous week. Where data was not available, the treating psychiatrist examined patient files and clinical documents to determine benzodiazepine use. Withdrawal and craving scores were also measured. RESULTS: Abstinence rates from benzodiazepines at one-, two-, and three-month follow ups were 65.4 %, 50.0 %, and 46.2 % respectively. When considering patient files and clinical documents for those lost to follow-up, abstinence rates were higher at 73.1 %, 65.4 % and 61.5 % at the one-, two-, and three-month follow ups respectively. Withdrawal and craving scores were higher in those that had returned to any benzodiazepine use. CONCLUSION: Self-reported rates of abstinence from benzodiazepines at three months was between 46.2 % and 61.5 %. Flumazenil may yield greater success than benzodiazepine tapering from high dose benzodiazepine use (≥30 mg diazepam equivalent). Further research should compare abstinence rates after treatment with flumazenil compared to benzodiazepine tapering in high dose benzodiazepine users.

Serum ionic dysequilibria in clinical opioid dependence: Cross-sectional and longitudinal studies.

INTRODUCTION: Despite an increasing awareness that the activity of excitable membranes is determined by the underlying ionic gradients across them, and their importance in drug dependency, we were not able to identify any reports of comparing the electrolyte composition of opioid-dependent and non-addicted controls. METHODS: Linear regression was used to compare clinical pathology blood results taken from 2699 opioid-dependent patients (ODP) and 5307 medical control (MC) patients on a total of 21,734 occasions for the period 1995-2015. The presence of a hepatitis C antibody test was used to separate OPD and MC patients. RESULTS: The mean age among ODP and MC was 33.51 ± 0.16 and 37.99 ± 0.23 years, respectively ( p < 0.0001). The groups were 71.5% and 54.2% male ( p < 0.0001). Drug use in this cohort has been reported previously. Analysis of sodium, haemoglobin and albumin were used to exclude marked effects of haemodilution/haemoconcentration. Repeated measures linear regression against age and time showed depressed levels of bicarbonate ( p < 0.0001) and potassium ( p < 0.05) and elevated levels of chloride ( p < 0.025) and anions ( p < 0.01) in ODP in both sexes. Multiple regression in mixed-effects models showed that these effects were all worse in females ( p = 0.0001). CONCLUSION: This data shows that opioid dependence is associated with significant changes in chloride, potassium, bicarbonate and anions in both sexes, and worse in females. This likely has implications for the electrophysiological properties of excitable membranes. It is consistent with the reported impairment of potassium-chloride exchangers in opioid dependence. Explication of the mechanisms responsible must await further studies.

Duration of opiate exposure as a determinant of arterial stiffness and vascular age in male opiate dependence: a longitudinal study.

WHAT IS KNOWN AND OBJECTIVE: Despite intriguing initial and associational studies, there remains little research on opiate-related arterial dysfunction and no longitudinal studies. As opiates act potently via P16INK4A/CDKN2A identified on GWAS screens, and as arterial ageing is a surrogate for organismal ageing, this area is of general concern. METHODS: Thirty-eight male controls compared with 198 opiate-dependent male patients were studied longitudinally using SphygmoCor pulse wave analysis. RESULTS AND DISCUSSION: Healthy male controls and opiate-dependent male patients were studied on 125 and 625 occasions, respectively. The mean (±SEM) chronological age (CA) was 42·32 ± 2·22 for controls and 35·04 ± 0·61 for opiate dependent (P = 0·0029). 94·4% and 13·2% smoked tobacco (P < 0·0001). Controlling for BMI and CA, there was a significant time: addictive status interaction for vascular age (P = 0·0127) and central augmentation pressure and index (both P < 0·02). Central systolic and diastolic pressures were also worse over time by addictive status (P < 0·005). At repeated measures multiple regression adjusted for classical risk factors, opiate dose and duration of opiate use remained significant. The dose-duration effect was significant in 8 terms and by time. A similar model quadratic in opiate duration was more powerfully predictive, suggesting the salience of the duration of opiate treatment (AIC 191·6898 and 191·5966, P = 0·0116). WHAT IS NEW AND CONCLUSION: Data suggest that increased length of opiate dependence is associated with advanced vascular stiffness and ageing and are therefore consistent with accelerated ageing organismally. The superiority of power functions of the opiate duration of exposure underscores the significance of the duration of treatment and of putative senescence induction.

Minor pathological changes are induced by naltrexone-poly(DL-lactide) implants in pregnant rats.

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 long-term 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.

The effects of maternally administered methadone, buprenorphine and naltrexone on offspring: review of human and animal data.

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 micro-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 micro-opioid receptor agonist and a kappa-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.

Blood naltrexone levels over time following naltrexone implant.

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 (>or=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.

A comparison of mental health hospital admissions in a cohort of heroin users prior to and after rapid opiate detoxification and oral naltrexone maintenance.

Mental health (MH) hospital admissions were investigated in a cohort (N=1184) of heroin dependent persons using linked health records. All MH in-patient admissions were extracted 36 months before to 36 months after commencing rapid opioid detoxification (ROD) and oral naltrexone. Results show that the incidence rate ratio (IRR) of drug-related and other MH admissions peaked in the 3 months immediately prior to treatment. All categories subsequently declined to baseline levels by 36 months following treatment. The authors conclude that treatment for heroin dependence reduces risk of MH admissions.

Histological changes over time around the site of sustained release naltrexone-poly(DL-lactide) implants in humans.

In order to assess the histological tissue changes over time around the site of implant, tissue biopsies were taken at 1 to 38 months post-implant from 54 (34 male) consenting human subjects who had received the Australian subcutaneous naltrexone-poly(DL-lactide) implant for heroin dependence. The implant consists of multiple tablets containing compressed naltrexone-poly[trans-3,6-dimethyl-1,4-dioxane-2,5-dione] (DL-lactide) loaded microspheres. Assessment of tissue samples by pathologists showed an early phase (up to 12 months post-implant) of inflammation, foreign body reaction, and fibrosis. This subsided gradually over the next 12 months until tissue returned to normal by 25+ months. Sufficient evidence was not available to conclude that the poly(DL-lactide) implant matrix was totally biodegradable within the study period. While implant material was not identified in most of the latter biopsies, its presence was noted in one biopsy at 26 months post-implant. Nevertheless the study results did demonstrate the implant's biocompatibility by the lack of inflammation, foreign body reaction, and fibrosis detected by 25+ months. It seems highly probable that surgical technique rather than the implant itself was associated with the additional finding of fat necrosis. Moderate fat necrosis was observed as a common feature of biopsies carried out during the first 6 months following implant. It subsided to mild levels over the next 18 months, and was notably absent by 25+ months. The results of the study indicated that the Australian naltrexone-poly(DL-lactide) implant is well tolerated and may have a role for use in the management of medical conditions such as heroin dependence.

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

The aim of this study was to assess blood free naltrexone and 6-beta-naltrexol levels with time following treatment with sequential sustained-release naltrexone preparations. Data were collected from blood samples analysed independently for naltrexone and 6-beta-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-beta-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-beta-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.

Blood naltrexone and 6-beta-naltrexol levels following naltrexone implant: comparing two naltrexone implants.

The aim of this study was to profile and compare blood naltrexone and 6-beta-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-beta-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-beta-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-beta-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.

Use of oral and implantable naltrexone in the management of the opioid impaired physician.

Doctors are at an increased risk for prescription drug use, particularly opioids and benzodiazpines. This use can interfere with work function and has major potential negative implications for patient safety. Oral naltrexone, an opioid antagonist, has been used as part of a management strategy for opioid dependent physicians. While some patients stabilize on oral naltrexone, others relapse to opioid use. An alternative method of naltrexone maintenance involves the injection or surgical insertion of a sustained release preparation of naltrexone. This approach dramatically improves compliance, removing the onus from the previously opioid impaired physician to use daily oral naltrexone. This article describes the cases of four opioid-impaired doctors who received naltrexone (either oral or implant) as part of their management. The authors conclude that monitoring daily oral naltrexone use and detecting early opioid relapse is difficult, placing both the opioid impaired physician and their patients at risk. In contrast, by using implantable naltrexone, compliance is assured and opioid abstinence can virtually be guaranteed for five months. It is argued that naltrexone implants offer a level of protection not achieved with any previous treatment. It is recommended that management should involve early and close collaboration between the treating doctor and the Medical Board, with initial treatment, ongoing monitoring and follow-up being a Medical Board requirement for registration.

Methadone and the pregnant user: a matter for careful clinical consideration.

The practice of placing all pregnant heroin users on methadone as the treatment of choice needs to be questioned. While it may be suitable for those who stabilise their illicit heroin use at or shortly after conception, its suitability for those who show little movement away from regular heroin use and its associated lifestyle is more circumspect. Neonates of women who continue heroin use throughout pregnancy are likely to be below birthweight and/or premature. As a consequence, they are in a less than optimal condition to cope with the additional assault caused by prescribed methadone such as neonatal withdrawal. This may help explain why the relative risk of neonatal mortality in women who continue illicit heroin use during pregnancy and are prescribed methadone, is greater than for those who continue to use heroin but are not prescribed methadone. Clinicians must take the time of maternal presentation and the likelihood of continued maternal heroin use into consideration when determining who is suitable for methadone and whether a reduced level of methadone will suffice. A number of different clinical scenarios are identified and possible management strategies discussed. The need to develop innovative services appropriate for pregnant women who continue regular heroin use, and for well-designed studies that define best practice for the management of these women is evident.

Impediments to screening for hazardous alcohol use and dependence in general hospital psychiatric inpatients.

OBJECTIVE: The Alcohol Use Disorders Identification Test (AUDIT) has been developed to screen for hazardous and harmful alcohol consumption. It has been used among a variety of primary care, general population and general hospital populations. However, with the exception of one study undertaken by the author and colleagues, the use of the AUDIT in general hospital psychiatric patients has not been reported. This paper reports on a substudy of this larger study whose aim was to determine the frequency of hazardous alcohol use and dependence among patients admitted to the psychiatric units of general hospitals in Perth, Western Australia, and discusses major reasons for non-AUDIT screening among this group. METHOD: In a 12-month period 990 patients aged 18-64 years and residing in the Perth metropolitan area were admitted to the psychiatric unit of the two hospitals. Using the AUDIT alcohol use in patients with four major types of psychiatric disorder, namely mood, adjustment, anxiety and psychotic disorders, was assessed. RESULTS: Of the 834 admissions targeted for AUDIT screening 263 were not screened. This non-screening represented 27-42% of patients in each of the major diagnostic categories. There was no significant difference in the proportion of patients screened versus not screened for mood, adjustment or schizophrenia/psychosis. There were however, significantly fewer patients with anxiety disorder screened compared with mood disorder. Those non-screened patients in major psychiatric groups had significantly shorter hospital stays than their diagnostic counterparts who were screened. The major reason for non-screening in all groups was due to patients leaving the psychiatric facility before they could be accessed. This included discharge before screening, transfer to another psychiatric facility and short admission. To a lesser extent cognitive dysfunction accounted for non-screening among major diagnostic groups. CONCLUSIONS: Failure to screen patients was largely due to short hospital stays. Screening was impeded by the brief window period, commonly 1 or 2 days, between the absence of acute psychiatric sequelae and discharge. This situation contrasts dramatically to the medical or surgical admission where major sequelae are largely resolved in 2-3 days and AUDIT screening can take place over the remaining 3-4 days prior to discharge. To be effective in the general hospital psychiatric setting, alcohol screening needs to be incorporated into the routine ward assessment procedures. The brevity of the AUDIT makes this possible. This would maximize the time available to implement an intervention programme to those found to be consuming alcohol at a hazardous or harmful level.

Adolescent emergency department presentations with alcohol- or other drug-related problems in Perth, Western Australia.

AIMS: To identify the morbidity, type of substance used and the pattern of presentation by adolescents with problems related to alcohol or other drug (AOD) use. DESIGN: A 4-week retrospective review of hospital records. SETTING: Four metropolitan hospitals in Perth, Australia. PARTICIPANTS: There were 1064 presentations by people aged 12-19 years of which 160 (15%) were related to AOD use. The median age of the AOD cases was 17 (interquartile range 16-19) of whom 97 (61%) were male and 19 (12%) were Indigenous Australians. FINDINGS: Alcohol was the most frequent precursor to presentation (66, 41%) followed by heroin (24, 15%) and prescription/over-the-counter drugs (24, 15%). Injury was the most common diagnosis at presentation (50, 31%), followed by overdose/drug use (47, 29%). A diagnosis of injury was significantly more likely following the use of alcohol than other categories of substances (chi(2) = 42.07, df = 3, p < 0.001). Deliberate self-harm (DSH) occurred in more female than male cases (chi2 = 7.4, df = 1, p < 0.01). Presentations were more frequent over the weekend (102, 64%) than on weekdays, and the length of stay was significantly shorter for weekend cases (Mann-Whitney U 2132, p < 0.05). CONCLUSIONS: Given the small window of opportunity to provide AOD treatment to youth following hospital presentation, a number of suggestions are made. From a harm-minimization perspective the focus of interventions should be on alcohol use by male youth and DSH associated with prescription/over-the-counter drug use by female adolescents. In addition, Indigenous youth are over-represented in hospital presentations, but there is currently a lack of evaluated interventions designed for them.

Obstetric and neonatal outcomes associated with maternal naltrexone exposure.

Poor maternal and neonatal outcomes are associated with the pregnant heroin user. These include increased antepartum haemorrhage, decreased neonatal birthweight and increased neonatal mortality Medically supervised withdrawal from heroin during pregnancy has, however, been discouraged due to possible risk to the fetus and because of the high incidence of return to regular illicit heroin use by the mother. In recent years, however, a number of withdrawal procedures using anaesthesia, oral sedation, or intravenous sedation, precipitated by naloxone and/or naltrexone have been developed and carried out successfully on pregnant heroin users. We have now collated information on 18 cases (19 detoxifications) from three countries (Portugal, Australia and the United Kingdom). These case study data, although limited, indicate that detoxification of the pregnant heroin user is possible without significant risk to the neonate or mother, with many women not returning to dependent heroin use following detoxification. Naltrexone maintenance has also been used in the non-pregnant heroin user to discourage illicit heroin use. Similarly to methadone, stabilisation on naltrexone may be associated with conception and pregnancy Over the past three years, 26 women have conceived while on the Western Australia naltrexone program. Due to the unknown teratogenic effects, most have ceased naltrexone intake at approximately seven or eight weeks gestation. In a number of instances, however, naltrexone maintenance has been recommenced following return to a dependent pattern of heroin use. As a consequence, neonates have had different periods of naltrexone exposure, building from the initial seven or eight weeks. We now report on seven women who have delivered and three who are well into their third trimester. Neonatal and obstetric features were unremarkable with good Apgar scores, birthweight and head circumference observed. In the three cases still in third-term gestation, normal fetal development has been observed at recent ultrasound examinations. These case data indicate that naltrexone maintenance may have a role in the management of the pregnant heroin user.

Suicide and attempted suicide among older adults in Western Australia.

BACKGROUND: Suicide rates are high in later life. Risk factors include male sex and depressive illness. This study investigated the relationship between suicidal behaviour and contact with mental health services among the elderly in Western Australia. METHODS: Record linkage was used to obtain records of hospital admissions and mental health service contacts for all suicide attempts and deaths in the period 1980-95. Standardized incidence ratios were calculated for the elderly, general population and people with mental health service contacts. Cox regression was used to evaluated potential risk factors for elderly people who were in contact with mental health services. RESULTS: People over 60 years of age accounted for 15% of suicides and 4.6% of attempted suicides. Suicide rates were 3.3 times higher in males and 4.4 times higher in females when compared to the general population of elderly people. For attempted suicide, the rate was 5.8 times higher in males and 6.6 times higher in females with prior contact with mental health services. Highest risk of suicide was found in patients with diagnoses of affective psychoses (RR = 3.7), adjustment reaction (RR = 3.2) or depressive disorder (RR = 2.8). The diagnosis of cancer was associated with decreased risk of suicide (RR = 3.6) and attempted suicide (RR = 1.9). CONCLUSIONS: Suicide rates are high among the elderly in Western Australia. Suicide is significantly associated with the diagnosis of mood disorder. Suicide attempts are less common, and are associated most strongly with mood and personality disorders. The decreased risk of self-harm behaviour among patients with cancer warrants further investigation.