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Nature Jun 2024All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders. Another recently appreciated...
All drugs of abuse induce long-lasting changes in synaptic transmission and neural circuit function that underlie substance-use disorders. Another recently appreciated mechanism of neural circuit plasticity is mediated through activity-regulated changes in myelin that can tune circuit function and influence cognitive behaviour. Here we explore the role of myelin plasticity in dopaminergic circuitry and reward learning. We demonstrate that dopaminergic neuronal activity-regulated myelin plasticity is a key modulator of dopaminergic circuit function and opioid reward. Oligodendroglial lineage cells respond to dopaminergic neuronal activity evoked by optogenetic stimulation of dopaminergic neurons, optogenetic inhibition of GABAergic neurons, or administration of morphine. These oligodendroglial changes are evident selectively within the ventral tegmental area but not along the axonal projections in the medial forebrain bundle nor within the target nucleus accumbens. Genetic blockade of oligodendrogenesis dampens dopamine release dynamics in nucleus accumbens and impairs behavioural conditioning to morphine. Taken together, these findings underscore a critical role for oligodendrogenesis in reward learning and identify dopaminergic neuronal activity-regulated myelin plasticity as an important circuit modification that is required for opioid reward.
Topics: Ventral Tegmental Area; Animals; Reward; Dopaminergic Neurons; Mice; Myelin Sheath; Morphine; Male; Nucleus Accumbens; Neuronal Plasticity; Oligodendroglia; GABAergic Neurons; Optogenetics; Analgesics, Opioid; Dopamine; Female; Mice, Inbred C57BL
PubMed: 38839962
DOI: 10.1038/s41586-024-07525-7 -
Journal of Pain and Symptom Management Jun 2024Strong opioids are the cornerstone in the treatment of cancer-related pain.
CONTEXT
Strong opioids are the cornerstone in the treatment of cancer-related pain.
OBJECTIVES
This study aims to compare analgesic effectiveness of different strong opioids for the treatment of cancer-related pain.
METHODS
PubMed and Embase were searched for RCTs that compared strong opioids for treatment of cancer-related pain against one another. A network meta-analysis was conducted and the related Surface Under the Cumulative RAnking (SUCRA)-based treatment ranks were calculated. Primary outcome was pain intensity (numerical rating scale (NRS)) and/or the percentage of patients with ≥50% pain reduction, after 1 and 2-4 weeks.
RESULTS
Sixteen RCTs (1813 patients) were included. Methadone showed, with a high certainty of evidence, increased ORs for treatment success at 1 week, compared with morphine, buprenorphine, fentanyl, and oxycodone, range 3.230-36.833. Methadone had the highest likelihood to be the treatment of preference (ToP) (SUCRA 0.9720). For fentanyl, ORs were lower, however significant and with high certainty. After 2-4 weeks, methadone again showed the highest likelihood for ToP, however, with moderate certainty and nonsignificant ORs. The combination of morphine/methadone, compared with morphine, buprenorphine, fentanyl, hydromorphone, methadone, and oxycodone achieved a treatment effect of mean NRS difference after 2-4 weeks between -1.100 and -1.528 and had the highest likelihood for ToP.
CONCLUSION
The results suggest that methadone possibly deserves further promotion as first-line treatment for the treatment of cancer-related pain.
PubMed: 38838946
DOI: 10.1016/j.jpainsymman.2024.05.022 -
JMIR Public Health and Surveillance Jun 2024We have previously demonstrated that opioid prescribing increased by 127% between 1998 and 2016. New policies aimed at tackling this increasing trend have been...
BACKGROUND
We have previously demonstrated that opioid prescribing increased by 127% between 1998 and 2016. New policies aimed at tackling this increasing trend have been recommended by public health bodies, and there is some evidence that progress is being made.
OBJECTIVE
We sought to extend our previous work and develop a data-driven approach to identify general practices and clinical commissioning groups (CCGs) whose prescribing data suggest that interventions to reduce the prescribing of opioids may have been successfully implemented.
METHODS
We analyzed 5 years of prescribing data (December 2014 to November 2019) for 3 opioid prescribing measures-total opioid prescribing as oral morphine equivalent per 1000 registered population, the number of high-dose opioids prescribed per 1000 registered population, and the number of high-dose opioids as a percentage of total opioids prescribed. Using a data-driven approach, we applied a modified version of our change detection Python library to identify reductions in these measures over time, which may be consistent with the successful implementation of an intervention to reduce opioid prescribing. This analysis was carried out for general practices and CCGs, and organizations were ranked according to the change in prescribing rate.
RESULTS
We identified a reduction in total opioid prescribing in 94 (49.2%) out of 191 CCGs, with a median reduction of 15.1 (IQR 11.8-18.7; range 9.0-32.8) in total oral morphine equivalence per 1000 patients. We present data for the 3 CCGs and practices demonstrating the biggest reduction in opioid prescribing for each of the 3 opioid prescribing measures. We observed a 40% proportional drop (8.9% absolute reduction) in the regular prescribing of high-dose opioids (measured as a percentage of regular opioids) in the highest-ranked CCG (North Tyneside); a 99% drop in this same measure was found in several practices (44%-95% absolute reduction). Decile plots demonstrate that CCGs exhibiting large reductions in opioid prescribing do so via slow and gradual reductions over a long period of time (typically over a period of 2 years); in contrast, practices exhibiting large reductions do so rapidly over a much shorter period of time.
CONCLUSIONS
By applying 1 of our existing analysis tools to a national data set, we were able to identify rapid and maintained changes in opioid prescribing within practices and CCGs and rank organizations by the magnitude of reduction. Highly ranked organizations are candidates for further qualitative research into intervention design and implementation.
Topics: Humans; Analgesics, Opioid; Retrospective Studies; Practice Patterns, Physicians'; Databases, Factual; Drug Prescriptions
PubMed: 38838327
DOI: 10.2196/51323 -
PloS One 2024In 2017, a university-based academic healthcare system changed the opioid default pill count from 30 to 12 pills. Modifying the electronic default pill count influences...
BACKGROUND
In 2017, a university-based academic healthcare system changed the opioid default pill count from 30 to 12 pills. Modifying the electronic default pill count influences short-term clinician prescribing practices. We sought to understand the long-term impact on postoperative opioid prescribing habits after an opioid default pill count reduction.
MATERIALS AND METHODS
A retrospective electronic medical record system (EMRS) review was conducted in a healthcare system comprised of seven affiliated hospitals. Patients who underwent a surgical procedure and were prescribed an opioid on discharge between 2017-2021 were evaluated. All prescriptions were converted into morphine equivalents (MME). Analyses were performed with the chi-square test and Bonferonni adjusted t-test.
RESULTS
191,379 surgical procedures were studied. The average quantity of opioids prescribed decreased from 32 oxycodone 5 mg tablets in 2017 to 21 oxycodone 5 mg tablets in 2021 (236 MME to 154 MME, p<0.001). The percentage of patients obtaining a refill within 90 days of surgery varied between 18.3% and 19.9% (p<0.001). Patients with a pre-existing opioid prescription and opioid-naïve patients both had significant reductions in prescription quantities above the default MME (79.7% to 60.6% vs. 65.3% to 36.9%, p<0.001). There was no significant change in refills for both groups (pre-existing 36.7% to 38.3% (p = 0.1) vs naïve 15.0% to 15.3% (p = 0.29)).
CONCLUSIONS
The benefits of decreasing the default opioid pill count continue to accumulate long after the original change. Physician uptake of small changes to default EMRS practices represents a sustainable and effective intervention to reduce the quantities of postoperative opioids prescribed without deleterious effects on outpatient opiate requirements.
Topics: Humans; Male; Female; Analgesics, Opioid; Middle Aged; Retrospective Studies; Pain, Postoperative; Drug Prescriptions; Practice Patterns, Physicians'; Adult; Aged; Electronic Health Records; Oxycodone
PubMed: 38833500
DOI: 10.1371/journal.pone.0304100 -
South African Family Practice :... May 2024Pharmacy professionals working in community pharmacies frequently provide pharmacist-initiated therapy, including codeine-containing medicines. Codeine is an opioid...
BACKGROUND
Pharmacy professionals working in community pharmacies frequently provide pharmacist-initiated therapy, including codeine-containing medicines. Codeine is an opioid with great potential for misuse, adding to the global opioid epidemic burden. Professional pharmacy personnel are the first intervention point in relation to management of codeine use. This study highlights the importance of pharmacy professionals' perceptions and behaviours in combatting the opioid epidemic.
METHODS
A descriptive cross-sectional study was conducted. Simple random sampling included pharmacy professionals in the metropolitan city of Johannesburg. An electronic questionnaire was distributed via e-mail and data analysed descriptively.
RESULTS
Findings indicate that pharmacy personnel routinely ask patients about codeine use (n = 48; 53.9%), avoid dispensing over-the-counter (OTC) codeine as an initial treatment (n = 61; 69%) and express confidence to identify and manage codeine misuse (n = 69; 77.5%). Despite this, increased patient demands for OTC codeine (n = 69; 77.5%) were concerning, highlighting the ease of availability from internet sources (n = 76; 85.4%) and multiple pharmacies (n = 84; 94.4%). Apprehension about the lack of patient awareness on adverse health consequences (n = 66; 74.2%) and the risk of codeine dependence (n = 79; 88.8%) was expressed.
CONCLUSION
Growing concern regarding availability and accessibility of codeine-containing medicines within the community pharmacy sector is highlighted. Adverse health consequences of codeine misuse and dependence are not understood by customers and the ineffective information provided by pharmacy personnel was highlighted as a concern.Contribution: The results of this study give insight to the influence of dispensing personnel's attitude towards the growing challenges with respect to codeine containing medication abuse.
Topics: Humans; Codeine; Cross-Sectional Studies; Female; Male; Adult; Surveys and Questionnaires; Analgesics, Opioid; Pharmacists; Nonprescription Drugs; South Africa; Attitude of Health Personnel; Middle Aged; Opioid-Related Disorders; Community Pharmacy Services; Health Knowledge, Attitudes, Practice
PubMed: 38832385
DOI: 10.4102/safp.v66i1.5862 -
BMJ Open Jun 2024Intraoperative opioids have been used for decades to reduce negative responses to nociception. However, opioids may have several, and sometimes serious, adverse effects....
Opioid-free anaesthesia with dexmedetomidine and lidocaine versus remifentanil-based anaesthesia in cardiac surgery: study protocol of a French randomised, multicentre and single-blinded OFACS trial.
INTRODUCTION
Intraoperative opioids have been used for decades to reduce negative responses to nociception. However, opioids may have several, and sometimes serious, adverse effects. Cardiac surgery exposes patients to a high risk of postoperative complications, some of which are common to those caused by opioids: acute respiratory failure, postoperative cognitive dysfunction, postoperative ileus (POI) or death. An opioid-free anaesthesia (OFA) strategy, based on the use of dexmedetomidine and lidocaine, may limit these adverse effects, but no randomised trials on this issue have been published in cardiac surgery.We hypothesised that OFA versus opioid-based anaesthesia (OBA) may reduce the incidence of major opioid-related complications after cardiac surgery.
METHODS AND ANALYSIS
Multicentre, randomised, parallel and single-blinded clinical trial in four cardiac surgical centres in France, including 268 patients scheduled for coronary artery bypass grafting under cardiac bypass, with or without aortic valve replacement. Patients will be randomised to either a control OBA protocol using remifentanil or an OFA protocol using dexmedetomidine/lidocaine. The primary composite endpoint is the occurrence of at least one of the following: (1) postoperative cognitive disorder evaluated by the Confusion Assessment Method for the Intensive Care Unit test, (2) POI, (3) acute respiratory distress or (4) death within the first 48 postoperative hours. Secondary endpoints are postoperative pain, morphine consumption, nausea-vomiting, shock, acute kidney injury, atrioventricular block, pneumonia and length of hospital stay.
ETHICS AND DISSEMINATION
This trial has been approved by an independent ethics committee ( on 23 February 2021). Results will be submitted in international journals for peer reviewing.
TRIAL REGISTRATION NUMBER
NCT04940689, EudraCT 2020-002126-90.
Topics: Humans; Dexmedetomidine; Lidocaine; Remifentanil; Cardiac Surgical Procedures; Single-Blind Method; Analgesics, Opioid; France; Postoperative Complications; Randomized Controlled Trials as Topic; Multicenter Studies as Topic; Pain, Postoperative
PubMed: 38830745
DOI: 10.1136/bmjopen-2023-079984 -
Molecular Pain 2024Hyperalgesic priming is a preclinical model of the transition from acute to chronic pain characterized by a leftward shift in the dose-response curve for and marked...
Hyperalgesic priming is a preclinical model of the transition from acute to chronic pain characterized by a leftward shift in the dose-response curve for and marked prolongation of prostaglandin E (PGE)-induced mechanical hyperalgesia, in vivo. In vitro, priming in nociceptors is characterized by a leftward shift in the concentration dependence for PGE-induced nociceptor sensitization. In the present in vitro study we tested the hypothesis that a mu-opioid receptor (MOR) agonist opioid analgesic, morphine, can produce priming by its direct action on nociceptors. We report that treatment of nociceptors with morphine, in vitro, produces a leftward shift in the concentration dependence for PGE-induced nociceptor sensitization. Our findings support the suggestion that opioids act directly on nociceptors to induce priming.
Topics: Morphine; Animals; Nociceptors; Dinoprostone; Receptors, Opioid, mu; Analgesics, Opioid; Male; Rats; Ganglia, Spinal; Hyperalgesia; Rats, Sprague-Dawley; Dose-Response Relationship, Drug
PubMed: 38828868
DOI: 10.1177/17448069241260348 -
International Journal of Nanomedicine 2024Opioids are irreplaceable analgesics owing to the lack of alternative analgesics that offer opioid-like pain relief. However, opioids have many undesirable central side...
BACKGROUND
Opioids are irreplaceable analgesics owing to the lack of alternative analgesics that offer opioid-like pain relief. However, opioids have many undesirable central side effects. Restricting opioids to peripheral opioid receptors could reduce those effects while maintaining analgesia.
METHODS
To achieve this goal, we developed Tet1-LNP (morphine), a neural-targeting lipid nanoparticle encapsulating morphine that could specifically activate the peripheral opioid receptor in the dorsal root ganglion (DRG) and significantly reduce the side effects caused by the activation of opioid receptors in the brain. Tet1-LNP (morphine) were successfully prepared using the thin-film hydration method. In vitro, Tet1-LNP (morphine) uptake was assessed in differentiated neuron-like PC-12 cells and dorsal root ganglion (DRG) primary cells. The uptake of Tet1-LNP (morphine) in the DRGs and the brain was assessed in vivo. Von Frey filament and Hargreaves tests were used to assess the antinociception of Tet1-LNP (morphine) in the chronic constriction injury (CCI) neuropathic pain model. Morphine concentration in blood and brain were evaluated using ELISA.
RESULTS
Tet1-LNP (morphine) had an average size of 131 nm. Tet1-LNP (morphine) showed high cellular uptake and targeted DRG in vitro. CCI mice treated with Tet1-LNP (morphine) experienced prolonged analgesia for nearly 32 h compared with 3 h with free morphine ( < 0.0001). Notably, the brain morphine concentration in the Tet1-LNP (morphine) group was eight-fold lower than that in the morphine group ( < 0.0001).
CONCLUSION
Our study presents a targeted lipid nanoparticle system for peripheral neural delivery of morphine. We anticipate Tet1-LNP (morphine) will offer a safe formulation for chronic neuropathic pain treatment, and promise further development for clinical applications.
Topics: Animals; Morphine; Ganglia, Spinal; Nanoparticles; Rats; PC12 Cells; Analgesics, Opioid; Male; Neuralgia; Mice; Lipids; Proto-Oncogene Proteins; Peripheral Nerves; Mixed Function Oxygenases; DNA-Binding Proteins; Liposomes
PubMed: 38828199
DOI: 10.2147/IJN.S453608 -
Drug Design, Development and Therapy 2024Oxycodone is a potent μ- and κ-opioid receptor agonist that can relieve both somatic and visceral pain. We assessed oxycodone- vs sufentanil-based multimodal analgesia... (Randomized Controlled Trial)
Randomized Controlled Trial Clinical Trial
PURPOSE
Oxycodone is a potent μ- and κ-opioid receptor agonist that can relieve both somatic and visceral pain. We assessed oxycodone- vs sufentanil-based multimodal analgesia on postoperative pain following major laparoscopic gastrointestinal surgery.
METHODS
In this randomised double-blind controlled trial, 40 adult patients were randomised (1:1, stratified by type of surgery) to receive oxycodone- or sufentanil-based multimodal analgesia, comprising bilateral transverse abdominis plane blocks, intraoperative dexmedetomidine infusion, flurbiprofen axetil, and oxycodone- or sufentanil-based patient-controlled analgesia. The co-primary outcomes were time-weighted average (TWA) of visceral pain (defined as intra-abdominal deep and dull pain) at rest and on coughing during 0-24 h postoperatively, assessed using the numerical rating scale (0-10) with a minimal clinically important difference of 1.
RESULTS
All patients completed the study (median age, 64 years; 65% male) and had adequate postoperative pain control. The mean (SD) 24-h TWA of visceral pain at rest was 1.40 (0.77) in the oxycodone group vs 2.00 (0.98) in the sufentanil group (mean difference=-0.60, 95% CI, -1.16 to -0.03; =0.039). Patients in the oxycodone group had a significantly lower 24-h TWA of visceral pain on coughing (2.00 [0.83] vs 2.98 [1.26]; mean difference=-0.98, 95% CI, -1.66 to -0.30; =0.006). In the subgroup analyses, the treatment effect of oxycodone vs sufentanil on the co-primary outcomes did not differ in terms of age (18-65 years or >65 years), sex (female or male), or type of surgery (colorectal or gastric). Secondary outcomes (24-h TWA of incisional and shoulder pain, postoperative analgesic usage, rescue analgesia, adverse events, and patient satisfaction) were comparable between groups.
CONCLUSION
For patients undergoing major laparoscopic gastrointestinal surgery, oxycodone-based multimodal analgesia reduced postoperative visceral pain in a statistically significant but not clinically important manner.
TRIAL REGISTRATION
Chinese Clinical Trial Registry (ChiCTR2100052085).
Topics: Humans; Oxycodone; Double-Blind Method; Middle Aged; Male; Female; Laparoscopy; Pain, Postoperative; Visceral Pain; Aged; Analgesics, Opioid; Adult; Digestive System Surgical Procedures; Dexmedetomidine; Sufentanil; Analgesia, Patient-Controlled; Flurbiprofen
PubMed: 38828025
DOI: 10.2147/DDDT.S464518 -
Drug Design, Development and Therapy 2024Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an...
PURPOSE
Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators.
PATIENTS AND METHODS
Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis.
RESULTS
Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42-5.28, false discovery rate adjusted- =3.55*10). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI.
CONCLUSION
The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.
Topics: Humans; Morphine; Purinergic P2Y Receptor Antagonists; Acute Coronary Syndrome; Male; Female; Middle Aged; Aged; Platelet Aggregation Inhibitors; Analgesics, Opioid
PubMed: 38828024
DOI: 10.2147/DDDT.S458299