A cross-national analysis of the association between years of implementation of opioid substitution treatments and drug-related deaths in Europe from 1995 to 2013

Marotta, Phillip; McCullagh, Charlotte

doi:10.1007/s10654-017-0342-z

Cited by 9 publications

(10 citation statements)

References 81 publications

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“…Opioid maintenance treatment (OMT) programs using Methadone, the most researched substitute for heroin, are life-saving as they keep people in treatment programs and reduce heroin use (Marotta and McCullagh 2018;Mattick et al 2009). Internationally, authorities endorse the use of OMT (Gust and McCormally 2018).…”

Section: Introductionmentioning

confidence: 99%

Overcoming Heroin Addiction without the Use of Pharmaceuticals: A Qualitative Interview Study

Nehlin

Willebrand

Brander

et al. 2020

Journal of Psychoactive Drugs

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Although opioid maintenance treatment lowers mortality and has proven efficacy in reducing opioid use, it is not an option for every person with an opioid addiction. Studies of the experiences of those who have overcome their addiction without pharmaceuticals are rare, but vital to understanding the quitting process and how it can be facilitated. This study investigated what persons with a previous heroin addiction perceived as helpful when overcoming their addiction without the use of pharmaceuticals, and what they consider important for health services to consider. Eleven adults with former heroin addiction participated. Most described the leaving process as prolonged and including many attempts. Experiences such as being worn out and numb, life-threatening overdoses, personal losses or a growing feeling of missing important stages in life fueled the decision process. Envisioning a future without drugs was described as an important component. To maintain the decision to refrain from heroin use the possibility to gain a new social context was crucial. Results imply that health care professionals should be proactive by seizing the moment of opportunity for change (e.g., after an overdose), and should be empathetic and never give up on a person. Those concerned with care, welfare and other support or control systems in society must cooperate to offer more personalized support.

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Section: Introductionmentioning

confidence: 99%

Overcoming Heroin Addiction without the Use of Pharmaceuticals: A Qualitative Interview Study

Nehlin

Willebrand

Brander

et al. 2020

Journal of Psychoactive Drugs

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“…However, in Europe 455,000 patients, out of a total of 22.8 million, prescribed opioids for chronic pain are believed to be dependent upon their medication (Kraus et al, 2016). There is an estimated opioid death rate of 1.8 per 100,000 people averaged over 30 European countries (Marotta et al, 2018). In Australia, the rate of prescription opioid overdose deaths has increased by 2.5 fold from 2001-2012, with more deaths attributed to prescription opioids than heroin (Roxburgh et al, 2017).…”

Section: Abbreviationsmentioning

confidence: 99%

“…side effects elicited through the binding of the μ receptor) can include; addiction (Compton et al, 2006), respiratory depression (Martins et al, 2015), coordination impairment, sedation (Aubrun et al, 2001), constipation, urinary retention, nausea, and vomiting (Ruan, 2007). The high abuse liability and addiction to prescription opioids is a major contributor to the opioid crisis worldwide with respiratory depression being the cause of death in opioid overdose cases (Marotta et al, 2018, Shipton et al, 2017, Vowles et al, 2015.…”

Section: Side Effect Profile Of Kurkinorin and Kurkinol Introductionmentioning

confidence: 99%

Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

Alder¹

2021

Preprint

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Chronic pain is a major problem worldwide, affecting 1 in 5 New Zealanders resulting in a decreased quality of life for the patient and a large socioeconomic problem costing an estimated $13-$14.5 billion a year. Current therapeutics target the mu opioid receptor (μ receptor) and include drugs such as morphine and fentanyl. While these drugs are highly effective in the treatment of strong acute pain, their long-term use is associated with tolerance to the analgesic effects and increasing rates of side effects such as respiratory depression and constipation. Due to their high abuse liability, they are also known to cause dependence and addiction when prescribed for extended periods. This is believed to have played a role in the opioid crisis in the United States and highlights the need for improved therapeutics for the treatment of chronic pain. One mechanism that has been proposed to generate μ receptor agonists for the treatment of chronic pain with reduced analgesic tolerance and safer side effects is the development of G-protein biased agonists. Such agonists selectively activate the canonical G-protein signalling to a greater extent than the non-canonical β-arrestin2 pathway. This is based on previous work in β-arrestin2 knockout mice where the antinociceptive effects were increased, while side effects, including respiratory depression, tolerance, and constipation are reduced, increasing the therapeutic window. In this thesis, we aimed to assess the anti-nociceptive and side effect behavioural profiles of two novel μ receptor agonists, kurkinol (bias = 0.14) and kurkinorin (bias = 0.57), with a varying bias for the G-protein pathway to assess the role of this paradigm. Evaluation of the behavioural profile of kurkinol and kurkinorin revealed that G-protein bias was correlated to increased anti-nociceptive potency and reduced tolerance in wildtype C57BL/6J mice. Furthermore, the anti-nociceptive potency of morphine was increased, and tolerance decreased in in β-arrestin2 knockout mice. While the level of tolerance was reduced for kurkinorin. However, in the chemotherapy-induced model of neuropathic pain, tolerance to kurkinol and kurkinorin developed at the same rate as morphine. Overall this work showed a poor correlation between G-protein bias and therapeutic window. With the G-protein selective kurkinol inducing worse respiratory depression, constipation, and motor coordination impairment compared to kurkinorin. Interestingly, respiratory depressive and constipation effects of kurkinol were not prevented in the β-arrestin2 knockout mice indicating that they are induced through the G-protein pathway. These results highlight the change that has occurred in the biased agonism field over the last 4 years, with the lack of reproducibility of key experiments and poor translation of G-protein biased μ receptor agonists resulting in improved therapeutic windows both clinically and pre-clinically. Moreover, recent research has shown that pathway efficacy (i.e. partial agonism) and not G-protein bias is responsible for the behavioural profiles of compounds previously identified as G-protein biased. We, therefore, decided to further investigate the cell signalling profiles of our two novel agonists to assess them for partial agonism and to assess downstream signalling molecules activated by G-protein and β-arrestin2. <div> </div> This revealed cell-specific inhibition of membrane hyperpolarisation in Hek293 and CHO cells stably expressing the human μ receptor, with kurkinol found to be the most potent in both cell lines, followed by kurkinorin, morphine, and [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO). However, no differences were identified between the μ receptor agonists in the activation of the inwardly rectifying channels in the CHO cell line. The assessment of pCREB (phosphorylated cAMP response-element binding protein) as a β-arrestin2 dependent pathway revealed poor activation by kurkinorin while kurkinol was a potent activator. Bias factors generated from this data showed poor correlations to therapeutic windows. While the differences om CREB phosphorylation was shown to have a stronger correlation to therapeutic windows generated from the behavioural data. Overall this thesis has identified kurkinorin as a μ receptor agonist that induces potent anti-nociception with reduced side effects, without strong-G-protein bias. We also show that the highly selective μ receptor agonist kurkinol has improved anti-nociception with a worse side effect profile adding to the growing body of literature showing bias is not a good predictor in its current state. Furthermore, the discrepancies between cell lines, differential activation of subcellular pathways, and lack of reproducibility between bias equations indicate that the field has massively oversimplified a complex system. Which has, most likely, resulted in the poor translation of in vitro bias factors to clinically available μ receptor agonists for chronic pain.

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“…Open access is a well-established treatment approach for OUD, and has proven positive effects on a number of outcomes in various subpopulations, 17 18 including positive effects on stabilisation of people with OUD, reducing the risk of relapse to illicit opioid use, 19 health-related variables such as (co)morbidity and mortality, [20][21][22][23][24][25] social-related variables such as criminality, 7 and well-being and quality of life. 26 Treatment participation (retention in treatment) improves outcomes of OMT, 27 28 while cycling in and out of OMT seems to be a common trajectory for many people with OUD.…”

Section: Introductionmentioning

confidence: 99%

Opioid maintenance treatment in the Czech Republic, Norway and Denmark: a study protocol of a comparative registry linkage study

et al. 2021

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IntroductionOpioid maintenance treatment (OMT) varies across settings and between countries. We plan to use data from several nationwide health and population registers to further improve the knowledge base established from earlier studies. Our aim is to study OMT adherence trajectories and to identify factors associated with improved outcomes for OMT patients across the Czech Republic, Norway and Denmark, in order to further improve OMT and our understanding of the key elements of treatment success.Methods and analysisThe registry-based cohort approach across the three countries allows us to link data from a range of registers on the individual level, by using personal identifiers in nationwide cohorts of OMT and non-OMT patients and the general non-using populations. A total of ~21 500 OMT patients over the last two decades in all three countries will be included in the study. The following outcome variables (based on the International Classification of Diseases, 10th Revision codes) will be obtained from relevant registers: treatment adherence to OMT, comorbidity (somatic and mental health), and all-cause and cause-specific mortality. Outcomes of the country-specific analyses will be pooled.Ethics and disseminationThe national OMT cohorts have been approved by the ethics committees in the respective countries. Data will be stored according to national and local guidelines and treated confidentially, and all data will be analysed separately for each country and compared across countries. Findings will be disseminated in peer-reviewed scientific journals, national and international conferences, and in briefings to inform clinical decision-making.

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A cross-national analysis of the association between years of implementation of opioid substitution treatments and drug-related deaths in Europe from 1995 to 2013

Cited by 9 publications

References 81 publications

Overcoming Heroin Addiction without the Use of Pharmaceuticals: A Qualitative Interview Study

Overcoming Heroin Addiction without the Use of Pharmaceuticals: A Qualitative Interview Study

Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

Opioid maintenance treatment in the Czech Republic, Norway and Denmark: a study protocol of a comparative registry linkage study

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