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Journal of the American College of... Jan 2021Opioids are the most potent of all analgesics. Although traditionally used solely for acute self-limited conditions and palliation of severe cancer-associated pain, a... (Review)
Review
Opioids are the most potent of all analgesics. Although traditionally used solely for acute self-limited conditions and palliation of severe cancer-associated pain, a movement to promote subjective pain (scale, 0 to 10) to the status of a "fifth vital sign" bolstered widespread prescribing for chronic, noncancer pain. This, coupled with rising misuse, initiated a surge in unintentional deaths, increased drug-associated acute coronary syndrome, and endocarditis. In response, the American College of Cardiology issued a call to action for cardiovascular care teams. Opioid toxicity is primarily mediated via potent μ-receptor agonism resulting in ventilatory depression. However, both overdose and opioid withdrawal can trigger major adverse cardiovascular events resulting from hemodynamic, vascular, and proarrhythmic/electrophysiological consequences. Although natural opioid analogues are devoid of repolarization effects, synthetic agents may be proarrhythmic. This perspective explores cardiovascular consequences of opioids, the contributions of off-target electrophysiologic properties to mortality, and provides practical safety recommendations.
Topics: Analgesics, Opioid; Cardiotoxicity; Cardiovascular Diseases; Humans; Methadone; Opioid-Related Disorders
PubMed: 33446314
DOI: 10.1016/j.jacc.2020.11.002 -
Physical Chemistry Chemical Physics :... Jan 2021Interactions of the analgesic medications dextropropoxyphene (DPP, opioid), paracetamol (PCL, nonnarcotic), tramadol (TDL, nonnarcotic), ibuprofen (IBN, nonsteroidal...
Interactions of the analgesic medications dextropropoxyphene (DPP, opioid), paracetamol (PCL, nonnarcotic), tramadol (TDL, nonnarcotic), ibuprofen (IBN, nonsteroidal anti-inflammatory drug (NSAID)), and naproxen (NPX, NSAID) with pristine graphene (GN) and nitrogen-doped GN (NGN; containing only graphitic N atoms) nanosheets were explored using density functional theory (DFT) in the gas and aqueous phases. Calculations in the aqueous phase were performed using the integral equation formalism polarized continuum model (IEFPCM). Calculated geometry-optimized structures, partial atomic charges (determined using Natural Bond Orbital analysis), highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps, work functions (determined using time-dependent DFT), and molecular electrostatic potential plots showed that the adsorption process is physical in nature (viz. physisorption), primarily due to noncovalent π-π and van der Waals interactions. In addition, calculated adsorption energies (ΔEad) were exergonic, indicating that formation of the analgesic/GN and analgesic/NGN complexes is thermodynamically favorable in the gas (ΔEad values for analgesic/GN and analgesic/NGN were in the range of -66.56 kJ mol-1 to -106.78 kJ mol-1) and aqueous phases (ΔEad values for analgesic/GN and analgesic/NGN complexes were in the range of -58.75 kJ mol-1 to -100.46 kJ mol-1). Generally, for GN and NGN, adsorption was more endergonic in the aqueous phase by as much as +10.41 kJ mol-1. Calculated solvation energies (ΔEsolvation) were exergonic for all analgesic/GN complexes (ΔEsolvation values were in the range of -56.50 kJ mol-1 to -66.17 kJ mol-1) and analgesic/NGN complexes (ΔEsolvation values were in the range of -77.26 kJ mol-1 to -87.96 kJ mol-1), with analgesic/NGN complexes exhibiting greater stability in aqueous solutions (∼20 kJ mol-1 more stable). In summary, the results of this theoretical study demonstrate that the adsorption and solvation of analgesics on GN and NGN nanosheets is thermodynamically favorable. In addition, generally, analgesic/NGN complexes exhibit higher adsorption affinities and solvation energies in the gas and aqueous phases. Therefore, GN and NGN nanosheets are potential adsorbents for extracting analgesic contaminants from aqueous environments such as aquatic ecosystems.
PubMed: 33355576
DOI: 10.1039/d0cp05543c -
Journal of Analytical Toxicology Feb 2022Point-of-care (POC) urine drug screening (UDS) assays provide immediate information for patient management. However, POC UDS assays can produce false-positive results,...
Point-of-care (POC) urine drug screening (UDS) assays provide immediate information for patient management. However, POC UDS assays can produce false-positive results, which may not be recognized until confirmatory testing is completed several days later. To minimize the potential for patient harm, it is critical to identify sources of interference. Here, we applied an approach based on statistical analysis of electronic health record (EHR) data to identify medications that may cause false positives on POC UDS assays. From our institution's EHR data, we extracted 120,670 POC UDS and confirmation results, covering 12 classes of target drugs, along with each individual's prior medication exposures. Our approach is based on the idea that exposure to an interfering medication will increase the odds of a false-positive UDS result. For a given assay-medication pair, we quantified the association between medication exposures and UDS results as an odds ratio from logistic regression. We evaluated interference experimentally by spiking compounds into drug-free urine and testing the spiked samples on the POC device. Our dataset included 446 false-positive UDS results (presumptive positive screen followed by negative confirmation). We quantified the odds ratio of false positives for 528 assay-medication pairs. Of the six assay-medication pairs we evaluated experimentally, two showed interference capable of producing a presumptive positive: labetalol on the 3,4-methylenedioxymethamphetamine (MDMA) assay (at 200 μg/mL) and ranitidine on the methamphetamine assay (at 50 μg/mL). Ranitidine also produced a presumptive positive for opiates at 1,600 μg/mL and for propoxyphene at 800 μg/mL. These findings highlight the generalizability and the limits of our approach to use EHR data to identify medications that interfere with clinical immunoassays.
Topics: Electronic Health Records; False Positive Reactions; Humans; Point-of-Care Systems; Substance Abuse Detection; Urinalysis
PubMed: 33216907
DOI: 10.1093/jat/bkaa179 -
European Journal of Hospital Pharmacy :... Sep 2020Pain management in the emergency department (ED) is a key issue that must be regularly evaluated. Practice evaluation gold standard remains patient file analysis, but is...
OBJECTIVE
Pain management in the emergency department (ED) is a key issue that must be regularly evaluated. Practice evaluation gold standard remains patient file analysis, but is highly time consuming. The aim of this study is to evaluate the interest of a defined daily dose (DDD) based analysis in the evaluation of pain management in the ED.
METHODS
A local indicator was elaborated based on the DDD concept: the defined dose per admission (DDA). Unlike the DDD that corresponds to a standardised total dose administered over a day, the DDA represents the average total dose administrated to a patient throughout the stay in the ED. A DDA was assigned to every analgesic, from step 1 to step 3. Oral and injectable forms were studied, but transdermal forms were not considered. DDA values were assimilated to the existing DDDs when these were officially established by the WHO. When values were not defined by the WHO, mean values observed in local practice were selected. Annual numbers of patients admitted to the ED and quantities of each analgesic supplied by the pharmacy ward were annually extracted from respective data files. Paediatric patients being treated at a specific separate ED, only adults were considered throughout the study. Raw quantities of analgesics used each year were converted to their equivalent amounts in DDA, and then expressed in numbers of DDA per 100 admissions (DDA/100A). This indicator allowed us to describe relative evolutions of analgesics prescriptions from 2006 to 2017.
RESULTS
Analgesic overall use rose from 18.4 to 30.2 DDA/100A between 2006 and 2017, representing a prescription increase of 64%. Throughout the study, step 1 analgesics rose from 10.8 to 19.3 DDA/100A (+79%), step 3 from 1.8 to 5.4 (+200%) and step 2 remained stable around 5.6 DDA/100A. The integration of orodispersible paracetamol tablets in 2013 allowed us to halve the consumption of injectable paracetamol in the long term and had no effect on classic paracetamol oral forms such as tablets or capsules. Tramadol increased from 41% to 78% among step 2 analgesics after the withdrawal of dextropropoxyphene in 2011. Codeine use shows a steady decline from 1.9 DDA/100A in 2011 to 0.72 in 2017.
DISCUSSION/CONCLUSION
The DDA concept appears to be an effective tool for assessing long-term analgesic-use trends at hospital EDs. This tool can also mitigate one major bias at EDs, that is the lack of traceability of analgesic administration in emergency contexts. This tool could be adjusted by integrating the average length of stay in the ED.
Topics: Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Dose-Response Relationship, Drug; Drug Administration Schedule; Emergency Service, Hospital; Hospitals, University; Humans; Pain Management; Pain Measurement
PubMed: 32839258
DOI: 10.1136/ejhpharm-2018-001749 -
The Cochrane Database of Systematic... Aug 2020Acute soft tissue injuries are common and costly. The best drug treatment for such injuries is not certain, although non-steroidal anti-inflammatory drugs (NSAIDs) are... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Acute soft tissue injuries are common and costly. The best drug treatment for such injuries is not certain, although non-steroidal anti-inflammatory drugs (NSAIDs) are often recommended. There is concern about the use of oral opioids for acute pain leading to dependence. This is an update of a Cochrane Review published in 2015.
OBJECTIVES
To assess the benefits or harms of NSAIDs compared with other oral analgesics for treating acute soft tissue injuries.
SEARCH METHODS
We searched the CENTRAL, 2020 Issue 1, MEDLINE (from 1946), and Embase (from 1980) to January 2020; other databases were searched to February 2019.
SELECTION CRITERIA
We included randomised or quasi-randomised controlled trials involving people with acute soft tissue injury (sprain, strain, or contusion of a joint, ligament, tendon, or muscle occurring within 48 hours of inclusion in the study), and comparing oral NSAIDs versus paracetamol (acetaminophen), opioid, paracetamol plus opioid, or complementary and alternative medicine. The outcomes were pain, swelling, function, adverse effects, and early re-injury.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed studies for eligibility, extracted data, and assessed risk of bias. We assessed the quality of the evidence using GRADE methodology.
MAIN RESULTS
We included 20 studies, with 3305 participants. Three studies included children only. The others included predominantly young adults; approximately 60% were male. Seven studies recruited people with ankle sprains only. Most studies were at low or unclear risk of bias; however, two were at high risk of selection bias, three were at high risk of bias from lack of blinding, and five were at high risk of selective outcome reporting bias. Some evidence relating to pain relief was high certainty. Other evidence was either moderate, low or very low certainty, reflecting study limitations, indirectness, imprecision, or combinations of these. Thus, we are certain or moderately certain about some of the estimates, and uncertain or very uncertain of others. Eleven studies, involving 1853 participants compared NSAIDs with paracetamol. There were no differences between the two groups in pain at one to two hours (1178 participants, 6 studies; high-certainty evidence), at days one to three (1232 participants, 6 studies; high-certainty evidence), and at day seven or later (467 participants, 4 studies; low-certainty evidence). There was little difference between the groups in numbers of participants with minimal swelling at day seven or later (77 participants, 1 study; low-certainty evidence). Very low-certainty evidence from three studies (386 participants) means we are uncertain of the finding of little difference between the two groups in return to function at day seven or later. There was low-certainty evidence from 10 studies (1504 participants) that NSAIDs may slightly increase the risk of gastrointestinal adverse events compared with paracetamol. There was low-certainty evidence from nine studies (1679 participants) of little difference in neurological adverse events between the NSAID and paracetamol groups. Six studies, involving 1212 participants compared NSAIDs with opioids. There was moderate-certainty evidence of no difference between the groups in pain at one hour (1058 participants, 4 studies), and low-certainty evidence for no difference in pain at days four or seven (706 participants, 1 study). There was very low-certainty evidence of no important difference between the groups in swelling (84 participants, 1 study). Participants in the NSAIDs group were more likely to return to function in 7 to 10 days (542 participants, 2 studies; low-certainty evidence). There was moderate-certainty evidence (1143 participants, 5 studies) that NSAIDs were less likely to result in gastrointestinal or neurological adverse events compared with opioids. Four studies, involving 240 participants, compared NSAIDs with the combination of paracetamol and an opioid. The applicability of findings from these studies is in question because the dextropropoxyphene combination analgesic agents used are no longer in general use. Very low-certainty evidence means we are uncertain of the findings of no differences between the two interventions in the numbers with little or no pain at day one (51 participants, 1 study), day three (149 participants, 2 studies), or day seven (138 participants, 2 studies); swelling (230 participants, 3 studies); return to function at day seven (89 participants, 1 study); and the risk of gastrointestinal or neurological adverse events (141 participants, 3 studies). No studies reported re-injury rates. No studies compared NSAIDs with oral complementary and alternative medicines, AUTHORS' CONCLUSIONS: Compared with paracetamol, NSAIDs make no difference to pain at one to two hours and at two to three days, and may make no difference at day seven or beyond. NSAIDs may result in a small increase in gastrointestinal adverse events and may make no difference in neurological adverse events compared with paracetamol. Compared with opioids, NSAIDs probably make no difference to pain at one hour, and may make no difference at days four or seven. NSAIDs probably result in fewer gastrointestinal and neurological adverse effects compared with opioids. The very low-certainly evidence for all outcomes for the NSAIDs versus paracetamol with opioid combination analgesics means we are uncertain of the findings of no differences in pain or adverse effects. The current evidence should not be extrapolated to adults older than 65 years, as this group was not well represented in the studies.
Topics: Acetaminophen; Acute Disease; Administration, Oral; Adult; Analgesics; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Bias; Child; Contusions; Female; Humans; Male; Middle Aged; Pain; Randomized Controlled Trials as Topic; Soft Tissue Injuries; Sprains and Strains; Time-to-Treatment; Young Adult
PubMed: 32797734
DOI: 10.1002/14651858.CD007789.pub3 -
Journal of Chromatography. B,... Sep 2020Opioids represent a broad family of compounds that can be used in several indications: analgesics, antitussives, opioid substitution therapy (e.g. methadone,...
Quantification of methadone, buprenorphine, naloxone, opioids, and their derivates in whole blood by liquid chromatography-high-resolution mass spectrometry: Analysis of their involvement in fatal forensic cases.
Opioids represent a broad family of compounds that can be used in several indications: analgesics, antitussives, opioid substitution therapy (e.g. methadone, buprenorphine…). When these products are misused, they are often addictive. Thus, we aimed to develop an analytical method able to rapidly quantify several opiates and opioids (6-monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, 2-ethyl-1,5-dimethyl-3,3-diphenylpyrrolidine, ethylmorphine, heroin, methadone, morphine, nalbuphine, naloxone, norbuprenorphine, norcodeine, norpropoxyphene, oxycodone and propoxyphene) in whole blood by ultra-high performance liquid chromatography combined with high resolution mass spectrometry (UHPLC-HRMS). The validated assay requires only 100 µL of the blood sample. The sample is prepared by a rapid liquid-liquid extraction using 5% zinc sulfate (W/V), methanol and acetonitrile. Calibration curves range from 0.98 to 1000 µg/L, except for buprenorphine (0.39-100 µg/L) and norbuprenorphine (0.20-100 µg/L). Inter- and intra-analytical accuracy was less than 15%. Therefore, we describe the development and full validation of an accurate, sensitive and precise assay using UHPLC-HRMS for the analysis of opioids in whole blood. After validation, this new assay is successfully applied on a routine laboratory application basis.
Topics: Chromatography, High Pressure Liquid; Forensic Toxicology; Humans; Limit of Detection; Linear Models; Liquid-Liquid Extraction; Mass Spectrometry; Methadone; Opiate Alkaloids; Reproducibility of Results
PubMed: 32540719
DOI: 10.1016/j.jchromb.2020.122226 -
British Journal of Clinical Pharmacology Feb 2021Analgesics are the most widely used medicines worldwide. In parallel, opioid abuse has increased and is of major concern. The accessibility of pharmacologically powerful...
AIMS
Analgesics are the most widely used medicines worldwide. In parallel, opioid abuse has increased and is of major concern. The accessibility of pharmacologically powerful medicines and the addictovigilance signals in France about the risk of opiates addiction call for an overview of analgesic use. The objective of this study was to investigate the use of analgesics reimbursed in France over a 10-year period through its prevalence.
METHODS
A cross-sectional study repeated yearly was conducted by using data from the French reimbursement database from 2006 to 2015. Analgesics were classified according to their pharmacological potency: prevalence of use for each category and sociodemographic characteristics of patients treated were analysed.
RESULTS
The annual prevalence of analgesic use was high and increased during the study period (59.8%, 253 976 users in 2015). In 2015, prevalence was always higher in women and increased with age, except for those older than 84 years. Peripheral analgesics were the most used (55.3%, 234 739 users). The prevalence of weak analgesic use decreased (21.3%, 90 257 users), mainly due to the definitive withdrawal of dextropropoxyphene in France in 2011, which was not offset by an increase in the consumption of other weak analgesics. For strong analgesics (1.2%, 5129 users), morphine was the most widely used, with a dramatic increase in oxycodone use, especially in the elderly.
CONCLUSION
The prevalence of analgesic use is high: approximately 31 million adults had at least 1 analgesic reimbursed in 2015. The most widely used analgesics were peripheral analgesics, far ahead of opioid analgesics.
Topics: Adult; Aged; Aged, 80 and over; Analgesics, Non-Narcotic; Analgesics, Opioid; Cross-Sectional Studies; Female; France; Humans; Opioid-Related Disorders
PubMed: 32496599
DOI: 10.1111/bcp.14415 -
Frontiers in Pharmacology 2019Wnt/β-catenin signaling is involved in various biological processes, including the development of the central nervous system. The dysfunction of mitochondria has been...
Wnt/β-catenin signaling is involved in various biological processes, including the development of the central nervous system. The dysfunction of mitochondria has been shown to participate in the progress of subarachnoid hemorrhage (SAH). Traumatic subarachnoid hemorrhage (tSAH) is a serious complication in acute craniocerebral trauma. Opioids can activate the canonical Wnt/β-catenin signaling pathway. c-Myc, a downstream protein of Wnt/β-catenin signaling, contributes to the fusion of mitochondria. Here, we investigated the protective roles of Propoxyphene (Pro) against Oxyhemoglobin (OxyHb)-induced primary cultured neuron apoptosis. The data indicated that Pro rescued active-β-catenin from OxyHb-induced decline. Furthermore, Pro attenuated OxyHb-induced apoptosis and fission of mitochondria in primary cortical neurons. However, the protective effects were abrogated under active-β-catenin-deficient conditions. Together, the data presented here showed that Pro, a weak opioid analgesic drug, attenuates OxyHb-induced mitochondria-dependent apoptosis in an active-β-catenin-c-Myc-dependent manner.
PubMed: 32082150
DOI: 10.3389/fphar.2019.01616 -
Fundamental & Clinical Pharmacology Aug 2020France is experiencing an increase in the number of opioid prescriptions and related fatalities. We carried out a retrospective observational study using data from the... (Observational Study)
Observational Study
France is experiencing an increase in the number of opioid prescriptions and related fatalities. We carried out a retrospective observational study using data from the Paris PCC over a 10-year period. The main objective was to obtain an epidemiological description of the severe reported cases. The secondary objectives were to assess the evolution of the number of these cases and their severity defined by the use of fentanyl and its derivatives, the use of the opioid-poisoning treatment naloxone, and the number of fatalities. During 2008-2017, 268 511 cases were recorded, including 1 122 cases of opioid-related poisoning that required medical management. These poisonings involved tramadol (43%), codeine (25%), dextropropoxyphene (13%), and morphine (8%); most resulted from self-exposure (60%). During the 10-year study period, 130 opioid-related fatalities were recorded in the Paris area, mainly resulting from suicides (39%) in men and were attributed to morphine (27%), tramadol (24%), and methadone (21%). We did not identify an increase in the number of severe opioid-related poisonings or fatalities or in the use of fentanyl or its derivatives. Conversely, we observed an increase in the use of naloxone, suggesting an increase in the severity of opioid poisonings. Our findings show that, until 2017, the opioid overdose epidemiology in the Paris area is different to that in the USA. The systematic analysis of data from the PCCs could be a good tool for health monitoring. To assess trends in France, a national study over a longer period would also be useful.
Topics: Adolescent; Adult; Analgesics, Opioid; Cause of Death; Drug Prescriptions; Female; Humans; Male; Middle Aged; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Paris; Poison Control Centers; Poisoning; Retrospective Studies; Suicide; Time Factors; Young Adult
PubMed: 31945200
DOI: 10.1111/fcp.12534