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North RJ, Cooper G, Mears L, Bothner B, Dlakić M, Merzdorf CS. Persistent Transcriptome Alterations in Zebrafish Embryos After Discontinued Opioid Exposure. Int J Mol Sci 2025; 26:4840. [PMID: 40429979 PMCID: PMC12111994 DOI: 10.3390/ijms26104840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2025] [Revised: 05/15/2025] [Accepted: 05/15/2025] [Indexed: 05/29/2025] Open
Abstract
Much attention has been paid to the public health crisis that has resulted from the opioid epidemic. Given the high number of opioid users that are of childbearing age, the impact of utero exposure is a serious concern. Unfortunately, there is little knowledge regarding the consequences of opioid exposure during early development. While neurobehavioral effects of opioid exposure are well-documented, effects of exposure on embryogenesis remain largely unexplored. To address this gap in knowledge, we investigated the effects of oxycodone and fentanyl exposure on gene expression in zebrafish (Danio rerio) embryos using whole embryo RNA sequencing. Embryos were exposed to environmentally relevant (oxycodone HCl 10.6 ng/L and fentanyl citrate 0.629 ng/L) and therapeutically relevant doses (oxycodone HCl 35.14 μg/L and fentanyl citrate 3.14 μg/L) from 2 to 24 h post-fertilization (hpf), followed by another 24 h of opioid-free development. mRNA profiling at 48 hpf revealed dose- and drug-specific gene expression changes. Lower doses of oxycodone and fentanyl both induced more differentially expressed transcripts (DETs) than higher doses, potentially indicative of opioid receptor desensitization occurring at higher concentrations. In total, 892 DETs (corresponding to 866 genes) were identified across all conditions suggesting continued differential gene expression well after cessation of opioid exposure. Gene ontology analysis revealed changes in gene expression relating to extracellular matrix (ECM) organization, cell adhesion, and visual and nervous system formation. Key pathways include those involved in axon guidance, synapse formation, and ECM biosynthesis/remodeling, all of which have potential implications on neural connectivity and sensory development. These findings demonstrate that very early developmental exposure to opioids induces persistent transcriptomic changes which may have lasting implications for vertebrate cellular functions. Overall, these data provide insights into the molecular mechanisms of opioid-induced alterations during development.
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Affiliation(s)
- Ryan J. North
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA; (R.J.N.); (L.M.); (M.D.)
| | - Gwendolyn Cooper
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA; (G.C.); (B.B.)
| | - Lucas Mears
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA; (R.J.N.); (L.M.); (M.D.)
| | - Brian Bothner
- Department of Chemistry and Biochemistry, Montana State University, Bozeman, MT 59717, USA; (G.C.); (B.B.)
| | - Mensur Dlakić
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA; (R.J.N.); (L.M.); (M.D.)
| | - Christa S. Merzdorf
- Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA; (R.J.N.); (L.M.); (M.D.)
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Durairaj P, Liu ZL. Brain Cytochrome P450: Navigating Neurological Health and Metabolic Regulation. J Xenobiot 2025; 15:44. [PMID: 40126262 PMCID: PMC11932283 DOI: 10.3390/jox15020044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 03/07/2025] [Accepted: 03/10/2025] [Indexed: 03/25/2025] Open
Abstract
Human cytochrome P450 (CYP) enzymes in the brain represent a crucial frontier in neuroscience, with far-reaching implications for drug detoxification, cellular metabolism, and the progression of neurodegenerative diseases. The brain's complex architecture, composed of interconnected cell types and receptors, drives unique neuronal signaling pathways, modulates enzyme functions, and leads to distinct CYP gene expression and regulation patterns compared to the liver. Despite their relatively low levels of expression, brain CYPs exert significant influence on drug responses, neurotoxin susceptibility, behavior, and neurological disease risk. These enzymes are essential for maintaining brain homeostasis, mediating cholesterol turnover, and synthesizing and metabolizing neurochemicals, neurosteroids, and neurotransmitters. Moreover, they are key participants in oxidative stress responses, neuroprotection, and the regulation of inflammation. In addition to their roles in metabolizing psychotropic drugs, substances of abuse, and endogenous compounds, brain CYPs impact drug efficacy, safety, and resistance, underscoring their importance beyond traditional drug metabolism. Their involvement in critical physiological processes also links them to neuroprotection, with significant implications for the onset and progression of neurodegenerative diseases. Understanding the roles of cerebral CYP enzymes is vital for advancing neuroprotective strategies, personalizing treatments for brain disorders, and developing CNS-targeting therapeutics. This review explores the emerging roles of CYP enzymes, particularly those within the CYP1-3 and CYP46 families, highlighting their functional diversity and the pathological consequences of their dysregulation on neurological health. It also examines the potential of cerebral CYP-based biomarkers to improve the diagnosis and treatment of neurodegenerative disorders, offering new avenues for therapeutic innovation.
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Affiliation(s)
- Pradeepraj Durairaj
- Department of Chemical and Biomedical Engineering, Florida State University, Tallahassee, FL 32310, USA
- Department of Chemical and Biomedical Engineering, Florida A&M University, Tallahassee, FL 32310, USA
| | - Zixiang Leonardo Liu
- Department of Chemical and Biomedical Engineering, Florida State University, Tallahassee, FL 32310, USA
- Department of Chemical and Biomedical Engineering, Florida A&M University, Tallahassee, FL 32310, USA
- Institute for Successful Longevity, Florida State University, Tallahassee, FL 32310, USA
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Beaucage-Charron J, Rinfret J, Trottier G, Sévigny MM, Burry L, Marsot A, Williamson D. Pharmacokinetics of Opioid Infusions in the Adult Intensive Care Unit Setting-A Systematic Review. Clin Pharmacokinet 2025; 64:323-334. [PMID: 40025366 DOI: 10.1007/s40262-025-01490-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2025] [Indexed: 03/04/2025]
Abstract
INTRODUCTION Pharmacokinetics (PKs) of drugs are often altered in the intensive care unit (ICU). Opioids are often used in the ICU, particularly as continuous infusions, and their characteristics lead them to undergo PK alterations. We conducted a systematic review to assess the PK of opioid infusions in the ICU. METHODS Embase, MEDLINE, PubMed, CINAHL, and Evidence-Based Medicine Reviews (EBMR) were searched from inception to March 2024. Studies were included if they evaluated PKs of opioid infusions in adult patients in the ICU. Two reviewers independently selected and extracted data. RESULTS Out of the 1040 records screened, 17 studies were included. Five studies were conducted on fentanyl, seven on morphine, one on hydromorphone, two on remifentanil, two on alfentanil, and one on sufentanil. Most studies where observational studies or case series. The mean age was 56 years old. Duration of the infusion varied between 3 h and 20 days. PKs of fentanyl, sufentanil, and hydromorphone were significantly impaired, whereas the PKs of morphine, alfentanil, and remifentanil were impaired to a lesser degree. The PK parameter that was most affected by critical illness was the half-life (T½). CONCLUSIONS To counter these PK alterations, new therapeutic avenues must be further explored in the ICU to individualize opioid infusions.
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Affiliation(s)
- Johannie Beaucage-Charron
- Department of Pharmacy, Hôpital Maisonneuve-Rosemont, CIUSSS de l'Est-de-l'Île-de-Montréal, 5415 Bd de l'Assomption, Montréal, QC, H1T 2M4, Canada.
| | - Justine Rinfret
- Department of Pharmacy, Hôpital Maisonneuve-Rosemont, CIUSSS de l'Est-de-l'Île-de-Montréal, 5415 Bd de l'Assomption, Montréal, QC, H1T 2M4, Canada
| | - Guillaume Trottier
- Direction of Education, Research and Innovation, Hôpital Maisonneuve-Rosemont, CIUSSS de l'Est-de-l'Île-de-Montréal, Montréal, Canada
| | - Marie-Maxim Sévigny
- Direction of Education, Research and Innovation, Hôpital Maisonneuve-Rosemont, CIUSSS de l'Est-de-l'Île-de-Montréal, Montréal, Canada
| | - Lisa Burry
- Department of Pharmacy, Mount Sinai Hospital, Toronto, Canada
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada
| | - Amélie Marsot
- Faculty of Pharmacy, Université de Montréal, Montréal, Canada
| | - David Williamson
- Faculty of Pharmacy, Université de Montréal, Montréal, Canada
- Department of Pharmacy, Hôpital du Sacré-Cœur de Montréal, CIUSSS du Nord-de-l'Île-de-Montréal, Montréal, Canada
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Davies K. Medicines management in children and young people: pharmacological approaches to treat pain. Nurs Child Young People 2024:e1540. [PMID: 39663782 DOI: 10.7748/ncyp.2024.e1540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/05/2024] [Indexed: 12/13/2024]
Abstract
Pain management in children is often more complex than in adults, since pain in children can be more challenging to assess and therefore more challenging to treat. It is essential that children's nurses have knowledge and understanding of the physiology of pain and the analgesics available to treat different types of pain. This article describes nociception and provides an overview of the three main groups of analgesics - non-opioids, opioids and adjuvants - that can be used in the pharmacological management of pain in children and young people.
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Affiliation(s)
- Kate Davies
- London South Bank University, and honorary research fellow in paediatric endocrinology, Queen Mary University of London, London, England
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Wang S, Hahn G, Kesselheim AS. Impact of Priority Review Voucher Eligibility on Research and Development of Medical Countermeasures. Clin Pharmacol Ther 2024; 116:1554-1559. [PMID: 39044346 DOI: 10.1002/cpt.3388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 07/06/2024] [Indexed: 07/25/2024]
Abstract
The priority review voucher was established to incentivize research and development of treatments for traditionally underfunded diseases and was extended to medical countermeasures from 2016 to 2023, despite limited evidence of an association between the voucher program and increased product development. To determine whether the voucher program has incentivized initiation of new medical countermeasures in clinical trials, we created three cohorts of material threats: (i) COVID-19, (ii) opioid pharmaceutical-based agents, and (iii) all others. Using the Citeline Trialtrove database, we determined the number of medical countermeasures initiated in clinical trials from 2009-2016 and 2017-2023. Eligibility of COVID-19 products for the voucher was confirmed with the issuance of a voucher for remdesivir in October 2020, so we compared January 2020-October 2020 to November 2020-July 2023. We fit two Poisson models-before and after voucher creation-within each cohort. Among COVID-19 medical countermeasures, there was a decrease in the proportion of drugs initiated before (4.5%; 95% CI, 1.0 to 8.3%) vs. after voucher eligibility (-5.1%; 95% CI, -6.1 to -4.0%) (P = 0.01). Among opioid pharmaceutical-based agents medical countermeasures, the rate of new drugs initiated did not change from 2009-2016 (8.1%, 95% CI, -4.4 to 22.6%) to 2017-2023 (5.6%; 95% CI, -3.2 to 15.2%) (P = 0.82). Among all other medical countermeasures, the rate of new drugs initiated also did not change from 2009-2016 (6.6%; 95% CI, -5.6 to 20.8%) to 2017-2023 (-14.8%; 95% CI, -29.2 to 2.0%) (P = 0.15). The priority review voucher program was not associated with stimulating new clinical testing of investigational medical countermeasures.
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Affiliation(s)
- Stephanie Wang
- Harvard University, Cambridge, Massachusetts, USA
- Program On Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Georg Hahn
- Program On Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Aaron S Kesselheim
- Program On Regulation, Therapeutics, and Law (PORTAL), Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Metcalfe RK, Dobischok S, Bansback N, MacDonald S, Byres D, Lajeunesse J, Harrison S, Koch B, Topping B, Brock T, Foreman J, Schechter M, Oviedo-Joekes E. Client preferences for the design and delivery of injectable opioid agonist treatment services: Results from a best-worst scaling task. Addiction 2024; 119:2139-2150. [PMID: 39054406 DOI: 10.1111/add.16620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 06/19/2024] [Indexed: 07/27/2024]
Abstract
BACKGROUND AND AIMS Clinical trials support injectable opioid agonist treatment (iOAT) for individuals with opioid use disorder (OUD) for whom other pharmacological management approaches are not well-suited. However, despite substantial research indicating that person-centered care improves engagement, retention and health outcomes for individuals with OUD, structural requirements (e.g. drug policies) often dictate how iOAT must be delivered, regardless of client preferences. This study aimed to quantify clients' iOAT delivery preferences to improve client engagement and retention. DESIGN Cross-sectional preference elicitation survey. SETTING Metro Vancouver, British Columbia, Canada. PARTICIPANTS 124 current and former iOAT clients. MEASUREMENTS Participants completed a demographic questionnaire package and an interviewer-led preference elicitation survey (case 2 best-worst scaling task). Latent class analysis was used to identify distinct preference groups and explore demographic differences between preference groups. FINDINGS Most participants (n = 100; 81%) were current iOAT clients. Latent class analysis identified two distinct groups of client preferences: (1) autonomous decision-makers (n = 73; 59%) and (2) shared decision-makers (n = 51; 41%). These groups had different preferences for how medication type and dosage were selected. Both groups prioritized access to take-home medication (i.e. carries), the ability to set their own schedule, receiving iOAT in a space they like and having other services available at iOAT clinics. Compared with shared decision-makers, fewer autonomous decision-makers identified as a cis-male/man and reported flexible preferences. CONCLUSIONS Injectable opioid agonist treatment (iOAT) clients surveyed in Vancouver, Canada, appear to prefer greater autonomy than they currently have in choosing OAT medication type, dosage and treatment schedule.
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Affiliation(s)
- Rebecca Kathleen Metcalfe
- Centre for Advancing Health Outcomes, Providence Health Care, St. Paul's Hospital, Vancouver, Canada
| | - Sophia Dobischok
- Centre for Advancing Health Outcomes, Providence Health Care, St. Paul's Hospital, Vancouver, Canada
- Department of Education and Counselling Psychology, McGill University, Montreal, Canada
| | - Nick Bansback
- Centre for Advancing Health Outcomes, Providence Health Care, St. Paul's Hospital, Vancouver, Canada
- School of Population and Public Health, University of British Columbia, Vancouver, Canada
| | - Scott MacDonald
- Providence Health Care, Providence Crosstown Clinic, Vancouver, Canada
| | - David Byres
- Provincial Health Services Authority, Vancouver, Canada
| | | | - Scott Harrison
- Providence Health Care, Providence Crosstown Clinic, Vancouver, Canada
| | - Bryce Koch
- Doctor Peter Center, Vancouver, BC, Canada
| | - Blue Topping
- Downtown Community Health Centre, Vancouver, Canada
| | - Terry Brock
- Lookout Housing and Health Society, Surrey, Canada
| | - Julie Foreman
- Hope to Health Research and Innovation Centre, Vancouver, Canada
| | - Martin Schechter
- Centre for Advancing Health Outcomes, Providence Health Care, St. Paul's Hospital, Vancouver, Canada
- School of Population and Public Health, University of British Columbia, Vancouver, Canada
| | - Eugenia Oviedo-Joekes
- Centre for Advancing Health Outcomes, Providence Health Care, St. Paul's Hospital, Vancouver, Canada
- School of Population and Public Health, University of British Columbia, Vancouver, Canada
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Gustafsson M, Silva V, Valeiro C, Joaquim J, van Hunsel F, Matos C. Misuse, Abuse and Medication Errors' Adverse Events Associated with Opioids-A Systematic Review. Pharmaceuticals (Basel) 2024; 17:1009. [PMID: 39204114 PMCID: PMC11357286 DOI: 10.3390/ph17081009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 07/26/2024] [Accepted: 07/29/2024] [Indexed: 09/03/2024] Open
Abstract
Opioids are the strongest analgesics available and are crucial in the treatment of acute and chronic pain. The line between these critical medications and how they are used beyond standard therapeutics in cases such as abuse, misuse, and medication errors needs to be understood, as it affects their safety, efficacy, and manner of use. The aim of this systematic review was to identify what is known about the adverse events resulting from the abuse, misuse, and medication errors associated with opioid use. A systematic search was conducted in the PubMed®, Scopus® and, EBSCO® databases to retrieve studies from the inception to December 2023 reporting abuse, misuse, and medication errors associated with medicinal opioid use. Two authors independently screened titles and abstracts and full text according to eligibility using Covidence® software. Full articles were examined by two independent reviewers, and disagreements were resolved by a third reviewer. The risk of bias was assessed by the JBI's critical appraisal tools. A total of 934 articles were screened by their title and abstract. Then, 151 articles were selected for full text screening. Of these, 34 studies were eligible for inclusion in this review. The included studies varied significantly in their population sizes, ranging from 9 individuals to 298,433 patients, and encompassed a diverse demographic, including all ages and both sexes. The studies consistently reported a range of adverse events associated with opioid use. Fentanyl, morphine, oxycodone, tramadol, and hydrocodone were frequently implicated. The data heterogeneity in this field resulted in challenges in drawing conclusions. The review highlights that some opioids, particularly fentanyl, morphine, and oxycodone, are frequently associated with preventable adverse drug reactions, abuse, and medication errors, underscoring the need for robust preventative measures and ongoing research to mitigate opioid-related harm.
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Affiliation(s)
- Moa Gustafsson
- Department of Pharmacology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 41390 Gothenburg, Sweden;
| | - Vítor Silva
- Unidade Local de Saúde de Coimbra, EPE, 3004-561 Coimbra, Portugal;
| | - Carolina Valeiro
- Eu2P European Programme in Pharmacovigilance and Pharmacoepidemiology, University Autónoma de Barcelona, 08193 Barcelona, Spain;
| | - João Joaquim
- Instituto Politécnico De Coimbra, ESTESC-Coimbra Health School, Farmácia, 3046-854 Coimbra, Portugal;
| | - Florence van Hunsel
- Netherlands Pharmacovigilance Centre Lareb, 5237 MH ’s-Hertogenbosch, The Netherlands;
- Department of PharmacoTherapy, Epidemiology & Economics, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, 9747 AG Groningen, The Netherlands
| | - Cristiano Matos
- Instituto Politécnico De Coimbra, ESTESC-Coimbra Health School, Farmácia, 3046-854 Coimbra, Portugal;
- QLV Research Consulting, 3030-193 Coimbra, Portugal
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8
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Kamiński P, Lorek M, Baszyński J, Tadrowski T, Gorzelańczyk EJ, Feit J, Tkaczenko H, Owoc J, Woźniak A, Kurhaluk N. Role of antioxidants in the neurobiology of drug addiction: An update. Biomed Pharmacother 2024; 175:116604. [PMID: 38692055 DOI: 10.1016/j.biopha.2024.116604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 04/13/2024] [Accepted: 04/16/2024] [Indexed: 05/03/2024] Open
Abstract
Relationships between protective enzymatic and non-enzymatic pro-antioxidant mechanisms and addictive substances use disorders (SUDs) are analyzed here, based on the results of previous research, as well as on the basis of our current own studies. This review introduces new aspects of comparative analysis of associations of pro-antixidant and neurobiological effects in patients taking psychoactive substances and complements very limited knowledge about relationships with SUDs from different regions, mainly Europe. In view of the few studies on relations between antioxidants and neurobiological processes acting in patients taking psychoactive substances, this review is important from the point of view of showing the state of knowledge, directions of diagnosis and treatment, and further research needed explanation. We found significant correlations between chemical elements, pro-antioxidative mechanisms, and lipoperoxidation in the development of disorders associated with use of addictive substances, therefore elements that show most relations (Pr, Na, Mn, Y, Sc, La, Cr, Al, Ca, Sb, Cd, Pb, As, Hg, Ni) may be significant factors shaping SUDs. The action of pro-antioxidant defense and lipid peroxidation depends on the pro-antioxidative activity of ions. We explain the strongest correlations between Mg and Sb, and lipoperoxidation in addicts, which proves their stimulating effect on lipoperoxidation and on the induction of oxidative stress. We discussed which mechanisms and neurobiological processes change susceptibility to SUDs. The innovation of this review is to show that addicted people have lower activity of dismutases and peroxidases than healthy ones, which indicates disorders of antioxidant system and depletion of enzymes after long-term tolerance of stressors. We explain higher level of catalases, reductases, ceruloplasmin, bilirubin, retinol, α-tocopherol and uric acid of addicts. In view of poorly understood factors affecting addiction, analysis of interactions allows for more effective understanding of pathogenetic mechanisms leading to formation of addiction and development the initiation of directed, more effective treatment (pharmacological, hormonal) and may be helpful in the diagnosis of psychoactive changes.
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Affiliation(s)
- Piotr Kamiński
- Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Division of Medical Biology and Biochemistry, Division of Ecology and Environmental Protection, M. Skłodowska-Curie St. 9, Bydgoszcz PL 85-094, Poland; University of Zielona Góra, Faculty of Biological Sciences, Institute of Biological Sciences, Department of Biotechnology, Prof. Z. Szafran St. 1, Zielona Góra PL 65-516, Poland.
| | - Małgorzata Lorek
- Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Division of Medical Biology and Biochemistry, Division of Ecology and Environmental Protection, M. Skłodowska-Curie St. 9, Bydgoszcz PL 85-094, Poland
| | - Jędrzej Baszyński
- Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Division of Medical Biology and Biochemistry, Division of Ecology and Environmental Protection, M. Skłodowska-Curie St. 9, Bydgoszcz PL 85-094, Poland
| | - Tadeusz Tadrowski
- Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Department of Dermatology and Venereology, Faculty of Medicine M. Skłodowska-Curie St. 9, Bydgoszcz PL 85-094, Poland
| | - Edward Jacek Gorzelańczyk
- Kazimierz Wielki University in Bydgoszcz, Institute of Philosophy, M.K. Ogińskiego St. 16, Bydgoszcz PL 85-092, Poland; Adam Mickiewicz University in Poznań, Faculty of Mathematics and Computer Science, Uniwersyt Poznański St, 4, Poznań PL 61-614, Poland; Primate Cardinal Stefan Wyszyński Provincial Hospital in Sieradz, Psychiatric Centre in Warta, Sieradzka St. 3, Warta PL 98-290, Poland; Nicolaus Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, Department of Theoretical Foundations of Biomedical Sciences and Medical Computer Science, Faculty of Pharmacy, Jagiellońska St. 15, Bydgoszcz PL 85-067, Poland
| | - Julia Feit
- Pallmed sp. z o.o., W. Roentgen St. 3, Bydgoszcz PL 85-796, Poland
| | - Halina Tkaczenko
- Pomeranian University in Słupsk, Institute of Biology, Arciszewski St. 22 B, Słupsk PL 76-200, Poland
| | - Jakub Owoc
- National Institute of Geriatrics, Rheumatology and Rehabilitation named after prof. dr hab. Eleonora Reicher, MD, Spartańska St. 1, Warszawa PL 02-637, Poland
| | - Alina Woźniak
- Nicholaus Copernicus University, Collegium Medicum in Bydgoszcz, Department of Medical Biology and Biochemistry, M. Karłowicz St. 24, Bydgoszcz PL 85-092, Poland
| | - Natalia Kurhaluk
- Pomeranian University in Słupsk, Institute of Biology, Arciszewski St. 22 B, Słupsk PL 76-200, Poland
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Jones CMP, Day RO, Koes BW, Latimer J, Maher CG, McLachlan AJ, Billot L, Shan S, Lin CWC. Opioids for back and neck pain: the OPAL trial - Authors' reply. Lancet 2024; 403:2379-2380. [PMID: 38823991 DOI: 10.1016/s0140-6736(24)00487-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 03/06/2024] [Indexed: 06/03/2024]
Affiliation(s)
- Caitlin M P Jones
- Sydney Musculoskeletal Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia; The Institute for Musculoskeletal Health, Sydney Local Health District, Sydney, NSW, Australia
| | - Richard O Day
- Department of Clinical Pharmacology and Toxicology, St Vincent's Hospital Sydney and St Vincent's Clinical Campus, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Bart W Koes
- Department of General Practice, Erasmus MC, Rotterdam, Netherlands; Center for Muscle and Joint Health, University of Southern Denmark, Odense, Denmark
| | - Jane Latimer
- Sydney Musculoskeletal Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia; The Institute for Musculoskeletal Health, Sydney Local Health District, Sydney, NSW, Australia
| | - Chris G Maher
- Sydney Musculoskeletal Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia; The Institute for Musculoskeletal Health, Sydney Local Health District, Sydney, NSW, Australia
| | - Andrew J McLachlan
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia
| | - Laurent Billot
- The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Sana Shan
- The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Chung-Wei Christine Lin
- Sydney Musculoskeletal Health, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2050, Australia; The Institute for Musculoskeletal Health, Sydney Local Health District, Sydney, NSW, Australia.
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Magel T, Arreola LAG, Guh D, MacDonald S, Harrison S, Schechter M, Oviedo-Joekes E. Building Capacity for Injectable Diacetylmorphine and Hydromorphone for the Treatment of Opioid Use Disorder: Identifying Typical Doses. J Psychoactive Drugs 2024:1-14. [PMID: 38590251 DOI: 10.1080/02791072.2024.2338734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 02/22/2024] [Indexed: 04/10/2024]
Abstract
Identifying typical doses of existing opioid use disorder medications, such as injectable opioid agonist treatment (iOAT), can support client and program needs, and potentially increase iOAT expansion. Longitudinal data from participants in a cohort study (n = 131), along with clinic dispensation records from August 2014 to April 2020, were used to examine physician prescribed as well as used doses of injectable diacetylmorphine and hydromorphone. Dosage groups, by medication and prescribed dose per session, were created for both hydromorphone and diacetylmorphine. A total of 534, 522 injections were registered during the study period among 129 participants. Mean received diacetylmorphine doses ranged from 106 to 989 mg per day, with most clients using 125-262 mg per session (mean 192.99 mg) and attending 2.40 sessions per day. Mean received hydromorphone doses ranged from 51.09 to 696.06 mg per day, with the majority using 88-154 mg per session (mean 121.32 mg; 2.43 sessions). Average daily doses remained stable overtime and, while mid-range doses were most typical, participants used the whole spectrum of allowable dose prescriptions. Evidence supporting typical doses of iOAT can be integrated into program planning to better allow providers and prescribers to anticipate program needs and engage in individualized care.
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Affiliation(s)
- Tianna Magel
- School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
| | | | - Daphne Guh
- Centre for Advancing Health Outcomes, Providence Health Care, St. Paul's Hospital, Vancouver, BC, Canada
| | - Scott MacDonald
- Providence Health Care, Providence Crosstown Clinic, Vancouver, BC, Canada
| | - Scott Harrison
- Providence Health Care, Urban Health and Substance Use, Vancouver, BC, Canada
| | - Martin Schechter
- School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
- Centre for Advancing Health Outcomes, Providence Health Care, St. Paul's Hospital, Vancouver, BC, Canada
| | - Eugenia Oviedo-Joekes
- School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada
- Centre for Advancing Health Outcomes, Providence Health Care, St. Paul's Hospital, Vancouver, BC, Canada
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11
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Kohaf N, Harby SA, Abd-Ellatief AF, Elsaid MA, Abdelmottaleb NA, Abd Elsalam TF. Comparison of Effectiveness and Safety of Oxycodone Hydrochloride and Fentanyl for Post-operative Pain Following Total Hip Arthroplasty: A Randomized Triple-Blind Trial. Anesth Pain Med 2024; 14:e142710. [PMID: 38725916 PMCID: PMC11078234 DOI: 10.5812/aapm-142710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 01/08/2024] [Accepted: 01/16/2024] [Indexed: 05/12/2024] Open
Abstract
Background Total hip replacement (THR) is frequently associated with intense post-surgical pain. Effective pain management is of crucial importance to improving patient's condition and increasing his/her satisfaction in the post-operative time. Objectives This study aimed to compare the analgesic effect and safety of oxycodone and fentanyl after THR. Methods Seventy-two cases scheduled for elective THR were included in this randomized, triple-blind trial. The patients were equally randomized into 2 groups: Fentanyl group (50 ug of fentanyl) and oxycodone group (oxycodone 4 mg). Drugs were received 20 min prior to the end of the operation. Results Post-operative visual analog scale (VAS) measurements at rest and movement at the post-anesthesia care unit (PACU) and in the ward, 2 h, 4 h, and 8 h post-operatively exhibited a significantly reduced value in the oxycodone group compared to the fentanyl group (P-value < 0.05). Time to first rescue for analgesia was delayed significantly in the oxycodone compared to the fentanyl group (P-value < 0.001). Fentanyl consumption (ug) in the 1st post-operative 12 h, 24 h, and 48 h decreased significantly in the oxycodone group compared to the fentanyl group (P-value < 0.001). Post-operative nausea, vomiting, headache, and pruritus were matched between the 2 groups (P > 0.05). Conclusions A bolus dose of 4 mg of oxycodone provided superior analgesic efficacy than 50 ug fentanyl as evidenced by significantly lower pain score, delayed onset to first request for analgesia, and the smaller amount of fentanyl consumption at 12, 24, and 48 h post-total hip arthroplasty compared to fentanyl. The incidence of adverse events was comparable between the 2 groups.
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Affiliation(s)
- Neveen Kohaf
- Lecturer of Clinical Pharmacy, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Salama A Harby
- Lecturer of Anesthesiology, Intensive Care and Pain Management, Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt
| | - Ahmed F Abd-Ellatief
- Lecturer of Anesthesiology, Intensive Care and Pain Management, Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt
| | - Mohamed A Elsaid
- Lecturer of Anesthesiology, Intensive Care and Pain Management, Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt
| | - Neazy A Abdelmottaleb
- Assistant Professor of Anesthesiology, Intensive Care and Pain Management, Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt
| | - Tamer F Abd Elsalam
- Lecturer of Anesthesiology, Intensive Care and Pain Management, Damietta Faculty of Medicine, Al-Azhar University, Damietta, Egypt
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12
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Gallagher JP, Twohig PA, Crnic A, Rochling FA. Illicit Drugs and Candidates for Endoscopy and Surgery. RECENT STRATEGIES IN HIGH RISK SURGERY 2024:127-144. [DOI: 10.1007/978-3-031-56270-9_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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13
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Kamens HM, Cramer S, Hanley RN, Chase S, Wickenheisser A, Horton WJ, Zhang N. Neuroimaging of opioid exposure: a review of preclinical animal models to inform addiction research. Psychopharmacology (Berl) 2023; 240:2459-2482. [PMID: 37857897 DOI: 10.1007/s00213-023-06477-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 10/01/2023] [Indexed: 10/21/2023]
Abstract
Opioid use results in thousands of overdose deaths each year. To address this crisis, we need a better understanding of the neurobiological mechanisms that drive opioid abuse. The noninvasive imaging tools positron emission tomography (PET), functional magnetic resonance imaging (fMRI), and manganese-enhanced magnetic resonance imaging (MEMRI) can be used to identify how brain activity responds to acute opioid exposure and adapts to chronic drug treatment. These techniques can be performed in humans and animal models, and brain networks identified in animals closely map to the human brain. Animal models have the advantage of being able to systematically examine the independent effects of opioid exposure in a controlled environment accounting for the complex factors that drive opioid misuse in humans. This review synthesizes literature that utilized noninvasive neuroimaging tools (PET, fMRI, and MEMRI) measuring brain activity correlates in animals to understand the neurobiological consequences of exposure to abused opioids. A PubMed search in September 2023 identified 25 publications. These manuscripts were divided into 4 categories based on the route and duration of drug exposure (acute/chronic, active/passive administration). Within each category, the results were generally consistent across drug and imaging protocols. These papers cover a 20-year range and highlight the advancements in neuroimaging methodology during that time. These advances have enabled researchers to achieve greater resolution of brain regions altered by opioid exposure and to identify patterns of brain activation across regions (i.e., functional connectivity) and within subregions of structures. After describing the existing literature, we suggest areas where additional research is needed.
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Affiliation(s)
- Helen M Kamens
- Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, 16802, USA.
| | - Samuel Cramer
- The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Rachel N Hanley
- Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Spencer Chase
- The Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Anna Wickenheisser
- Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, 16802, USA
| | - William J Horton
- Department of Biobehavioral Health, The Pennsylvania State University, University Park, PA, 16802, USA
| | - Nanyin Zhang
- Department of Biomedical Engineering, The Pennsylvania State University, University Park, PA, 16802, USA
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14
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Moss L, Hijma H, Demitrack M, Kim J, Groeneveld GJ, van Velzen M, Niesters M, Olofsen E, Dahan A. Neurocognitive Effect of Biased µ-Opioid Receptor Agonist Oliceridine, a Utility Function Analysis and Comparison with Morphine. Anesthesiology 2023; 139:746-756. [PMID: 37656771 DOI: 10.1097/aln.0000000000004758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/03/2023]
Abstract
BACKGROUND Oliceridine (Olinvyk) is a μ-opioid receptor agonist that in contrast to conventional opioids preferentially engages the G-protein-coupled signaling pathway. This study was designed to determine the utility function of oliceridine versus morphine based on neurocognitive tests and cold pressor test. METHODS The study had a randomized, double-blind, placebo-controlled, partial block three-way crossover design. Experiments were performed in 20 male and female volunteers. The subjects received intravenous oliceridine (1 or 3 mg; cohorts of 10 subjects/dose), morphine (5 or 10 mg; cohorts of 10 subjects/dose), or placebo on three separate occasions. Before and after dosing, neurocognitive tests, cold pressor test, and plasma drug concentrations were obtained at regular intervals. Population pharmacokinetic-pharmacodynamic analyses served as the basis for construction of a utility function, which is an objective function of probability of benefit minus probability of harm. Antinociception served as the measure of benefit, and slowing of saccadic peak velocity and increased body sway as the measures of neurocognitive harm. RESULTS The oliceridine and morphine C50 values, i.e., the effect-site concentrations causing 50% effect, were as follows: antinociception, 13 ± 2 and 23 ± 7 ng/ml; saccadic peak velocity, 90 ± 14 and 54 ± 15 ng/ml; and body sway, 10 ± 2 and 5.6 ± 0.8 ng/ml, respectively. The ratio oliceridine/morphine of the therapeutic indices, C50(benefit)/C50(harm), were 0.34 (95% CI, 0.17 to 0.7; P < 0.01) for saccadic peak velocity and 0.33 (0.16 to 0.50; P < 0.01) for body sway. The oliceridine utility was positive across the effect-site concentration 5 to 77 ng/ml, indicative of a greater probability of benefit than harm. The morphine utility was not significantly different from 0 from 0 to 100 ng/ml. Over the concentration range 15 to 50 ng/ml, the oliceridine utility was superior to that of morphine (P < 0.01). Similar observations were made for body sway. CONCLUSIONS These data indicate that over the clinical concentration range, oliceridine is an analgesic with a favorable safety profile over morphine when considering analgesia and neurocognitive function. EDITOR’S PERSPECTIVE
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Affiliation(s)
- Laurence Moss
- Center for Human Drug Research, Leiden, The Netherlands
| | - Hemme Hijma
- Center for Human Drug Research, Leiden, The Netherlands
| | | | | | - Geert Jan Groeneveld
- Center for Human Drug Research, Leiden, The Netherlands; and Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Monique van Velzen
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marieke Niesters
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Erik Olofsen
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Albert Dahan
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands; and PainLess Foundation, Leiden, The Netherlands
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15
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Coates S, Lazarus P. Hydrocodone, Oxycodone, and Morphine Metabolism and Drug-Drug Interactions. J Pharmacol Exp Ther 2023; 387:150-169. [PMID: 37679047 PMCID: PMC10586512 DOI: 10.1124/jpet.123.001651] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Revised: 08/18/2023] [Accepted: 08/21/2023] [Indexed: 09/09/2023] Open
Abstract
Awareness of drug interactions involving opioids is critical for patient treatment as they are common therapeutics used in numerous care settings, including both chronic and disease-related pain. Not only do opioids have narrow therapeutic indexes and are extensively used, but they have the potential to cause severe toxicity. Opioids are the classical pain treatment for patients who suffer from moderate to severe pain. More importantly, opioids are often prescribed in combination with multiple other drugs, especially in patient populations who typically are prescribed a large drug regimen. This review focuses on the current knowledge of common opioid drug-drug interactions (DDIs), focusing specifically on hydrocodone, oxycodone, and morphine DDIs. The DDIs covered in this review include pharmacokinetic DDI arising from enzyme inhibition or induction, primarily due to inhibition of cytochrome p450 enzymes (CYPs). However, opioids such as morphine are metabolized by uridine-5'-diphosphoglucuronosyltransferases (UGTs), principally UGT2B7, and glucuronidation is another important pathway for opioid-drug interactions. This review also covers several pharmacodynamic DDI studies as well as the basics of CYP and UGT metabolism, including detailed opioid metabolism and the potential involvement of metabolizing enzyme gene variation in DDI. Based upon the current literature, further studies are needed to fully investigate and describe the DDI potential with opioids in pain and related disease settings to improve clinical outcomes for patients. SIGNIFICANCE STATEMENT: A review of the literature focusing on drug-drug interactions involving opioids is important because they can be toxic and potentially lethal, occurring through pharmacodynamic interactions as well as pharmacokinetic interactions occurring through inhibition or induction of drug metabolism.
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Affiliation(s)
- Shelby Coates
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
| | - Philip Lazarus
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington
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16
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De Rosa F, Giannatiempo B, Charlier B, Coglianese A, Mensitieri F, Gaudino G, Cozzolino A, Filippelli A, Piazza O, Dal Piaz F, Izzo V. Pharmacological Treatments and Therapeutic Drug Monitoring in Patients with Chronic Pain. Pharmaceutics 2023; 15:2088. [PMID: 37631302 PMCID: PMC10457775 DOI: 10.3390/pharmaceutics15082088] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/29/2023] [Accepted: 07/24/2023] [Indexed: 08/27/2023] Open
Abstract
Pain is an unpleasant sensory and emotional experience that affects every aspect of a patient's life and which may be treated through different pharmacological and non-pharmacological approaches. Analgesics are the drugs most commonly used to treat pain, and in specific situations, the use of opioids may be considered with caution. These drugs, in fact, do not always induce optimal analgesia in patients, and several problems are associated with their use. The purpose of this narrative review is to describe the pharmacological approaches currently used for the management of chronic pain. We review several aspects, from the pain-scale-based methods currently available to assess the type and intensity of pain, to the most frequently administered drugs (non-narcotic analgesics and narcotic analgesics), whose pharmacological characteristics are briefly reported. Overall, we attempt to provide an overview of different pharmacological treatments while also illustrating the relevant guidelines and indications. We then report the strategies that may be used to reduce problems related to opioid use. Specifically, we focus our attention on therapeutic drug monitoring (TDM), a tool that could help clinicians select the most suitable drug and dose to be used for each patient. The actual potential of using TDM to optimize and personalize opioid-based pain treatments is finally discussed based on recent scientific reports.
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Affiliation(s)
- Federica De Rosa
- Department of Medicine, Surgery and Dentistry, Postgraduate School of Clinical Pharmacology and Toxicology, University of Salerno, 84084 Fisciano, Italy; (F.D.R.); (B.G.); (B.C.); (A.C.); (A.F.)
- University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy; (A.C.); (O.P.)
| | - Bruno Giannatiempo
- Department of Medicine, Surgery and Dentistry, Postgraduate School of Clinical Pharmacology and Toxicology, University of Salerno, 84084 Fisciano, Italy; (F.D.R.); (B.G.); (B.C.); (A.C.); (A.F.)
| | - Bruno Charlier
- Department of Medicine, Surgery and Dentistry, Postgraduate School of Clinical Pharmacology and Toxicology, University of Salerno, 84084 Fisciano, Italy; (F.D.R.); (B.G.); (B.C.); (A.C.); (A.F.)
- University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy; (A.C.); (O.P.)
| | - Albino Coglianese
- University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy; (A.C.); (O.P.)
- Department of Medicine, Surgery and Dentistry, Postgraduate School of Clinical Pathology and Clinical Biochemistry, University of Salerno, 84084 Fisciano, Italy
| | - Francesca Mensitieri
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84084 Fisciano, Italy; (F.M.); (G.G.)
| | - Giulia Gaudino
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84084 Fisciano, Italy; (F.M.); (G.G.)
| | - Armando Cozzolino
- Department of Medicine, Surgery and Dentistry, Postgraduate School of Clinical Pharmacology and Toxicology, University of Salerno, 84084 Fisciano, Italy; (F.D.R.); (B.G.); (B.C.); (A.C.); (A.F.)
| | - Amelia Filippelli
- Department of Medicine, Surgery and Dentistry, Postgraduate School of Clinical Pharmacology and Toxicology, University of Salerno, 84084 Fisciano, Italy; (F.D.R.); (B.G.); (B.C.); (A.C.); (A.F.)
- University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy; (A.C.); (O.P.)
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84084 Fisciano, Italy; (F.M.); (G.G.)
| | - Ornella Piazza
- University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy; (A.C.); (O.P.)
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84084 Fisciano, Italy; (F.M.); (G.G.)
| | - Fabrizio Dal Piaz
- University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy; (A.C.); (O.P.)
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84084 Fisciano, Italy; (F.M.); (G.G.)
| | - Viviana Izzo
- University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy; (A.C.); (O.P.)
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84084 Fisciano, Italy; (F.M.); (G.G.)
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Elder HJ, Walentiny DM, Beardsley PM. Theophylline reverses oxycodone's but not fentanyl's respiratory depression in mice while caffeine is ineffective against both opioids. Pharmacol Biochem Behav 2023; 229:173601. [PMID: 37414364 PMCID: PMC10599235 DOI: 10.1016/j.pbb.2023.173601] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 07/02/2023] [Accepted: 07/03/2023] [Indexed: 07/08/2023]
Abstract
RATIONALE The opioid epidemic remains a pressing public health crisis in the United States. Most of these overdose deaths are a result of lethal respiratory depression. In recent years the increasing incidence of opioid-involved overdose deaths has been driven by fentanyl, which is more resistant to adequate reversal by naloxone (NARCAN ®) than semi-synthetic or classical morphinan predecessors like oxycodone and heroin. For this and other reasons (e.g., precipitating withdrawal) non-opioidergic pharmacotherapies to reverse opioid-depressed respiration are needed. Methylxanthines are a class of stimulant drugs including caffeine and theophylline which exert their effects primarily via adenosine receptor antagonism. Evidence suggests methylxanthines can stimulate respiration by enhancing neural activity in respiratory nuclei in the pons and medulla independent of opioid receptors. This study aimed to determine whether caffeine and theophylline can stimulate respiration in mice when depressed by fentanyl and oxycodone. METHODS Whole-body plethysmography was used to characterize fentanyl and oxycodone's effects on respiration and their reversal by naloxone in male Swiss Webster mice. Next, caffeine and theophylline were tested for their effects on basal respiration. Finally, each methylxanthine was evaluated for its ability to reverse similar levels of respiratory depression induced by fentanyl or oxycodone. RESULTS AND CONCLUSIONS Oxycodone and fentanyl dose-dependently reduced respiratory minute volume (ml/min; MVb) that was reversible by naloxone. Caffeine and theophylline each significantly increased basal MVb. Theophylline, but not caffeine, completely reversed oxycodone-depressed respiration. In contrast, neither methylxanthine elevated fentanyl-depressed respiration at the doses tested. Despite their limited efficacy for reversing opioid-depressed respiration when administered alone, the methylxanthines safety, duration, and mechanism of action supports further evaluation in combination with naloxone to augment its reversal of opioid-depressed respiration.
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Affiliation(s)
- Harrison J Elder
- Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - D Matthew Walentiny
- Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Patrick M Beardsley
- Department of Pharmacology & Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA; Center for Biomarker Research & Precision Medicine, Virginia Commonwealth University School of Pharmacy, Richmond, VA, USA.
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Lambert DG. Opioids and opioid receptors; understanding pharmacological mechanisms as a key to therapeutic advances and mitigation of the misuse crisis. BJA OPEN 2023; 6:100141. [PMID: 37588171 PMCID: PMC10430815 DOI: 10.1016/j.bjao.2023.100141] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 04/05/2023] [Accepted: 04/12/2023] [Indexed: 08/18/2023]
Abstract
Opioids are a mainstay in acute pain management and produce their effects and side effects (e.g., tolerance, opioid-use disorder and immune suppression) by interaction with opioid receptors. I will discuss opioid pharmacology in some controversial areas of enquiry of anaesthetic relevance. The main opioid target is the µ (mu,MOP) receptor but other members of the opioid receptor family, δ (delta; DOP) and κ (kappa; KOP) opioid receptors also produce analgesic actions. These are naloxone-sensitive. There is important clinical development relating to the Nociceptin/Orphanin FQ (NOP) receptor, an opioid receptor that is not naloxone-sensitive. Better understanding of the drivers for opioid effects and side effects may facilitate separation of side effects and production of safer drugs. Opioids bind to the receptor orthosteric site to produce their effects and can engage monomer or homo-, heterodimer receptors. Some ligands can drive one intracellular pathway over another. This is the basis of biased agonism (or functional selectivity). Opioid actions at the orthosteric site can be modulated allosterically and positive allosteric modulators that enhance opioid action are in development. As well as targeting ligand-receptor interaction and transduction, modulating receptor expression and hence function is also tractable. There is evidence for epigenetic associations with different types of pain and also substance misuse. As long as the opioid narrative is defined by the 'opioid crisis' the drive to remove them could gather pace. This will deny use where they are effective, and access to morphine for pain relief in low income countries.
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Oviedo-Joekes E, Dobischok S, Carvajal J, MacDonald S, McDermid C, Klakowicz P, Harrison S, LaJeunesse J, Chow N, Brown M, Gill S, Schechter M. Clients' experiences on North America's first take-home injectable opioid agonist treatment (iOAT) program: a qualitative study. BMC Health Serv Res 2023; 23:553. [PMID: 37237256 PMCID: PMC10215060 DOI: 10.1186/s12913-023-09558-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/16/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND To support public health measures during the COVID-19 pandemic, oral opioid agonist treatment (OAT) take-home doses were expanded in Western countries with positive results. Injectable OAT (iOAT) take-home doses were previously not an eligible option, and were made available for the first time in several sites to align with public health measures. Building upon these temporary risk-mitigating guidelines, a clinic in Vancouver, BC continued to offer two of a possible three daily doses of take-home injectable medications to eligible clients. The present study explores the processes through which take-home iOAT doses impacted clients' quality of life and continuity of care in real-life settings. METHODS Three rounds of semi-structured qualitative interviews were conducted over a period of seventeen months beginning in July 2021 with eleven participants receiving iOAT take-home doses at a community clinic in Vancouver, British Columbia. Interviews followed a topic guide that evolved iteratively in response to emerging lines of inquiry. Interviews were recorded, transcribed, and then coded using NVivo 1.6 using an interpretive description approach. RESULTS Participants reported that take-home doses granted them the freedom away from the clinic to have daily routines, form plans, and enjoy unstructured time. Participants appreciated the greater privacy, accessibility, and ability to engage in paid work. Furthermore, participants enjoyed greater autonomy to manage their medication and level of engagement with the clinic. These factors contributed to greater quality of life and continuity of care. Participants shared that their dose was too essential to divert and that they felt safe transporting and administering their medication off-site. In the future, all participants would like more accessible treatment such as access longer take-home prescriptions (e.g., one week), the ability to pick-up at different and convenient locations (e.g., community pharmacies), and a medication delivery service. CONCLUSIONS Reducing the number of daily onsite injections from two or three to only one revealed the diversity of rich and nuanced needs that added flexibility and accessibility in iOAT can meet. Actions such as licencing diverse opioid medications/formulations, medication pick-up at community pharmacies, and a community of practice that supports clinical decisions are necessary to increase take-home iOAT accessibility.
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Affiliation(s)
- Eugenia Oviedo-Joekes
- Centre for Health Evaluation & Outcome Sciences, Providence Health Care, St. Paul's Hospital, 575- 1081 Burrard St, Vancouver, BC, V6Z 1Y6, Canada.
- School of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver, BC, V6T 1Z3, Canada.
| | - Sophia Dobischok
- Centre for Health Evaluation & Outcome Sciences, Providence Health Care, St. Paul's Hospital, 575- 1081 Burrard St, Vancouver, BC, V6Z 1Y6, Canada
| | - José Carvajal
- Centre for Health Evaluation & Outcome Sciences, Providence Health Care, St. Paul's Hospital, 575- 1081 Burrard St, Vancouver, BC, V6Z 1Y6, Canada
| | - Scott MacDonald
- Providence Health Care, Providence Crosstown Clinic, 84 West Hastings Street, Vancouver, BC, V6B 1G6, Canada
| | - Cheryl McDermid
- Providence Health Care, Providence Crosstown Clinic, 84 West Hastings Street, Vancouver, BC, V6B 1G6, Canada
| | - Piotr Klakowicz
- Providence Health Care, Providence Crosstown Clinic, 84 West Hastings Street, Vancouver, BC, V6B 1G6, Canada
| | - Scott Harrison
- Providence Health Care, Providence Crosstown Clinic, 84 West Hastings Street, Vancouver, BC, V6B 1G6, Canada
| | - Julie LaJeunesse
- Providence Health Care, Providence Crosstown Clinic, 84 West Hastings Street, Vancouver, BC, V6B 1G6, Canada
| | - Nancy Chow
- Providence Health Care, Providence Crosstown Clinic, 84 West Hastings Street, Vancouver, BC, V6B 1G6, Canada
| | - Murray Brown
- Providence Health Care, Providence Crosstown Clinic, 84 West Hastings Street, Vancouver, BC, V6B 1G6, Canada
| | - Sam Gill
- Providence Health Care, Providence Crosstown Clinic, 84 West Hastings Street, Vancouver, BC, V6B 1G6, Canada
| | - Martin Schechter
- Centre for Health Evaluation & Outcome Sciences, Providence Health Care, St. Paul's Hospital, 575- 1081 Burrard St, Vancouver, BC, V6Z 1Y6, Canada
- School of Population and Public Health, University of British Columbia, 2206 East Mall, Vancouver, BC, V6T 1Z3, Canada
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Amend N, Thiermann H, Worek F, Wille T. A pharmacologically pre-contracted smooth muscle bowel model for the study of highly-potent opioid receptor agonists and antagonists. Toxicol Lett 2023:S0378-4274(23)00187-X. [PMID: 37245850 DOI: 10.1016/j.toxlet.2023.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 02/24/2023] [Accepted: 05/22/2023] [Indexed: 05/30/2023]
Abstract
Isolated organ models are a versatile tool for pharmacological and toxicological research. Small bowel has been used to assess the inhibition of smooth muscle contraction by opioids. In the present study, we set out to establish a pharmacologically stimulated rat bowel model. The effects of carfentanil, remifentanil and the new synthetic opioid U-48800 and their respective antagonists naloxone, nalmefene and naltrexone were studied in a small bowel model in rats. The IC50 values of the tested opioids were as follows: carfentanil (IC50 = 0.02 µmol/L, CI 0.02-0.03 µmol/L) ≫ remifentanil (IC50 = 0.51 µmol/L, CI 0.40-0.66 µmol/L) ≫ U-48800 (IC50 = 1.36 µmol/L, CI 1.20-1.54 µmol/L). The administration of the opioid receptor antagonists naloxone, naltrexone and nalmefene led to progressive, parallel rightward shifts of the dose-response curves. Naltrexone was most potent in antagonizing the effects of U-48800, whereas naltrexone and nalmefene were most effective in antagonizing the effects of carfentanil. In summary, the current model seems to be a robust tool to study opioid effects in a small bowel model without the necessity of using electrical stimulation.
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Affiliation(s)
- Niko Amend
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937 Munich, Germany.
| | - Horst Thiermann
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937 Munich, Germany
| | - Franz Worek
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937 Munich, Germany
| | - Timo Wille
- Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstr. 11, 80937 Munich, Germany
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21
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Soyer A, Leterrier S, Breuil L, Goislard M, Leroy C, Saba W, Thibault K, Bo GD, Bottlaender M, Caillé F, Goutal S, Tournier N. Validation of a pharmacological imaging challenge using 11C-buprenorphine and 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography to study the effects of buprenorphine to the rat brain. Front Neurosci 2023; 17:1181786. [PMID: 37234261 PMCID: PMC10205997 DOI: 10.3389/fnins.2023.1181786] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 04/17/2023] [Indexed: 05/27/2023] Open
Abstract
Aim Buprenorphine mainly acts as an agonist of mu-opioid receptors (mu-OR). High dose buprenorphine does not cause respiratory depression and can be safely administered to elicit typical opioid effects and explore pharmacodynamics. Acute buprenorphine, associated with functional and quantitative neuroimaging, may therefore provide a fully translational pharmacological challenge to explore the variability of response to opioids in vivo. We hypothesized that the CNS effects of acute buprenorphine could be monitored through changes in regional brain glucose metabolism, assessed using 18F-FDG microPET in rats. Materials and methods First, level of receptor occupancy associated with a single dose of buprenorphine (0.1 mg/kg, s.c) was investigated through blocking experiments using 11C-buprenorphine PET imaging. Behavioral study using the elevated plus-maze test (EPM) was performed to assess the impact of the selected dose on anxiety and also locomotor activity. Then, brain PET imaging using 18F-FDG was performed 30 min after injection of unlabeled buprenorphine (0.1 mg/kg, s.c) vs. saline. Two different 18F-FDG PET acquisition paradigms were compared: (i) 18F-FDG injected i.v. under anesthesia and (ii) 18F-FDG injected i.p. in awake animals to limit the impact of anesthesia. Results The selected dose of buprenorphine fully blocked the binding of 11C-buprenorphine in brain regions, suggesting complete receptor occupancy. This dose had no significant impact on behavioral tests used, regardless of the anesthetized/awake handling paradigm. In anesthetized rats, injection of unlabeled buprenorphine decreased the brain uptake of 18F-FDG in most brain regions except in the cerebellum which could be used as a normalization region. Buprenorphine treatment significantly decreased the normalized brain uptake of 18F-FDG in the thalamus, striatum and midbrain (p < 0.05), where binding of 11C-buprenorphine was the highest. The awake paradigm did not improve sensitivity and impact of buprenorphine on brain glucose metabolism could not be reliably estimated. Conclusion Buprenorphine (0.1 mg/kg, s.c) combined with 18F-FDG brain PET in isoflurane anesthetized rats provides a simple pharmacological imaging challenge to investigate the CNS effects of full receptor occupancy by this partial mu-OR agonist. Sensitivity of the method was not improved in awake animals. This strategy may be useful to investigate de desensitization of mu-OR associated with opioid tolerance in vivo.
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Affiliation(s)
- Amélie Soyer
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
| | - Sarah Leterrier
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
| | - Louise Breuil
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
| | - Maud Goislard
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
| | - Claire Leroy
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
| | - Wadad Saba
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
| | - Karine Thibault
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, Bretigny sur Orge, France
| | - Gregory Dal Bo
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
- Department of Toxicology and Chemical Risks, Armed Forces Biomedical Research Institute, Bretigny sur Orge, France
| | - Michel Bottlaender
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
| | - Fabien Caillé
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
| | - Sébastien Goutal
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
| | - Nicolas Tournier
- Laboratoire d’Imagerie Biomédicale Multimodale (BioMaps), CEA, CNRS, Inserm, Service Hospitalier Frédéric Joliot, Université Paris-Saclay, Orsay, France
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22
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Marcianò G, Vocca C, Evangelista M, Palleria C, Muraca L, Galati C, Monea F, Sportiello L, De Sarro G, Capuano A, Gallelli L. The Pharmacological Treatment of Chronic Pain: From Guidelines to Daily Clinical Practice. Pharmaceutics 2023; 15:pharmaceutics15041165. [PMID: 37111650 PMCID: PMC10144480 DOI: 10.3390/pharmaceutics15041165] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/30/2023] [Accepted: 04/04/2023] [Indexed: 04/29/2023] Open
Abstract
In agreement with the International Association for the Study of Pain, chronic pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. To date, there are several types of pain: nociceptive, neuropathic, and nociplastic. In the present narrative review, we evaluated the characteristics of the drugs used for each type of pain, according to guidelines, and their effects in people with comorbidity to reduce the development of severe adverse events.
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Affiliation(s)
- Gianmarco Marcianò
- Operative Unit of Pharmacology and Pharmacovigilance, "Mater Domini" Hospital, 88100 Catanzaro, Italy
| | - Cristina Vocca
- Operative Unit of Pharmacology and Pharmacovigilance, "Mater Domini" Hospital, 88100 Catanzaro, Italy
| | - Maurizio Evangelista
- Department of Anesthesia, Resuscitation and Pain Therapy, Sacred Heart Catholic University, 00100 Rome, Italy
| | - Caterina Palleria
- Operative Unit of Pharmacology and Pharmacovigilance, "Mater Domini" Hospital, 88100 Catanzaro, Italy
| | - Lucia Muraca
- Department of Primary Care, ASP 7, 88100 Catanzaro, Italy
| | - Cecilia Galati
- Research Center FAS@UMG, Department of Health Science, University Magna Graecia, 88100 Catanzaro, Italy
| | - Francesco Monea
- Research Center FAS@UMG, Department of Health Science, University Magna Graecia, 88100 Catanzaro, Italy
| | - Liberata Sportiello
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, 80138 Naples, Italy
- Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Giovambattista De Sarro
- Operative Unit of Pharmacology and Pharmacovigilance, "Mater Domini" Hospital, 88100 Catanzaro, Italy
- Research Center FAS@UMG, Department of Health Science, University Magna Graecia, 88100 Catanzaro, Italy
| | - Annalisa Capuano
- Campania Regional Centre for Pharmacovigilance and Pharmacoepidemiology, 80138 Naples, Italy
- Department of Experimental Medicine, Section of Pharmacology "L. Donatelli", University of Campania "Luigi Vanvitelli", Via Costantinopoli 16, 80138 Naples, Italy
| | - Luca Gallelli
- Operative Unit of Pharmacology and Pharmacovigilance, "Mater Domini" Hospital, 88100 Catanzaro, Italy
- Research Center FAS@UMG, Department of Health Science, University Magna Graecia, 88100 Catanzaro, Italy
- Medifarmagen Srl, University of Catanzaro and Mater Domini Hospital, 88100 Catanzaro, Italy
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23
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Hellinga M, Algera MH, Olofsen E, van der Schrier R, Sarton E, van Velzen M, Dahan A, Niesters M. Oral Oxycodone-Induced Respiratory Depression during Normocapnia and Hypercapnia: A Pharmacokinetic-Pharmacodynamic Modeling Study. Clin Pharmacol Ther 2023; 113:1080-1088. [PMID: 36744649 DOI: 10.1002/cpt.2863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Accepted: 01/31/2023] [Indexed: 02/07/2023]
Abstract
The widely prescribed opioid oxycodone may cause lethal respiratory depression. We compared the effects of oxycodone on breathing and antinociception in healthy young volunteers. After pharmacokinetic/pharmacodynamic (PK/PD) modeling, we constructed utility functions to combine the wanted and unwanted end points into a single function. We hypothesized that the function would be predominantly negative over the tested oxycodone concentration range. Twenty-four male and female volunteers received 20 (n = 12) or 40 (n = 12) mg oral oxycodone immediate-release tablets. Hypercapnic ventilatory responses (visit 1) or responses to 3 nociceptive assays (pain pressure, electrical, and thermal tests; visit 2) were measured at regular intervals for 7 hours. the PK/PD analyses, that included carbon dioxide kinetics, stood at the basis of the utility function: probability of antinociception minus probability of respiratory depression. Oxycodone had rapid onset/offset times (30-40 minutes) with potency values (effect-site concentration causing 50% of effect) ranging from 0.05 to 0.13 ng/mL for respiratory variables obtained at hypercapnia and antinociceptive responses. Ventilation at an extrapolated end-tidal carbon dioxide partial pressure of 55 mmHg, was used for creation of 3 utility functions, one for each of the nociceptive tests. Contrary to expectation, the utility functions were close to zero or positive over the clinical oxycodone concentration range. The similar or better likelihood for antinociception relative to respiratory depression may be related to oxycodone's receptor activation profile or to is high likeability that possibly alters the modulation of nociceptive input. Oxycodone differs from other μ-opioids, such as fentanyl, that have a consistent negative utility.
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Affiliation(s)
- Marieke Hellinga
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Marijke Hyke Algera
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Erik Olofsen
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Elise Sarton
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Monique van Velzen
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Albert Dahan
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands.,PainLess Foundation, Leiden, The Netherlands
| | - Marieke Niesters
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
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24
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Lodhia JV, Eyre L, Smith M, Toth L, Troxler M, Milton RS. Management of thoracic trauma. Anaesthesia 2023; 78:225-235. [PMID: 36572548 DOI: 10.1111/anae.15934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2022] [Indexed: 12/28/2022]
Abstract
Managing major thoracic trauma begins with identifying and anticipating injuries associated with the mechanism of injury. The key aims are to reduce early mortality and the impact of associated complications to expedite recovery and restore the patient to their pre-injury state. While imaging is imperative to identify the extent of thoracic trauma, some pathology may require immediate treatment. The majority can be managed with adequate pleural drainage, but respiratory failure and poor gas exchange may require either non-invasive or invasive ventilation. Ventilation strategies to protect from complications such as barotrauma, volutrauma and ventilator-induced lung injury are important to consider. The management of pain is vital in reducing respiratory complications. A multimodal strategy using local, regional and systemic analgesia may mitigate respiratory side effects of opioid use. With optimal pain management, physiotherapy can be fully utilised to reduce respiratory complications and enhance early recovery. Thoracic surgeons should be consulted early for consideration of surgical management of specific injuries. With a greater understanding of the mechanisms of injury and the appropriate use of available resources, favourable outcomes can be reached in this cohort of patients. Overall, a multidisciplinary and holistic approach results in the best patient outcomes.
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Affiliation(s)
- J V Lodhia
- Department of Thoracic Surgery, St James University Hospital, Leeds, UK
| | - L Eyre
- Department of Anaesthesia, St James University Hospital, Leeds, UK
| | - M Smith
- Department of Rehabilitation Medicine, Leeds General Infirmary, Leeds, UK
| | - L Toth
- Department of Orthopaedics, Leeds General Infirmary, Leeds, UK
| | - M Troxler
- Department of Vascular Surgery, Leeds General Infirmary, Leeds, UK
| | - R S Milton
- Department of Thoracic Surgery, St James University Hospital, Leeds, UK
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25
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Rau J, Hemphill A, Araguz K, Cunningham R, Stefanov A, Weise L, Hook MA. Adverse Effects of Repeated, Intravenous Morphine on Recovery after Spinal Cord Injury in Young, Male Rats Are Blocked by a Kappa Opioid Receptor Antagonist. J Neurotrauma 2022; 39:1741-1755. [PMID: 35996351 PMCID: PMC10039279 DOI: 10.1089/neu.2022.0208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Immediately following spinal cord injury (SCI) patients experience pain associated with injury to the spinal cord and nerves as well as with accompanying peripheral injuries. This pain is usually treated with opioids, and most commonly with morphine. However, in a rodent model we have shown that, irrespective of the route of administration, morphine administered in the acute phase of SCI undermines long-term locomotor recovery. Our previous data suggest that activation of kappa opioid receptors (KORs) mediates these negative effects. Blocking KORs with norbinaltorphimine (norBNI), prior to a single dose of epidural morphine, prevented the morphine-induced attenuation of locomotor recovery. Because numerous cellular changes occur with chronic opioid administration compared with a single dose, the current study tested whether norBNI was also effective in a more clinically relevant paradigm of repeated, intravenous morphine administration after SCI. We hypothesized that blocking KOR activation during repeated, intravenous morphine administration would also protect recovery. Supporting this hypothesis, we found that blocking KOR activation in young, male rats prevented the negative effects of morphine on locomotor recovery, although neither norBNI nor morphine had an effect on long-term pain at the doses used. We also found that norBNI treatment blocked the adverse effects of morphine on lesion size. These data suggest that a KOR antagonist given in conjunction with morphine may provide a clinical strategy for effective analgesia without compromising locomotor recovery after SCI.
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Affiliation(s)
- Josephina Rau
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, Texas, USA
- Texas A&M Institute for Neuroscience, Bryan, Texas, USA
| | - Annebel Hemphill
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, Texas, USA
| | - Kendall Araguz
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, Texas, USA
| | - Rachel Cunningham
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, Texas, USA
| | - Alexander Stefanov
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, Texas, USA
- Texas A&M Institute for Neuroscience, Bryan, Texas, USA
| | - Lara Weise
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, Texas, USA
| | - Michelle A. Hook
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, Texas, USA
- Texas A&M Institute for Neuroscience, Bryan, Texas, USA
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26
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Treatment History and Interest in Injectable Opioid Agonist Treatment With Hydromorphone Among People Who Inject Drugs. J Addict Med 2022:01271255-990000000-00101. [PMID: 36255107 DOI: 10.1097/adm.0000000000001093] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVES Injectable opioid agonist treatment (iOAT) is a novel approach to treating opioid use disorder (OUD) that is typically reserved for treatment-experienced persons who inject drugs (PWID) with long-standing OUD. This study examined PWID's past OUD treatment histories and their attitudes toward iOAT with hydromorphone. METHODS This cross-sectional study recruited syringe services program participants with OUD in New York City. Participants self-reported past OUD care episodes (detoxification; outpatient, inpatient, or medication treatment; or mutual aid groups) and current interest in iOAT with hydromorphone (assessed on a 4-point scale with 3 or 4 considered "interested"). Participants with 2 or more treatment episodes in the past 5 years were considered treatment-experienced. We examined whether the number of past care episodes was associated with interest in iOAT. RESULTS Of 108 PWID, most participants were male (68.5%) and Hispanic (68.5%) with a mean age of 43 years (±10.8). Nearly all (98.1%) had severe OUD and had received past OUD care (96.3%), with the mean number of care episodes being 17.4 (SD, ±15.9). Most participants (59.8%) were treatment-experienced. Interest in iOAT with hydromorphone was high (64.8%), but there was no significant association between total past care episodes and expressing interest in iOAT (odds ratio, 1.02; 95% confidence interval, 0.99-1.05). CONCLUSION Participants were highly treatment-experienced, and iOAT interest was high regardless of prior OUD treatment. New OUD treatment options, such as iOAT with hydromorphone, would be welcomed by PWID whose OUD has not remitted with conventional treatment as well as other PWID.
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27
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Qasem AMA, Rowan MG, Blagbrough IS. Poisonous Piperidine Plants and the Biodiversity of Norditerpenoid Alkaloids for Leads in Drug Discovery: Experimental Aspects. Int J Mol Sci 2022; 23:12128. [PMID: 36292987 PMCID: PMC9603787 DOI: 10.3390/ijms232012128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 10/04/2022] [Accepted: 10/07/2022] [Indexed: 11/16/2022] Open
Abstract
There are famous examples of simple (e.g., hemlock, Conium maculatum L.) and complex (e.g., opium poppy, Papaver somniferum L., Papaveraceae) piperidine-alkaloid-containing plants. Many of these are highly poisonous, whilst pepper is well-known gastronomically, and several substituted piperidine alkaloids are therapeutically beneficial as a function of dose and mode of action. This review covers the taxonomy of the genera Aconitum, Delphinium, and the controversial Consolida. As part of studying the biodiversity of norditerpenoid alkaloids (NDAS), the majority of which possess an N-ethyl group, we also quantified the fragment occurrence count in the SciFinder database for NDA skeletons. The wide range of NDA biodiversity is also captured in a review of over 100 recently reported isolated alkaloids. Ring A substitution at position 1 is important to determine the NDA skeleton conformation. In this overview of naturally occurring highly oxygenated NDAs from traditional Aconitum and Delphinium plants, consideration is given to functional effect and to real functional evidence. Their high potential biological activity makes them useful candidate molecules for further investigation as lead compounds in the development of selective drugs.
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28
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Song Y, He Q, Huang W, Yang L, Zhou S, Xiao X, Wang Z, Huang W. New insight into the analgesic recipe: A cohort study based on smart patient-controlled analgesia pumps records. Front Pharmacol 2022; 13:988070. [PMID: 36299897 PMCID: PMC9589502 DOI: 10.3389/fphar.2022.988070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 08/15/2022] [Indexed: 11/23/2022] Open
Abstract
Purpose: Intravenous patient-controlled analgesia (IV-PCA) has been widely used; however, regimen criteria have not yet been established. In China, the most often used opioid is sufentanil, for which repeated doses are a concern, and empirical flurbiprofen axetil (FBP) as an adjuvant. We hypothesized that hydromorphone would be a better choice and also evaluated the effectiveness of FBP as an adjuvant. Methods: This historical cohort study was conducted in two tertiary hospitals in China and included 12,674 patients using hydromorphone or sufentanil for IV-PCA between April 1, 2017, and January 30, 2021. The primary outcome was analgesic insufficiency at static (AIS). The secondary outcomes included analgesic insufficiency with movement (AIM) and common opioid-related adverse effects such as postoperative nausea and vomiting (PONV) and dizziness. Results: Sufentanil, but not the sufentanil-FBP combination, was associated with higher risks of AIS and AIM compared to those for hydromorphone (OR 1.64 [1.23, 2.19], p < 0.001 and OR 1.42 [1.16, 1.73], p < 0.001). Hydromorphone combined with FBP also decreased the risk of both AIS and AIM compared to those for pure hydromorphone (OR 0.74 [0.61, 0.90], p = 0.003 and OR 0.80 [0.71, 0.91], p < 0.001). However, the risk of PONV was higher in patients aged ≤35 years using FBP (hydromorphone-FBP vs. hydromorphone and sufentanil-FBP vs. hydromorphone, OR 1.69 [1.22, 2.33], p = 0.001 and 1.79 [1.12, 2.86], p = 0.015). Conclusion: Hydromorphone was superior to sufentanil for IV-PCA in postoperative analgesia. Adding FBP may improve the analgesic effects of both hydromorphone and sufentanil but was associated with an increased risk of PONV in patients <35 years of age.
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Affiliation(s)
- Yiyan Song
- Department of Anesthesia, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Qiulan He
- Department of Anesthesia, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenzhong Huang
- Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia
| | - Lu Yang
- Department of Anesthesia, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shaopeng Zhou
- Department of Anesthesia, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Xiaoyu Xiao
- Department of Anesthesia, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai, China
| | - Zhongxing Wang
- Department of Anesthesia, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Zhongxing Wang, ; Wenqi Huang,
| | - Wenqi Huang
- Department of Anesthesia, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Zhongxing Wang, ; Wenqi Huang,
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29
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Bedene A, Dahan A, Rosendaal FR, van Dorp ELA. Opioid epidemic: lessons learned and updated recommendations for misuse involving prescription versus non-prescription opioids. Expert Rev Clin Pharmacol 2022; 15:1081-1094. [PMID: 36068971 DOI: 10.1080/17512433.2022.2114898] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
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.
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Affiliation(s)
- Ajda Bedene
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.,Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Albert Dahan
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Frits R Rosendaal
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Eveline L A van Dorp
- Department of Anesthesiology, Leiden University Medical Center, Leiden, The Netherlands
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McKendrick G, McDevitt DS, Shafeek P, Cottrill A, Graziane NM. Anterior cingulate cortex and its projections to the ventral tegmental area regulate opioid withdrawal, the formation of opioid context associations and context-induced drug seeking. Front Neurosci 2022; 16:972658. [PMID: 35992922 PMCID: PMC9388764 DOI: 10.3389/fnins.2022.972658] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Clinical evidence suggests that there are correlations between activity within the anterior cingulate cortex (ACC) following re-exposure to drug-associated contexts and drug craving. However, there are limited data contributing to our understanding of ACC function at the cellular level during re-exposure to drug-context associations as well as whether the ACC is directly related to context-induced drug seeking. Here, we addressed this issue by employing our novel behavioral procedure capable of measuring the formation of drug-context associations as well as context-induced drug-seeking behavior in male mice (8-12 weeks of age) that orally self-administered oxycodone. We found that mice escalated oxycodone intake during the long-access training sessions and that conditioning with oxycodone was sufficient to evoke conditioned place preference (CPP) and drug-seeking behaviors. Additionally, we found that thick-tufted, but not thin-tufted pyramidal neurons (PyNs) in the ACC as well as ventral tegmental area (VTA)-projecting ACC neurons had increased intrinsic membrane excitability in mice that self-administered oxycodone compared to controls. Moreover, we found that global inhibition of the ACC or inhibition of VTA-projecting ACC neurons was sufficient to significantly reduce oxycodone-induced CPP, drug seeking, and spontaneous opioid withdrawal. These results demonstrate a direct role of ACC activity in mediating context-induced opioid seeking among other behaviors, including withdrawal, that are associated with the DSM-V criteria of opioid use disorder.
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Affiliation(s)
- Greer McKendrick
- Neuroscience Program, Penn State College of Medicine, Hershey, PA, United States
- Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, PA, United States
| | - Dillon S. McDevitt
- Neuroscience Program, Penn State College of Medicine, Hershey, PA, United States
- Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, PA, United States
| | - Peter Shafeek
- Medicine Program, Penn State College of Medicine, Hershey, PA, United States
| | - Adam Cottrill
- Neuroscience Program, Penn State College of Medicine, Hershey, PA, United States
- Department of Anesthesiology and Perioperative Medicine, Penn State College of Medicine, Hershey, PA, United States
| | - Nicholas M. Graziane
- Departments of Anesthesiology and Perioperative Medicine and Pharmacology, Penn State College of Medicine, Hershey, PA, United States
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Bioequivalence, Drugs with Narrow Therapeutic Index and the Phenomenon of Biocreep: A Critical Analysis of the System for Generic Substitution. Healthcare (Basel) 2022; 10:healthcare10081392. [PMID: 35893214 PMCID: PMC9394341 DOI: 10.3390/healthcare10081392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/22/2022] [Accepted: 07/23/2022] [Indexed: 11/17/2022] Open
Abstract
The prescription of generic drugs represents one of the main cost-containment strategies of health systems, aimed at reducing pharmaceutical expenditure. In this context, most regulatory authorities encourage or obligate dispensing generic drugs because they are far less expensive than their brand-name alternatives. However, drug substitution can be critical in particular situations, such as the use of drugs with a narrow therapeutic index (NTI). Moreover, generics cannot automatically be considered bioequivalent with each other due to the biocreep phenomenon. In Italy, the regulatory authority has established the Transparency Lists which include the medications that will be automatically substituted for brand-name drugs, except in exceptional cases. This is a useful tool to guide prescribers and guarantee pharmaceutical sustainability, but it does not consider the biocreep phenomenon.
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Mattioli I, Bettiol A, Crescioli G, Bonaiuti R, Prisco D, Mannaioni G, Lombardi N, Vannacci A. Hospitalisations related to benzodiazepine, Z-drug, and opioid treatment in Italy: a claim on the risks associated with inappropriate use. Eur J Clin Pharmacol 2022; 78:1511-1519. [PMID: 35732964 PMCID: PMC9365734 DOI: 10.1007/s00228-022-03354-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Accepted: 06/08/2022] [Indexed: 11/25/2022]
Abstract
Purpose Benzodiazepines (BZD), Z-drugs (ZD), and opioids share a high risk of abuse. This study assessed and characterised adverse events (AEs) related to BDZ, ZD, and opioids leading to emergency department (ED) visits in the Italian setting. Methods ED accesses related to BDZ, ZD, and/or opioids were analysed from the MEREAFaPS database. Information on AEs, suspected and concomitant medications was retrieved. Multivariate logistic regression was used to estimate the reporting odds ratios (RORs) of hospitalisation according to the different treatments. Results A total of 5,970 pharmacovigilance reports involving BZD/ZD (n = 3,106), opioids (n = 2,767), or their combination (n = 97) were analysed. Compared to opioids, patients with BZD/ZD-related AEs were often younger (51 vs 64 years), more frequently presented 2+ suspected medications (13 vs 3%), and often had a history of abuse (4%). Twenty-three percent of BZD/ZD-related AEs were related to drug abuse (vs 2% of opioid-related ones) and frequently required patient hospitalisation (52% vs 24%), despite the significantly lower clinical complexity of these patients as compared to those on opioids. An increased risk of hospitalisation was found for flurazepam (ROR 1.62; 95% CI, 1.18–2.22), prazepam (2.66; 1.05–6.70), lorazepam (1.26; 1.07–1.49), and morphine (1.76; 1.11–2.79). Conclusions These results indicate that, in Italy, the inappropriate use of BZD/ZD is a relevant heath issue, often leading to serious AEs requiring patients’ ED visits and hospitalisation, especially in young women and patients with a history of substance abuse. Supplementary information The online version contains supplementary material available at 10.1007/s00228-022-03354-7.
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Affiliation(s)
- Irene Mattioli
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alessandra Bettiol
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Giada Crescioli
- Section of Pharmacology and Toxicology, Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Viale G. Pieraccini, 6, 50139, Florence, Italy.
- Tuscan Regional Centre of Pharmacovigilance, Florence, Italy.
| | - Roberto Bonaiuti
- Section of Pharmacology and Toxicology, Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Viale G. Pieraccini, 6, 50139, Florence, Italy
| | - Domenico Prisco
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Guido Mannaioni
- Section of Pharmacology and Toxicology, Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Viale G. Pieraccini, 6, 50139, Florence, Italy
- Medical Toxicology Unit and Poison Control Centre, Careggi University Hospital, Florence, Italy
| | - Niccolò Lombardi
- Section of Pharmacology and Toxicology, Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Viale G. Pieraccini, 6, 50139, Florence, Italy
- Tuscan Regional Centre of Pharmacovigilance, Florence, Italy
| | - Alfredo Vannacci
- Section of Pharmacology and Toxicology, Department of Neurosciences, Psychology, Drug Research and Child Health, University of Florence, Viale G. Pieraccini, 6, 50139, Florence, Italy
- Tuscan Regional Centre of Pharmacovigilance, Florence, Italy
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Zhang T, Li M, Han X, Nie G, Zheng A. Effect of Different Absorption Enhancers on the Nasal Absorption of Nalmefene Hydrochloride. AAPS PharmSciTech 2022; 23:143. [PMID: 35578146 DOI: 10.1208/s12249-022-02252-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Accepted: 03/10/2022] [Indexed: 11/30/2022] Open
Abstract
The purpose of this work is to explore the effects of novel absorption enhancers on the nasal absorption of nalmefene hydrochloride (NMF). First, the influence of absorption enhancers with different concentrations and types and drug concentrations on the nasal absorption of NMF was investigated in vivo in rats. The absorption enhancers studied include n-dodecyl-β-D-maltoside (DDM), hydroxypropyl-β-cyclodextrin (HP-β-CD), and polyethylene glycol (15)-hydroxy Stearate (Solutol®HS15). At the same time, the in situ toad palate model and rat nasal mucosa model were used to assess the cilia toxicity. The results showed that all the absorption enhancers investigated significantly promote the nasal absorption of NMF, but with different degrees and trends. Among them, the 0.5% (w/v) DDM had the strongest enhancement effect, followed by 0.5% (w/v) Solutol®HS15, 0.25% (w/v) DDM, 0.25% (w/v) Solutol®HS15, 0.1% (w/v) Solutol®HS15, 0.1% (w/v) DDM, and 0.25% (w/v) HP-β-CD, with absolute bioavailability of 76.49%, 72.14%, 71.00%, 69.46%, 60.41%, 59.42%, and 55.18%, respectively. All absorption enhancers exhibited good safety profiles in nasal ciliary toxicity tests. From the perspective of enhancing effect and safety, we considered DDM to be a promising nasal absorption enhancer. And in addition to DDM, Solutol®HS15 can also promote intranasal absorption of NMF, which will provide another option for the development of nalmefene hydrochloride nasal spray.
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Kremer HJ. Time to initiate randomized controlled clinical trials with methadone in cancer patients. F1000Res 2022; 8:1835. [PMID: 35601274 PMCID: PMC9091806 DOI: 10.12688/f1000research.20454.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/10/2022] [Indexed: 11/20/2022] Open
Abstract
Public media coverage has fueled a demand for methadone as potential cure for cancer itself. Because patients have asked for respective prescriptions, clinical societies issued statements warning against the use of methadone as long as preclinical findings have not been supported by clinical evidence. In fact, not all preclinical data clearly support relevant effects. However, strong epidemiologic data suggest beneficial effects of methadone on cancer. Alternative explanations, namely better safety of methadone or hidden selection bias, seem less likely. This uncertainty can only be resolved by randomized controlled clinical trials. This review discusses all relevant data pertinent to methadone and cancer, uncovers supportive epidemiologic data, and suggests possible study designs.
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Zhao J, Cai S, Zhang L, Rao Y, Kang X, Feng Z. Progress, Challenges, and Prospects of Research on the Effect of Gene Polymorphisms on Adverse Reactions to Opioids. Pain Ther 2022; 11:395-409. [PMID: 35429333 PMCID: PMC9098754 DOI: 10.1007/s40122-022-00374-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Accepted: 03/07/2022] [Indexed: 11/28/2022] Open
Abstract
The abuse of opioids has become one of the most serious concerns in the world. Opioid use can cause serious adverse reactions, including respiratory depression, postoperative nausea and vomiting, itching, and even death. These adverse reactions are also important complications of clinical application of opioid drugs that may affect patient safety and recovery. Due to the fear of adverse reactions of opioids, clinicians often do not dare to use opioids in an adequate or appropriate amount, thus affecting the clinical medication strategy and the quality of treatment for patients. The prediction of adverse reactions to opioids is one of the most concerned problems in clinical practice. At present, the correlation between gene polymorphism and the efficacy of opiates has been widely studied and preliminarily confirmed, but the research on the effect of gene polymorphism on the adverse reactions of opiates is relatively limited. Existing studies have made encouraging progress in predicting the incidence and severity of adverse opioid reactions and clinical management by using genetic testing, but most of these studies are single-center, small-sample clinical studies or animal experiments, which have strong limitations. When the same receptor or enzyme is studied by different experimental methods, different or even opposite conclusions can be drawn. These phenomena indicate that the correlation between gene polymorphism and adverse opioid reaction still needs further research and demonstration. At present, it is still too early to use genetic testing to predict opioid adverse reactions in clinic. In this paper, the correlation between gene polymorphism and adverse opioid reactions and a small number of clinical applications were reviewed in terms of pharmacokinetics and pharmacodynamics, in order to provide some suggestions for future research and clinical drug decision making.
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Patel AB, Satarasinghe PN, Valencia V, Wenzel JL, Webb JC, Wolf JS, Osterberg EC. Opiate Prescriptions Vary among Common Urologic Procedures: A Claims Dataset Analysis. J Clin Med 2022; 11:jcm11051329. [PMID: 35268419 PMCID: PMC8911322 DOI: 10.3390/jcm11051329] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/20/2022] [Accepted: 02/24/2022] [Indexed: 01/27/2023] Open
Abstract
Objectives: This study aimed to better understand differences in the total days’ supply and fills of common opiates following urologic procedures. Materials and Methods: The Truven Health MarketScan® database was used to extract CPT codes from adults 18 years or older who underwent a urologic procedure with 90-day follow-up from 2012−2015 within the Austin−Round Rock, Texas metropolitan service area. A multivariate analysis and first hurdle modeling with a logistic outcome for any opiates was used to (1) assess differences in opioid prescribing patterns, (2) investigate opioid prescription outcomes, and (3) explore variability among opiate prescription patterns across seven urologic procedure categories. Results: Among the 2312 patients who met the inclusion criteria, 23.7% received an opiate, with an average total day’s supply of 6.20 (range 2.61−10.59). The proportion of patients receiving opiates varied significantly by procedure type (p = 0.028). Patients that had reconstructive procedures had the highest proportion of any opiates and the highest number of mean opiate prescriptions among the seven procedure categories (42% received opiates, p = 0.028, mean opiate prescriptions were 1.0 among all patients, p = 0.026). After adjustments, the multivariate analysis demonstrated that patients undergoing reconstructive procedures filled more opiate prescriptions (odds ratio (OR) = 1.86, 95% confidence interval (CI) = 1.00−3.50, p = 0.05) compared to other subcategories. Of those that received opiates, reconstructive patients had a shorter time to fills (mean −18.4 days, CI −8.40 to −28.50, p < 0.001). Conclusion: Patients undergoing reconstructive procedures are prescribed and fill more opiates compared to other common urological procedures. The standardization and implementation of postoperative pain regimens may help curtail this variability.
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Tharakan T, Minhas S, Jayasena CN. Male Sexual and Reproductive Health. COMPREHENSIVE PHARMACOLOGY 2022:94-124. [DOI: 10.1016/b978-0-12-820472-6.00036-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Sun Z, Huai Z, He Q, Liu Z. A General Picture of Cucurbit[8]uril Host-Guest Binding. J Chem Inf Model 2021; 61:6107-6134. [PMID: 34818004 DOI: 10.1021/acs.jcim.1c01208] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Describing, understanding, and designing complex interaction networks within macromolecular systems remain challenging in modern chemical research. Host-guest systems, despite their relative simplicity in both the structural feature and interaction patterns, still pose problems in theoretical modeling. The barrel-shaped supramolecular container cucurbit[8]uril (CB8) shows promising functionalities in various areas, e.g., catalysis and molecular recognition. It can stably coordinate a series of structurally diverse guests with high affinities. In this work, we examine the binding of seven commonly abused drugs to the CB8 host, aiming at providing a general picture of CB8-guest binding. Extensive sampling of the configurational space of these host-guest systems is performed, and the binding pathway and interaction patterns of CB8-guest complexes are investigated. A thorough comparison of widely used fixed-charge models for drug-like molecules is presented. Iterative refitting of the atomic charges suggests significant conformation dependence of charge generation. The initial model generated at the original conformation could be inaccurate for new conformations explored during conformational search, and the newly fitted charge set improves the prediction-experiment correlation significantly. Our investigations of the configurational space of CB8-drug complexes suggest that the host-guest interactions are more complex than expected. Despite the structural simplicities of these molecules, the conformational fluctuations of the host and the guest molecules and orientations of functional groups lead to the existence of an ensemble of binding modes. The insights of the binding thermodynamics, performance of fixed-charge models, and binding patterns of the CB8-guest systems are useful for studying and elucidating the binding mechanism of other host-guest complexes.
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Affiliation(s)
- Zhaoxi Sun
- Beijing National Laboratory for Molecular Sciences, Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
| | - Zhe Huai
- XtalPi-AI Research Center (XARC), 9F, Tower A, Dongsheng Building, No. 8, Zhongguancun East Road, Haidian District, Beijing 100083, P.R. China
| | - Qiaole He
- AI Department of Enzymaster (Ningbo) Bio-Engineering Co., Ltd., North Century Avenue 333, Ningbo 315100, China
| | - Zhirong Liu
- Beijing National Laboratory for Molecular Sciences, Institute of Theoretical and Computational Chemistry, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China
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Nedergaard RB, Hansen TM, Nissen TD, Mark EB, Brock C, Drewes AM. The effects of tapentadol and oxycodone on central processing of tonic pain. Clin Neurophysiol 2021; 132:2342-2350. [PMID: 34454260 DOI: 10.1016/j.clinph.2021.07.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/18/2021] [Accepted: 07/10/2021] [Indexed: 10/20/2022]
Abstract
OBJECTIVE The present study investigated differences between opioids to experimental tonic pain in healthy men. METHODS Twenty-one males participated in this cross-over-trial. Interventions twice daily were oxycodone (10 mg), tapentadol (50 mg) and placebo for 14 days. Tonic pain was induced on day 1, 4 and 14 by immersing the hand in 2 °C water for 120 s. Electroencephalography was recorded during test pain at baseline and after 14 days. Spectral analysis and source localization were investigated in predefined frequency bands. RESULTS A decreased perception of pain on day 4 persisted throughout the 14 days compared to baseline (p < 0.006). Oxycodone decreased the electroencephalography spectral power in the delta and theta bands and increased power in the alpha1, alpha2 and beta1 bands (p < 0.03). Tapentadol increased spectral power in the alpha1 band (p < 0.001). Source localization revealed that oxycodone decreased activity of the temporal and limbic region in the delta band, and frontal lobe in the alpha2 and beta1 bands, whereas tapentadol decreased alpha1 band activity in the temporal lobe compared to placebo. CONCLUSION Oxycodone and tapentadol reduced pain perception and changed the central processing of tonic pain. SIGNIFICANCE Different mechanisms of action were involved, where oxycodone affected cortical structures more than tapentadol.
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Affiliation(s)
- Rasmus Bach Nedergaard
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Tine Maria Hansen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Thomas Dahl Nissen
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Esben Bolvig Mark
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark
| | - Christina Brock
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Asbjørn Mohr Drewes
- Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
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Computational design of β-fluorinated morphine derivatives for pH-specific binding. Chem Phys Lett 2021. [DOI: 10.1016/j.cplett.2021.138723] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Niu L, Chen L, Luo Y, Huang W, Li Y. Oxycodone versus morphine for analgesia after laparoscopic endometriosis resection. BMC Anesthesiol 2021; 21:194. [PMID: 34289814 PMCID: PMC8293543 DOI: 10.1186/s12871-021-01417-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Accepted: 06/29/2021] [Indexed: 11/10/2022] Open
Abstract
Background The objective of this study was to compare the analgesic potency of oxycodone versus morphine after laparoscopic deep infiltrating endometriosis resection. Methods Fifty patients undergoing laparoscopic deep infiltrating endometriosis resection were randomized to receive oxycodone or morphine intravenous-PCA after surgery. The primary outcome was opioid consumption during the 24 h after surgery. Secondary outcomes included time to first request for analgesia, the number of bolus, pain, sedation, nausea, vomiting, respiratory depression, and bradycardia. The prominent pain that caused patients to press the analgesic device was also recorded. Results Oxycodone consumption (14.42 ± 2.83) was less than morphine consumption (20.14 ± 3.83). Compared with the morphine group, the total number of bolus (78 vs 123) was less and the average time to first request for analgesia (97.27 ± 59.79 vs 142.17 ± 51) was longer in the oxycodone group. The incidence of nausea was higher in the morphine group than in the oxycodone group at 0–2 h (45.45% vs 17.19%), 2–4 h (50% vs 17.19%),12–24 h (40.91% vs 13.04%) and 0–24 h (39.17% vs 19.13%). The overall incidence of vomiting was higher in the morphine group (27.27% vs 13.92%). There was no difference in visual analogue scale score, the incidence of respiratory depression, and bradycardia between groups. Of the three types of pain that prompted patients to request analgesia, the incidence of visceral pain was highest (59.9%, P < 0.01). Conclusion Oxycodone was more potent than morphine for analgesia after laparoscopic endometriosis resection, and oxycodone has fewer side effects than morphine. Name of the registry: Chinese Clinical Trial Registry Trial registration number: ChiCTR1900021870 URL of trial registry record:http://www.chictr.org.cn/edit.aspx?pid=35799&htm=4 Date of registration: 2019/3/13 0:00:00
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Affiliation(s)
- Lijun Niu
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University No.58, Zhongshan 2nd Road, Guangzhou, 510080, China
| | - Lihong Chen
- Department of Anesthesiology, The Six Affiliated Hospital, Sun Yat-sen University No. 26, Erheng Road, Guangzhou, 510655, China
| | - Yanhua Luo
- Department of Anesthesiology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, No.54 Xianlie South Road, Guangzhou, 510060, China
| | - Wenkao Huang
- Department of Anesthesiology, Nanfang Hospital, Southern Medical University, 1838 Guangzhou Avenue North, Guangzhou, China
| | - Yunsheng Li
- Department of Anesthesiology, The First Affiliated Hospital, Sun Yat-sen University No.58, Zhongshan 2nd Road, Guangzhou, 510080, China.
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Croosu SS, Frøkjaer JB, Drewes AM, Hansen TM. Tapentadol and oxycodone affect resting-state functional brain connectivity: A randomized, placebo-controlled trial. J Neuroimaging 2021; 31:956-961. [PMID: 34196442 DOI: 10.1111/jon.12902] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/24/2021] [Accepted: 06/07/2021] [Indexed: 11/29/2022] Open
Abstract
BACKGROUND AND PURPOSE The changes in functional brain connectivity induced by treatment with analgesics are poorly investigated. Unfortunately, results from clinical studies investigating treatments in patients with pain are often confounded by co-medication and comorbidity. Thalamus is central in sensory processing, and we hypothesized that functional connectivity between thalamus and other brain areas in healthy volunteers was different in treatment with oxycodone, representing a pure opioid, compared to treatment with tapentadol, which has a dual effect on the opioidergic and adrenergic systems. METHODS Twenty-one healthy male volunteers were included in a randomized, double-blind, three-armed, placebo-controlled, cross-over study. All received tapentadol (50 mg extended release), oxycodone (10 mg extended release), or placebo twice daily for 14 days. Resting-state functional magnetic resonance imaging data were obtained before and after treatment. Seed-based functional connectivity analyses were performed between thalamus and other brain regions. RESULTS Compared to placebo, tapentadol increased functional connectivity between left thalamus and precentral cortex (P = .048), whereas oxycodone decreased functional connectivity between bilateral thalamus and the anterior cingulate cortex (P ≤ .005). CONCLUSIONS This study has shown that the functional connectivity between thalamus and other brain areas central in pain processing was different for the tapentadol and oxycodone treatments compared to placebo. This supports that the two treatments exert different mechanism of action. Further studies with larger sample sizes need to be carried out in order to validate this.
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Affiliation(s)
- Suganthiya S Croosu
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Jens B Frøkjaer
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Asbjørn M Drewes
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Tine M Hansen
- Mech-Sense, Department of Radiology, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.,Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark
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Kopruszinski CM, Swiokla J, Lee YS, Navratilova E, VanderVeen L, Yang M, Liu Y, Miyazaki T, Schmidt WK, Zalevsky J, Porreca F. Preclinical Assessment of the Analgesic Pharmacology of NKTR-181 in Rodents. Cell Mol Neurobiol 2021; 41:949-960. [PMID: 32107752 PMCID: PMC11448559 DOI: 10.1007/s10571-020-00816-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 02/16/2020] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Pharmacological evaluation of the mu-opioid receptor (MOR) agonist properties of NKTR-181 in rodent models. METHODS Graded noxious stimulus intensities were used in rats to establish the antinociceptive potency and efficacy of NKTR-181 relative to morphine, fentanyl, and oxycodone. Characteristics of MOR agonist actions, as measured by antinociceptive tolerance and cross-tolerance, as well as opioid-induced hyperalgesia (OIH) and naloxone-precipitated withdrawal in NKTR-181- and morphine-dependent in mice, were compared. RESULTS NKTR-181 showed dose- and time-related antinociception with similar maximal effects to morphine in the rat and mouse hot-water tail-flick test. No sex or species differences were observed in NKTR-181 or morphine antinociception. Rats treated with NKTR-181 and morphine exhibited decreases in both potency and maximal efficacy as nociceptive stimulus intensity was increased from a water temperature of 50 °C to 54 °C. Evaluation of antinociception at a high stimulus intensity revealed that oxycodone and fentanyl exhibited greater efficacy than either NKTR-181 or morphine. The relative potency difference between NKTR-181 and morphine across all tail-flick studies was determined to be 7.6-fold (90% confidence interval, 2.6, 21.5). The peak antinociceptive effect of NKTR-181 was delayed compared to that of the other opioids and cumulative drug effects were not observed. Repeated treatment with escalating, approximately equi-analgesic doses of NKTR-181 or morphine, produced antinociceptive tolerance and cross-tolerance. Under these pharmacological conditions, OIH and naloxone-precipitated physical dependence were similar for NKTR-181 and morphine. CONCLUSIONS NKTR-181 had a slower onset, but similar efficacy, to morphine in the models studied supporting reduced abuse potential while maintaining analgesic effect in comparison with current opioids.
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Affiliation(s)
| | - Juliana Swiokla
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Yeon Sun Lee
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | - Edita Navratilova
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA
| | | | - Miao Yang
- Nektar Therapeutics, San Francisco, CA, USA
| | - Yi Liu
- Nektar Therapeutics, San Francisco, CA, USA
| | | | | | | | - Frank Porreca
- Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, USA.
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Lopes GS, Bielinski S, Moyer AM, Jacobson DJ, Wang L, Jiang R, Larson NB, Miller VM, Zhu Y, Cavanaugh DC, St Sauver J. Sex differences in type and occurrence of adverse reactions to opioid analgesics: a retrospective cohort study. BMJ Open 2021; 11:e044157. [PMID: 34193479 PMCID: PMC8246359 DOI: 10.1136/bmjopen-2020-044157] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVES Sex as a biological variable affects response to opioids. However, few reports describe the prevalence of specific adverse reactions to commonly prescribed opioids in men and women separately. A large cohort was used to investigate sex differences in type and occurrence of adverse reactions associated with use of codeine, tramadol, oxycodone and hydrocodone. DESIGN Retrospective cohort study. SETTING Participants in the Right Drug, Right Dose, Right Time (RIGHT) Study. PARTICIPANTS The medical records of 8457 participants in the RIGHT Study who received an opioid prescription between 1 January 2004 and 31 December 2017 were reviewed 61% women, 94% white, median age (Q1-Q3)=58 (47-66). PRIMARY AND SECONDARY OUTCOME MEASURES Adverse reactions including gastrointestinal, skin, psychiatric and nervous system issues were collected from the allergy section of each patient's medical record. Sex differences in the risk of adverse reactions due to prescribed opioids were modelled using logistic regression adjusted for age, body mass index, race and ethnicity. RESULTS From 8457 participants (of which 449 (5.3%) reported adverse reactions), more women (6.5%) than men (3.4%) reported adverse reactions to at least one opioid (OR (95% CI)=2.3 (1.8 to 2.8), p<0.001). Women were more likely to report adverse reactions to tramadol (OR (95% CI)=2.8 (1.8 to 4.4), p<0.001) and oxycodone (OR (95% CI)=2.2 (1.7 to 2.9), p<0.001). Women were more likely to report gastrointestinal (OR (95% CI)=3.1 (2.3 to 4.3), p<0.001), skin (OR (95% CI)=2.1 (1.4 to 3.3), p=0.001) and nervous system issues (OR (95% CI)=2.3 (1.3 to 4.2), p=0.004). CONCLUSIONS These findings support the importance of sex as a biological variable to be factored into pain management studies.
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Affiliation(s)
- Guilherme S Lopes
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Suzette Bielinski
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Ann M Moyer
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Debra J Jacobson
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Liwei Wang
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Ruoxiang Jiang
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Nicholas B Larson
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Virginia M Miller
- Department of Surgery and Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
| | - Ye Zhu
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Dana C Cavanaugh
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Jennifer St Sauver
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
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Zandonai T, Escorial M, Peiró AM. Codeine and Tramadol Use in Athletes: A Potential for Abuse. Front Pharmacol 2021; 12:661781. [PMID: 34177579 PMCID: PMC8222773 DOI: 10.3389/fphar.2021.661781] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Accepted: 05/19/2021] [Indexed: 02/03/2023] Open
Affiliation(s)
- Thomas Zandonai
- Sports Research Centre, Department of Sport Sciences, Miguel Hernández University of Elche, Elche, Spain.,Department of Pharmacology, Paediatrics and Organic Chemistry, Miguel Hernández University of Elche, Elche, Spain
| | - Mónica Escorial
- Department of Pharmacology, Paediatrics and Organic Chemistry, Miguel Hernández University of Elche, Elche, Spain.,Neuropharmacology on Pain and Functional Diversity (NED), Institute of Health and Biomedical Research of Alicante (ISABIAL Foundation), Alicante, Spain
| | - Ana M Peiró
- Department of Pharmacology, Paediatrics and Organic Chemistry, Miguel Hernández University of Elche, Elche, Spain.,Neuropharmacology on Pain and Functional Diversity (NED), Institute of Health and Biomedical Research of Alicante (ISABIAL Foundation), Alicante, Spain.,Pain Unit, Department of Health of Alicante-General Hospital, Alicante, Spain
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A Large-Scale Observational Study on the Temporal Trends and Risk Factors of Opioid Overdose: Real-World Evidence for Better Opioids. Drugs Real World Outcomes 2021; 8:393-406. [PMID: 34037960 PMCID: PMC8324607 DOI: 10.1007/s40801-021-00253-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/22/2021] [Indexed: 11/25/2022] Open
Abstract
Background The USA is in the midst of an opioid overdose epidemic. To address the epidemic, we conducted a large-scale population study on opioid overdose. Objectives The primary objective of this study was to evaluate the temporal trends and risk factors of inpatient opioid overdose. Based on its patterns, the secondary objective was to examine the innate properties of opioid analgesics underlying reduced overdose effects. Methods A retrospective cross-sectional study was conducted based on a large-scale inpatient electronic health records database, Cerner Health Facts®, with (1) inclusion criteria for participants as patients admitted between 1 January, 2009 and 31 December, 2017 and (2) measurements as opioid overdose prevalence by year, demographics, and prescription opioid exposures. Results A total of 4,720,041 patients with 7,339,480 inpatient encounters were retrieved from Cerner Health Facts®. Among them, 30.2% patients were aged 65+ years, 57.0% female, 70.1% Caucasian, 42.3% single, 32.0% from the South, and 80.8% in an urban area. From 2009 to 2017, annual opioid overdose prevalence per 1000 patients significantly increased from 3.7 to 11.9 with an adjusted odds ratio (aOR): 1.16, 95% confidence interval (CI) 1.15–1.16. Compared to the major demographic counterparts, being in (1) age group: 41–50 years (overall aOR 1.36, 95% CI 1.31–1.40) or 51–64 years (overall aOR 1.35, 95% CI 1.32–1.39), (2) marital status: divorced (overall aOR 1.19, 95% CI 1.15–1.23), and (3) census region: West (overall aOR 1.32, 95% CI 1.28–1.36) were significantly associated with a higher odds of opioid overdose. Prescription opioid exposures were also associated with an increased odds of opioid overdose, such as meperidine (overall aOR 1.09, 95% CI 1.06–1.13) and tramadol (overall aOR 2.20, 95% CI 2.14–2.27). Examination on the relationships between opioid analgesic properties and their association strengths, aORs, and opioid overdose showed that lower aOR values were significantly associated with (1) high molecular weight, (2) non-interaction with multi-drug resistance protein 1 or interaction with cytochrome P450 3A4, and (3) non-interaction with the delta opioid receptor or kappa opioid receptor. Conclusions The significant increasing trends of opioid overdose at the inpatient care setting from 2009 to 2017 suggested an ongoing need for efforts to combat the opioid overdose epidemic in the USA. Risk factors associated with opioid overdose included patient demographics and prescription opioid exposures. Moreover, there are physicochemical, pharmacokinetic, and pharmacodynamic properties underlying reduced overdose effects, which can be utilized to develop better opioids. Supplementary Information The online version contains supplementary material available at 10.1007/s40801-021-00253-8.
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Rodriguez Cairoli F, Appiani F, Sambade JM, Comandé D, Camacho Arteaga L, Ciapponi A. Efficacy and safety of opioid therapy guided by pharmacogenetics: a systematic review. Pharmacogenomics 2021; 22:573-586. [PMID: 34013775 DOI: 10.2217/pgs-2021-0021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Aim: To perform a systematic review to determine the efficacy/safety of PGx-guided opioid therapy for chronic/postoperative pain. Materials & methods: We searched PubMed and other specialized databases. Articles were considered if they compared the efficacy/safety of PGx-guided opioid therapy versus usual care. The risk of bias assessment was performed using Cochrane tools. Results: A total of 3794 records were retrieved. Only five were included for data extraction. A lower requirement of analgesics during postoperative in the PGx-guided intervention arm was reported in two studies. Also, two studies reported significant pain improvement in favor of the PGx-guided therapy when analyzing the subgroup of patients with a high-risk CYP2D6 phenotype. Conclusion: Despite the findings described, information on the efficacy/safety of this intervention is scarce.
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Affiliation(s)
- Federico Rodriguez Cairoli
- Instituto de Efectividad Clínica y Sanitaria (IECS), Dr. Emilio Ravignani, Buenos Aires, 2024 (C1014CPV), Argentina.,Neuropsychopharmacology Unit, Pharmacology Division, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Francisco Appiani
- Neuropsychopharmacology Unit, Pharmacology Division, Hospital de Clínicas José de San Martín, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - Juan Manuel Sambade
- Servicio de Clínica Médica, Hospital "Prof. Dr. Bernardo Houssay" Asociado a la Universidad de Buenos Aires, Municipalidad de Vicente Lopez, Buenos Aires, Argentina
| | - Daniel Comandé
- Instituto de Efectividad Clínica y Sanitaria (IECS), Dr. Emilio Ravignani, Buenos Aires, 2024 (C1014CPV), Argentina
| | - Lina Camacho Arteaga
- Department of Clinical Pharmacology, University Hospital Hall d' Hebron, Barcelona, Spain
| | - Agustín Ciapponi
- Instituto de Efectividad Clínica y Sanitaria (IECS), Dr. Emilio Ravignani, Buenos Aires, 2024 (C1014CPV), Argentina
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Goulooze SC, Ista E, van Dijk M, Tibboel D, Krekels EHJ, Knibbe CAJ. Towards Evidence-Based Weaning: a Mechanism-Based Pharmacometric Model to Characterize Iatrogenic Withdrawal Syndrome in Critically Ill Children. AAPS JOURNAL 2021; 23:71. [PMID: 34002290 PMCID: PMC8128736 DOI: 10.1208/s12248-021-00586-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 03/22/2021] [Indexed: 11/30/2022]
Abstract
For the management of iatrogenic withdrawal syndrome (IWS) in children, a quantitative understanding of the dynamics of IWS of commonly used opioids and sedatives is lacking. Here, we introduce a new mechanism-based pharmacokinetic-pharmacodynamic (PKPD) modeling approach for studying IWS in pediatric clinical datasets. One thousand seven hundred eighty-two NRSwithdrawal scores of IWS severity were analyzed, which were collected from 81 children (age range: 1 month–18 years) that received opioids or sedatives by continuous infusion for 5 days or more. These data were successfully fitted with a PKPD model consisting of a plasma and a dependence compartment that well characterized the dynamics of IWS from morphine, fentanyl, and ketamine. The results suggest that (1) instead of decreasing the infusion rate by a set percentage at set intervals, it would be better to lengthen the weaning period when higher infusion rates are administered prior to weaning; (2) for fentanyl specifically, the risk of IWS might be lower when weaning with smaller dose reductions every 12 h instead of weaning with greater dose reductions every 48 h. The developed PKPD model can be used to evaluate the risk of IWS over time and the extent to which it is affected by different weaning strategies. The results yield hypotheses that could guide future clinical research on optimal weaning strategies. The mechanism-based PKPD modeling approach can be applied in other datasets to characterize the IWS dynamics of other drugs used in pediatric intensive care.
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Affiliation(s)
- Sebastiaan C Goulooze
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands.,LAP&P Consultants BV, Leiden, The Netherlands
| | - Erwin Ista
- Pediatric Surgery, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Monique van Dijk
- Pediatric Surgery, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands.,Division of Nursing Science, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Dick Tibboel
- Pediatric Surgery, Erasmus Medical Center-Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Elke H J Krekels
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands
| | - Catherijne A J Knibbe
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands. .,Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, The Netherlands.
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50
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Häuser W, Morlion B, Vowles KE, Bannister K, Buchser E, Casale R, Chenot J, Chumbley G, Drewes AM, Dom G, Jutila L, O'Brien T, Pogatzki‐Zahn E, Rakusa M, Suarez–Serrano C, Tölle T, Krčevski Škvarč N. European* clinical practice recommendations on opioids for chronic noncancer pain - Part 1: Role of opioids in the management of chronic noncancer pain. Eur J Pain 2021; 25:949-968. [PMID: 33655607 PMCID: PMC8248186 DOI: 10.1002/ejp.1736] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Opioid use for chronic non-cancer pain (CNCP) is complex. In the absence of pan-European guidance on this issue, a position paper was commissioned by the European Pain Federation (EFIC). METHODS The clinical practice recommendations were developed by eight scientific societies and one patient self-help organization under the coordination of EFIC. A systematic literature search in MEDLINE (up until January 2020) was performed. Two categories of guidance are given: Evidence-based recommendations (supported by evidence from systematic reviews of randomized controlled trials or of observational studies) and Good Clinical Practice (GCP) statements (supported either by indirect evidence or by case-series, case-control studies and clinical experience). The GRADE system was applied to move from evidence to recommendations. The recommendations and GCP statements were developed by a multiprofessional task force (including nursing, service users, physicians, physiotherapy and psychology) and formal multistep procedures to reach a set of consensus recommendations. The clinical practice recommendations were reviewed by five external reviewers from North America and Europe and were also posted for public comment. RESULTS The key clinical practice recommendations suggest: (a) first optimizing established non-pharmacological treatments and non-opioid analgesics and (b) considering opioid treatment if established non-pharmacological treatments or non-opioid analgesics are not effective and/or not tolerated and/or contraindicated. Evidence- and clinical consensus-based potential indications and contraindications for opioid treatment are presented. Eighteen GCP recommendations give guidance regarding clinical evaluation, as well as opioid treatment assessment, monitoring, continuation and discontinuation. CONCLUSIONS Opioids remain a treatment option for some selected patients with CNCP under careful surveillance. SIGNIFICANCE In chronic pain, opioids are neither a universal cure nor a universally dangerous weapon. They should only be used for some selected chronic noncancer pain syndromes if established non-pharmacological and pharmacological treatment options have failed in supervised pain patients as part of a comprehensive, multi-modal, multi-disciplinary approach to treatment. In this context alone, opioid therapy can be a useful tool in achieving and maintaining an optimal level of pain control in some patients.
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Affiliation(s)
- Winfried Häuser
- Department Internal Medicine 1Klinikum SaarbrückenSaarbrückenGermany
- Department of Psychosomatic Medicine and PsychotherapyTechnische Universität MünchenMunichGermany
| | - Bart Morlion
- Center for Algology & Pain ManagementUniversity Hospitals LeuvenLeuvenBelgium
| | | | - Kirsty Bannister
- Institute of Psychiatry, Psychology and NeuroscienceKing's College LondonLondonUK
| | - Eric Buchser
- Pain Management and Neuromodulation Centre EHC HospitalMorgesSwitzerland
| | - Roberto Casale
- Neurorehabilitation UnitDepartment of RehabilitationHABILITABergamoItaly
| | - Jean‐François Chenot
- Department of General PracticeInstitute for Community MedicineUniversity Medicine GreifswaldGermany
| | - Gillian Chumbley
- Imperial College Healthcare NHS TrustCharing Cross HospitalLondonUK
| | - Asbjørn Mohr Drewes
- Mech‐SenseDepartment of Gastroenterology & HepatologyAalborg University HospitalDenmark
| | - Geert Dom
- Collaborative Antwerp Psychiatric Research Institute (CAPRI)Antwerp UniversityAntwerpenBelgium
| | | | - Tony O'Brien
- College of Medicine & HealthUniversity College CorkCorkRepublic of Ireland
| | - Esther Pogatzki‐Zahn
- Department of Anaesthesiology, Intensive Care and Pain MedicineUniversity Hospital Münster UKMMunsterGermany
| | - Martin Rakusa
- Department of NeurologyUniversity Medical CentreMariborSlovenia
| | | | - Thomas Tölle
- Department of NeurologyTechhnische Universität MünchenMünchenGermany
| | - Nevenka Krčevski Škvarč
- Department of Anesthesiology, Intensive Care and Pain TreatmentFaculty of Medicine of University MariborMariborSlovenia
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