Use of analgesics in intentional drug overdose presentations to hospital before and after the withdrawal of distalgesic from the Irish market

BACKGROUND: Distalgesic, the prescription-only analgesic compound of paracetamol (325 mg) and dextropropoxyphene (32.5 mg) known as co-proxamol in the UK, was withdrawn from the Irish market as of January 2006. This study aimed to evaluate the impact of the withdrawal of distalgesic in terms of intentional drug overdose (IDO) presentations to hospital emergency departments (EDs) nationally. METHODS: A total of 42,849 IDO presentations to 37 of the 40 hospitals EDs operating in Ireland in 2003-2008 were recorded according to standardised procedures. Data on sales of paracetamol-containing drugs to retail pharmacies for the period 1998-2008 were obtained from IMS Health. RESULTS: The withdrawal of distalgesic from the Irish market resulted in an immediate reduction in sales to retail pharmacies from 40 million tablets in 2005 to 500,000 tablets in 2006 while there was a 48% increase in sales of other prescription compound analgesics. The rate of IDO presentations to hospital involving distalgesic in 2006- 2008 was 84% lower than in the three years before it was withdrawn (10.0 per 100,000). There was a 44% increase in the rate of IDO presentations involving other prescription compound analgesics but the magnitude of this rate increase was five times smaller than the magnitude of the decrease in distalgesic-related IDO presentations. There was a decreasing trend in the rate of presentations involving any paracetamol-containing drug that began in the years before the distalgesic withdrawal. CONCLUSIONS: The withdrawal of distalgesic has had positive benefits in terms of IDO presentations to hospital in Ireland and provides evidence supporting the restriction of availability of means as a prevention strategy for suicidal behaviour.

Impact of the smoke-free workplace legislation on smoking behaviour, risk perception & stigmatisation

The Republic of Ireland became the first European country to implement nationwide smoke-free workplace legislation. Aims: To determine prevalence of smoking among bar workers and estimate the impact of the smoke-free workplace legislation on their smoking behaviour to that of a comparable general population sample. To approximate the influence of tobacco control measures on risk perception of second-hand smoke (SHS) among the general population. To explore the de-normalisation of smoking behaviour and the potential increased stigmatisation of smokers and their smoking. Methods: Prevalence estimates and behavioural changes were examined among a random sample of bar workers before and 1 year after the smoke-free legislation; comparisons made with a general population sub-sample. Changes in risk knowledge related to SHS exposure were based on general population data. Qualitative interviews were conducted among a purposive sample of smokers and non-smokers four years after the implementation of the legislation. Results: Smoking prevalence was extremely high among bar workers. Smoking prevalence dropped in bar workers and significantly among the general population 1 year post ban while cigarette consumption dropped significantly among bar workers. Disparity in knowledge between smokers and non-smoker of risk associated with SHS exposure reduced. Lack of understanding of the risk of ear infections in children posed by SHS exposure was notable. Evidence for advanced de-normalisation of smoking behaviour and intensification of stigma because of the introduction of the legislation was dependent on many factors, quality of smoking facilities played a key role. Conclusions: Ireland’s smoke-free legislation was associated with a drop in prevalence and cigarette consumption. Disparity in knowledge between smokers and non-smokers of the risk posed by SHS exposure reduced however the risk of ear infections in children needs to be effectively disseminated. The proliferation of ‘good’ smoking areas may diminish the potential to reduce smoking behaviour and de-normalise smoking.

P-glycoprotein inhibition as a strategy to increase drug delivery across the blood-brain barrier: focus on antidepressants

Depression is among the leading causes of disability worldwide. Currently available antidepressant drugs have unsatisfactory efficacy, with up to 60% of depressed patients failing to respond adequately to treatment. Emerging evidence has highlighted a potential role for the efflux transporter P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), in the aetiology of treatment-resistant depression. In this thesis, the potential of P-gp inhibition as a strategy to enhance the brain distribution and pharmacodynamic effects of antidepressant drugs was investigated. Pharmacokinetic studies demonstrated that administration of the P-gp inhibitors verapamil or cyclosporin A (CsA) enhanced the BBB transport of the antidepressants imipramine and escitalopram in vivo. Furthermore, both imipramine and escitalopram were identified as transported substrates of human P-gp in vitro. Contrastingly, human P-gp exerted no effect on the transport of four other antidepressants (amitriptyline, duloxetine, fluoxetine and mirtazapine) in vitro. Pharmacodynamic studies revealed that pre-treatment with verapamil augmented the behavioural effects of escitalopram in the tail suspension test (TST) of antidepressant-like activity in mice. Moreover, pre-treatment with CsA exacerbated the behavioural manifestation of an escitalopram-induced mouse model of serotonin syndrome, a serious adverse reaction associated with serotonergic drugs. This finding highlights the potential for unwanted side-effects which may occur due to increasing brain levels of antidepressants by P-gp inhibition, although further studies are needed to fully elucidate the mechanism(s) at play. Taken together, the research outlined in this thesis indicates that P-gp may restrict brain concentrations of escitalopram and imipramine in patients. Moreover, we show that increasing the brain distribution of an antidepressant by P-gp inhibition can result in an augmentation of antidepressant-like activity in vivo. These findings raise the possibility that P-gp inhibition may represent a potentially beneficial strategy to augment antidepressant treatment in clinical practice. Further studies are now warranted to evaluate the safety and efficacy of this approach.

Language legislation in Ireland and the United Kingdom: Exploring the gaps between theory and practice

The central objective in this thesis is to explore the gaps between the normative justifications advanced for language rights and language legislative protection and the effective realisation of those rights and legislative provisions in practice. This objective is achieved by examining the scope and application of language rights and legislative provisions within language legislation in Ireland and the United Kingdom. Drawing on Canadian jurisprudence advocating for language rights to be recognised as “purposeful”, the thesis considers the extent to which Ireland and the United Kingdom have limited the acceptance of positive obligations as they relate to the provision of language services in the public sphere. In arguing that language rights are distinct in nature, the thesis suggests that in order for language rights to be effectively realised, an approach to language rights and language legislation more generally must be underpinned by a substantive vision of equality, otherwise language rights and legislative provisions merely amount to symbolic recognition and vacuous rhetoric as opposed to being substantive and enabling rights and provisions. Having said that, the thesis also recognises and elucidates the practical difficulties that arise in the realisation of language rights and language legislative provisions and in doing so seeks to stimulate further dialogue about the nature and limits of language rights and language legislation.

Towards a new model of criminal justice system in the era of globalised criminality: the biggest challenges for criminal process legislation

The main objective of this thesis is the critical analysis of the evolution of the criminal justice systems throughout the past decade, with special attention to the fight against transnational terrorism. It is evident – for any observer - that such threats and the associated risk that terrorism entails, has changed significantly throughout the past decade. This perception has generated answers – many times radical ones – by States, as they have committed themselves to warrant the safety of their populations and to ease a growing sentiment of social panic. This thesis seeks to analyse the characteristics of this new threat and the responses that States have developed in the fight against terrorism since 9/11, which have questioned some of the essential principles and values in place in their own legal systems. In such sense, freedom and security are placed into perspective throughout the analysis of the specific antiterrorist legal reforms of five different States: Israel, Portugal, Spain, the United Kingdom and the United States of America. On the other hand, in light of those antiterrorist reforms, it will be questioned if it is possible to speak of the emergence of a new system of criminal justice (and of a process of a convergence between common law and civil law systems), built upon a control and preventive security framework, significantly different from traditional models. Finally, this research project has the fundamental objective to contribute to a better understanding on the economic, social and civilization costs of those legal reforms regarding human rights, the rule of law and democracy in modern States.

Strategies to prevent potentially inappropriate prescribing and adverse drug reactions in older patients

INTRODUCTION: Potentially inappropriate prescribing (PIP) is a major contributor to adverse drug reactions and overall increased healthcare costs. The aim of this thesis was to identify, develop and implement strategies with the potential to prevent PIP and ADRs in older patients. METHODS: A systematic review of the qualitative literature (Meta-synthesis); A qualitative study in Irish hospitals; A randomised controlled trial (RCT) to assess the impact of an online educational module on doctors’ prescribing knowledge and confidence; Exploration of the potential for a frailty index score to enable doctors identify patients at increased risk of PIP and ADRs; Exploration of the potential for the SHiM tool to enable doctors to optimise prescribing for older patients. RESULTS: The meta-synthesis identified four key concepts: (i) Desire to please the patient; (ii) Feeling of being forced to prescribe; (iii) Tension between experience and guidelines; (iv) Prescriber fear. Similar themes also emerged from the qualitative study. In the RCT, the online educational module resulted in a highly significant 22% difference in test scores between intervention and control groups. The studies exploring the frailty index score showed a significant positive relationship between a patient’s frailty status and their likelihood of experiencing PIP/ADRs. Patients above a frailty threshold of 0.16 were at least twice as likely to experience PIP/ADRs. SHiM was found to be a useful tool in terms of reconciling patients’ medications. However, the evidence for it being capable of preventing clinically relevant adverse events was poor. CONCLUSION:Qualitative research in this thesis has proposed novel theories relating to the causative factors of PIP in older patients. In doing so, it has identified several areas for intervention and laid down a road map for future research.