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Pharmaceuticals (Basel, Switzerland) Dec 2023Although traditional opioids such as morphine and oxycodone are commonly used in the management of acute postoperative pain, novel opioids may play a role as... (Review)
Review
Although traditional opioids such as morphine and oxycodone are commonly used in the management of acute postoperative pain, novel opioids may play a role as alternatives that provide potent pain relief while minimizing adverse effects. In this review, we discuss the mechanisms of action, findings from preclinical studies and clinical trials, and potential advantages of several novel opioids. The more established include oliceridine (biased ligand activity to activate analgesia and downregulate opioid-related adverse events), tapentadol (mu-opioid agonist and norepinephrine reuptake inhibitor), and cebranopadol (mu-opioid agonist with nociceptin opioid peptide activity)-all of which have demonstrated success in the clinical setting when compared to traditional opioids. On the other hand, dinalbuphine sebacate (DNS; semi-synthetic mu partial antagonist and kappa agonist), dual enkephalinase inhibitors (STR-324, PL37, and PL265), and endomorphin-1 analog (CYT-1010) have shown good efficacy in preclinical studies with future plans for clinical trials. Rather than relying solely on mu-opioid receptor agonism to relieve pain and risk opioid-related adverse events (ORAEs), novel opioids make use of alternative mechanisms of action to treat pain while maintaining a safer side-effect profile, such as lower incidence of nausea, vomiting, sedation, and respiratory depression as well as reduced abuse potential.
PubMed: 38256863
DOI: 10.3390/ph17010029 -
Neuropharmacology Oct 2023Over the past two decades, the escalating prescription of opioid medications for pain management has culminated in a widespread opioid epidemic, significantly impacting...
Over the past two decades, the escalating prescription of opioid medications for pain management has culminated in a widespread opioid epidemic, significantly impacting public health, social dynamics, and economic stability. The urgent need for improved treatments for opioid addiction necessitates a deeper understanding of its biological underpinnings, with genetic variations playing a crucial role in individual susceptibility to opioid use disorder (OUD) and influencing clinical practices. In this study, we leverage the genetic diversity of four rat strains (ACI/N, BN/NHsd, WKY/N, and F344/N) to examine the contribution of genetic factors to oxycodone metabolism and addiction-like behaviors. We used the extended access to intravenous oxycodone self-administration procedure (12 h/day, 0.15 mg/kg/injection) to comprehensively characterize oxycodone-related behaviors and pharmacokinetics. We measured escalation of oxycodone self-administration, motivation for drug consumption, tolerance to the analgesic effects of oxycodone, withdrawal-induced hyperalgesia, and oxycodone-induced respiratory depression. Additionally, we examined oxycodone-seeking behavior after four weeks of withdrawal by reintroducing the animals to environmental and cue stimuli previously associated with oxycodone self-administration. The findings revealed notable strain differences in several behavioral measures, including oxycodone metabolism. Intriguingly, BN/NHsd and WKY/N strains exhibited similar drug intake and escalation patterns but displayed significant disparities in oxycodone and oxymorphone metabolism. Minimal sex differences were observed within strains, primarily relating to oxycodone metabolism. In conclusion, this study identifies strain differences in the behavioral responses and pharmacokinetics associated with oxycodone self-administration in rats, providing a robust foundation for identifying genetic and molecular variants associated with various facets of the opioid addiction process.
Topics: Rats; Female; Male; Animals; Oxycodone; Rats, Inbred ACI; Rats, Inbred F344; Rats, Inbred WKY; Analgesics, Opioid; Opioid-Related Disorders; Self Administration
PubMed: 37327971
DOI: 10.1016/j.neuropharm.2023.109635 -
Assessment of the potential of novel and classical opioids to induce respiratory depression in mice.British Journal of Pharmacology Dec 2023Opioid-induced respiratory depression limits the use of μ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The...
BACKGROUND AND PURPOSE
Opioid-induced respiratory depression limits the use of μ-opioid receptor agonists in clinical settings and is the main cause of opioid overdose fatalities. The relative potential of different opioid agonists to induce respiratory depression at doses exceeding those producing analgesia is understudied despite its relevance to assessments of opioid safety. Here we evaluated the respiratory depressant and anti-nociceptive effects of three novel opioids and relate these measurements to their in vitro efficacy.
EXPERIMENTAL APPROACH
Respiration was measured in awake, freely moving male CD-1 mice using whole body plethysmography. Anti-nociception was measured using the hot plate test. Morphine, oliceridine and tianeptine were administered intraperitoneally, whereas methadone, oxycodone and SR-17018 were administered orally. Receptor activation and arrestin-3 recruitment were measured in HEK293 cells using BRET assays.
KEY RESULTS
Across the dose ranges examined, all opioids studied depressed respiration in a dose-dependent manner, with similar effects at the highest doses, and with tianeptine and oliceridine showing reduced duration of effect, when compared with morphine, oxycodone, methadone and SR-17018. When administered at doses that induced similar respiratory depression, all opioids induced similar anti-nociception, with tianeptine and oliceridine again showing reduced duration of effect. These data were consistent with the in vitro agonist activity of the tested compounds.
CONCLUSION AND IMPLICATIONS
In addition to providing effective anti-nociception, the novel opioids, oliceridine, tianeptine and SR-17018 depress respiration in male mice. However, the different potencies and kinetics of effect between these novel opioids may be relevant to their therapeutic application in different clinical settings.
Topics: Male; Humans; Animals; Mice; Analgesics, Opioid; Oxycodone; HEK293 Cells; Morphine; Respiratory Insufficiency; Methadone
PubMed: 37489013
DOI: 10.1111/bph.16199 -
Scientific Reports Aug 2023Anesthesia for laparoscopic sleeve gastrectomy and perioperative management remains a challenge. Several clinical studies indicate that opioid-free anesthesia (OFA) may... (Randomized Controlled Trial)
Randomized Controlled Trial
Anesthesia for laparoscopic sleeve gastrectomy and perioperative management remains a challenge. Several clinical studies indicate that opioid-free anesthesia (OFA) may be beneficial, but there is no consensus on the most optimal anesthesia technique in clinical practice. The aim of our study was to assess the potential benefits and risks of intraoperative OFA compared to multimodal analgesia (MMA) with remifentanil infusion. In a prospective, randomized study, we analyzed 59 patients' data. Primary outcome measures were oxycodone consumption and reported pain scores (numerical rating scale, NRS) at 1, 6, 12, and 24th hours after surgery. Postoperative sedation on the Ramsay scale, nausea and vomiting on the PONV impact scale, desaturation episodes, pruritus, hemodynamic parameters, and hospital stay duration were also documented and compared. There were no significant differences in NRS scores or total 24-h oxycodone requirements. In the first postoperative hour, OFA group patients needed an average of 4.6 mg of oxycodone while the MMA group 7.72 mg (p = 0.008, p < 0.05 statistically significant). The PONV impact scale was significantly lower in the OFA group only in the first hour after the operation (p = 0.006). Patients in the OFA group required higher doses of ephedrine 23.67 versus 15.69 mg (p = 0.039) and more intravenous fluids 1160 versus 925.86 ml (p = 0.007). The mode of anesthesia did not affect the pain scores or the total dose of oxycodone in the first 24 postoperative hours. Only in the first postoperative hour were an opioid-sparing effect and reduction of PONV incidence seen in the OFA group when compared with remifentanil-based anesthesia. However, patients in the OFA group showed significantly greater hemodynamic lability necessitating higher vasopressor doses and more fluid volume.
Topics: Humans; Analgesics, Opioid; Remifentanil; Oxycodone; Prospective Studies; Postoperative Nausea and Vomiting; Pain, Postoperative; Anesthesia; Laparoscopy; Gastrectomy
PubMed: 37542100
DOI: 10.1038/s41598-023-39856-2 -
International Journal of Molecular... Aug 2023The pharmacological treatment of postherpetic neuralgia (PHN) is unsatisfactory, and there is a clinical need for new approaches. Several drugs under advanced clinical...
The pharmacological treatment of postherpetic neuralgia (PHN) is unsatisfactory, and there is a clinical need for new approaches. Several drugs under advanced clinical development are addressed in this review. A systematic literature search was conducted in three electronic databases (Medline, Web of Science, Scopus) and in the ClinicalTrials.gov register from 1 January 2016 to 1 June 2023 to identify Phase II, III and IV clinical trials evaluating drugs for the treatment of PHN. A total of 18 clinical trials were selected evaluating 15 molecules with pharmacological actions on nine different molecular targets: Angiotensin Type 2 Receptor (AT2R) antagonism (olodanrigan), Voltage-Gated Calcium Channel (VGCC) α2δ subunit inhibition (crisugabalin, mirogabalin and pregabalin), Voltage-Gated Sodium Channel (VGSC) blockade (funapide and lidocaine), Cyclooxygenase-1 (COX-1) inhibition (TRK-700), Adaptor-Associated Kinase 1 (AAK1) inhibition (LX9211), Lanthionine Synthetase C-Like Protein (LANCL) activation (LAT8881), N-Methyl-D-Aspartate (NMDA) receptor antagonism (esketamine), mu opioid receptor agonism (tramadol, oxycodone and hydromorphone) and Nerve Growth Factor (NGF) inhibition (fulranumab). In brief, there are several drugs in advanced clinical development for treating PHN with some of them reporting promising results. AT2R antagonism, AAK1 inhibition, LANCL activation and NGF inhibition are considered first-in-class analgesics. Hopefully, these trials will result in a better clinical management of PHN.
Topics: Humans; Drugs, Investigational; Nerve Growth Factor; Neuralgia, Postherpetic; Pregabalin; Randomized Controlled Trials as Topic
PubMed: 37629168
DOI: 10.3390/ijms241612987 -
JACS Au Mar 2024Opioids collectively cause over 80,000 deaths in the United States annually. The ability to rapidly identify these compounds in seized drug samples on-site will be...
Opioids collectively cause over 80,000 deaths in the United States annually. The ability to rapidly identify these compounds in seized drug samples on-site will be essential for curtailing trafficking and distribution. Chemical reagent-based tests are fast and simple but also notorious for giving false results due to poor specificity, whereas portable Raman spectrometers have excellent selectivity but often face interference challenges with impure drug samples. In this work, we develop on-site sensors for morphine and structurally related opioid compounds based on in vitro-selected oligonucleotide affinity reagents known as aptamers. We employ a parallel-and-serial selection strategy to isolate aptamers that recognize heroin, morphine, codeine, hydrocodone, and hydromorphone, along with a toggle-selection approach to isolate aptamers that bind oxycodone and oxymorphone. We then utilize a new high-throughput sequencing-based approach to examine aptamer growth patterns over the course of selection and a high-throughput exonuclease-based screening assay to identify optimal aptamer candidates. Finally, we use two high-performance aptamers with of ∼1 μM to develop colorimetric dye-displacement assays that can specifically detect opioids like heroin and oxycodone at concentrations as low as 0.5 μM with a linear range of 0-16 μM. Importantly, our assays can detect opioids in complex chemical matrices, including pharmaceutical tablets and drug mixtures; in contrast, the conventional Marquis test completely fails in this context. These aptamer-based colorimetric assays enable the naked-eye identification of specific opioids within seconds and will play an important role in combatting opioid abuse.
PubMed: 38559723
DOI: 10.1021/jacsau.3c00801 -
The Journal of Bone and Joint Surgery.... Dec 2023Minimal pain and opioid use after operative treatment for pediatric supracondylar humeral fractures have been previously described; however, opioid-prescribing practices... (Clinical Trial)
Clinical Trial
BACKGROUND
Minimal pain and opioid use after operative treatment for pediatric supracondylar humeral fractures have been previously described; however, opioid-prescribing practices in the United States remain variable. We hypothesized that children without an opioid prescription would report similar postoperative pain compared with children prescribed opioids following closed reduction and percutaneous pinning (CRPP) of supracondylar humeral fractures.
METHODS
Children who were 3 to 12 years of age and were undergoing CRPP for a closed supracondylar humeral fracture were prospectively enrolled in a multicenter, comparative study. Following a standardized dosing protocol, oxycodone, ibuprofen, and acetaminophen were prescribed at 2 hospitals (opioid cohort), and 2 other hospitals prescribed ibuprofen and acetaminophen alone (non-opioid cohort). The children's medication use and the daily pain that they experienced (scored on the Wong-Baker FACES Scale) were recorded at postoperative days 1 to 7, 10, 14, and 21, using validated text-message protocols. Based on an a priori power analysis, at least 64 evaluable subjects were recruited per cohort.
RESULTS
A total of 157 patients were evaluated (81 [52%] in the opioid cohort and 76 [48%] in the non-opioid cohort). The median age at the time of the surgical procedure was 6.2 years, and 50% of the subjects were male. The mean postoperative pain scores were low overall (<4 of 10), and there were no significant differences in pain ratings between cohorts at any time point. No patient demographic or injury characteristics were correlated with increased pain or medication use. Notably, of the 81 patients in the opioid cohort, 28 (35%) took no oxycodone and 40 (49%) took 1 to 3 total doses across the postoperative period. Patients rarely took opioids after postoperative day 2. A single patient in the non-opioid cohort (1 [1%] of 76) received a rescue prescription of opioids after presenting to the emergency department with postoperative cast discomfort.
CONCLUSIONS
Non-opioid analgesia following CRPP for pediatric supracondylar humeral fractures was equally effective as opioid analgesia. When oxycodone was prescribed, 84% of children took 0 to 3 total doses, and opioid use fell precipitously after postoperative day 2. To improve opioid stewardship, providers and institutions can consider discontinuing the routine prescription of opioids following this procedure.
LEVEL OF EVIDENCE
Therapeutic Level II . See Instructions for Authors for a complete description of levels of evidence.
Topics: Child; Female; Humans; Male; Acetaminophen; Analgesia; Analgesics, Non-Narcotic; Analgesics, Opioid; Humeral Fractures; Ibuprofen; Oxycodone; Pain, Postoperative; Prospective Studies; Child, Preschool
PubMed: 37956188
DOI: 10.2106/JBJS.23.00223 -
British Journal of Pain Oct 2023The prescription of opioids in emergency care has been associated with harm, including overdose and dependence. The aim of this trial was to assess restriction of access...
BACKGROUND
The prescription of opioids in emergency care has been associated with harm, including overdose and dependence. The aim of this trial was to assess restriction of access to oxycodone (ROXY), in combination with education and guideline modifications, versus education and guideline modifications alone (standard care) to reduce oxycodone administration in the Emergency Department (ED).
METHODS
An unblinded, active control, randomised controlled trial was conducted in an adult tertiary ED. Participants were patients aged 18-75 years who had analgesics administered in the ED. The primary intervention was ROXY, through removal of all oxycodone immediate release tablets from the ED imprest, with availability of a small supply after senior clinician approval. The intervention did not restrict prescription of discharge medications. The primary outcome measure was oxycodone administration rates. Secondary outcomes were administration rates of other analgesic medications, time to initial analgesics and oxycodone prescription on discharge.
RESULTS
There were 2258 patients eligible for analysis. Oxycodone was administered to 80 (6.1%) patients in the ROXY group and 221 (23.3%) patients in the standard care group (relative risk (RR) 0.26; 95% CI: 0.21 to 0.33; < .001). Tapentadol was prescribed more frequently in the ROXY group (RR 2.17; 95% CI: 1.71-2.74), while there were no differences in prescription of other analgesic medications. On discharge, significantly fewer patients were prescribed oxycodone (RR 0.51; 95% CI: 0.39-0.66) and no differences were observed in prescription rates of other analgesic medications. There was no difference in time to first analgesic (HR 0.94; 95% CI: 0.86-1.02).
CONCLUSIONS
Restricted access to oxycodone was superior to education and guideline modifications alone for reducing oxycodone use in the ED and reducing discharge prescriptions of oxycodone from the ED. The addition of simple restrictive interventions is recommended to enable rapid changes to clinician behaviour to reduce the potential harm associated with the prescribing of oxycodone in the ED.
PubMed: 38107754
DOI: 10.1177/20494637231189031 -
Gut Microbes 2024Opioids, such as morphine and oxycodone, are widely used for pain management associated with chronic pancreatitis (CP); however, their impact on the progression and pain...
Opioids, such as morphine and oxycodone, are widely used for pain management associated with chronic pancreatitis (CP); however, their impact on the progression and pain sensitivity of CP has never been evaluated. This report investigates the impact of opioid use on the severity of CP, pain sensitivity, and the gut microbiome. C57BL/6 mice were divided into control, CP, CP with morphine/oxycodone, and either morphine or oxycodone alone groups. CP was induced by administration of caerulein (50ug/kg/h, i.p. hourly x7, twice a week for 10 weeks). The mouse-to-pancreas weight ratio, histology, and Sirius red staining were performed to measure CP severity. Tail flick and paw pressure assays were used to measure thermal and mechanical pain. DNA was extracted from the fecal samples and subjected to whole-genome shotgun sequencing. Germ-free mice were used to validate the role of gut microbiome in sensitizing acute pancreatic inflammation. Opioid treatment exacerbates CP by increasing pancreatic necrosis, fibrosis, and immune-cell infiltration. Opioid-treated CP mice exhibited enhanced pain hypersensitivity and showed distinct clustering of the gut microbiome compared to untreated CP mice, with severely compromised gut barrier integrity. Fecal microbiota transplantation (FMT) from opioid-treated CP mice into germ-free mice resulted in pancreatic inflammation in response to a suboptimal caerulein dose. Together, these analyses revealed that opioids worsen the severity of CP and induce significant alterations in pain sensitivity and the gut microbiome in a caerulein CP mouse model. Microbial dysbiosis plays an important role in sensitizing the host to pancreatic inflammation.
Topics: Animals; Mice; Analgesics, Opioid; Oxycodone; Dysbiosis; Ceruletide; Gastrointestinal Microbiome; Mice, Inbred C57BL; Pancreatitis, Chronic; Morphine; Pain; Inflammation
PubMed: 38329115
DOI: 10.1080/19490976.2024.2310291 -
Supportive Care in Cancer : Official... Oct 2023Although opioids have been shown to be effective for cancer pain, opioid-induced adverse events (AEs) are common. To date, little is known about the differences in risks...
PURPOSE
Although opioids have been shown to be effective for cancer pain, opioid-induced adverse events (AEs) are common. To date, little is known about the differences in risks of AEs by opioid type. This study was performed to compare the prevalence of AEs across opioids commonly used for analgesic treatment in Japan.
METHODS
This study was conducted as a preplanned secondary analysis of a multicenter prospective longitudinal study of inpatients with cancer pain who received specialized palliative care for cancer pain relief. We assessed daily AEs until termination of follow-up. We rated the severity of AEs based on the Common Terminology Criteria for Adverse Events version 5.0. We computed adjusted odds ratios for each AE (constipation, nausea and vomiting, delirium, and drowsiness) with the following variables: opioid, age, sex, renal dysfunction, and primary cancer site.
RESULTS
In total, 465 patients were analyzed. Based on the descriptive analysis, the top four most commonly used opioids were included in the analysis: oxycodone, hydromorphone, fentanyl, and tramadol. With respect to the prevalence of AEs among all analyzed patients, delirium (n = 25, 6.3%) was the most frequent, followed by drowsiness (n = 21, 5.3%), nausea and vomiting (n = 19, 4.8%), and constipation (n = 28, 4.6%). The multivariate logistic analysis showed that no single opioid was identified as a statistically significant independent predictor of any AE.
CONCLUSION
There was no significant difference in the prevalence of AEs among oxycodone, fentanyl, hydromorphone, and tramadol, which are commonly used for analgesic treatment in Japan.
Topics: Humans; Analgesics, Opioid; Oxycodone; Hydromorphone; Cancer Pain; Tramadol; Prospective Studies; Japan; Prevalence; Longitudinal Studies; Fentanyl; Constipation; Nausea; Vomiting; Delirium
PubMed: 37843639
DOI: 10.1007/s00520-023-08099-2