Globally benzodiazepines remain one of the most prescribed medication groups, especially in the primary care setting. With such high levels of prescribing it is not surprising that benzodiazepine dependence is common, cutting across all socioeconomic levels. Despite recognition of the potential for the development of iatrogenic dependence and the lack of any effective treatment, benzodiazepines continue to be widely prescribed in general practice. Conventional dependence management, benzodiazepine tapering, is commonly a protracted process over several weeks or months. It is often associated with significant withdrawal symptoms and craving leading to patient drop out and return to use. Accordingly, there is a worldwide need to find effective pharmacotherapeutic interventions for benzodiazepine dependence. One drug of increasing interest is the GABAA benzodiazepine receptor antagonist/partial agonist, flumazenil. Multiple bolus intravenous infusions of low dose flumazenil used either with or without benzodiazepine tapering can reduce withdrawal sequelae, and/or longer term symptoms in the months following withdrawal. Preliminary data suggest that continuous intravenous or subcutaneous flumazenil infusion for 4 days significantly reduces acute benzodiazepine withdrawal sequelae. The subcutaneous infusion was shown to be tissue compatible so the development of a longer acting (i.e. several weeks) depot flumazenil formulation has been explored. This could be capable of managing both acute and longer term benzodiazepine withdrawal sequelae. Preliminary in vitro water bath and in vivo biocompatibility data in sheep show that such an implant is feasible and so is likely to be used in clinical trials in the near future.

ObjectivesMany reports exist of the cardiovascular toxicity of smoked cannabis but none of arterial stiffness measures or vascular age (VA). In view of its diverse toxicology, the possibility that cannabis-exposed patients may be ageing more quickly requires investigation.DesignCross-sectional and longitudinal, observational. Prospective.SettingSingle primary care addiction clinic in Brisbane, Australia.Participants11 cannabis-only smokers, 504 tobacco-only smokers, 114 tobacco and cannabis smokers and 534 non-smokers. Exclusions: known cardiovascular disease or therapy or acute exposure to alcohol, amphetamine, heroin or methadone.InterventionRadial arterial pulse wave tonometry (AtCor, SphygmoCor, Sydney) performed opportunistically and sequentially on patients between 2006 and 2011.Main outcome measureAlgorithmically calculated VA. Secondary outcomes: other central haemodynamic variables.ResultsDifferences between group chronological ages (CA, 30.47±0.48 to 40.36±2.44, mean±SEM) were controlled with linear regression. Between-group sex differences were controlled by single-sex analysis. Mean cannabis exposure among patients was 37.67±7.16 g-years. In regression models controlling for CA, Body Mass Index (BMI), time and inhalant group, the effect of cannabis use on VA was significant in males (p=0.0156) and females (p=0.0084). The effect size in males was 11.84%. A dose–response relationship was demonstrated with lifetime exposure (p<0.002) additional to that of tobacco and opioids. In both sexes, the effect of cannabis was robust to adjustment and was unrelated to its acute effects. Significant power interactions between cannabis exposure and the square and cube of CA were demonstrated (from p<0.002).ConclusionsCannabis is an interactive cardiovascular risk factor (additional to tobacco and opioids), shows a prominent dose–response effect and is robust to adjustment. Cannabis use is associated with an acceleration of the cardiovascular age, which is a powerful surrogate for the organismal–biological age. This likely underlies and bi-directionally interacts with its diverse toxicological profile and is of considerable public health and regulatory importance.

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.

Screening and assessment (Chapter 2): screening techniques to identify patients with alcohol problems, and subsequent assessments for clinicians to undertake before providing specific treatments or interventions.• Interventions, treatments, relapse prevention and aftercare (Chapter 3): a range of varying interventions and treatments, including brief interventions, brief e-health interventions, psychosocial interventions, alcohol withdrawal management, pharmacotherapy options, and peer support programs. In the final section of this chapter, relapse prevention, aftercare, and long term follow-up strategies are discussed.• Considerations for specific populations (Chapter 4): the management of alcohol problems and treatment considerations for specific population groups of interest in Australia -genderspecific considerations, adolescents and young people, pregnant and breastfeeding women, Aboriginal and Torres Strait Islander peoples, culturally and linguistically diverse groups, sexually diverse and gender diverse populations, older people, and cognitively impaired people.• Understanding comorbidities (Chapter 5): the importance of considering a range of comorbidities when providing treatment for alcohol problems. Polydrug use, comorbid mental disorders, and physical-related comorbidities are discussed.The content of this supplement is based on the various chapters of the full Guidelines for the Treatment of Alcohol Problems, which were based on reviews of the evidence, including well designed meta-analyses and randomised controlled trials, wherever possible. Where this evidence was not available, recommendations were based on the best available research or clinical experience. Each recommendation in the guidelines is accompanied with a level of evidence based on National Health and Medical Research Council evidence recommendations (Box 2), 21 with "A" representing the most evidence and "GPP" (good practice point) indicating a recommendation with no evidence.For more on the Guidelines for the Treatment of Alcohol Problems, visit https://alcoh oltre atmen tguid elines.com.au/. Acknowledgements:The Guidelines for the Treatment of Alcohol Problems project was funded by the Australian Government, under the Drug and Alcohol Program. We would like to express our gratitude to members of the Guidelines Steering Committee for providing invaluable guidance and advice on this project. We thank Daniel Winter, Sophia Little, Brennan Geiger and James Pham for providing research and administrative support, and Joshua Watt for providing clinical support, across sections of this supplement. Finally, we thank Donna Ah Chee, Kylie Lee, Teagan Weatherall, Craig Holloway and Martin Nean for conversations and work which informed the Aboriginal and Torres Strait Islander peoples section in the guidelines and Chapter 4 of this supplement.Competing interests: Paul Haber has been funded by the Lambert Initiative for Cannabinoid Therapeutics at the University of Sydney to undertake clinical trials of cannabinoid treatment for alcohol withdra...