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PURPOSE: Oxycodone is a potent μ- and κ-opioid receptor agonist that can relieve both somatic and visceral pain. We assessed oxycodone- vs sufentanil-based multimodal analgesia on postoperative pain following major laparoscopic gastrointestinal surgery. METHODS: In this randomised double-blind controlled trial, 40 adult patients were randomised (1:1, stratified by type of surgery) to receive oxycodone- or sufentanil-based multimodal analgesia, comprising bilateral transverse abdominis plane blocks, intraoperative dexmedetomidine infusion, flurbiprofen axetil, and oxycodone- or sufentanil-based patient-controlled analgesia. The co-primary outcomes were time-weighted average (TWA) of visceral pain (defined as intra-abdominal deep and dull pain) at rest and on coughing during 0-24 h postoperatively, assessed using the numerical rating scale (0-10) with a minimal clinically important difference of 1. RESULTS: All patients completed the study (median age, 64 years; 65% male) and had adequate postoperative pain control. The mean (SD) 24-h TWA of visceral pain at rest was 1.40 (0.77) in the oxycodone group vs 2.00 (0.98) in the sufentanil group (mean difference=-0.60, 95% CI, -1.16 to -0.03; P=0.039). Patients in the oxycodone group had a significantly lower 24-h TWA of visceral pain on coughing (2.00 [0.83] vs 2.98 [1.26]; mean difference=-0.98, 95% CI, -1.66 to -0.30; P=0.006). In the subgroup analyses, the treatment effect of oxycodone vs sufentanil on the co-primary outcomes did not differ in terms of age (18-65 years or >65 years), sex (female or male), or type of surgery (colorectal or gastric). Secondary outcomes (24-h TWA of incisional and shoulder pain, postoperative analgesic usage, rescue analgesia, adverse events, and patient satisfaction) were comparable between groups. CONCLUSION: For patients undergoing major laparoscopic gastrointestinal surgery, oxycodone-based multimodal analgesia reduced postoperative visceral pain in a statistically significant but not clinically important manner. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR2100052085).

Purpose: The operative treatment of mid-shaft clavicle fractures shows benefit in union rates, return to work, and lower pain scores relative to non-operative treatment. We sought to determine if the surgical treatment of isolated mid-shaft clavicle fractures would result in fewer opioids prescribed as compared to those managed non-operatively. Methods: All mid-shaft clavicle fractures treated at a Level 1 trauma center were identified from 2012 to 2016. Demographics, fracture characteristics, surgical complications/outcomes, non-operative outcomes, and all narcotics prescribed for 6 months post-injury were collected. Narcotic prescriptions, in morphine equivalents (ME), were obtained through the state prescription drug monitoring program (PDMP). Results: One hundred and ten operative and 48 non-operative patients were included. Age, gender, previous alcohol, tobacco or drug use, and final range of motion were similar between groups. Pre-treatment fracture shortening (1.8 cm vs. 0.7 cm, p < 0.001) and displacement (150% vs. 70%, p < 0.001) were greater in the operative group. Total ME's (604 vs. 187, p < 0.001) and post-operative ME's (420 vs. 187, p < 0.001) were greater for the operative group. In either group, no other variable influenced ME's prescribed. Conclusion: Clavicles treated operatively receive substantially more opiates than those treated non-operatively, despite data suggesting that operative treatment makes clavicle fractures less painful. The total amount of narcotic analgesics obtained by operatively treated patients was over three times that obtained by non-operatively managed patients, which equates to 55 5 mg oxycodone pills or 85 5 mg hydrocodone pills per patient. While there may certainly be advantages to the operative treatment of clavicle fractures, they must be weighed against the risks of a significant increase in opiate prescribing and potential consumption. [ABSTRACT FROM AUTHOR]

Opioid-seeking behaviors depend on glutamatergic plasticity in the nucleus accumbens core (NAcc). Here we investigated whether the behavioral and synaptic effects of opioids are influenced by acid-sensing ion channel 1A (ASIC1A). We tested the effects of ASIC1A on responses to several opioids and found that Asic1a−/− mice had elevated behavioral responses to acute opioid administration as well as opioid seeking behavior in conditioned place preference (CPP). Region-restricted restoration of ASIC1A in NAcc was sufficient to reduce opioid CPP, suggesting NAcc is an important site of action. We next tested the effects of oxycodone withdrawal on dendritic spines in NAcc. We found effects of oxycodone and ASIC1A that contrasted with changes previously described following cocaine withdrawal. Finally, we examined α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated and N-methyl-D-aspartic acid (NMDA) receptor-mediated synaptic currents in NAcc. Oxycodone withdrawal, like morphine withdrawal, increased the AMPAR/NMDAR ratio in Asic1a+/+ mice, whereas oxycodone withdrawal reduced the AMPAR/NMDAR ratio in Asic1a−/− mice. A single dose of oxycodone was sufficient to induce this paradoxical effect in Asic1a−/− mice, suggesting an increased sensitivity to oxycodone. We conclude that ASIC1A plays an important role in the behavioral and synaptic effects of opioids and may constitute a potential future target for developing novel therapies. [ABSTRACT FROM AUTHOR]

Background: The use of opioids occasionally causes tinnitus. However, there is a paucity of data regarding the use of peripherally acting μ-opioid receptor antagonists for opioid-associated tinnitus in patients with cancer. Actual case: A 74-year-old male with pancreatic cancer complained of abdominal pain. Two days after initiating oxycodone therapy, the patient experienced tinnitus during body movements. Although peripheral tinnitus disappeared after discontinuing oxycodone, it reappeared with hydromorphone or tapentadol administration. Possible courses of action: Drug cessation is a preferred intervention for drug-induced tinnitus; however, the cessation of opioids may not be feasible in patients with cancer who are already taking opioids. Formulation of a plan: Based on the presumed mechanism of peripheral tinnitus, the use of peripherally acting μ-opioid receptor antagonists was planned, and 200 μg/day of naldemedine was prescribed for tinnitus relief. Outcome: Tinnitus disappeared immediately after initiating naldemedine, and the pain was well-controlled. The effect was preserved after increasing or switching opioids. Lessons: The use of peripherally acting μ-opioid receptor antagonists may be an option to treat opioid-associated tinnitus without compromising the analgesic effects. View: Further clinical data regarding the secondary effect of peripherally acting μ-opioid receptor antagonists on opioid-associated complications other than constipation are required. [ABSTRACT FROM AUTHOR]

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.

Opioid dependence has become a public health problem in several countries. A cohort study was used to assess first-time dispensed opioids, in 2012–2015, by drug type, doses, oral morphine equivalents, and diagnoses, in Sweden. First-time opioid users aged 18–64 years, previously cancer-free and opioid-naïve for at least 6.5 years, were studied. Time trends in opioid use in Sweden 2006–2021 were also studied. During the study, 617,568 patients were dispensed opioids for the first time. The crude proportion of first-time opioid users in the population was 2.7% in 2012 and 2.6% in 2015. The combination product of codeine and paracetamol was the most frequent dispensed opioid with 322,818 patients (52.3%), followed by tramadol (120,271, 19.6%) and oxycodone (104,418, 16.9%). From 2012 to 2015, tramadol as first dispensed opioid dropped from 26.5% to 13.7% and oxycodone increased from 10.0% to 24.4%. For the four most commonly dispensed opioids, the median initial dispensal ranged from 250 to 400 oral morphine equivalents. The most common indication was fracture of the lower leg during inpatient care and back pain for specialized outpatient care. Trends in dispensed opioids in Sweden show a shift from tramadol to oxycodone, but do not show an increase in total opioid use. [ABSTRACT FROM AUTHOR]

Over the past decades, extensive preclinical research has been conducted to develop vaccinations to protect against substance use disorder caused by opioids, nicotine, cocaine, and designer drugs. Morphine or fentanyl derivatives are small molecules, and these compounds are not immunogenic, but when conjugated as haptens to a carrier protein will elicit the production of antibodies capable of reacting specifically with the unconjugated hapten or its parent compound. The position of the attachment in opioid haptens to the carrier protein will influence the specificity of the antiserum produced in immunized animals with the hapten–carrier conjugate. Immunoassays for the determination of opioid drugs are based on the ability of drugs to inhibit the reaction between drug-specific antibodies and the corresponding drug–carrier conjugate or the corresponding labelled hapten. Pharmacological studies of the hapten–carrier conjugates resulted in the development of vaccines for treating opioid use disorders (OUDs). Immunotherapy for opioid addiction includes the induction of anti-drug vaccines which are composed of a hapten, a carrier protein, and adjuvants. In this review we survey the design of opioid haptens, the development of the opioid radioimmunoassay, and the results of immunotherapy for OUDs. [ABSTRACT FROM AUTHOR]

BackgroundFentanyl- and methamphetamine-based counterfeit prescription drugs have driven escalating overdose death rates in the US, however their presence in Mexico has not been assessed. Our ethnographic team has conducted longitudinal research focused on illicit drug markets in Northern Mexico since 2018. In 2021-2022, study participants described the arrival of new, unusually potent tablets sold as ostensibly controlled substances, without a prescription, directly from pharmacies that cater to US tourists.AimsTo characterize the availability of counterfeit and authentic controlled substances at pharmacies in Northern Mexico available to English-speaking tourists without a prescription.MethodsWe employed an iterative, exploratory, mixed methods design. Longitudinal ethnographic data was used to characterize tourist-oriented micro-neighborhoods and guide the selection of n=40 pharmacies in n=4 cities in Northern Mexico. In each pharmacy, samples of "oxycodone", "Xanax", and "Adderall" were sought as single pills, during English-language encounters, after which detailed ethnographic accounts were recorded. We employed immunoassay-based testing strips to check each pill for the presence of fentanyls, benzodiazepines, amphetamines, and methamphetamines. We used Fourier-Transform Infrared Spectroscopy to further characterize drug contents.ResultsOf n=40 pharmacies, one or more of the requested controlled substances could be obtained with no prescription (as single pills or in bottles) at 28 (70.0%) and as single pills at 19 (47.5%). Counterfeit pills were obtained at 11 pharmacies (27.5%). Of n=45 samples sold as one-off controlled substances, 18 were counterfeit. 7 of 11 (63.6%) samples sold as "Adderall" contained methamphetamine, 8 of 27 (29.6%) samples sold as "Oxycodone" contained fentanyl, and 3 "Oxycodone" samples contained heroin. Pharmacies providing counterfeit drugs were uniformly located in tourist-serving micro-neighborhoods, and generally featured English-language advertisements for erectile dysfunction medications and "painkillers". Pharmacy employees occasionally expressed concern about overdose risk and provided harm reduction guidance.DiscussionThe availability of fentanyl-, heroin-, and methamphetamine-based counterfeit medications in tourist-oriented independent pharmacies in Northern Mexico represents a public health risk, and occurs in the context of 1) the normalization of medical tourism as a response to rising unaffordability of healthcare in the US, 2) plummeting rates of opioid prescription in the US, affecting both chronic pain patients and the availability of legitimate pharmaceuticals on the unregulated market, 3) the rise of fentanyl-based counterfeit opioids as a key driver of the fourth, and deadliest-to-date, wave of the opioid crisis. It was not possible to distinguish counterfeit medications based on appearance of pills or geography of pharmacies, because identically-appearing authentic and counterfeit versions were often sold in close geographic proximity. Nevertheless, people who consume drugs may be more trusting of controlled substances purchased directly from pharmacies. Due to Mexico's limited opioid overdose surveillance infrastructure, the current death rate from these substances remains unknown.

ABSTRACTOpioids, 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.

The evolving landscape of opioid prescription practices necessitates a comprehensive understanding of emerging patterns, particularly among new opioid users discharged from emergency departments. This study delves into the intricate realm of opioid utilization by elucidating the prevalence of their prescriptions. A retrospective analysis of electronic health records was conducted, including a cohort of 71 patients who received opioid prescriptions upon discharge from emergency departments from 1 January 2022 to 30 June 2022. Demographic characteristics and prescription details were systematically examined. This study illuminates tramadol's prominence, with 84% of prescriptions and a Defined Daily Dose (DDD) morphine equivalent of 60 mg, as the primary choice as a new opioid, a finding that draws attention due to the closely aligned dosages with morphine equivalents. This discovery prompts a critical reassessment of tramadol's therapeutic role, considering its multifaceted nature encompassing serotonergic effects and heightened fall risks. This study advocates for a nuanced and vigilant approach to tramadol prescription, cognizant of its potential risks and therapeutic implications, and highlights the imperative of optimizing data quality and traceability within electronic health records to enhance patient care and facilitate future research endeavors. [ABSTRACT FROM AUTHOR]

Opioid use disorder (OUD) is an ongoing public health concern in the United States, and relatively little work has addressed how genetic background contributes to OUD. Understanding the genetic contributions to oxycodone‐induced analgesia could provide insight into the early stages of OUD development. Here, we present findings from a behavioral phenotyping protocol using several inbred strains from the Hybrid Rat Diversity Panel. Our behavioral protocol included a modified "up‐down" von Frey procedure to measure inherent strain differences in the sensitivity to a mechanical stimulus on the hindpaw. We also performed the tail immersion assay, which measures the latency to display tail withdrawal in response to a hot water bath. Initial withdrawal thresholds were taken in drug‐naïve animals to record baseline thermal sensitivity across the strains. Oxycodone‐induced analgesia was measured after administration of oxycodone over the course of 2 h. Both mechanical and thermal sensitivity are shaped by genetic factors and display moderate heritability (h2 = 0.23–0.40). All strains displayed oxycodone‐induced analgesia that peaked at 15–30 min and returned to baseline by 2 h. There were significant differences between the strains in the magnitude and duration of their analgesic response to oxycodone, although the heritability estimates were quite modest (h2 = 0.10–0.15). These data demonstrate that genetic background confers differences in mechanical sensitivity, thermal sensitivity, and oxycodone‐induced analgesia. [ABSTRACT FROM AUTHOR]

Opioid prescribing and dispensing from emergency departments is a noteworthy issue given widespread opioid misuse and diversion in many countries, contributing both physical and economic harm to the population. High patient numbers and the stochastic nature of acute emergency presentations to emergency departments (EDs) introduce challenges for prescribers who are considering opioid stewardship principles. This study investigated the effect of changes to electronic prescribing software on prescriptions with an auto-populated quantity of oxycodone immediate release (IR) from an Australian tertiary emergency department following the implementation of national recommendations for reduced pack sizes. A retrospective review of oxycodone IR prescriptions over two six-month periods between 2019 and 2021 was undertaken, either side of a software adjustment to reduce the default quantities of tablets prescribed from 20 to 10. Patient demographic details were collected, and prescriber years of practice calculated for inclusion in linear mixed effects regression modelling. A reduction in the median number of tablets prescribed per prescription following the software changes (13.5 to 10.0, p < 0.001) with little change in the underlying characteristics of the patient or prescriber populations was observed, as well as an 11.65% reduction in the total number of tablets prescribed. The prescriber's years of practice, patient age and patient sex were found to influence increased prescription sizes. Reduced quantity of oxycodone tablets prescribed was achieved by alteration of prescribing software prefill parameters, providing further evidence to support systems-based policy interventions to influence health care providers behaviour and to act as a forcing function for prescribers to consider opioid stewardship principles. [ABSTRACT FROM AUTHOR]

The objective of this case report is to illustrate pharmacogenomics (PGx)-guided oxycodone treatment, given the conflicting data on the analgesic response from oxycodone in Cytochrome P450 (CYP)2D6 poor metabolizers (PMs). PGx-guided therapy can help improve treatment outcomes. This case report describes a 58-year-old patient who was prescribed oxycodone for chronic pain management. The patient presented with a history of inadequate pain control despite analgesic treatment with oxycodone (morphine milliequivalent [MME] = 22.5). Pharmacogenetic testing revealed that the patient was a CYP2D6 Poor Metabolizer (PM), which may shed light on the observed lack of analgesic response to oxycodone. The clinical pharmacist recommended switching to an alternative opioid not metabolized via the CYP2D6 pathway. The patient was subsequently switched to hydromorphone (MME = 16), resulting in improved pain control and fewer side effects. The newer hydromorphone dose accounted for a 30% MME dose reduction. The patient's initial average and worst pain score were 7 and 9 out of 10, respectively, per the numeric rating scale (NRS). Upon follow-up with the patient in two weeks, her average and worst pain scores improved to 3 and 3.5 out of 10, respectively, per the NRS. Further PGx testing results led to an overall positive outcome, such as her willingness to participate in physical therapy as a result of improved pain scores. This case highlights the importance of considering individual variability in drug metabolism when prescribing medications, particularly opioids such as oxycodone, to ensure optimal therapeutic outcomes and minimize the risk of adverse events in CYP2D6 PMs. [ABSTRACT FROM AUTHOR]

Context: Equianalgesic tools are commonly utilized to guide dose of analgesic therapy, but there is no national consensus on equianalgesic calculations in the United States. Objectives: To propose a summary of current opioid equianalgesic data that include variations and trends among national institutions. Methods: Opioid equianalgesic tools were obtained between May and September 2021. For meperidine, tramadol, codeine, hydrocodone, morphine, oxycodone, oxymorphone, hydromorphone, levorphanol, fentanyl, and tapentadol, details of adjustment for incomplete tolerance, opioid equianalgesic ratios, and formulation types were collected and analyzed. Baseline opioid pharmaco kinetic data were obtained through manufacturer labels on FDA databases, including half-life (T1/2), volume of distribution (Vd), clearance (Cl), area under the curve (AUC), max concentration (Cmax), and time to max concentration (Tmax). Results: Thirty-two institutions equianalgesic tools were included with each study opioid appearing on an average of 23 institutions tools. Few tools contained guidance on levorphanol or tapentadol; or included minimum and maximum recommended doses. All tools included guidance on fentanyl, hydromorphone, oxycodone, morphine, and hydrocodone. A minority of tools included guidance on cross-tolerance considerations (n = 12, 37.5%). Oral-tramadol-to-oral-morphine and oral-hydromorphone-to-intravenous (IV)-hydromorphone had the largest variances across equianalgesic tools (6.7 ± 2.8 and 4.06 ± 1.2 mg, respectively). Conclusion: Opioid equianalgesia tools from across the United States demonstrated significant variation in their inclusion of guidance on adjustment for incomplete cross-tolerance, oral-to-IV, and oral-to-oral opioid equianalgesic ratios, and which opioids and formulations were listed. Tramadol and hydromorphone had the most variation in their equianalgesic guidance among the opioids.

BackgroundUltrasound-guided percutaneous cryoneurolysis is an analgesic technique in which a percutaneous probe is used to reversibly ablate a peripheral nerve(s) using exceptionally low temperature, and has yet to be evaluated with randomized, controlled trials. Pain after mastectomy can be difficult to treat, and the authors hypothesized that the severity of surgically related pain would be lower on postoperative day 2 with the addition of cryoanalgesia compared with patients receiving solely standard-of-care treatment.MethodsPreoperatively, participants at one enrolling center received a single injection of ropivacaine, 0.5%, paravertebral nerve block at T3 or T4, and perineural catheter. Participants subsequently underwent an active or sham ultrasound-guided percutaneous cryoneurolysis procedure of the ipsilateral T2 to T5 intercostal nerves in a randomized, patient- and observer-masked fashion. Participants all received a continuous paravertebral block with ropivacaine, 0.2%, until the early morning of discharge (usually postoperative day 2). The primary endpoint was the average pain level measured using a 0 to 10 numeric rating scale the afternoon of postoperative day 2. Participants were followed for 1 yr.ResultsOn postoperative day 2, participants who had received active cryoneurolysis (n = 31) had a median [interquartile range] pain score of 0 [0 to 1.4] versus 3.0 [2.0 to 5.0] in patients given sham (n = 29): difference -2.5 (97.5% CI, -3.5 to -1.5), P < 0.001. There was evidence of superior analgesia through month 12. During the first 3 weeks, cryoneurolysis lowered cumulative opioid use by 98%, with the active group using 1.5 [0 to 14] mg of oxycodone compared with 72 [20 to 120] mg in the sham group (P < 0.001). No oral analgesics were required by any patient between months 1 and 12. After 1 yr chronic pain had developed in 1 (3%) active compared with 5 (17%) sham participants (P < 0.001).ConclusionsPercutaneous cryoneurolysis markedly improved analgesia without systemic side effects or complications after mastectomy.Editor’s perspective

Opioid use disorder (OUD) and opioid overdoses are public health emergencies. In 2021, 80,000 opioid overdose associated deaths were reported in the United States. Despite the availability of treatment strategies, including medications for opioid use disorder (MOUD) and naloxone, opioid overdoses continue to increase at an alarming rate. Opioid vaccines are a novel approach to combat the growing crisis with several candidates recently entering human clinical trials. In this study, we investigated Qβ bacteriophage virus-like particles (VLPs) as a vaccine platform for immunogenic display of oxycodone. A derivative of oxycodone was conjugated to pre-formed Qβ VLPs using a sulfhydryl-amine reactive heterobifunctional crosslinker with high loading of oxycodone. In mice, intramuscular immunization with Qβ-oxycodone elicited high-titer, high-avidity and long-lasting antibody responses. Qβ-oxycodone was also immunogenic after storage at ambient room temperature for over two weeks, demonstrating that the vaccine is highly thermostable. In mice, immunization with Qβ-oxycodone elicited antibodies that sequester oxycodone in the serum, an important mechanism for preventing the adverse effects of opioid activity. Finally, Qβ-oxycodone is immunogenic in nonhuman primates, eliciting serum oxycodone antibodies after intramuscular immunization of rhesus macaques. These data establish Qβ-oxycodone as a promising opioid vaccine candidate. [ABSTRACT FROM AUTHOR]

Background: Recognizing the seriousness of the misuse and abuse of medical narcotics, the South Korean government introduced the world's first narcotic management system, the Narcotics Information Management System (NIMS). This study aimed to explore the recent one-year opioid prescribing patterns in South Korea using the NIMS database. Methods: This study analyzed opioid prescription records in South Korea for the year 2022, utilizing the dispensing/administration dataset provided by NIMS. Public data from the Korean Statistical Information Service were also utilized to explore prescription trends over the past four years. The examination covered 16 different opioid analgesics, assessed by the total number of units prescribed based on routes of administration, type of institutions, and patients' sex and age group. Additionally, the disposal rate for each ingredient was computed. Results: In total, 206,941 records of 87,792,968 opioid analgesic units were analyzed. Recently, the overall quantity of prescribed opioid analgesic units has remained relatively stable. The most prescribed ingredient was oral oxycodone, followed by tapentadol and sublingual fentanyl. Tertiary hospitals had the highest number of dispensed units (49.4%), followed by community pharmacies (40.2%). The highest number of prescribed units was attributed to male patients in their 60s. The disposal rates of the oral and transdermal formulations were less than 0.1%. Conclusions: Opioid prescription in South Korea features a high proportion of oral formulations, tertiary hospital administration, pharmacy dispensing, and elderly patients. Sustained education and surveillance of patients and healthcare providers is required. [ABSTRACT FROM AUTHOR]

BackgroundPrevalence of fentanyl-laced counterfeit prescription pills has been increasing in the US, possibly placing a wider population at risk for unintentional exposure. We aimed to determine whether there have been shifts in the number of fentanyl seizures and in the form of fentanyl seized in the US.MethodsWe examined quarterly national seizure data from High Intensity Drug Trafficking Areas to determine the number of drug seizures in the US containing fentanyl from January 2018 through December 2021. Generalized additive models were used to estimate trends in the number and weight of pill and powder seizures containing fentanyl.ResultsThere was an increase both in the number of fentanyl-containing powder seizures (from 424 in 2018 Quarter 1 [Q1] to 1539 in 2021 Quarter 4 [Q4], β = 0.94, p

Buprenorphine is increasingly used to treat pain in patients with sickle cell disease but optimal timing and approach for transitioning patients from full agonist opioids to buprenorphine is unknown. We present the case of a 22-year-old woman with sickle cell disease and acute on chronic pain who transitioned from high-dose oxycodone to buprenorphine/naloxone during a hospital stay for vaso-occlusive episode. Utilizing a microdosing approach to minimize pain and withdrawal, buprenorphine/naloxone was gradually uptitrated while she received full agonist opioids. During the transition, she experienced some withdrawal in the setting of swallowed buprenorphine/naloxone tablets, which were intended to be dosed sublingually. Nevertheless, the transition was tolerable to the patient and her pain and function significantly improved with buprenorphine treatment. This case also highlights the challenges and unique considerations that arise when providing care for the hospitalized patient who is also incarcerated.

Substance use disorder is associated with accelerated disease progression in people with human immunodeficiency virus (HIV; PWH). Problem opioid use, including high-dose opioid therapy, prescription drug misuse, and opioid abuse, is high and increasing in the PWH population. Oxycodone is a broadly prescribed opioid in both the general population and PWH. Here, we allowed HIV transgenic (Tg) rats and wildtype (WT) littermates to intravenously self-administer oxycodone under short-access (ShA) conditions, which led to moderate, stable, "recreational"-like levels of drug intake, or under long-access (LgA) conditions, which led to escalated (dependent) drug intake. HIV Tg rats with histories of oxycodone self-administration under LgA conditions exhibited significant impairment in memory performance in the novel object recognition (NOR) paradigm. RNA-sequencing expression profiling of the medial prefrontal cortex (mPFC) in HIV Tg rats that self-administered oxycodone under ShA conditions exhibited greater transcriptional evidence of inflammation than WT rats that self-administered oxycodone under the same conditions. HIV Tg rats that self-administered oxycodone under LgA conditions exhibited transcriptional evidence of an increase in neuronal injury and neurodegeneration compared with WT rats under the same conditions. Gene expression analysis indicated that glucocorticoid-dependent adaptations contributed to the gene expression effects of oxycodone self-administration. Overall, the present results indicate that a history of opioid intake promotes neuroinflammation and glucocorticoid dysregulation, and excessive opioid intake is associated with neurotoxicity and cognitive impairment in HIV Tg rats.

We present a case series to demonstrate proof-of-concept for the off-label use of an auricular neuromodulation device-originally developed to treat symptoms associated with opioid withdrawal-to instead provide analgesia and opioid-sparing following knee and hip arthroplasties. Within the recovery room, an auricular neuromodulation device (near-field stimulator system 2 [NSS-2] Bridge, Masimo) was applied to 5 patients. Average daily pain at rest and while moving was a median of 0 to 2 as measured on the 0 to 10 numeric rating scale, while median daily oxycodone use was 0 to 2.5 mg until device removal at home on postoperative day 5. One patient avoided opioid use entirely.

ObjectivesThere has been increased focus nationally on limiting opioid prescriptions. National data demonstrates a decrease in annual opioid prescriptions among emergency medicine physicians. We analyzed data from 2012 to 2020 from a large academic health system in California to understand trends in opioid prescribing patterns for emergency department (ED) discharged patients and assessed the potential impact of two initiatives at limiting local opioid prescriptions.MethodsIn 2012-2020, monthly ED visit data was used to evaluate the total number of outpatient opioid prescriptions and percent of ED visits with opioid prescriptions (as primary outcomes). Descriptive statistics, graphic representation, and segmented regression with interrupted times series were used based on two prespecified time points associated with intensive local initiatives directed at limiting opioid prescribing1) comprehensive emergency medicine resident education and 2) electronic health record (EHR)-based intervention.ResultsBetween March 2012 and July 2020, a total of 41,491 ED discharged patients received an opioid prescription. The three most commonly prescribed drugs were hydrocodone (84.1%), oxycodone (10.8%), and codeine (2.8%). After implementing comprehensive emergency medicine resident education, the total number of opioid prescriptions, the percentage of opioid prescriptions over total ED visit numbers and the total tablet number showed decreasing trends (p's ≤ 0.01), in addition to the natural (pre-intervention) decreasing trends. In contrast, later interventions in the EHR tended to show attenuated decreasing trends.ConclusionsFrom 2012 to 2020, we found that total opioid prescriptions decreased significantly for discharged ED patients. This trend is seen nationally. However, our specific interventions further heightened this downward trend. Evidence-based legislation, policy changes, and educational initiatives that impact prescribing practices should guide future efforts.

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; p <.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. [ABSTRACT FROM AUTHOR]

It is estimated that nearly a third of people who abuse drugs started with prescription opioid medicines. Approximately, 11.5 million Americans used prescription drugs recreationally in 2016, and in 2018, 46,802 Americans died as the result of an opioid overdose, including prescription opioids, heroin, and illicitly manufactured fentanyl (National Institutes on Drug Abuse (2020) Opioid Overdose Crisis. https://www.drugabuse.gov/drugs-abuse/opioids/opioid-overdose-crisis . Accessed 06 June 2020). Yet physicians will continue to prescribe oral opioids for moderate-to-severe pain in the absence of alternative therapeutics, underscoring the importance in understanding how drug choice can influence detrimental outcomes. One of the opioid prescription medications that led to this crisis is oxycodone, where misuse of this drug has been rampant. Being one of the most highly prescribed opioid medications for treating moderate-to-severe pain as reflected in the skyrocketed increase in retail sales of 866% between 1997 and 2007, oxycodone was initially suggested to be less addictive than morphine. The false-claimed non-addictive formulation of oxycodone, OxyContin, further contributed to the opioid crisis. Abuse was often carried out by crushing the pills for immediate burst release, typically by nasal insufflation, or by liquefying the pills for intravenous injection. Here, we review oxycodone pharmacology and abuse liability as well as present the hypothesis that oxycodone may exhibit a unique pharmacology that contributes to its high likability and abuse susceptibility. We will discuss various mechanisms that likely contribute to the high abuse rate of oxycodone including clinical drug likability, pharmacokinetics, pharmacodynamics, differences in its actions within mesolimbic reward circuity compared to other opioids, and the possibility of differential molecular and cellular receptor interactions that contribute to its selective effects. We will also discuss marketing strategies and drug difference that likely contributes to the oxycodone opioid use disorders and addiction.

The rat oxycodone and cocaine biobanks contain samples that vary by genotypes (by using genetically diverse genotyped HS rats), phenotypes (by measuring addiction-like behaviors in an advanced SA model), timepoints (samples are collected longitudinally before, during, and after SA, and terminally at three different timepoints in the addiction cycle: intoxication, withdrawal, and abstinence or without exposure to drugs through age-matched naive rats), samples collected (organs, cells, biofluids, feces), preservation (paraformaldehyde-fixed, snap-frozen, or cryopreserved) and application (proteomics, transcriptomics, microbiomics, metabolomics, epigenetics, anatomy, circuitry analysis, biomarker discovery, etc.Substance use disorders (SUDs) are pervasive in our society and have substantial personal and socioeconomical costs. A critical hurdle in identifying biomarkers and novel targets for medication development is the lack of resources for obtaining biological samples with a detailed behavioral characterization of SUD. Moreover, it is nearly impossible to find longitudinal samples. As part of two ongoing large-scale behavioral genetic studies in heterogeneous stock (HS) rats, we have created two preclinical biobanks using well-validated long access (LgA) models of intravenous cocaine and oxycodone self-administration (SA) and comprehensive characterization of addiction-related behaviors. The genetic diversity in HS rats mimics diversity in the human population and includes individuals that are vulnerable or resilient to compulsive-like responding for cocaine or oxycodone. Longitudinal samples are collected throughout the experiment, before exposure to the drug, during intoxication, acute withdrawal, and protracted abstinence, and include naive, age-matched controls. Samples include, but are not limited to, blood plasma, feces and urine, whole brains, brain slices and punches, kidney, liver, spleen, ovary, testis, and adrenal glands. Three preservation methods (fixed in formaldehyde, snap-frozen, or cryopreserved) are used to facilitate diverse downstream applications such as proteomics, metabolomics, transcriptomics, epigenomics, microbiomics, neuroanatomy, biomarker discovery, and other cellular and molecular approaches. To date, >20,000 samples have been collected from over 1000 unique animals and made available free of charge to non-profit institutions through https://www.cocainebiobank.org/ and https://www.oxycodonebiobank.org/.

ContextOn October 6, 2014, the United States Drug Enforcement Administration (DEA) implemented a regulatory change for hydrocodone combination products (HCPs), moving them from Schedule III to II, in an effort to decrease drug overdoses. Existing research suggests this regulatory action reduced HCP prescribing and dispensing; however, there is limited research assessing its possible effects on overdoses and accidental exposures.ObjectiveTo analyze the changes in opioid exposures reported to the California Poison Control System (CPCS) before and after DEA rescheduling of HCPs.MethodsWe collected monthly exposure data reported to CPCS from 2012 to 2019 and conducted interrupted time series analyses to assess changes in exposures after rescheduling for HCPs, tramadol, oxycodone, morphine, codeine, fentanyl, and heroin. Additional analyses were done to assess any changes in exposures resulting in severe outcomes (moderate or major health effects). For HCPs, we also conducted logistic regressions to identify characteristics of exposures resulting in severe outcomes before and after rescheduling.ResultsOverall monthly opioid exposures reported to CPCS decreased after DEA rescheduling of HCPs. These decreases were significant for HCP, tramadol, and morphine (p

Narcolepsy type 1 is a primary sleep disorder caused by deficient hypocretin transmission leading to excessive daytime sleepiness and cataplexy. Opioids have been suggested to increase the number of hypocretin-producing neurons. We aimed to assess opioid use and its self-reported effect on narcolepsy type 1 symptom severity through a literature review and questionnaire study. We systematically reviewed literature on opioid use in narcolepsy. We also recruited 100 people with narcolepsy type 1 who completed an online questionnaire on opioid use in the previous three years. The main questionnaire topics were the indication for use, and the possible effects on narcolepsy symptom severity. Structured follow-up interviews were conducted when opioid use was reported. The systematic literature review mainly showed improvements in narcolepsy symptom severity. Recent opioid use was reported by 16/100 questionnaire respondents, who had used 20 opioids (codeine: 7/20, tramadol: 6/20, oxycodone: 6/20, fentanyl: 1/20). Narcolepsy symptom changes were reported in 11/20. Positive effects on disturbed nocturnal sleep (9/20), excessive daytime sleepiness (4/20), hypnagogic hallucinations (3/17), cataplexy (2/18), and sleep paralysis (1/13) were most pronounced for oxycodone (4/6) and codeine (4/7). Opioids were relatively frequently used compared to a similarly young general Dutch sample. Oxycodone and, to a lesser extent, codeine were associated with self-reported narcolepsy symptom severity improvements. Positive changes in disturbed nocturnal sleep and daytime sleepiness were most frequently reported, while cataplexy effects were less pronounced. Randomised controlled trials are now needed to verify the potential of opioids as therapeutic agents for narcolepsy. • We investigated the effects of opioids use on narcolepsy symptom severity. • Opioids mainly improved disturbed nocturnal sleep and excessive daytime sleepiness. • Narcolepsy symptom relief was clearest for oxycodone or codeine. • Randomised controlled trials are needed to verify the therapeutic potency of opioids. • Concurrent opioid and sodium oxybate use should be more carefully monitored. [ABSTRACT FROM AUTHOR]

Purpose: Regional anesthesia (RA) is used for pain control, but its impacts on the orthopedic trauma population are not well known. This study evaluated the impact of peripheral nerve blocks after distal tibia and ankle fracture repair on opioid use and pain scores and quantified the magnitude and duration of any changes. Methods: This retrospective cohort study included patients treated operatively for distal tibia and ankle fractures over a 5-year period, both with and without peripheral nerve blocks. Total inpatient 5 mg oxycodone equivalents (OEs) used in the post-operative period, from 0–24, 24–48, to 48–72 h and maximum visual analog scale (VAS) pain ratings from 0–24, 24–48, to 48–72 h were recorded. Results: 540 non-polytrauma patients and 183 polytrauma patients were included. Patients in the non-polytrauma group who received nerve blocks required fewer opioids on post-operative day (POD) 1 compared to the non-nerve block group (4.8 [95% CI 4.2–5.4] vs. 10.5 [95% CI: 9.2–11.8]; p < 0.001) and had lower VAS scores on POD1 (5.0 [95% CI 4.6–5.4] vs. 7.7 [95% CI: 7.3–8.1]; p < 0.001). However, there were no differences between these groups on POD2 or POD3 and no differences at any timepoints in the polytrauma group. Conclusion: Patients with isolated distal tibia and ankle fractures who receive peripheral nerve blocks demonstrate modest reductions in inpatient opioids and pain scores on POD1. However, there are no clear benefits beyond this point. Furthermore, polytrauma patients do not experience any reductions in opioid consumption or pain scores. [ABSTRACT FROM AUTHOR]

Purpose We describe the implementation of CYP2D6-focused pharmacogenetic testing to guide opioid prescribing in a quaternary care, nonprofit pediatric academic medical center. Summary Children are often prescribed oral opioids after surgeries, for cancer pain, and occasionally for chronic pain. In 2004, Cincinnati Children's Hospital Medical Center implemented pharmacogenetic testing for CYP2D6 metabolism phenotype to inform codeine prescribing. The test and reports were updated to align with changes over time in the testing platform, the interpretation of genotype to phenotype, the electronic health record, and Food and Drug Administration (FDA) guidance. The use of the test increased when a research project required testing and decreased as prescribing of oxycodone increased due to FDA warnings about codeine. Education about the opioid-focused pharmacogenetic test was provided to prescribers (eg, the pain and sickle cell teams) as well as patients and families. Education and electronic health record capability increased provider compliance with genotype-guided postsurgical prescribing of oxycodone, although there was a perceived lack of utility for oxycodone prescribing. Conclusion The implementation of pharmacogenetic testing to inform opioid prescribing for children has evolved with accumulating evidence and guidelines, requiring changes in reporting of results and recommendations. [ABSTRACT FROM AUTHOR]

μ-Opioid receptors (MORs) are densely expressed in different brain regions known to mediate reward. One such region is the striatum where MORs are densely expressed, yet the role of these MOR populations in modulating reward is relatively unknown. We have begun to address this question by using a series of genetically engineered mice based on the Cre recombinase/loxP system to selectively delete MORs from specific neurons enriched in the striatum: dopamine 1 (D1) receptors, D2 receptors, adenosine 2a (A2a) receptors, and choline acetyltransferase (ChAT). We first determined the effects of each deletion on opioid-induced locomotion, a striatal and dopamine-dependent behavior. We show that MOR deletion from D1 neurons reduced opioid (morphine and oxycodone)-induced hyperlocomotion, whereas deleting MORs from A2a neurons resulted in enhanced opioid-induced locomotion, and deleting MORs from D2 or ChAT neurons had no effect. We also present the effect of each deletion on opioid intravenous self-administration. We first assessed the acquisition of this behavior using remifentanil as the reinforcing opioid and found no effect of genotype. Mice were then transitioned to oxycodone as the reinforcer and maintained here for 9 d. Again, no genotype effect was found. However, when mice underwent 3 d of extinction training, during which the drug was not delivered, but all cues remained as during the maintenance phase, drug-seeking behavior was enhanced when MORs were deleted from A2a or ChAT neurons. These findings show that these selective MOR populations play specific roles in reward-associated behaviors.

Genetic factors are theorized to contribute to the substantial inter-individual variability in opioid abuse/addiction. To advance the behavioral genetics of prescription opioid abuse, our prior work identified the 129S1/SvlmJ (S1) and related 129P3/J (P3) mouse substrains, respectively, as low and high opioid-taking. Herein, we related our prior results to measures of sucrose reward/reinforcement, basal anxiety, opioid-induced place-conditioning, locomotor activity and Straub tail reaction, as well as behavioral and physiological signs of withdrawal. Substrains were also re-examined for higher-dose oxycodone and fentanyl intake under limited-access drinking procedures. S1 mice failed to acquire sucrose self-administration under various operant-conditioning procedures and exhibited lower sucrose intake in the home-cage. However, sucrose intake under limited-access procedures escalated in both substrains with repeated sucrose experience. S1 mice exhibited less spontaneous locomotor activity, as well as less opioid-induced locomotor activity and Straub tail reaction, than P3 mice and failed to exhibit an oxycodone-induced place-preference. The lack of conditioned behavior by S1 mice was unrelated to behavioral signs of withdrawal-induced negative affect or dependence severity, but might reflect high levels of basal anxiety-like behavior. Intriguingly, S1 and P3 mice initially exhibited equivalent oxycodone and fentanyl consumption in the home-cage; however opioid intake escalated only in P3 mice with repeated opioid experience. No sex differences were observed for any of our measures. These data provide additional evidence for robust differences in opioid addiction-related behaviors between P3 and S1 substrains and suggest that anxiety, learning, and/or motivational impairments might confound interpretation of operant- and place-conditioning studies employing the S1 substrain.

RationaleOver 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.ObjectivesWe 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.ResultsBoth 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.ConclusionsThe 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.

Background and purposeAdolescents are regularly exposed to ∆9 -tetrahydrocannabinol (THC) via smoking and, more recently, vaping cannabis extracts. Growing legalization of cannabis for medical and recreational purposes, combined with decreasing perceptions of harm, makes it increasingly important to determine the consequences of frequent adolescent exposure for motivated behaviour and lasting tolerance in response to THC.Experimental approachesMale and female rats inhaled THC vapour, or that from the propylene glycol (PG) vehicle, twice daily for 30 min from postnatal day (PND) 35-39 and PND 42-46 using an e-cigarette system. Thermoregulatory responses to vapour inhalation were assessed by radio-telemetry during adolescence and from PND 86-94. Chow intake was assessed in adulthood. Blood samples were obtained from additional adolescent groups following initial THC inhalation and after 4 days of twice daily exposure. Additional groups exposed repeatedly to THC or PG during adolescence were evaluated for intravenous self-administration of oxycodone as adults.Key resultsFemale, not male, adolescents developed tolerance to the hypothermic effects of THC inhalation in the first week of repeated exposure despite similar plasma THC levels. Each sex exhibited tolerance to THC hypothermia in adulthood after repeated adolescent THC. However, enhanced potency was found in females. Repeated THC male rats consumed more food than their PG-treated control group, without significant bodyweight differences. Adolescent THC did not alter oxycodone self-administration in either sex but increased fentanyl self-administration in females.Conclusions and implicationsRepeated THC vapour inhalation in adolescent rats has lasting consequences observable in adulthood.

Background: Liquid opioids (controlled drugs) in multidose bottles (MDBs) are associated with measurement losses, overfill variance, gradual contamination, and potential theft. Western Australian state poisons regulations and policies require rigorous accountability and previous reports have highlighted shortcomings in historical arrangements. Aim: To describe the process and outcomes of a transition to unit dose pod (UDP) formulations for oral liquid opioids at our institution. Method: A UDP of oral oxycodone liquid was developed in partnership with a third‐party compounder and piloted on a paediatric ward. Additional UDP opioid formulations were developed and gradually replaced MDBs across our institution. Reportable discrepancies and staff satisfaction were compared between MDBs and UDPs. This project was registered as a quality improvement project (GEKO 27758) and considered exempt from human research and ethics approval by the South Metropolitan Health Service Human Research Ethics Committee. Results: Between May 2017 and May 2018, 3062 UDPs were distributed with nil discrepancies, and 133 MDBs were distributed with 16 discrepancies (0% vs 12%). Most staff (92%) reported more efficient inventory counts and improved confidence in product integrity for UDPs. Staff administrative overhead required to manage reportable discrepancies from volume errors was essentially eliminated. Five UDP opioid formulations were implemented in 27 inpatient wards including methadone‐maintenance UDPs for inpatient use. By late 2020, UDPs were in use across 19 hospitals in Western Australia (WA), with annual use exceeding 33 000 units. Conclusion: The UDP simplifies the management of controlled drug liquids by eliminating discrepancies associated with MDBs inventory management and increasing staff confidence in product quality, leading to significant uptake across WA. [ABSTRACT FROM AUTHOR]

Objective: This study provides an overview of opioid dispensing in Queensland from 2008 to 2018 by recipient age, drug, oral morphine equivalent and remoteness. Methods: Data were obtained from the Queensland Monitoring of Drugs of Dependence System database for 2008–18 and analysed using data from the Australian Bureau of Statistics to account for population growth. Opioid dispensing by age, drug, oral morphine equivalent and remoteness were assessed. Results: The number of prescriptions for Schedule 8 opioid medicines dispensed in Queensland increased from 190 to 430 per 1000 population over the study period (2.3-fold increase). Oxycodone had the largest increase in dispensing over the study period of 3.1-fold, with tapentadol increasing rapidly since initial Pharmaceutical Benefits Scheme listing in 2013 to the third most dispensed opioid by 2018. By 2018, opioid dispensing among the oldest Queenslanders, those aged 85+ years, occurred at triple the rate for those aged 65–84 years. When adjusted to report oral morphine equivalents (OME) in milligrams (mg), there has been an increase of approximately 1.9-fold over the study period. Results were also presented by geographical area, including a heatmap and analysis by remoteness. Prescriptions dispensed per 1000 population were 416 for major cities, 551 for inner regional and 445 for outer regional, and highlight that inner and outer regional areas have higher rates of prescriptions when compared to major cities (32 and 7% higher, respectively). Conclusion: This study highlights changes in opioid prescription dispensing by drug and OME, as well as the variation in dispensing rates when accounting for remoteness. Further studies to link statewide databases, and to better understand drivers for differences in dispensing by location, will provide valuable insights to further inform policy and service provision. What is known about the topic? Opioid dispensing is known to have increased in Australia over recent decades. However, most existing data hails from the Pharmaceutical Benefits Scheme (PBS), which has small gaps in quantifying opioids that are not subsidised. What does this paper add? This retrospective study uses an alternative database, adding information about non-PBS dispensing of tapentadol and buprenorphine, accompanied by rates of opioid dispensing in Queensland by age, oral morphine equivalent and geographical area. What are the implications for practitioners? This research highlights recent changes in opioid dispensing and opportunities for further studies to best inform practice improvement. [ABSTRACT FROM AUTHOR]

Summary: Opioid harm can vary by opioid type. This observational study examined the effect of opioid type (oxycodone vs. tapentadol) on rates of persistent postoperative opioid use ('persistence'). We linked hospital and community pharmacy data for surgical patients who were dispensed discharge opioids between 1 January 2016 and 30 September 2021. Patients were grouped by opioid experience ('opioid‐naive' having received no opioids in the 3 months before discharge) and formulation of discharge opioid (immediate release only or modified release ± immediate release). Mixed‐effects logistic regression models predicted persistence (continued use of any opioid at 90 days after discharge), controlling for key persistence risk factors. Of the 122,836 patients, 2.31% opioid‐naive and 27.24% opioid‐experienced patients met the criteria for persistence. For opioid‐naive patients receiving immediate release opioids, there was no significant effect of opioid type. Tapentadol modified release was associated with significantly lower odds of persistence compared with oxycodone modified release, OR (95%CI) 0.81 (0.69–0.94) for opioid‐naive patients and 0.81 (0.71–0.93) for opioid‐experienced patients. Among patients who underwent orthopaedic surgery (n = 19,832), regardless of opioid experience or opioid formulation, the odds of persistence were significantly lower for those who received tapentadol compared with oxycodone. This was one of the largest and most extensive studies of persistent postoperative opioid use, and the first that specifically examined persistence with tapentadol. There appeared to be lower odds of persistence for tapentadol compared with oxycodone among key subgroups, including patients prescribed modified release opioids and those undergoing orthopaedic surgery. [ABSTRACT FROM AUTHOR]

Original brand extended-release (ER) oxycodone tablets (OC) for oral use were reformulated (ORF) with abuse-deterrent properties (ADP) against inhalation and injection routes in August 2010. This product transition provided an opportunity to compare "before and after" reformulation abuse trends. Our goal was to assess the change in abuse of brand oxycodone ER from before and after introduction of ORF. Change in self-reported non-oral "OxyContin" abuse in the previous 30 days during two years pre- and four years post-reformulation was assessed among adults evaluated for substance use and treatment planning using the Addiction Severity Index-Multimedia Version (ASI-MV). Comparator opioids were used to provide a frame of reference for changes in abuse due to competing population-level opioid abuse interventions and other factors unrelated to the reformulation. A proportion (PR) and abuse report dispensing ratio (ARDR) are reported because a single measure of abuse has not been identified that can optimally describe opioid abuse or changes in opioid abuse. Interrupted time-series analyses indicated an immediate decline in non-oral abuse measures post-reformulation (PR = −52.1%; ARDR = −32.2%). Significant decreases from pre- to post-reformulation in non-oral abuse overall were observed (PR [95% CI] = −30.7% [-46.9%, −9.5%]; ARDR = −29.3% [-37.5%, −20.1%]). Comparator opioids did not demonstrate similar trends over the period. Methodology applied in this study suitably assessed the effectiveness of an ADP product. Among individuals assessed for substance use, a differential decline in non-oral abuse of brand ER oxycodone was observed since introduction of ORF. [ABSTRACT FROM AUTHOR]

Opioids are highly addictive substances with a relapse rate of over 90%. While preclinical models of chronic opioid exposure exist for studying opioid dependence, none recapitulate the relapses observed in human opioid addiction. The mechanisms associated with opioid dependence, the accompanying withdrawal symptoms, and the relapses that are often observed months or years after opioid dependence are poorly understood. Therefore, we developed a novel model of chronic opioid exposure whereby the level of administration is self-directed with periods of behavior acquisition, maintenance, and then extinction alternating with reinstatement. This profile arguably mirrors that seen in humans, with initial opioid use followed by alternating periods of abstinence and relapse. Recent evidence suggests that dietary interventions that reduce inflammation, including omega-3 polyunsaturated fatty acids (n-3 PUFAs), may reduce substance misuse liability. Using the self-directed intake model, we characterize the observed profile of opioid use and demonstrate that an n-3-PUFA-enriched diet ameliorates oxycodone-seeking behaviors in the absence of drug availability and reduces anxiety. Guided by the major role gut microbiota have on brain function, neuropathology, and anxiety, we profile the microbiome composition and the effects of chronic opioid exposure and n-3 PUFA supplementation. We demonstrate that the withdrawal of opioids led to a significant depletion in specific microbiota genera, whereas n-3 PUFA supplementation increased microbial richness, phylogenetic diversity, and evenness. Lastly, we examined the activation state of microglia in the striatum and found that n-3 PUFA supplementation reduced the basal activation state of microglia. These preclinical data suggest that a diet enriched in n-3 PUFAs could be used as a treatment to alleviate anxiety induced opioid-seeking behavior and relapse in human opioid addiction.

Growing nonmedical use of prescription opioids is a global problem, motivating research on ways to reduce use and combat addiction. Medical cannabis ("medical marijuana") legalization has been associated epidemiologically with reduced opioid harms and cannabinoids have been shown to modulate effects of opioids in animal models. This study was conducted to determine if Δ9-tetrahydrocannabinol (THC) enhances the behavioral effects of oxycodone. Male rats were trained to intravenously self-administer (IVSA) oxycodone (0.15 mg/kg/infusion) during 1 h, 4 h or 8 h sessions. Following acquisition rats were exposed to THC by vapor inhalation (1 h and 8 h groups) or injection (0-10 mg/kg, i.p.; all groups) prior to IVSA sessions. Fewer oxycodone infusions were obtained by rats following vaporized or injected THC compared with vehicle treatment prior to the session. Follow-up studies demonstrated parallel dose-dependent effects of THC, i.p., on self-administration of different per-infusion doses of oxycodone and a preserved loading dose early in the session. These patterns are inconsistent with behavioral suppression. Additional groups of male and female Wistar rats were assessed for nociception following inhalation of vaporized THC (50 mg/mL), oxycodone (100 mg/mL) or the combination. Tail withdrawal latency was increased more by the THC/oxycodone combination compared to either drug alone. Similar additive antinociceptive effects were produced by injection of THC (5.0 mg/kg, i.p.) and oxycodone (2.0 mg/kg, s.c.). Together these data demonstrate additive effects of THC and oxycodone and suggest the potential use of THC to enhance therapeutic efficacy, and to reduce the abuse, of opioids.

Abuse of prescription opioids is a growing public health crisis in the United States, with drug overdose deaths increasing dramatically over the past 15 years. Few preclinical studies exist on the reinforcing effects of oxycodone or on the development of therapies for oxycodone abuse. This study was conducted to determine if immunopharmacotherapy directed against oxycodone would be capable of altering oxycodone-induced antinociception and intravenous self-administration. Male Wistar rats were administered a small-molecule immunoconjugate vaccine (Oxy-TT) or the control carrier protein, tetanus toxoid (TT), and trained to intravenously self-administer oxycodone (0.06 or 0.15 mg/kg/infusion). Brain oxycodone concentrations were 50% lower in Oxy-TT rats compared to TT rats 30 min after injection (1 mg/kg, s.c.) whereas plasma oxycodone was 15-fold higher from drug sequestration by circulating antibodies. Oxy-TT rats were also less sensitive to 1-2 mg/kg, s.c. oxycodone on a hot water nociception assay. Half of the Oxy-TT rats failed to acquire intravenous self-administration under the 0.06 mg/kg/infusion training dose. Oxycodone self-administration of Oxy-TT rats trained on 0.15 mg/kg/infusion was higher than controls; however under progressive ratio (PR) conditions the Oxy-TT rats decreased their oxycodone intake, unlike TT controls. These data demonstrate that active vaccination provides protection against the reinforcing effects of oxycodone. Anti-oxycodone vaccines may entirely prevent repeated use in some individuals who otherwise would become addicted. Vaccination may also reduce dependence in those who become addicted and therefore facilitate the effects of other therapeutic interventions which either increase the difficulty of drug use or incentivize other behaviors.

Rationale: In utero opioid exposure is associated with lower weight and a neonatal opioid withdrawal syndrome (NOWS) at birth, along with longer-term adverse neurodevelopmental outcomes and mood disorders. While NOWS is sometimes treated with continued opioids, clinical studies have not addressed if long-term neurobehavioral outcomes are worsened with continued postnatal exposure to opioids. In addition, pre-clinical studies comparing in utero only opioid exposure to continued post-natal opioid administration for withdrawal mitigation are lacking. Objectives: Here, we sought to understand the impact of continued postnatal opioid exposure on long term behavioral consequences. Methods: We implemented a rodent perinatal opioid exposure model of oxycodone (Oxy) exposure that included Oxy exposure until birth (short Oxy) and continued postnatal opioid exposure (long Oxy) spanning gestation through birth and lactation. Results: Short Oxy exposure was associated with a sex-specific increase in weight gain trajectory in adult male mice. Long Oxy exposure caused an increased weight gain trajectory in adult males and alterations in nociceptive processing in females. Importantly, there was no evidence of long-term social behavioral deficits, anxiety, hyperactivity, or memory deficits following short or long Oxy exposure. Conclusions: Our findings suggest that offspring with prolonged opioid exposure experienced some long-term sequelae compared to pups with opioid cessation at birth. These results highlight the potential long-term consequences of opioid administration as a mitigation strategy for clinical NOWS symptomology and suggest alternatives should be explored. [ABSTRACT FROM AUTHOR]

Objective: This study was designed to test the hypothesis that patients prescribed hydrocodone consume a similar number of tablets as those prescribed oxycodone after surgery. Summary of Background Data: In October 2017, the Michigan Opioid Prescribing Engagement Network released opioid prescribing guidelines for surgeries. For each procedure, these guidelines recommended prescribing 50% more tablets of hydrocodone than tablets of oxycodone to adjust for potency differences. These guidelines were simplified in January 2019 to recommend the same number of 5 mg hydrocodone tablets as 5 mg oxycodone tablets for each procedure. Methods: Retrospective, observational analysis of opioid-naïve adults who underwent surgical procedures across 64 hospitals in Michigan and were prescribed 5 mg tablets of hydrocodone or oxycodone between January 1, 2018 and May 31, 2019. The primary outcome was number of tablets consumed. We defined a meaningful difference in consumption as 5 pills a priori. Secondary outcomes included self-reported pain, satisfaction, and opioid refills. Results: A total of 6842 patients were included. Adjusting for covariates, patients prescribed hydrocodone consumed 7 tablets (95% confidence interval 6.79–7.18) while patients prescribed oxycodone consumed 6 tablets (95% confidence interval 5.58–6.40.) Comparing patients prescribed oxycodone with those prescribed hydrocodone, there were no differences in satisfaction, pain, or refills. Conclusions: Although patients prescribed hydrocodone consumed more tablets than patients prescribed oxycodone, this difference was not clinically significant and did not result in differences in satisfaction, pain, or refills. Perioperative opioid prescribing guidelines may recommend the same number of 5 mg oxycodone and hydrocodone tablets without sacrificing patient-reported outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Rates of relapse to drug use during abstinence are among the highest for opioid use disorder (OUD). In preclinical studies, reinstatement to drug-seeking has been extensively studied as a model of relapse-but the work has been primarily in males. We asked whether biological sex contributes to behaviors comprising self-administration of the prescription opioid oxycodone in rats, and we calculated the relative contribution of these behavioral measures to reinstatement in male and female rats. Materials and methods: Rats were trained to self-administer oxycodone (8 days, training phase), after which we examined oxycodone selfadministration behaviors for an additional 14 days under three conditions in male and female rats: short access (ShA, 1 h/d), long access (LgA, 6 h/d), and saline self-administration. All rats were then tested for cue-induced reinstatement of drug-seeking after a 14-d forced abstinence period. We quantified the # of infusions, front-loading of drug intake, non-reinforced lever pressing, inter-infusion intervals, escalation of intake, and reinstatement responding on the active lever. Results: Both male and female rats in LgA and ShA conditions escalated oxycodone intake to a similar extent. However, males had higher levels of non-reinforced responding than females under LgA conditions, and females had greater levels of reinstatement responding than males. We then correlated each addiction-related measure listed above with reinstatement responding in males and females and ranked their respective relative contributions. Although the majority of behavioral measures associated with oxycodone self-administration did not show sex differences on their own, when analyzed together using partial least squares regression, their relative contributions to reinstatement were sex-dependent. Front-loading behavior was calculated to have the highest relative contribution to reinstatement in both sexes, with long and short inter-infusion intervals having the second greatest contribution in females and males, respectively. Discussion: Our results demonstrate sex differences in some oxycodone self-administration measures. More importantly, we demonstrate that a sexdependent constellation of self-administration behaviors can predict the magnitude of reinstatement, which holds great promise for relapse prevention in people. [ABSTRACT FROM AUTHOR]

Objectives: Little data is available on opioid usage in the adult population for benign oropharyngeal surgery. The objective here is to evaluate opioid prescribing patterns, opioid consumption, and patient pain patterns following benign oropharyngeal surgery, specifically tonsillectomy and adenoidectomy, tonsillectomy alone, and expansion sphincter pharyngoplasty. Methods: Patients aged ≥18 years old and received a tonsillectomy, tonsillectomy and adenoidectomy, or expansion sphincter pharyngoplasty between November 2019 and August 2020 were included. Patients were provided a survey which included a visual analog scale for recording their pain postoperatively and the amount of opioid they had remaining. Results: About 103 patients completed the post-operative questionnaire. Patients were prescribed 38 837 morphine milligram equivalents and used 28 644: approximately 26% went unused, which is the equivalent of 1346 5 mg oxycodone pills. Opioid consumption correlated with the initial dosage: patients consumed 12% more narcotic on average as the initial prescription went upwards by 50 morphine milligram equivalents. Obstructive sleep apnea, history of smoking, and being female predicted increased opioid usage in this cohort. Pain was reported the highest on postoperative day 1. A prescription of approximately 225 morphine milligram equivalents (150 mg oxycodone) was associated with decreased opioid use in this cohort. Larger initial prescriptions did not result in fewer requests for refills. Conclusion: A significant amount of opioid medication went unused in this study. A prescription of 225 morphine milligram equivalents (or 150 mg oxycodone) provided appropriate analgesia for the majority of patients. Larger prescriptions may result in increased opioid consumption and may not reduce the amount of refills. More study is needed to confirm these findings. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Opioid use disorder is a global problem and better treatments are needed. • This study assessed the safety and toxicity profile of an anti-oxycodone vaccine. • No vaccine-induced adverse effects or toxicity were observed. • Results from this study enabled initiation of a Phase I clinical trial (NCT04458545). Opioid use disorders (OUD) and overdose represent a public health threat, resulting in thousands of deaths annually worldwide. Vaccines offer a promising treatment for OUD and potentially the prevention of fatal overdoses. The Oxy(Gly) 4 -sKLH Conjugate Vaccine, Adsorbed (Oxy(Gly) 4 -sKLH) has shown promising pre-clinical efficacy at reducing the behavioral and pharmacological effects of oxycodone. To support its clinical evaluation, a GLP toxicology study was performed to address the safety of Oxy(Gly) 4 -sKLH. Sprague Dawley rats were vaccinated with either aluminum adjuvant (alum) or vaccine adsorbed on alum. Low and high doses of Oxy(Gly) 4 -sKLH, equivalent to a 1X or 47X human dose, respectively, were administered every two weeks for a total of four vaccinations. Both vaccine doses induced high antibody titers. Vaccine-related toxicity was assessed postmortem in one experimental group after receiving the fourth immunization of the vaccine's high dose. For the remaining experimental groups, rats were challenged with 1.5 mg/kg/day s.c. oxycodone for 7 days after the fourth vaccination to assess whether concurrent exposure to oxycodone in vaccinated animals resulted in toxicity. All rats, except a subset of the aluminum control and the high dose vaccine groups, were sacrificed following oxycodone exposure. These subsets were allowed a four weeks recovery period prior to euthanasia. In this study, no Oxy(Gly) 4 -sKLH-related hematology, clinical chemistry, urinalysis, body weight, organ weight, or anatomic pathology toxicological findings were observed. These results demonstrate that the Oxy(Gly) 4 -sKLH vaccine is well tolerated, is immunogenic even at low doses, and does not produce undesired side effects in rats. [ABSTRACT FROM AUTHOR]

Effective and safe pain management in children can be complex and challenging. It remains an important goal in order to minimize acute distress, behavioural changes, central sensitization and hyperalgesia. Neonates may be susceptible to long-term neurodevelopmental changes due to the neuroplasticity of their immature brains, and adequate analgesia may help ameliorate these changes. The focus of this review is to look at systemic analgesic options available for children, infants and neonates. This review includes a brief description of important pharmacokinetic, pharmacodynamic and pharmacogenomic issues that can influence the effectiveness and safety of these medications, while highlighting the impact organ-immaturity in neonates can have on pain processing and analgesic pharmacology. [ABSTRACT FROM AUTHOR]

Tapentadol and oxycodone are commonly used analgesics. Preclinical studies have shown that oxycodone modulates brain metabolites related to opioid pathways, whereas tapentadol also affects noradrenergic activity. However, knowledge about the function of the medications in the human brain is limited. The aim was to investigate effects of tapentadol and oxycodone on brain glutamate, the most important neurotransmitter in pain processing. Magnetic resonance spectroscopy was obtained in 21 healthy subjects from the anterior cingulate cortex, prefrontal cortex, and insula at baseline and after 14 days of treatment with either 50 mg tapentadol, 10 mg oxycodone (equipotent dose, both extended release) or placebo twice daily in a randomized double‐blind cross‐over study. Compared to baseline, decreased glutamate/creatine levels were identified in anterior cingulate cortex after tapentadol (1.26 ± 0.14 vs. 1.35 ± 0.18, P =.04) and oxycodone (1.26 ± 0.10 vs. 1.35 ± 0.12, P =.05) treatments, both with 7% reduction. This indicates that both analgesics modulate the glutamatergic system at the supraspinal level in humans. [ABSTRACT FROM AUTHOR]