/pdf/neurogenic-inflammation-as-a-novel-treatment-target-for-3n08l2eq.pdf

Neurogenic inflammation as a novel treatment target for chronic pain syndromes

Background Into the 21st century, the conflation of high rates of chronic pain, systemic gaps in treatment availability and access, and the arrival of potent new opioid medications (e.g., slow-release oxycodone) facilitated strong increases in medical opioid dispensing in Canada. These persisted until post-2010 alongside rising opioid-related adverse (e.g., morbidity/mortality) outcomes. We examine patterns, trends and determinants of opioid dispensing in Canada, and specifically its 10 provinces, for the years 2005-2020. Methods Raw data on prescription opioid dispensing were obtained from a large national community-based pharmacy database (IQVIA/Compuscript), converted into Defined-Daily-Doses/1,000 population/day for 'strong' and 'weak' opioid categories per standard methods. Dispensing by opioid category and formulations by province/year was assessed descriptively; regression analysis was applied to examine possible segmentation of over-time strong opioid dispensing. Results All provinces reported starkly increasing strong opioid dispensing peaking 2011-2016, and subsequent marked declines. About half reported lower strong opioid dispensing in 2020 compared to 2005, with continuous inter-provincial differences of > 100 %; weak opioids also declined post-2011/12. Segmented regression suggests breakpoints for strong opioids in 2011/12 and 2015/16, coinciding with main interventions (e.g., selective opioid delisting, new prescribing guidelines) towards more restrictive opioid utilization control. Conclusions We characterized an era of marked rise and fall, while featuring stark inter-provincial heterogeneity in opioid dispensing in Canada. While little evidence for improvements in pain care outcomes exists, the starkly inverting opioid utilization have been associated with extensive population-level harms (e.g., misuse, morbidity, mortality) over-time. This national case study raises fundamental questions for opioid-related health policy and practice.

/pdf/patterns-trends-and-determinants-of-medical-opioid-58mgddy5lk.pdf

Patterns, trends and determinants of medical opioid utilization in Canada 2005–2020: characterizing an era of intensive rise and fall

In the past twenty years, the consumption of opioid medications has reached significant proportions, leading to a rise in drug misuse and abuse and increased opioid dependence and related fatalities. Thus, the purpose of this study was to determine whether there are pharmacovigilance signals of abuse, misuse, and dependence and their nature for the following prescription opioids: codeine, dihydrocodeine, fentanyl, oxycodone, pentazocine, and tramadol. Both the pharmacovigilance datasets EudraVigilance (EV) and the FDA Adverse Events Reporting System (FAERS) were analyzed to identify and describe possible misuse-/abuse-/dependence-related issues. A descriptive analysis of the selected Adverse Drug Reactions (ADRs) was performed, and pharmacovigilance signal measures (i.e., reporting odds ratio, proportional reporting ratio, information component, and empirical Bayesian geometric mean) were computed for preferred terms (PTs) of abuse, misuse, dependence, and withdrawal, as well as PTs eventually related to them (e.g., aggression). From 2003 to 2018, there was an increase in ADR reports for the selected opioids in both datasets. Overall, 16,506 and 130,293 individual ADRs for the selected opioids were submitted to EV and FAERS, respectively. Compared with other opioids, abuse concerns were mostly recorded in relation to fentanyl and oxycodone, while tramadol and oxycodone were more strongly associated with drug dependence and withdrawal. Benzodiazepines, antidepressants, other opioids, antihistamines, recreational drugs (e.g., cocaine and alcohol), and several new psychoactive substances, including mitragynine and cathinones, were the most commonly reported concomitant drugs. ADRs reports in pharmacovigilance databases confirmed the availability of data on the abuse and dependence of prescription opioids and should be considered a resource for monitoring and preventing such issues. Psychiatrists and clinicians prescribing opioids should be aware of their misuse and dependence liability and effects that may accompany their use, especially together with concomitant drugs.

https://www.mdpi.com/1424-8247/15/6/675/pdf?version=1653646969

Pharmacovigilance Signals of the Opioid Epidemic over 10 Years: Data Mining Methods in the Analysis of Pharmacovigilance Datasets Collecting Adverse Drug Reactions (ADRs) Reported to EudraVigilance (EV) and the FDA Adverse Event Reporting System (FAERS)

Major differences exist between the United States and Europe regarding opioid-related morbidity and mortality. Regulatory restrictions, drug policy measures and large-scale implementation of proven-effective opioid dependence treatments and harm reduction strategies are advocated to effectively tackle the opioid crisis in the United States, using successful examples practised in Europe. The United States faces an opioid epidemic, with 91.8 million (37.8%) adults using prescription opioids (POs), 11.5 million (4.7%) adults misusing POs, 1.9 million (0.8%) people suffering from a PO use disorder in 2015 and 49 860 opioid-related deaths (ORDs) in 2019 [1, 2]. Initially, the increase in ORD was mainly due to POs, but since 2010 ORDs are mainly due to illicit heroin, and since 2014 to illicitly manufactured fentanyls (IMFs). Regulatory measures in the last decade decreased the availability of POs and patients who were meanwhile dependent upon POs shifted to heroin and later IMFs. Currently, IMFs are involved in about 75% of all ORDs in the United States. Although in western Europe PO consumption increased by almost 40% between 2005 and 2015 [8967 daily defined doses (DDDs)/million per year in 2015], it remained only approximately half of the US volume in 2015 (16 491 DDDs/million per day). However, this increase in PO consumption was paralleled by a stable, relatively low number of 8000 ORDs (mainly heroin and methadone ORDs) in Europe (16/million), which is almost 10 times lower than in the United States (156 ORD/million) [3]. Overall, Europe is not experiencing an opioid overdose crisis, with Scotland (and, to a lesser extent, England, Wales and Northern Ireland) as the exception. In Scotland, the rate of 206 ORDs/million is even higher than in the United States [4-6]. This high rate of ORDs in Scotland was driven by a high number of problematic opioid users, a high frequency of polydrug use, particularly opioids with illicit benzodiazepines and the relatively low coverage and limited efficacy of the addiction treatment system [7]. A comparison of Europe and the United States shows that the following differences may explain at least some of the differences in PO consumption and ORDs: (a) regulation of prescription drugs with more short treatments without automatic refills in Europe, (b) availability of illicit drugs with no IMFs available in most European countries, (c) pharmaceutical advertising with no direct-to-consumer advertising in Europe, (d) attitudes about medical use of POs with more psychological pain management strategies instead of opioids as a remedy for pain problems in Europe, (e) law enforcement with de-penalization of possession of opioids for personal consumption in most European countries, (f) national drug policy with more emphasis on public health and harm reduction in Europe, (g) regulatory frameworks for pharmaceutical drugs with prescription drug monitoring programmes (PDMPs) to prevent doctor-shopping in most European countries and (h) opioid dependence treatment with higher availability, better accessibility and full financial reimbursement of addiction treatments, including different forms of opioid agonist treatment, in almost all European countries [8, 9]. To reduce the number PO-prescriptions and iatrogenic opioid addictions in the United States, regulations should be developed that restrict such prescriptions for acute pain and chronic pain for chronic non-cancer pain only, provided that all patients receive adequate pain relief. Moreover, POs, preferably in abuse-deterrent formulations, should generally be prescribed for short periods with no automatic refills. PDMPs effectively limit doctor-shopping and diversion of POs, but only if prescriber access is mandatory. However, these measures may have the unintended consequence that those with an opioid use disorder move to illicit opioids (e.g. IMFs), potentially increasing the number of ORDs. To reduce the number of ORDs, illicit opioid consumers must gain access to drug-testing services and free naloxone take-home kits and supervised consumption rooms, further facilitated by de-penalization of possession and consumption of illicit opioids. As evidence-based treatments are highly underutilized in the United States, high-quality addiction treatment services should become available, with full financial reimbursement, offering both abstinence-orientated treatments and opioid agonist treatments with methadone, buprenorphine and—for non-responders—injectable heroin or hydromorphone [10]. A prerequisite for any successful strategy to end the opioid crisis is sufficient funding. In 2021 an important $945 million NIH initiative was launched: ‘Helping to End Addiction Long-term’ (HEAL) to speed scientific solutions to stem the national opioid public health crisis. Although important, this initiative will not offer direct solutions for the current crisis, whereas immediate implementation of prescription regulations and financial support for evidence-based addiction treatment and harm reduction services would almost certainly slow down or even (partly) resolve the opioid crisis in the United States and Scotland. Furthermore, most opioid dependence cases and ORDs occur in those who are either uninsured, unemployed or have a low income [1, 7]. This calls for better health insurance plans and reduction of social, ethnic and financial inequalities: important tools to reduce opioid dependence and ORDs and, more generally, to improve public health and social wellbeing. Finally, we would like to note that, like the United States and Scotland, Canada also experiences a serious opioid crisis, even though it has universal health care, better access to (imperfect) treatment and harm reduction services and less social and financial inequalities than the United States, suggesting that only a simultaneous implementation of a combination of measures, with emphasis on harm reduction strategies to counter the devastating effects of IMFs, can eventually resolve the opioid crisis in these constituencies. Wim van den Brink was a consultant for Indivior and still is a consultant for D&A Pharma, Camurus, Opiant Pharmaceuticals and Clearmind Medicine. M.P. and J.v.A. have no disclosures to make. WvdB conceptualized the paper and provided further comments. MP added some issues and provided further comments. JvA wrote the first draft and provided further comments. 

Geerd Dom

Papers

Is Europe also facing an opioid crisis?-A survey of European Pain Federation chapters.