Naloxone : actions of an antagonist

The opioid antagonist naloxone has a special place in pharmacology __ it has no intrinsic action of its own, but it is able to save lives in the case of life threatening side-effects caused by other drugs. Naloxone is an antagonist for all opioid receptors, but most specifically for the _-opioid receptor, which is the receptor through which opioids such as morphine and fentanyl exert their effects. Those effects include first and foremost analgesia, but also nausea and vomiting, sedation and life-threatening respiratory depression. It is in the case of the latter effect that naloxone can be life-saving, as it is able to reverse respiratory depression. Paradoxically, naloxone, as an antagonist, was a side product of the search for an opioid agonist, one without addictive properties. For many centuries, the addictive properties of opium (and later morphine) were the cause of severe medical and social problems. However, there was (and still is) no alternative to morphine when it comes to analgesia. The solution to this problem was expected to come in the form of a non-addictive opioid agonist and since the start of the twentieth century, scientists have been working to find such a compound. This search has been fruitless with regard to a non-addictive opioid agonist, but has produced several opioid antagonistic drugs. Minor alterations to a drug__s chemical structure can change an agonist into an antagonist. The first opioid antagonist, N-allylnorcodeine was discovered in 1915, by changing a methyl group in the codeine molecule to an allyl group.1 After this discovery, however, the research in non-addictive opioids lay dormant for a while and it would take until 1944 for a second member of the opioid antagonist class, N-allylnormorphine (or nalorphine), to be characterized. Nalorphine showed antagonism for morphine induced respiratory depression,2 but was later found to be a _-opioid receptor agonist as well, with severe dysphoric side-effects (due to its agonism of the opioid receptor).3 Further experimentation with nalorphine__s chemical structure finally yielded N-allylnoroxymorphone, or naloxone, in 1960.4UBL - phd migration 201

Association between prescription opioid use and unplanned intensive care unit admission and mortality in the adult population of the Netherlands: a registry study

Background: Opioid overdoses are increasing in the Netherlands, and there may be other harms associated with prescription opioid use. We investigated the relationship between prescription opioid use and unplanned ICU admission and death. Methods: This is an analysis of linked government registries of the adult Dutch population (age >= 18 years) alive on January 1, 2018. The co-primary outcomes were ICU admission and death up to 1 year. Crude event rates and eventspecific adjusted hazard rates (aHRs) with 95% confidence intervals (CIs) were calculated using multivariable analysis for people with and without exposure to an opioid prescription. Results: We included 13 813 173 individuals, of whom 32 831 were admitted to the ICU and 152 259 died during the 1 year follow-up. Rates of ICU admission and death amongst people who reimbursed an opioid prescription were 5.87 and 62.2 per 1000 person-years, and rates of ICU admission and death in those without a prescription were 2.03 and 6.34, respectively. Exposed individuals had a higher rate of both ICU admission (aHR 2.53; 95% CI: 2.45e2.60) and death (aHR 7.11; 95% CI: 7.02e7.19) compared with unexposed individuals. Both outcomes were more frequent amongst prescription opioid users across a range of subgroups. Conclusions: The rate of ICU admission and death was higher amongst prescription opioid users than non-users in the full cohort and in subgroups. These findings represent an important public health concern.Clinical epidemiolog

Efficacy of ketamine in relieving neuropathic pain: a systematic review and meta-analysis of animal studies

In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia. Searches in PubMed and EMBASE identified 31 unique studies. Four meta-analyses were conducted. The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference 1.6, 95% confidence interval 1.1-2.1). Subgroup analyses showed no effect of species, administration route, or dose. A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in our second analysis (7 comparisons) with similar effects in ketamine-treated and control animals. Chronic ketamine administration (9 comparisons) caused profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7-6.5). The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70% loss of effect 24 days after end of treatment. No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes. These results indicate long-term ketamine anti-allodynic effects after chronic exposure (>3 days) but not after a single administration. Given several limitations, extrapolation of the animal data to the human condition is tenuous.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

A retrospective study on persistent pain after childbirth in the Netherlands

Research into fetal development and medicin

Does nociception monitor-guided anesthesia affect opioid consumption? a systematic review of randomized controlled trials

Monitors that estimate nociception during anesthesia may be used to guide opioid and other analgesics administration to optimize anesthesia care and possibly outcome. We reviewed the literature to evaluate current evidence of the effect of nociception-guided management over standard anesthesia practice during surgery. A systematic review of the literature on the effect of nociception monitoring on anesthesia practice was conducted. Reports were eligible if they compared nociception-guided anesthesia to standard practice during surgery. Primary endpoint of this review is intraoperative opioid consumption. Secondary endpoints included hemodynamic control, postoperative pain and pain treatment. We identified 12 randomized controlled trials that compared one of five different nociception monitoring techniques to standard anesthesia care. Most studies were single center studies of small sample size. Six studies reported intraoperative opioid consumption as primary outcome. There was considerable variability with respect to surgical procedure and anesthesia technique. For nociception monitors that were investigated by more than one study, analysis of the pooled data was performed. The surgical plethysmographic index was the only monitor for which an intra operative opioid sparing effect was found. For the other monitors, either no effect was detected, or pooled analysis could not be performed due to paucity of study data. On secondary outcomes, no consistent effect of nociception-guided anesthesia could be established. Although some nociception monitors show promising results, no definitive conclusions regarding the effect of nociception monitoring on intraoperative opioid consumption or other anesthesia related outcome can be drawn. Clinical trial numberPROSPERO ID 102913.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

Opioid epidemic: lessons learned and updated recommendations for misuse involving prescription versus non-prescription opioids

Introduction In the past decades, the opioid crisis has heavily impacted parts of the US society and has been followed by an increase in the use of opioids worldwide. It is of paramount importance that we explore the origins of the US opioid epidemic to develop best practices to tackle the rising tide of opioid overdoses. Areas covered In this expert review, we discuss opioid (over)prescription, change in perception of pain, and false advertisement of opioid safety as the leading causes of the US opioid epidemic. Then, we review the evidence about opioid dependence and addiction potential and provide current knowledge about predictors of aberrant opioid-related behavior. Lastly, we discuss different approaches that were considered or undertaken to combat the rising tide of opioid-related deaths by regulatory bodies, pharmaceutical companies, and health-care professionals. For this expert review, we considered published articles relevant to the topic under investigation that we retrieved from Medline or Google scholar electronic database. Expert opinion The opioid epidemic is a dynamic process with many underlying mechanisms. Therefore, no single approach may be best suited to combat it. In our opinion, the best way forward is to employ multiple strategies to tackle different underlying mechanisms.Clinical epidemiolog

Opioid epidemic: lessons learned and updated recommendations for misuse involving prescription versus non-prescription opioids

Introduction In the past decades, the opioid crisis has heavily impacted parts of the US society and has been followed by an increase in the use of opioids worldwide. It is of paramount importance that we explore the origins of the US opioid epidemic to develop best practices to tackle the rising tide of opioid overdoses. Areas covered In this expert review, we discuss opioid (over)prescription, change in perception of pain, and false advertisement of opioid safety as the leading causes of the US opioid epidemic. Then, we review the evidence about opioid dependence and addiction potential and provide current knowledge about predictors of aberrant opioid-related behavior. Lastly, we discuss different approaches that were considered or undertaken to combat the rising tide of opioid-related deaths by regulatory bodies, pharmaceutical companies, and health-care professionals. For this expert review, we considered published articles relevant to the topic under investigation that we retrieved from Medline or Google scholar electronic database. Expert opinion The opioid epidemic is a dynamic process with many underlying mechanisms. Therefore, no single approach may be best suited to combat it. In our opinion, the best way forward is to employ multiple strategies to tackle different underlying mechanisms

Risk of drug-related upper gastrointestinal bleeding in the total population of the Netherlands: a time-trend analysis

Objective Many prescribed and over-the-counter medications, for example, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with upper gastrointestinal bleeding (UGIB). Recently, a decrease in prescribing of NSAIDs was observed in the Netherlands, but whether a similar decreasing trend could be observed in the incidence of severe UGIB (either fatal or requiring hospitalisation), contingent on medication prescription, is unknown.Design We conducted a cohort study using Dutch national statistics on pharmacy claims, hospitalisation and mortality between 2013 and 2018. We explored the incidence of sex-specific and age-specific severe UGIB in four (sub)populations: (A) total population, (B) without a filled prescrption for NSAIDs, (C) without filled prescriptions for NSAIDs and antithrombotic agents, (D) without any risk factors for UGIB.Results The cumulative incidence of severe UGIB did not decrease throughout the study period, regardless of the subgroup analysis. In the total population, it was 199 per 100 000 inhabitants (95% Cl 197 to 201) in 2013-2014 and 260 (95% Cl 258 to 263) in 2017-2018. The absolute risk of severe UGIB was 50% lower in the subgroup B than in the full cohort. It decreased further by 50% in the subgroup D when compared with subgroup B. The risk of severe UGIB was 1.5-1.9 fold higher in young women than in young men; an indication of over-the-counter NSAIDs use being more prevalent in women than men in this age group.Conclusion We found no evidence to support a relationship between reduced prescribing of NSAIDs and the incidence of severe UGIB in the Netherlands since 2013. The relationship was also not observed when we removed the effect of risk factors.Clinical epidemiolog

Efficacy of ketamine in relieving neuropathic pain

In humans, proof of long-term efficacy of ketamine treatment in neuropathic pain is lacking. To improve our understanding of ketamine behavior under various administration conditions, we performed a systematic review and meta-analyses of controlled studies on the efficacy of ketamine in mice and rats with a disease model of nerve injury on relief of allodynia. Searches in PubMed and EMBASE identified 31 unique studies. Four meta-analyses were conducted. The first analysis included 19 comparisons on a single ketamine dose and measurement of effect within 3 hours of dosing and showed an appreciable effect (standardized mean difference 1.6, 95% confidence interval 1.1-2.1). Subgroup analyses showed no effect of species, administration route, or dose. A single administration was insufficient to sustain relief of allodynia at 24 or 72 hours after dosing, as observed in our second analysis (7 comparisons) with similar effects in ketamine-treated and control animals. Chronic ketamine administration (9 comparisons) caused profound relief of allodynia when tested during ketamine exposure (effect size 5.1, 3.7-6.5). The final analysis (6 comparisons) showed that chronic administration caused a slow loss of relief of allodynia with 70% loss of effect 24 days after end of treatment. No subgroups analyses were possible in the last 3 meta-analyses due to small group sizes. These results indicate long-term ketamine anti-allodynic effects after chronic exposure (>3 days) but not after a single administration. Given several limitations, extrapolation of the animal data to the human condition is tenuous.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

Upside down you're turning me: inverted Takotsubo pattern cardiomyopathy

Perioperative Medicine: Efficacy, Safety and Outcom