Psychiatric risk factors for chronic high-dose opioid prescribing: register-based cohort study

Background Chronic high-dose (CHD) prescription opioid use is a major public health concern. Although CHD opioid use has been associated with psychiatric disorders, the causality could go both ways. Some studies have already linked psychiatric disorders to an increased risk of transitioning to chronic opioid use, and longitudinal data identifying psychiatric disorders as predictors of CHD opioid use could shed further light on this issue. Aims To prospectively examine the relationship between the presence of a psychiatric disorder and subsequent development of CHD opioid use in primary care patients newly receiving opioids. Method Data were included from 137 778 primary care patients in The Netherlands. Cox regression modelling was used to examine the association between psychiatric disorders prior to a new opioid prescription and subsequent CHD opioid use (≥90 days; ≥50 mg/day oral morphine equivalents) in the subsequent 2 years. Results Of all patients receiving a new opioid prescription, 2.0% developed CHD opioid use. A psychiatric disorder before the start of an opioid prescription increased the risk of CHD opioid use (adjusted hazard ratio HR = 1.74; 95% CI 1.62–1.88), specifically psychotic disorders, substance use disorders, neurocognitive disorders and multiple co-occurring psychiatric episodes. Similarly, pharmacotherapy for psychosis, substance use disorders and mood and/or anxiety disorders increased the risk of CHD opioid use. Psychiatric polypharmacy conferred the greatest risk of developing CHD opioid use. Conclusions Psychiatric disorders increase the risk of developing CHD opioid use in patients newly receiving prescription opioids. To reduce the public health burden of CHD opioid use, careful monitoring and optimal treatment of psychiatric conditions are advised when opioid therapy is initiated

Mid-life microbiota crises: middle age is associated with pervasive neuroimmune alterations that are reversed by targeting the gut microbiome

Male middle age is a transitional period where many physiological and psychological changes occur leading to cognitive and behavioural alterations, and a deterioration of brain function. However, the mechanisms underpinning such changes are unclear. The gut microbiome has been implicated as a key mediator in the communication between the gut and the brain, and in the regulation of brain homeostasis, including brain immune cell function. Thus, we tested whether targeting the gut microbiome by prebiotic supplementation may alter microglia activation and brain function in ageing. Male young adult (8 weeks) and middle-aged (10 months) C57BL/6 mice received diet enriched with a prebiotic (10% oligofructose-enriched inulin) or control chow for 14 weeks. Prebiotic supplementation differentially altered the gut microbiota profile in young and middle-aged mice with changes correlating with faecal metabolites. Functionally, this translated into a reversal of stress-induced immune priming in middle-aged mice. In addition, a reduction in ageing-induced infiltration of Ly-6Chi monocytes into the brain coupled with a reversal in ageing-related increases in a subset of activated microglia (Ly-6C+) was observed. Taken together, these data highlight a potential pathway by which targeting the gut microbiome with prebiotics can modulate the peripheral immune response and alter neuroinflammation in middle age. Our data highlight a novel strategy for the amelioration of age-related neuroinflammatory pathologies and brain function

Differential gene expression in the mesocorticolimbic system of innately high- and low-impulsive rats

Impulsivity is an important component of many psychiatric illnesses and has been associated with a number of psychiatric disorders such as bipolar disorder and attention deficit / hyperactivity disorder (ADHD). Exploring the different aspects of impulsive behaviour and assigning these to specific neurobiological pathways would advance our interpretation of disorders for which impulsivity is key. Pharmacological studies have implicated a number of neurotransmitters in impulsivity, which in turn have been shown to be affected by several genes in both rodent and human studies of impulsivity. Here, we examine impulsivity-related differences in gene expression in finer detail, using the 2-choice serial reaction time task (2-CSRTT) to assess the molecular signature of impulsivity in brain regions previously linked to impulsive behaviour. Wistar rats were rated as high, (n = 6), intermediate, (n = 12) or low impulsive (n = 6), based on premature responses in the 2-CSRTT, after which RNA was extracted from the nucleus accumbens core (NAcc) and ventral prefrontal cortex (vPFC). RNA from the NAcc and vPFC of high and low impulsivity rats (n = 6 per group) was analysed for differential gene expression patterns and exon usage using RNA poly-A tail sequencing. Pnisr, Mal, and Tspan2 were significantly increased in the NAcc of highly impulsive rats, whereas Ube3a was significantly decreased. No differences were seen in the vPFC. In addition to changes in gene expression, Tspan2 displayed differential exon usage in impulsive rats, while functionally, gene expression changes were related to membrane depolarisation and changes in exon usage were linked to sphingolipid breakdown. The changes in gene expression and exon usage observed in this study represent an important step towards defining the molecular architecture of impulsivity. This study therefore represents an important starting point for analysis of the biological role of impulsivity in addiction and other neurological conditions associated with impulsive phenotypes

Is Europe facing an opioid crisis like the US? An analysis of opioid use and related adverse effects in 19 European countries between 2010 and 2018

Background and Aims Given the ongoing opioid crisis in the United States (US), we investigated the opioid situation in Europe. The aims of the study are to provide an overview of trends in prescription opioid use and opioid related adversities between 2010 and 2018 for different opioids in 19 European countries and to present a comparison with similar data from the US. Methods A multi-source database study with national data from 19 European countries evaluating trends between 2010 and 2018 in (1) prescription opioid (PO) consumption, (2) high-risk (HR) opioid users, (3) opioid-related hospital admissions, (4) opioid-related overdose deaths, (5) opioid use disorder treatment entries, and (6) patients in opioid substitution therapy (OST). Within and between-country comparisons and comparisons with data from the US were made. Results There was considerable variation between European countries. Most countries showed increased PO consumption with the largest increase and the highest consumption in the United Kingdom (UK) compared to the rest of Europe and the US in 2018 (UK: 58,088 defined daily doses for statistical purposes/1000 population/day). In 2018 Scotland had the highest rates (per 100,000 population) of HR opioid users (16.2), opioid-related hospital admissions (118), opioid-related deaths (22.7), opioid use disorder treatment admissions (190), and OST patients (555) of all included European countries. These rates were similar or even higher than those in the US in 2018. Other countries with high rates of opioid-related adversities were Northern-Ireland (synthetic and 'other' opioids), Ireland (heroin and methadone), and England (all opioids). All other countries had no or little increase in opioid-related adversities. Conclusions Apart from the British Isles and especially Scotland, there is no indication of an opioid crisis comparable to that in the US in the 19 European countries that were part of this study. More research is needed to identify drivers and develop interventions to stop the emerging opioid crisis in the UK and Ireland

Ulcerative colitis patients with an inflammatory response upon mesalazine cannot be desensitized: a randomized study

Background and aims. Mesalazine is a key drug in the treatment of ulcerative colitis (UC). Intolerance to mesalazine has been described, including fever and gastrointestinal symptoms. Several case reports reported successful desensitization of patients with mesalazine intolerance. The aim was to assess the number of UC patients who are persistently intolerant to mesalazine after single-blinded rechallenge and to test the effectiveness of a rapid desensitization protocol in UC patients demonstrated mesalazine intolerance. Methods. This is a prospective, singlie-blind randomized study in UC patients who discontinued mesalazine because of intolerance. Patients with severe reactions were excluded. Eligible patients underwent a skin patch test with mesalazine followed by a single-blinded randomized crossover rechallenge with 500 mg mesalazine or placebo. Patients with symptoms upon rechallenge were admitted to the hospital for 3 days oral desensitization. Results. Nine of the 37 identified UC patients who discontinued mesalazine because of intolerance were included. All nine patients had negative patch tests, seven patients had symptoms (fever, nausea, vomiting and diarrhea) within 2 h upon rechallenge. Four of these seven patients participated in the desensitization protocol and in none a successful desensitization could be performed. All four had an inflammatory intolerance reaction with rise in C-reactive protein. There were no elevations in serum tryptase or urinary-methylhistamine levels observed and no signs of immediate type allergic reactions, like urticaria, bronchial obstruction or anaphylaxis. Conclusion. We recommend not to rechallenge UC patients with an inflammatory response upon mesalazine and these patients will not benefit from a rapid desensitization protocol

A non-invasive, low-cost study design to determine the release profile of colon drug delivery systems:A feasibility study

PURPOSE: Conventional bioavailability testing of dosage forms based on plasma concentration-time graphs of two products in a two-period, crossover-design, is not applicable to topical treatment of intestinal segments. We introduce an isotope dual-label approach ((13)C- and (15)N(2)-urea) for colon drug delivery systems that can be performed in a one-day, non-invasive study-design. METHODS: Four healthy volunteers took an uncoated or a ColoPulse-capsule containing (13)C-urea and an uncoated capsule containing (15)N(2)-urea. In case of colon-release (13)C-urea is fermented and (13)C detected as breath (13)CO(2). Absorbed (13)C-urea and (15)N-urea are detected in urine. RESULTS: C and (15)N in urine released from uncoated capsules showed a ratio of 1.01 ± 0.06. The (13)C/(15)N-recovery ratio after intake of a ColoPulse-capsule was constant and lower >12 h post-dose (median 0.22, range 0.13-0.48). The (13)C/(15)N-ratio in a single urine sample at t ≥ 12 h predicted the 24 h non-fermented fraction (13)C of <26 %. Breath (13)CO(2) indicated delayed (>3 h) release and a fermented fraction (13)C >54 %. CONCLUSIONS: Breath and urine (13)C and (15)N data describe the release-profile and local bioavailability of a colon delivery device. This allows non-invasive bioavailability studies for evaluation of colon-specific drug delivery systems without radioactive exposure and with increased power and strongly reduced costs

Monitoring Opioids in Europe: The Need for Shared Definitions and Measuring Drivers of Opioid Use and Related Harms

The past 20 years, the USA is facing a serious opioid crisis initiated by an increase in prescription opioid use. Europe has also seen an increase in prescription opioid use, but the extent of related harm is still largely unknown. Given the impact of the US opioid epidemic, it is important to closely monitor signs of emerging opioid-related problems to guarantee early warnings and timely actions. Shared and meaningful definitions for opioid use and related harms, and relevant information about specific drivers for opioid use and related problems are needed for an adequate policy response. In this commentary, we discuss these definitions, the need to know more about the specific drivers for increased opioid use, its related harm, and proposals for strategies to move forward. Policy recommendations include making a distinction between licit and illicit opioids when monitoring and reporting on opioid-related harm, and using oral morphine equivalents to quantify prescription opioid use in a clinically relevant and comparable manner. A major topic of further research is exploring unique and universal drivers of prescription opioid (mis)use across Europe, in particular the role of opioid diversion