Doses Of Oxycodone Research Articles

The effect of anlotinib on the pharmacokinetic profile of oxycodone and the underlying mechanism

PurposeCancer patients experience pain during medical treatment. Therefore, anticancer drugs and painkillers are often prescribed together. This study aims to determine the interaction between anlotinib and oxycodone and reveal the underlying mechanism. MethodsUPLC-MS/MS, an efficient and sensitive method, was used for the simultaneous determination of oxycodone and oxycodone metabolites. Sprague-Dawley rats were given oxycodone with or without anlotinib. Then, UPLC-MS/MS was used to determine the blood concentration of oxycodone. To study the interaction mechanism, rat and human liver microsomes (HLMs) were used for determining enzyme kinetics. ResultsLong-term administration of oxycodone combined with anlotinib resulted in significantly increased pharmacokinetic parameters AUC(0-t), AUC(0-∞), and Cmax for oxycodone, indicating that anlotinib inhibited oxycodone. In vitro kinetic measurements indicated that anlotinib inhibited the metabolism of oxycodone through a mixed mechanism. Further studies indicated that in HLMs, anlotinib strongly inhibited the metabolism of oxycodone. ConclusionThis study showed that anlotinib inhibited the metabolism of oxycodone both in vitro and in vivo. It is recommended that the dose of oxycodone should be reconsidered when oxycodone is combined with anlotinib in clinical practice.

Comparison of a Small Dose of Oxycodone and Sufentanil for the Prevention of Sufentanil-Induced Cough during General Anesthesia Induction: A Prospective Randomized Controlled Trial.

Background Sufentanil is widely used during anesthesia induction. However, it can cause coughing via different mechanisms. This study is aimed at evaluating the effectiveness of a small dose of oxycodone and sufentanil in suppressing sufentanil-induced cough (SIC) during general anesthesia induction. Methods Of the 174 patients scheduled for elective surgery, 144 were eligible and randomly divided into 3 groups (n = 48). Five minutes before sufentanil bolus (0.4 μg/kg), patients in group O received 0.02 mg/kg oxycodone intravenously within 5 s, those in group S received 0.02 μg/kg sufentanil within 5 s, and those in group N received an equal volume of 0.9% normal saline within 5 s. Sufentanil was diluted to 5 μg/ml and administered within 5 s after pretreatment. The incidence and severity of cough in the three groups were evaluated within 1 minute after sufentanil injection during the anesthesia induction. Their mean arterial pressure (MAP) and heart rate (HR) were recorded at T0 (after entering the operation), T1 (3 minutes after pretreatment), T2 (before intubation), and T3 (1 minute after intubation). Results The incidences of cough in group N, group O, and group S were 20 (41.6%), 7 (14.5%), and 6 (12.5%), respectively. Compared with group N, patients from group O and group S exhibited significantly reduced incidence and severity of cough, and the severity of cough in group O and group S was significantly reduced compared with group N (P < 0.05). No significant differences in the rangeability of MAP and HR were noted at the four time points in the three groups (P > 0.05). Conclusion. Preconditioning using intravenous oxycodone (0.02 mg/kg) or sufentanil (0.02 μg/kg) could represent an effective approach to reducing SIC in anesthesia induction and was associated with relatively stable hemodynamic state during general anesthesia. This trial is registered at Chinese Clinical Trial Registry with registration number ChiCTR1900021087.

Effect of gender factor on the effective dose of oxycodone for inhibiting responses to laryngeal mask airway insertion in elderly patients undergoing ophthalmic surgery

Objective: To evaluate the effect of gender factor on the effective dose of oxycodone for inhibiting responses to laryngeal mask airway (LMA) insertion in elderly patients undergoing ophthalmic surgery. Methods: From June to October 2021, 56 elderly patients, including 26 females and 30 males, aged from 65 to 80 (72±5) years, with a body mass index (BMI) of 18.5-24.9 kg/m2 and American Society of Anesthesiologists (ASA) physical status of Ⅰ or Ⅱ, who underwent elective ophthalmic surgery requiring LMA insertion in the Beijing Tongren Hospital affiliated to Capital Medical University were selected. Patients were divided into two groups according to gender: elderly female group and elderly male group. The modified Dixon sequential method was used. Oxycodone 0.10 mg/kg was injected intravenously in the first patient. Etomidate 0.2 mg/kg and cisatracurium 0.1 mg/kg were administrated 5 min later. After 3 min, the laryngeal mask was placed when the bispectral index (BIS) ≤60. The positive response to LMA insertion was defined as an increase in the maximum mean arterial pressure or the maximum heart rate>20% of the baseline value within 2 min after insertion. When the response to LMA insertion was positive, the dose of oxycodone was increased in the next patient, otherwise the dose was decreased, and the ratio of adjacent dose was 1.1. This process was repeated until the 7th turning point occurred. The half-maximal effective doses (ED50) and 95% confidence intervals (CI) of oxycodone for inhibiting laryngeal mask insertion were calculated and compared between the two groups. Meanwhile, the adverse reactions during anesthesia induction were observed. Results: All 26 patients in the elderly female group completed the test, but one patient in the elderly male group withdrew due to poor alignment of laryngeal mask, and finally 29 patients completed the study. There were 13 cases and 14 cases who had positive response to LMA insertion in the elderly female and male groups, respectively. The ED50 (95%CI) of oxycodone for inhibiting laryngeal mask insertion in the elderly male group was 0.096 (0.083-0.112) mg/kg, which was higher than that in the elderly female group [0.081 (0.073-0.098) mg/kg, P=0.008]. No adverse reactions such as choking cough, muscle tremor, hypoxemia, nausea, vomiting, reflux and aspiration occurred in 55 patients, except that one patient in the elderly female group had transient hypotension after induction, which improved after symptomatic treatment. Conclusion: The ED50 of oxycodone for inhibiting laryngeal mask insertion reaction in ophthalmic surgery is different in patients with different genders, which is 0.096 (0.083-0.112) mg/kg in the elderly male group and 0.081 (0.073-0.098) mg/kg in the elderly female group.

Model-Based Analysis of the Influence of Alcohol Use and Age on Pharmacokinetics-Pharmacodynamics of Oral Oxycodone in Middle-Age and Older Community-Dwelling Adults.

Little is known about how opioid responses vary by age and in the presence of alcohol consumption. This model-based pharmacokinetic (PK)-pharmacodynamic (PD) analysis quantified the impact of age and alcohol use on pupillometry and cold pressor test (CPT) PD based on data from an open-label study of a single, immediate-release 10-mg oral oxycodone in middle-age and older adults (aged 35-85) without severe functional limitations. PK and pupillometry assessments were obtained on 11 occasions over 8 hours. Cold pressor test was administered at 1.5, 5, and 8 hours after oxycodone dosing. The study population consisted of 62 older adults (aged ≥60) and 66 middle-aged adults (aged 35-59), with 82% meeting the unhealthy drinking criteria. Oral oxycodone PK were well described using a 1-compartment model with a sequential 0 to first-order absorption process. Inhibitory maximum effect and linear direct effect PD models described the respective pupillometry and cold pressor test data using simultaneous PK-PD analysis in MONOLIX. Recent alcohol use measures were selected a priori as covariates. This analysis demonstrated an influence of age on clearance and body weight on the distribution volume of oxycodone; alcohol consumption was not noted to alter oxycodone PK. Oxycodone pupillometry PD were influenced by the level of subject-reported alcohol consumption (Alcohol Use Disorders Identification Test for Consumption), alcohol use biomarker-blood phosphatidylethanol, previous cannabis use, and age. Over the opioid exposure range of the study, none of the covariables including alcohol and age were noted to affect cold pressor test pharmacodynamics. Additional clinical studies are needed to further investigate the clinical consequences of opioid-alcohol-age interaction.

R‐(‐)2,5‐dimethoxy‐4‐iodoamphetamine (DOI) Blunts the Discriminative Stimulus Properties of Oxycodone

AimsA record ~100,000 fatalities due to drug overdoses was reported in the U.S. for the twelve months preceding April 2021. Opioids account for most deaths, and recurrent opioid use may lead to the development of opioid use disorder (OUD), a debilitating chronic disorder. Current medication‐assisted OUD treatment (e.g., buprenorphine) mitigates withdrawal, reduces mortality, and reduces intake of abused opioids. Still, the opioid epidemic crystalized the need to identify novel non‐opioid therapeutics to improve the odds of successful OUD recovery. In the last decade, there has been a resurgence of interest in serotonergic psychedelics for the treatment of psychiatric disorders, including substance use disorders. Psychedelic compounds act through agonist actions at the serotonin (5‐HT) 5‐HT2A receptor (5‐HT2AR) and there is some literature to suggest functional interactions between 5‐HT2AR and opioids. We tested the hypothesis that the psychedelic 5‐HT2AR agonist R‐(‐)2,5‐dimethoxy‐4‐iodoamphetamine (DOI) will disrupt the discriminative stimulus properties of the commonly misused prescription opioid oxycodone. The drug discrimination paradigm is a rigorous laboratory procedure for modeling the interoceptive effects of drugs and is widely recognized as useful in establishing ligand potency and effectiveness in vivo, as well as interrogating abuse liability.MethodsMale, Sprague‐Dawley rats (n = 13) were trained to discriminate an injection (s.c.) of oxycodone (1 mg/kg) from saline (1 ml/kg) in a two‐lever, water‐reinforced paradigm. Pharmacological testing began upon establishment of the stable oxycodone vs. saline discrimination. Substitution tests with DOI (0‐0.2 mg/kg; s.c.) and combination tests with DOI plus oxycodone were conducted interspersed with maintenance sessions. Percent oxycodone‐lever responding, response rates and latency to the first response were analyzed with an experimentwise error rate of α=0.05.ResultsAll rats acquired the oxycodone vs. saline discrimination to stability. Substitution tests indicated that all DOI doses resulted in percent oxycodone‐lever responding significantly different from the training dose of oxycodone (p&lt; 0.05). Pretreatment with DOI (0.1, 0.2 mg/kg) significantly reduced the percent oxycodone‐lever responding (0.5 mg/kg), relative to pretreatment with vehicle (p &lt; 0.05). The selective 5‐HT2AR antagonist M100907 prevented DOI‐induced suppression of oxycodone‐lever responding (p &lt; 0.05).ConclusionsThe current studies reveal that the psychedelic DOI does not substitute for oxycodone, but does suppress the stimulus effects of oxycodone, an effect which is reversed by the 5‐HT2AR antagonist M100907. Taken together, these studies provide support for expanded interrogation of the efficacy of 5‐HT2AR agonists in counteracting the behavioral effects of opioids.

The effects of fentanyl, oxycodone, and butorphanol on gastrointestinal function in patients undergoing laparoscopic hysterectomy: a prospective, double-blind, randomized controlled trial

BackgroundPerioperative opioid use is associated with postoperative bowel dysfunction, which causes longer hospital stay and higher healthcare costs. This study aimed to investigate the effect of the equivalent doses of fentanyl, oxycodone, and butorphanol on bowel function in patients undergoing laparoscopic hysterectomy.MethodsIn this randomized controlled trial, 135 patients undergoing laparoscopic hysterectomy received postoperative intravenous patient-controlled analgesia (IV-PCA) with fentanyl 8.3 μg/kg, butorphanol 0.16 mg/kg, and oxycodone 0.5 mg/kg (1: 20: 60), respectively. The primary outcome measure was the recovery of bowel function. We also evaluated and recorded the following nine indicators: pain score, sedation level, leukocyte count, percentage of neutrophils, plasma potassium levels, time to first ambulation, postoperative side effects, patients' satisfaction, and postoperative hospital length of stay.ResultsThe mean time to flatus was significantly prolonged in Group B (45.2 ± 11.6 h) compared with Group F (33.1 ± 11.2 h, P < 0.001) and Group O (36.2 ± 10.9 h, P = 0.001). The incidence of somnolence and dizziness prove higher in Group B (P < 0.001). No statistical difference was observed in the mean time to tolerate oral diet, time to defecation, analgesic outcome, satisfaction score, time to first ambulation, and postoperative hospital length of stay.ConclusionsCompared with fentanyl and oxycodone, butorphanol prolonged the recovery of bowel function with more severe somnolence and dizziness, suggesting that butorphanol is not well suitable for IV-PCA in patients undergoing laparoscopic hysterectomy.Trial registrationClinicalTrials.gov-NCT04295109. Date of registration: March, 2020.

Effects of Ultramicronized N-Palmitoylethanolamine Supplementation on Tramadol and Oxycodone Analgesia and Tolerance Prevention.

Chronic pain management requires increasing doses of opioids, the milestone of painkillers, which may result in the onset of tolerance with exacerbated side effects. Maintaining stable analgesia with low doses of opioids is thus imperative. N-palmitoylethanolamine (PEA) is an endogenous lipid compound endowed with pain-relieving as well as anti-inflammatory properties. The ultramicronized formulation of PEA was recently demonstrated to be able to modulate morphine’s effects, delaying tolerance and improving efficacy. To evaluate the possible application to other opioids, in this study, we analysed the capacity of ultramicronized PEA to regulate analgesia and tolerance induced by oxycodone and tramadol. Pre-emptive and continuative treatment with ultramicronized PEA (30 mg kg−1, daily, per os) delayed the onset of opioid tolerance and enhanced opioid analgesia when it was acutely administered in association with tramadol (20 mg kg−1, daily, subcutaneously) or oxycodone (0.5 mg kg−1, daily, subcutaneously). Moreover, PEA exerted antinociceptive effects on tolerant rats, suggesting the use of PEA together with opioids for stable, long-lasting analgesia. To that purpose, the oxycodone dose needed to be increased from 0.3 mg kg−1 (day 1) up to 1 mg kg−1 (day 31) in the oxycodone + vehicle group; the tramadol dose was progressively enhanced from 15 mg kg−1 to 50 mg kg−1 in 31 days in the tramadol + vehicle group. Acute oral co-treatment with PEA (120 mg kg−1) achieved the same analgesia without increasing the dose of both opioids. The behavioural effects of PEA on opioid chronic treatment paralleled a decrease in astrocyte activation in the dorsal horn of the spinal cord (a marker of the development of opioid tolerance) and with a modulation of mRNA expression of IL-6 and serpin-A3. In conclusion, pre- and co-administration of ultramicronized PEA delayed the development of tramadol tolerance, potentiating either oxycodone or tramadol analgesia and allowing a long-lasting analgesic effect with a low opioid dose regimen. The use of PEA is suggested for clinical purposes to support the opioid-based management of persistent pain.

The Median Effective Concentration (EC50) of Epidural Ropivacaine With Different Doses of Oxycodone During Limb Surgery in Elderly Patients

BackgroundOxycodone can be used both intravenously and epidurally in elderly patients because of its strong analgesic effect and more slight respiratory inhibition compared with other opioids at the same effect. In this study, we determined the median effective concentration (EC50) of epidural ropivacaine required for great saphenous vein surgery in elderly patients in order to describe its pharmacodynamic interaction with oxycodone.MethodsOne hundred forty-one elderly patients scheduled for high ligation and stripping of the great saphenous vein surgery were allocated into three groups in a randomized, double-blinded manner as follows: Q2.5 group (2.5 mg oxycodone), Q5.0 group (5.0 mg oxycodone), and C group (normal saline). Anesthesia, was achieved with epidural ropivacaine and oxycodone. The EC50 of ropivacaine for surgery with different doses of oxycodone was adjusted by using an up-and-down sequential methods with an adjacent concentration gradient at a factor of 0.9 to inhibit analgesia. Anesthesia associated adverse events and recovery, characteristics were also recorded.ResultsThe EC50 of ropivacaine for the great saphenous vein surgery in elderly patients was 0.399% (95% CI, 0.371–0.430%) in the Q2.5 group, 0.396% (95% CI, 0.355–0.441%) in the Q5.0 group, and 0.487% (95% CI, 0.510–0.465%) in the C group, respectively (P < 0.05). Specially, the EC50 of ropivacaine in the Q2.5 and Q5.0 groups was lower than that in the C group (P < 0.01), But the difference between the Q2.5 group and the Q5.0 group was not significant (P > 0.05). There was no significant difference in the Bromage score from the motor block examination, heart rate (HR) or mean arterial pressure (MAP) at each observation time point after epidural administration among the three groups (P > 0.05). No serious adverse reactions occurred in any of the three groups.ConclusionOxycodone combined with ropivacaine epidural anesthesia can reduce the EC50 of ropivacaine required for elderly patients undergoing the great saphenous vein surgery. There was no significant difference in anesthesia associated adverse events among the three groups. The recommended dose of oxycodone is 2.5 mg.

Differential Effects of Cannabidiol and a Novel Cannabidiol Analog on Oxycodone Place Preference and Analgesia in Mice: an Opioid Abuse Deterrent with Analgesic Properties.

Background and Purpose: This study sought to determine whether cannabidiol (CBD) or a CBD derivative, CBD monovalinate monohemisuccinate (CBD-val-HS), could attenuate the development of oxycodone reward while retaining its analgesic effects. Experimental Approach: To determine the effect on oxycodone reward, animals were enrolled in the conditioned place preference paradigm and received either saline or oxycodone (3.0 mg/kg) in combination with either CBD or CBD-val-HS utilizing three sets of drug-/no drug-conditioning trials. To determine if the doses of CBD or CBD-val-HS that blocked opioid reward would affect nociceptive processes, animals were enrolled in the hot plate and abdominal writhing assays when administered alone or in combination with a subanalgesic (1.0 mg/kg) or analgesic (3.0 mg/kg) dose of oxycodone. Key Results: Results from condition place preference demonstrated CBD was not able attenuate oxycodone place preference while CBD-val-HS attenuated these rewarding effects at 8.0 mg/kg and was void of rewarding or aversive properties. In contrast to CBD, CBD-val-HS alone produced analgesic effects in both nociceptive assays but was most effective compared with oxycodone against thermal nociception. Of interest, there was a differential interaction of CBD and CBD-val-HS×oxycodone across the two nociceptive assays producing subadditive responses on the hot plate assay, whereas additive responses were observed in the abdominal writhing assay. Conclusion: These findings suggest CBD-val-HS alone, a nonrewarding analgesic compound, could be useful in pain management and addiction treatment settings.

Elevated customary alcohol consumption attenuates opioid effects

BackgroundRegular alcohol consumption is on the rise among older adults and has the potential of altering the subjective experience of pain and response to pain medications. This study examined the cognitive, analgesic and side effect response to oxycodone in middle age and older adults with elevated levels of customary alcohol consumption in a human laboratory setting. MethodsAfter refraining from alcohol for one day, eligible participants underwent baseline assessment cognition and side effects by means of questionnaires that were repeated at three time points (90 min, 5 and 8 h) following administration of a 10 mg oral dose of oxycodone. Response to pain stimulus (Cold Pressor Test (CPT)), pupil size, and plasma oxycodone were also measured. ResultsOne hundred twenty-eight adults (age 35–85) completed the study day. Compared to those with lower customary alcohol consumption, participants with elevated alcohol consumption showed attenuated opioid-induced pupil constriction and cognitive decline on objective measures of working memory, sustained attention, inhibitory control, coordination on a simulated driving task, and subjective dysphoric effects with enhanced subjective euphoric effects. Oxycodone pharmacokinetics, pain tolerance to CPT, and Berg balance were impacted comparably between alcohol consumption groups. Women endorsed greater negative drug effects, whereas men endorsed positive drug effects. ConclusionIndependent of subject's age, elevated customary alcohol consumption attenuates opioid central effects (i.e., pupil miosis, impaired cognition) and gender influences subjective drug effects. Clinicians should consider alcohol consumption and gender when prescribing opioid medications.

Sex and Estrous Cycle Differences in Analgesia and Brain Oxycodone Levels.

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.

MP34-13 A PROSPECTIVE ANALYSIS OF OPIOID USE FOLLOWING OUTPATIENT PEDIATRIC UROLOGIC SURGERY

You have accessJournal of UrologyHealth Services Research: Quality Improvement & Patient Safety II (MP34)1 Sep 2021MP34-13 A PROSPECTIVE ANALYSIS OF OPIOID USE FOLLOWING OUTPATIENT PEDIATRIC UROLOGIC SURGERY Rachael Sherrer, Ann Byrne, Fardod O'Kelly, Ruthie Su, and Walid Farhat Rachael SherrerRachael Sherrer More articles by this author , Ann ByrneAnn Byrne More articles by this author , Fardod O'KellyFardod O'Kelly More articles by this author , Ruthie SuRuthie Su More articles by this author , and Walid FarhatWalid Farhat More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002043.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: While opioids have a role in multimodal post-operative analgesia, there is increasing data which suggests they may not be routinely required after pediatric surgery. With this lack of consensus on opioid use after pediatric urologic procedures, we sought to examine impact of patient characteristics and surgery type on opioid usage in our outpatient urologic surgery cohort. METHODS: This prospective study was approved by the hospital’s Institutional Review Board. Opioid use data was prospectively collected over a 12-month period (January to December 2020) via routine institutional post-operative telephone calls to parents of patients undergoing outpatient urologic surgery. Patient characteristics (age, sex, race), surgery type, and opioid prescription and refill information were recorded. Those who underwent a simultaneous procedure with another specialty or were admitted to the hospital were excluded. All patients were prescribed scheduled acetaminophen and ibuprofen for 48 hours after surgery, then as needed, and up to a maximum of 5 doses of oxycodone. The count of opioid doses was modelled using negative binomial regression with robust standard errors. RESULTS: 263 patients underwent outpatient urologic surgery over the 12-month period. 182 predominantly male (99%) patients met inclusion criteria, with mean age of 5.1 years and mean 4.9 opioid doses prescribed per patient. There were 138 genital, 21 inguinal, 17 laparoscopic, and 6 cystoscopic procedures. Mean opioid use was one single dose, and 94 (52%) patients used no opioids. The mean number of excess, unused prescribed doses per patient was 4. Eleven patients used all doses prescribed, and one received a refill (5 additional doses). Table 1 outlines opioid use by surgery, age, and race. These were not independent predictors of opioid use on multivariable analysis, although there was a trend toward increased use in adolescents. CONCLUSIONS: Our findings suggest that opioids are in fact likely over-prescribed after outpatient pediatric urologic surgery, with 93% of patients not requiring all of their opioid prescription and 52% not using any opioids at all. While overall opioid requirements were low across all sub-cohorts, there was a trend toward increased use in adolescents which should be factored into education with this group. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e621-e621 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rachael Sherrer More articles by this author Ann Byrne More articles by this author Fardod O'Kelly More articles by this author Ruthie Su More articles by this author Walid Farhat More articles by this author Expand All Advertisement Loading ...

Assessment of Opioid Use and Analgesic Requirements After Endoscopic Sinus Surgery

The opioid epidemic has generated interest in optimizing opioid prescribing after common surgeries. Recent studies have shown a broad range of analgesic prescription patterns following endoscopic sinus surgery (ESS). To compare the efficacy of different analgesic regimens after ESS. This multi-institutional, nonblinded randomized clinical trial was conducted at 6 tertiary centers across the US and Canada and included participants who underwent ESS for acute or chronic rhinosinusitis. The study was conducted from March 2019 to March 2020, and the data were analyzed in November to December 2020. All participants received acetaminophen, 650 mg, as the first-line analgesic. From there, patients were randomized to either oxycodone rescue (oxycodone, 5 mg, as second-line therapy) or ibuprofen rescue (ibuprofen, 600 mg, as second-line therapy, with oxycodone, 5 mg, reserved for breakthrough pain). Baseline characteristics and disease severity were collected at enrollment. Medication logs, pain scores, and epistaxis measures were collected until postoperative day 7. The primary outcome was the postoperative visual analog scale score for pain. Brief Pain Inventory Pain Severity and Pain Interference Scores were also collected. A total of 118 patients were randomized (62 [52.5%] oxycodone rescue, 56 [47.5%] ibuprofen rescue; mean [SD] age, 46.7 [16.3] years; 44 women [44.0%]; 83 White [83.0%], 7 Black [7.0%], and 7 Asian individuals [7.0%]). After exclusions for loss to follow-up and noncompliance, 51 remained in the oxycodone rescue group and 49 in the ibuprofen rescue group. The groups had similar demographic characteristics and disease severity. Thirty-two (63%) in the oxycodone rescue group had adequate pain management with acetaminophen only, while 19 (37%) consumed at least 1 oxycodone dose. In the ibuprofen rescue group, 18 (16%) required only acetaminophen, 28 (57%) used only acetaminophen and ibuprofen, and the remaining 13 (26%) consumed 1 or more oxycodone doses. The groups had similar average acetaminophen (9.69 vs 7.96 doses; difference, 1.73; 95% CI, -1.37 to 4.83) and oxycodone (1.89 vs 0.77 doses; difference, 1.13; 95% CI, -0.11 to 2.36) use. Both groups had similar postoperative visual analog scale scores. A subanalysis that compared opioids users with nonusers showed clinically significant lower pain scores in nonusers at multiple postoperative points. In this randomized clinical trial, most patients who underwent ESS could be treated postoperatively using a nonopioid regimen of either acetaminophen alone or acetaminophen and ibuprofen. Ibuprofen as a second-line therapy did not reduce overall narcotic consumption, but the overall narcotic use was low in both groups. ClinicalTrials.gov Identifier: NCT03783702.

A non-injected opioid analgesia protocol for acute pain crisis in adolescents and adults with sickle cell disease.

Initial management of the acute pain crisis (APC) of sickle cell disease (SCD) is often unsatisfactory, and might be improved by developing a standardised analgesia protocol. Here, we report the first stages in developing a standard oral protocol for adolescents and adults. Initially, we performed a dose finding study to determine the maximal tolerated dose of sublingual fentanyl (MTD SLF) given on arrival in the acute care facility, when combined with repeated doses of oral oxycodone. We used a dose escalation algorithm with two dosing ranges based on patient’s weight (<50 kg or >50 kg). We also made a preliminary evaluation of the safety and efficacy of the protocol. The study took place in a large tertiary centre in London, UK. Ninety patients in the age range 14–60 years were pre-consented and 31 treatment episodes were evaluated. The first 21 episodes constituted the dose escalation study, establishing the MTD SLF at 600 mcg (>50 kg) or 400 mcg (<50 kg). Further evaluation of the protocol indicated no evidence of severe opioid toxicity, nor increased incidence of acute chest syndrome (ACS). Between 0 and 6 hours, the overall gradient of reduction of visual analogue pain score (visual analogue scale (VAS)) was 0.32 centimetres (cm) per hour (95% confidence interval (CI) = 0.20 to 0.44, p < 0.001). For episodes on MTD SLF, there was median (interquartile range (IQR)) reduction in VAS score of 2.8 cm (0–4.2) and 59% had at least a 2.6-cm reduction. These results are supportive of further evaluation of this protocol for acute analgesia of APC in a hospital setting and potentially for supervised home management.

Population Pharmacokinetics of Oxycodone and Metabolites in Patients with Cancer-Related Pain.

Simple SummaryPatients with moderate to severe cancer-related pain are frequently treated with oxycodone, a strong-acting opioid. However, treatment with oxycodone does not always lead to sufficient analgesic action. In order to determine which factors affect treatment outcomes, we performed an observational study and developed a population pharmacokinetic model. The model described oxycodone, nor-oxycodone and nor-oxymorphone pharmacokinetics. The association between oxycodone or oxycodone metabolites’ exposure with pain scores and adverse events was not significant. The combined oxycodone, nor-oxycodone and nor-oxymorphone model is a good starting point for further unravelling the factors that affect the pharmacokinetic/pharmacodynamic relation of oxycodone and its metabolites.Oxycodone is frequently used for treating cancer-related pain, while not much is known about the factors that influence treatment outcomes in these patients. We aim to unravel these factors by developing a population-pharmacokinetic model to assess the pharmacokinetics of oxycodone and its metabolites in cancer patients, and to associate this with pain scores, and adverse events. Hospitalized patients with cancer-related pain, who were treated with oral oxycodone, could participate. Pharmacokinetic samples and patient-reported pain scores and occurrence and severity of nine adverse events were taken every 12 h. In 28 patients, 302 pharmacokinetic samples were collected. A one-compartment model for oxycodone and each metabolite best described oxycodone, nor-oxycodone, and nor-oxymorphone pharmacokinetics. Furthermore, oxycodone exposure was not associated with average and maximal pain scores, and oxycodone, nor-oxycodone, and nor-oxymorphone exposure were not associated with adverse events (all p > 0.05). This is the first model to describe the pharmacokinetics of oxycodone including the metabolites nor-oxycodone and nor-oxymorphone in hospitalized patients with cancer pain. Additional research, including more patients and a more timely collection of pharmacodynamic data, is needed to further elucidate oxycodone (metabolite) pharmacokinetic/pharmacodynamic relationships. This model is an important starting point for further studies to optimize oxycodone dosing regiments in patients with cancer-related pain.

POS0837 THE USE OF CANNABIDIOL IN THE TREATMENT OF PAIN RELATED TO SCLERODERMA DIGITAL ULCERS

Background:Systemic Sclerosis-SSc is an autoimmune disease, characterized by fibrosis due to immune-mediated microangiopathy. Digital ulcers-DUs represent frequent complications, they are recurrent, painful and often resistant to traditional treatments. Standard therapy, in particular oral opioids, is often inadequate or limited by side effect. Cannabidiol-CBD, is the major non-psychotropic component of the Cannabis sativa, recent studies on its effectiveness as an anxiolytic, anti-inflammatory, and antipsychotic drug showed promising results, in the setting of chronic pain too.Objectives:We evaluated the efficacy of CBD drop in pain management in a cohort of SSc patients using standard rating scale VAS, PSQI and HAQ. We further assessed the safety profile and the potential use as opioid-sparing.Methods:From January to November 2019 we consecutively enrolled 31 SSc patients (F/M 26/5, mean age 53.0±14.6SD-years) referred to our Scleroderma Unit. All patients satisfied the EULAR/ACR SSc classification criteria. All cases were complicated by painful DUs resistant to analgesics and pain was classified as severe, according to WHO guidelines. CBD drops consist of cannabis sativa seed in olive oil, 10% CBD, laboratory tested to confirm a tetrahydrocannabinol-THC level&lt;0.3%. The CBD oil was administrated sublingually twice-a-day. All patients started with CBD 3 drops twice-a-day, and progressively increased to the maximum dosage of 6 drops twice-a-day (from 27.6 g to 55.2 g dose/day). All patients continued local/systemic treatments for SSc: 24/31 subjects performed calcium-channel blockers, 31/31 prostanoids infusion, 24/31 anti-endothelin drugs. All subjects were provided with a daily diary to record self-evaluation of pain using VAS, PSQI, hours of sleep per night, use of other analgesics, eventual side effects. HAQ-DI was also administrated. These indicators were assessed baseline and during follow-up. Safety of CBD was evaluated by patient’s records of side effects. All data were analyzed by paired t-test. This investigation was a monocentric, prospective study. Ethical approval was obtained from the Competent Ethics Committee (protocol n. 282/15) and all participants gave written consent.Results:CBD was administered for a mean period of 5.9±3.2SD-months. After the first month, VAS decreased from 94.80±8.72SD to 54.70±9.40SD (p&lt;0.0001), PSQI decreased from 9.27±2.9SD to 4.47±1.06SD (p&lt;0.001), total hours of sleep increased from 2.56±1.28 SD to 5.67±0.85SD (p&lt; 0.0001). The additional analgesic therapy was necessary in 22/31 patients: 6/22 only paracetamol, 12/22 paracetamol+oxycodone reducing the dosage of oxycodone at the minimum, 2/22 oxycodone 20 mg twice-a-day, 2/22 need fentanyl transdermal patch. After 3 months, VAS further reduced to 40.90±12.90, PSQI decreased to 3.1±1.4SD, the mean total hours of sleep per night was 6.10±0.79SD and the HAQ-DI decreased from 2.19±0.67SD (baseline) to 0.79±0.46SD at the last patients’ evaluation. At the end of the observation, 18/31 patients (58%) showed DUs healing. We also interestingly reported improvement of dysphagia and appetite in 70%, and an improvement in constipation related to opiods in 48%. No patients experienced severe side effects in particular no psychoactive aspects. Mild side effects, namely dry mouth was referred by 9/31 (29%), mild abdominal pain and changes in appetite by 10/31 (32%). No interaction with other drugs was observed.Conclusion:Our study suggests that oral CBD is effective and safe in maintaining analgesia in SSc patients with DUs. Furthermore, CBD could be helpful in opioids tapering and to treat dysphagia, even if these observations need focused investigations. In conclusion, CBD might be a useful tool to manage chronic pain in SSc-DUs. These data provide a compelling rationale for further research to clarify the therapeutic potential of CBD in SSc.Disclosure of Interests:None declared

Effectiveness of Fascia Iliaca Compartment Block after Elective Total Hip Replacement: A Prospective, Randomized, Controlled Study.

Objective: An assessment of the feasibility of fascia iliaca compartment block (FICB) combined with nonopioid analgesics and patient controlled analgesia (PCA), oxycodone, in the perioperative anaesthetic management for elective total hip replacement (THR). Design: A randomised, single-center, open-label study. Setting: A single hospital. The study was conducted from October 2018 to May 2019. Participants: In total, 109 patients were scheduled for elective total hip replacement. Interventions: Postoperative FICB with 0.375% ropivacaine in conjunction with nonopioid analgesics (paracetamol, metamizole, and pregabalin) and oxycodone as rescue analgesia. Measurements: Pain intensity was measured using the Numeric Pain Rating Scale (NRS) at rest and during rehabilitation, the total dose of postoperative oxycodone required, the occurrence of opioid-related adverse events, patient hospitalisation time, and level of satisfaction. Follow-up period: 48 h. Main Results: A total of 109 patients were randomised into two groups and, of these, 9 were subsequently excluded from the analysis (three conversions to general anaesthesia, two failures to perform FICB, four failures to use the PCA pump). Patients in the FICB group received standard intravenous analgesia with FICB, and those in the control group were managed with standard intravenous analgesia only. Pain level measured with NRS was significantly lower at rest and during rehabilitation in the FICB group. Oxycodone use in the first 48 h was significantly higher in the control group (p < 0.001); additionally, the time to the first dose of rescue analgesia was significantly shorter (p < 0.001). In the control group, there was a higher rate of side effects and a significantly longer hospitalisation time (p < 0.001). Similarly, higher satisfaction with the applied analgesic treatment was noted in the FICB group. Conclusions: FICB in elective THR treatments is an effective form of analgesia, which reduces the need for opioids, the number of complications, the length of hospitalisation, and which ensures a high level of patient satisfaction with the analgesic treatment used. Trial registration: ClinicalTrials.gov No. NCT04690647.

Validation and characterization of oxycodone physical dependence in C57BL/6J mice

Opioid use disorder is a growing concern in the United States. Mice were used to investigate the mechanisms involving opioid physical dependence and for evaluating medications for treating opioid use disorders. While there are many preclinical reports describing protocols for inducing physical dependence upon morphine, there are fewer preclinical reports describing more contemporary abused prescription opiates. The goal of this study was to characterize and validate a mouse model of oxycodone dependence. Male C57BL/6J mice were injected with saline or increasing doses of oxycodone (9–33 mg/kg) twice daily for 8 days. On the 9th day, mice were challenged with 1 mg/kg naloxone and observed for somatic signs. Mice were pretreated with oxycodone (17, 33, or 75 mg/kg) prior to withdrawal to determine if it could attenuate somatic withdrawal signs. Additional mouse groups were pretreated with 1 mg/kg clonidine. Lastly, we measured somatic signs for 6, 24, and 48 h post-withdrawal during spontaneous and precipitated withdrawal. Pretreating with oxycodone or clonidine dose-dependently prevented the emergence of withdrawal signs. Mice chronically treated with oxycodone exhibited more withdrawal signs than vehicle at 24 h after the final injection during spontaneous withdrawal. In contrast, mice that received repeated naloxone challenges showed peak withdrawal signs at 6 h, and withdrawal signs were significantly greater at all time points compared to vehicle. Reversal of withdrawal effects by positive controls, and establishing spontaneous and precipitated withdrawal paradigms, serve as validation of this model and provide a means to examine novel therapeutics to treat opioid withdrawal.

Impact of a revised postoperative care plan on pain and recovery trajectory following pediatric tonsillectomy.

A previous cohort of adenotonsillectomy patients at our institution demonstrated moderate-severe post-tonsillectomy pain scores lasting a median (range) duration of 6 (0-23) days and postdischarge nausea and vomiting affecting 8% of children on day 1 following surgery. In this subsequent cohort, we evaluate the impact of changes to our discharge medication and parental education on post-tonsillectomy pain and recovery profile. In this follow-on, prospective observational cohort study, all patients undergoing tonsillectomy at our institution during the study period were discharged with standardized analgesia. Parents received a revised education package and a medication diary which were not provided to the previous cohort. Pain scores, rates of nausea and vomiting, medication usage and unplanned representation rates were collected by telephone from parents. Sixty-nine patients were recruited. Moderate-severe pain lasted a median (range) of 5 (0-12) days. Twenty-nine (42%) had pain scores ≥4/10 beyond postoperative day 7. By postoperative day 5, only 37 (53%) parents continued to administer regular analgesia. The median number of oxycodone doses used was 5 (0-22), and only 28 (41%) parents had disposed of leftover oxycodone within 1month of surgery. Twenty-four (35%) patients experienced nausea or vomiting postdischarge. The median (range) time for return to normal activities was 6 (0-14) days. Thirty-two/sixty-nine (46%) patients had unplanned medical representations. Most occurred between postoperative day 5 and 7. Pain contributed to 16 (35%) representations. Despite extensive changes to our discharge protocols parents continued to report a prolonged period of pain, post operative nausea and vomiting, and behavioral changes. Further work is required to examine barriers to compliance with simple analgesia and education in appropriate methods of opioid disposal.

Effective dose of intravenous oxycodone depending on sex and age for attenuation of intubation-related hemodynamic responses

Background/aimPreoperative intravenous oxycodone may help to prevent or attenuate intubation-related hemodynamic responses (IRHRs), but its pharmacokinetics differs according to age and sex. Therefore, we investigated the 95% effective dose (ED95) of intravenous oxycodone for attenuating all IRHRs, depending on the age and sex of the study population. Materials and methodsAll patients were allocated to one of 6 groups: 1) 20–40 year old males, 2) 41–65yearold males, 3) 66–80 year old males, 4) 20–40 year old females, 5) 41–65yearold females, and 6) 66–80 year old females (groups YM, OM, EM, YF, OF, and EF, respectively). Using Dixon’s up-and-down method, the first patient in each group was slowly injected with intravenous oxycodone (0.1 mg kg-1) 20 min before intubation. The subsequent patient received the next oxycodone dose, which was decreased or increased by 0.01 mg kg-1, depending on the “success” or “failure” of attenuation of all IRHRs to within 20% of the baseline values at 1 min after intubation in the previous patient. After obtaining 8 crossover points, predictive ED95 was estimated with probit regression analysis.ResultsED95 varied greatly according to age and sex. ED95was 0.133 mg kg-1, 0.181 mg kg-1, 0.332 mg kg-1, 0.183 mg kg-1, 0.108 mg kg-1, and 0.147 mg kg-1in groups YM, OM, EM, YF, OF, and EF, respectively.ConclusionED95 is higher in males with increasing age but is ambiguous for females. ED95 is higher in males than in females over 40 years of age but is higher in females than in males under 41 years of age. However, after considering the age and sex of the study population, these results can be used as reference doses for further studies to verify the clinical effects of oxycodone for attenuating all IRHRs.