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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 -
Molecular Neurobiology Dec 2021Sex differences in opioid analgesia occur in rodents and humans, and could be due to differences in drug and metabolite levels. Thus, we investigated the sex and cycle...
Sex differences in opioid analgesia occur in rodents and humans, and could be due to differences in drug and metabolite levels. Thus, we investigated the sex and cycle differences in analgesia (nociception) from oxycodone in rats and related these to sex and cycle differences in brain and plasma oxycodone and metabolite levels. Since numerous opioids are CYP2D enzyme substrates and variation in CYP2D alters opioid drug levels and response, we also initiated studies to see if the sex and cycle differences observed might be due to differences in brain CYP2D activity. Across oxycodone doses, females in diestrus had higher analgesia (using tail flick latency) compared to males and females in estrus; we also demonstrated a direct effect of estrous cycle on analgesia within females. Consistent with the analgesia, females in diestrus had highest brain oxycodone levels (assessed using microdialysis) compared to males and females in estrus. Analgesia correlated with brain oxycodone, but not brain oxymorphone or noroxycodone levels, or plasma drug or metabolite levels. Propranolol (a CYP2D mechanism-based inhibitor), versus vehicle pre-treatments, increased brain oxycodone, and decreased brain oxymorphone/oxycodone drug level ratios (an in vivo CYP2D activity phenotype in the brain) in males and females in estrus, but not in females in diestrus. Brain oxymorphone/oxycodone inversely correlated with analgesia. Together, both sex and estrous cycle impact oxycodone analgesia and brain oxycodone levels, likely through regulation of brain CYP2D oxycodone metabolism. As CYP2D6 is expressed in human brain, perhaps similar sex and cycle influences also occur in humans.
Topics: Analgesia; Analgesics, Opioid; Animals; Brain; Estrous Cycle; Female; Male; Oxycodone; Pain Measurement; Rats; Rats, Wistar; Sex Characteristics
PubMed: 34581987
DOI: 10.1007/s12035-021-02560-1 -
European Journal of Medical Research Jan 2021Intravenous opioids are administered for the management of visceral pain after laparoscopic surgery. Whether oxycodone has advantages over other opioids in the treatment... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Intravenous opioids are administered for the management of visceral pain after laparoscopic surgery. Whether oxycodone has advantages over other opioids in the treatment of visceral pain is not yet clear.
METHODS
In this study, the analgesic efficiency and adverse events of oxycodone and other opioids, including alfentanil, sufentanil, fentanyl, and morphine, in treating post-laparoscopic surgery visceral pain were evaluated. This review was conducted according to the methodological standards described in the Cochrane Handbook for Systematic Reviews of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement. The PubMed, Embase, and Cochrane databases were searched in December 2019.
RESULTS
Ten studies were included in this review. The sample size was 695 participants. The results showed that compared with morphine and fentanyl, oxycodone had a more potent analgesic efficacy on the first day after laparoscopic surgery, especially during the first 0.5 h. There was no significant difference in sedation between the two groups. Compared to morphine and fentanyl, oxycodone was more likely to lead to dizziness and drowsiness. Overall, patient satisfaction did not differ significantly between oxycodone and other opioids.
CONCLUSIONS
Oxycodone is superior to other analgesics within 24 h after laparoscopic surgery, but its adverse effects should be carefully considered.
Topics: Alfentanil; Analgesics, Opioid; Fentanyl; Humans; Laparoscopy; Morphine; Oxycodone; Pain; Pain Management; Sufentanil
PubMed: 33422129
DOI: 10.1186/s40001-020-00463-w -
The Cochrane Database of Systematic... Aug 2021This is an update of the original Cochrane Review first published in Issue 10, 2016. For people with advanced cancer, the prevalence of pain can be as high as 90%.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This is an update of the original Cochrane Review first published in Issue 10, 2016. For people with advanced cancer, the prevalence of pain can be as high as 90%. Cancer pain is a distressing symptom that tends to worsen as the disease progresses. Evidence suggests that opioid pharmacotherapy is the most effective of these therapies. Hydromorphone appears to be an alternative opioid analgesic which may help relieve these symptoms.
OBJECTIVES
To determine the analgesic efficacy of hydromorphone in relieving cancer pain, as well as the incidence and severity of any adverse events.
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase and clinical trials registers in November 2020. We applied no language, document type or publication status limitations to the search.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that compared hydromorphone with placebo, an alternative opioid or another active control, for cancer pain in adults and children. Primary outcomes were participant-reported pain intensity and pain relief; secondary outcomes were specific adverse events, serious adverse events, quality of life, leaving the study early and death.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data. We calculated risk ratio (RR) and 95% confidence intervals (CI) for binary outcomes on an intention-to-treat (ITT) basis. We estimated mean difference (MD) between groups and 95% CI for continuous data. We used a random-effects model and assessed risk of bias for all included studies. We assessed the evidence using GRADE and created three summary of findings tables.
MAIN RESULTS
With four new identified studies, the review includes a total of eight studies (1283 participants, with data for 1181 participants available for analysis), which compared hydromorphone with oxycodone (four studies), morphine (three studies) or fentanyl (one study). All studies included adults with cancer pain, mean age ranged around 53 to 59 years and the proportion of men ranged from 42% to 67.4%. We judged all the studies at high risk of bias overall because they had at least one domain with high risk of bias. We found no studies including children. We did not complete a meta-analysis for the primary outcome of pain intensity due to skewed data and different comparators investigated across the studies (oxycodone, morphine and fentanyl). Comparison 1: hydromorphone compared with placebo We identified no studies comparing hydromorphone with placebo. Comparison 2: hydromorphone compared with oxycodone Participant-reported pain intensity We found no clear evidence of a difference in pain intensity (measured using a visual analogue scale (VAS)) in people treated with hydromorphone compared with those treated with oxycodone, but the evidence is very uncertain (3 RCTs, 381 participants, very low-certainty evidence). Participant-reported pain relief We found no studies reporting participant-reported pain relief. Specific adverse events We found no clear evidence of a difference in nausea (RR 1.13 95% CI 0.74 to 1.73; 3 RCTs, 622 participants), vomiting (RR 1.18, 95% CI 0.72 to 1.94; 3 RCTs, 622 participants), dizziness (RR 0.91, 95% CI 0.58 to 1.44; 2 RCTs, 441 participants) and constipation (RR 0.92, 95% CI 0.72 to 1.19; 622 participants) (all very low-certainty evidence) in people treated with hydromorphone compared with those treated with oxycodone, but the evidence is very uncertain. Quality of life We found no studies reporting quality of life. Comparison 3: hydromorphone compared with morphine Participant-reported pain intensity We found no clear evidence of a difference in pain intensity (measured using the Brief Pain Inventory (BPI) or VAS)) in people treated with hydromorphone compared with those treated with morphine, but the evidence is very uncertain (2 RCTs, 433 participants; very low-certainty evidence). Participant-reported pain relief We found no clear evidence of a difference in the number of clinically improved participants, defined by 50% or greater pain relief rate, in the hydromorphone group compared with the morphine group, but the evidence is very uncertain (RR 0.99, 95% CI 0.84 to 1.18; 1 RCT, 233 participants; very low-certainty evidence). Specific adverse events At 24 days of treatment, morphine may reduce constipation compared with hydromorphone, but the evidence is very uncertain (RR 1.56, 95% CI 1.12 to 2.17; 1 RCT, 200 participants; very low-certainty evidence). We found no clear evidence of a difference in nausea (RR 0.94, 95% CI 0.66 to 1.30; 1 RCT, 200 participants), vomiting (RR 0.87, 95% CI 0.58 to 1.31; 1 RCT, 200 participants) and dizziness (RR 1.15, 95% CI 0.71 to 1.88; 1 RCT, 200 participants) (all very low-certainty evidence) in people treated with hydromorphone compared with those treated with morphine, but the evidence is very uncertain. Quality of life We found no studies reporting quality of life. Comparison 4: hydromorphone compared with fentanyl Participant-reported pain intensity We found no clear evidence of a difference in pain intensity (measured by numerical rating scale (NRS)) at 60 minutes in people treated with hydromorphone compared with those treated with fentanyl, but the evidence is very uncertain (1 RCT, 82 participants; very low-certainty evidence). Participant-reported pain relief We found no studies reporting participant-reported pain relief. Specific adverse events We found no studies reporting specific adverse events. Quality of life We found no studies reporting quality of life.
AUTHORS' CONCLUSIONS
The evidence of the benefits and harms of hydromorphone compared with other analgesics is very uncertain. The studies reported some adverse events, such as nausea, vomiting, dizziness and constipation, but generally there was no clear evidence of a difference between hydromorphone and morphine, oxycodone or fentanyl for this outcome. There is insufficient evidence to support or refute the use of hydromorphone for cancer pain in comparison with other analgesics on the reported outcomes. Further research with larger sample sizes and more comprehensive outcome data collection is required.
Topics: Adult; Analgesics, Opioid; Cancer Pain; Child; Humans; Hydromorphone; Male; Middle Aged; Morphine; Neoplasms; Oxycodone
PubMed: 34350974
DOI: 10.1002/14651858.CD011108.pub3 -
Pain Research & Management 2020Radiotherapy is commonly used to treat cancer patients. Besides the curable effect, radiotherapy also could relieve the pain of cancer patients. However, cancer pain is... (Review)
Review
Radiotherapy is commonly used to treat cancer patients. Besides the curable effect, radiotherapy also could relieve the pain of cancer patients. However, cancer pain is gradually alleviated about two weeks after radiotherapy. In addition, cancer patients who receive radiotherapy may also suffer from pain flare or radiotherapy-induced side effects such as radiation esophagitis, enteritis, and mucositis. Pain control is reported to be inadequate during the whole course of radiotherapy (before, during, and after radiotherapy), and quality of life is seriously affected. Hence, radiotherapy is suggested to be combined with analgesic drugs in clinical guidelines. Previous studies have shown that radiotherapy combined with oxycodone hydrochloride can effectively alleviate cancer pain. In this review, we firstly presented the necessity of analgesia during the whole course of radiotherapy. We also sketched the role of oxycodone hydrochloride in radiotherapy of bone metastases and radiotherapy-induced oral mucositis. Finally, we concluded that oxycodone hydrochloride shows good efficacy and tolerance and could be used for pain management before, during, and after radiotherapy.
Topics: Analgesics, Opioid; Female; Humans; Male; Oxycodone; Pain; Pain Management; Quality of Life; Radiation Injuries
PubMed: 32089760
DOI: 10.1155/2020/7565962 -
Anesthesiology and Pain Medicine Feb 2024Total hip replacement (THR) is frequently associated with intense post-surgical pain. Effective pain management is of crucial importance to improving patient's condition...
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.
PubMed: 38725916
DOI: 10.5812/aapm-142710 -
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 -
World Journal of Emergency Medicine 2024To describe trends in oxycodone and oxycodone-containing analgesic prescribing for the treatment of back pain among adults in emergency departments (EDs) in the USA from...
BACKGROUND
To describe trends in oxycodone and oxycodone-containing analgesic prescribing for the treatment of back pain among adults in emergency departments (EDs) in the USA from 2007 to 2018.
METHODS
Data were gathered from the National Hospital Ambulatory Medical Care Survey (NHAMCS) from 2007 to 2018. The study population included individuals of all ages presenting to USA EDs. The NHAMCS reasons for visit and oxycodone drug ID codes were used to isolate patients with back pain. The main outcome was the proportion of oxycodone and oxycodone-containing analgesics prescribed for back pain in the EDs over the specified time period.
RESULTS
There was a relative decrease in the overall administration of oxycodone for back pain in the EDs by 62.3% from 2007 (244,000 visits) to 2018 (92,000 visits). The proportion of ED patients prescribed with oxycodone-containing analgesics for back pain increased among patients aged 45 years and older (from 43.8% to 57.6%), female patients (from 54.5% to 62.0%), black patients (from 22.5% to 30.4%), and Hispanic/Latino patients (from 9.4% to 19.6%). Oxycodone/acetaminophen was most prescribed and accounted for 90.2% of all oxycodone-containing analgesics in 2007, with a decrease to 68.5% in 2018. Pure oxycodone was the second most prescribed medication, accounting for 6.1% in 2007 and 31.5% in 2018.
CONCLUSION
The overall number of oxycodone-containing analgesics decreased significantly from 2007 to 2018. However, that number trended upward in 45-year-old and older, female, black, or Hispanic/Latino patients from 2007 to 2018. The total amount of pure oxycodone increased significantly from 2007 to 2008.
PubMed: 38855375
DOI: 10.5847/wjem.j.1920-8642.2024.002 -
Psychopharmacology May 2020Over the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a...
RATIONALE
Over the last decade, oxycodone has become one of the most widely abused drugs in the USA. Oxycodone use disorder (OUD) is a serious health problem that has prompted a need to develop animal models of OUD that have both face and predictive validity. Oxycodone use in humans is more prevalent in women and leads to pronounced hyperalgesia and irritability during withdrawal. However, unclear is whether current animal models of oxycodone self-administration recapitulate these characteristics in humans.
OBJECTIVES
We assessed the face validity of a model of extended-access oxycodone self-administration in rats by examining the escalation of oxycodone intake and behavioral symptoms of withdrawal, including irritability-like behavior and mechanical nociception, in male and female Wistar rats.
RESULTS
Both male and female rats escalated their oxycodone intake over fourteen 12-h self-administration sessions. After escalation, female rats administered more drug than male rats. No differences in plasma oxycodone levels were identified, but males had a significantly higher level of oxycodone in the brain at 30 min. Extended access to oxycodone significantly decreased aggressive-like behavior and increased defensive-like behaviors when tested immediately after a 12-h self-administration session, followed by a rebound increase in aggressive-like behavior 12 h into withdrawal. Tests of mechanical nociception thresholds during withdrawal indicated pronounced hyperalgesia. No sex differences in irritability-like behavior or pain sensitivity were observed.
CONCLUSIONS
The present study demonstrated the face validity of the extended access model of oxycodone self-administration by identifying sex differences in the escalation of oxycodone intake and pronounced changes in pain and affective states.
Topics: Analgesics, Opioid; Animals; Brain; Emotions; Female; Male; Oxycodone; Pain Threshold; Rats; Rats, Wistar; Self Administration; Sex Characteristics; Substance Withdrawal Syndrome
PubMed: 32114633
DOI: 10.1007/s00213-020-05479-y -
Journal of Analytical Toxicology Feb 2022The purpose of this research was to develop and validate an analytical method for the detection and quantification of noroxymorphone-3β-D-glucuronide (NOMG),...
The purpose of this research was to develop and validate an analytical method for the detection and quantification of noroxymorphone-3β-D-glucuronide (NOMG), oxymorphone-3β-D-glucuronide (NOMG), noroxymorphone (NOM), oxymorphone (OM), 6α-oxycodol (αOCL), 6β-oxycodol (βOCL), noroxycodone (NOC) and oxycodone (OC) in urine by liquid chromatography tandem mass spectrometry to be used in a human study. The method was validated according to the Academy Standards Board Standard Practices for Method Development in Forensic Toxicology. The method was then applied to a single-dose pilot study of a subject. Urine samples were collected from the subject after ingesting 10-mg OC as an immediate-release tablet. Additionally, urine specimens (n = 15) that had previously been confirmed positive for OC were analyzed using the validated method. The calibration range for NOMG and OMG was 0.05-10 μg/mL; for all other analytes, it was 0.015-10 μg/mL. Validation parameters such as bias, precision, carryover and dilution integrity, all met the validation criteria. After the method was validated, urine samples from the first subject in the controlled dose study were analyzed. It was observed that OC, NOC and OMG contained the highest concentrations and were present in either the 0.5 or 1 h void. NOC and OMG were detected until the 48 h collection, while OC was detectable till the 24 h collection. Time to reach maximum concentration (Tmax) in the urine was achieved within 1.5 h for OC and within 3 h for NOC and OMG. Maximum concentration (Cmax) in the urine for OC, NOC and OMG was 3.15, 2.0 and 1.56 μg/mg, respectively. OC concentrations in authentic urines ranged from 0.015 to 12 μg/mL. Ranges for NOMG and OMG were 0.054-9.7 μg/mL and 0.14-67 μg/mL, respectively. A comprehensive method for the quantification of NOMG, OMG, NOM, OM, αOCL, βOCL, NOC and OC in urine was optimized and met the validation criteria. The concentrations of NOMG and OMG presented in this study provide the details needed in the forensic community to better comprehend OC pharmacokinetics.
Topics: Chromatography, Liquid; Humans; Oxycodone; Oxymorphone; Pilot Projects; Tandem Mass Spectrometry
PubMed: 33270113
DOI: 10.1093/jat/bkaa186