Prepacked Take-Home Analgesia in Outpatient Hand Surgery Reduces Opioid Dispensation.

BACKGROUND: Adequate postoperative pain treatment is important for quality of life, patient satisfaction, rehabilitation, function, and total opioid consumption, and might lower both the risk of chronic postoperative pain and the costs for society. Prolonged opioid consumption is a well-known risk factor for addiction. Previous studies in upper extremity surgery have shown that total opioid consumption is a third of the amount prescribed, which can be explained by package size. The aim of this study was to examine whether implementation of prepacked takehome analgesia bags reduced the quantity of prescribed and dispensed opioids. MATERIAL AND METHODS: We introduced prepacked take-home analgesia bags for postoperative pain treatment in outpatient surgery. The bags came in two sizes, each containing paracetamol, etoricoxib, and oxycodone. The first 147 patients who received the prepacked analgesia bags were included in the study, and received a questionnaire one month after surgery covering self-assessed pain (visual analog scale of 0-10) and satisfaction (0-5), as well as opioid consumption. Prescription data after introducing the analgesia bags were compared with data before the bags were introduced. RESULTS: Of the 147 patients included in the study, 58 responded. Compared to standard prescription (small bag group: 14 oxycodone immediate release capsules (5 mg), large bag group: additional 28 oxycodone extended release tablets (5 mg), based on the smallest available package), the patients in the small analgesia bag group received 50% less oxycodone and 67% less for the large bag group. Patients with small bags consumed a median of 0.0 mg oxycodone and those with large bags consumed a median of 25.0 mg oxycodone. The median satisfaction was 5.0 (range: 2-5) and the median pain score was acceptable at the first postoperative day. Prescription data showed a significant reduction of 60.0% in the total amount of prescribed opioids after the introduction of prepacked analgesia bags. CONCLUSIONS: The introduction of prepacked analgesia bags dramatically reduced the quantity of opioids prescribed after outpatient hand surgery. Patient satisfaction was high and the postoperative pain level was acceptable. KEY WORDS: analgesia, hand surgery, opioids, outpatint surgery, wrist surgery.

RECORD, a high-throughput, customizable system that unveils behavioral strategies leveraged by rodents during foraging-like decision-making.

Translational studies benefit from experimental designs where laboratory organisms use human-relevant behaviors. One such behavior is decision-making, however studying complex decision-making in rodents is labor-intensive and typically restricted to two levels of cost/reward. We design a fully automated, inexpensive, high-throughput framework to study decision-making across multiple levels of rewards and costs: the REward-COst in Rodent Decision-making (RECORD) system. RECORD integrates three components: 1) 3D-printed arenas, 2) custom electronic hardware, and 3) software. We validated four behavioral protocols without employing any food or water restriction, highlighting the versatility of our system. RECORD data exposes heterogeneity in decision-making both within and across individuals that is quantifiably constrained. Using oxycodone self-administration and alcohol-consumption as test cases, we reveal how analytic approaches that incorporate behavioral heterogeneity are sensitive to detecting perturbations in decision-making. RECORD is a powerful approach to studying decision-making in rodents, with features that facilitate translational studies of decision-making in psychiatric disorders.

METTL14-mediated upregulation of lncRNA HOTAIR represses PP1α expression by promoting H3K4me1 demethylation in oxycodone-treated mice.

N6-methyladenosine (m6A) methylation is a vital epigenetic mechanism associated with drug addiction. However, the relationship between m6A modification and oxycodone rewarding is less well explored. Based on an open field test, the present study evaluated oxycodone rewarding using chromatin immunoprecipitation PCR, immunofluorescence, and RNA sequencing. A marked increase in METTL14 protein and a decrease in PP1α protein due to oxycodone abundance in the striatal neurons were observed in a dose- and time-dependent manner. Oxycodone markedly increased LSD1 expression, and decreased H3K4me1 expression in the striatum. In the open field test, intra-striatal injection of METTL14 siRNA, HOTAIR siRNA, or LSD1 shRNA blocked oxycodone-induced increase in locomotor activity. The downregulation of PP1α was also inhibited after treatment with METTL14/HOTAIR siRNA and LSD1 shRNA. Enhanced binding of LSD1 with CoRest and of CoRest with the PP1α gene induced by oxycodone was also reversed by LSD1 shRNA. In addition, H3K4me1 demethylation was also blocked by the treatment. In summary, the investigation confirmed that METTL14-mediated upregulation of HOTAIR resulted in the repression of PP1α, which in turn facilitated the recruitment of LSD1, thus catalyzing H3K4me1 demethylation and promoting oxycodone addiction.

Effect of Oxycodone-Based Multimodal Analgesia on Visceral Pain After Major Laparoscopic Gastrointestinal Surgery: A Randomised, Double-Blind, Controlled Trial.

Purpose: Oxycodone is a potent µ- and κ-opioid receptor agonist that can relieve both somatic and visceral pain. We assessed oxycodone- vs sufentanil-based multimodal analgesia on postoperative pain following major laparoscopic gastrointestinal surgery. Methods: In this randomised double-blind controlled trial, 40 adult patients were randomised (1:1, stratified by type of surgery) to receive oxycodone- or sufentanil-based multimodal analgesia, comprising bilateral transverse abdominis plane blocks, intraoperative dexmedetomidine infusion, flurbiprofen axetil, and oxycodone- or sufentanil-based patient-controlled analgesia. The co-primary outcomes were time-weighted average (TWA) of visceral pain (defined as intra-abdominal deep and dull pain) at rest and on coughing during 0-24 h postoperatively, assessed using the numerical rating scale (0-10) with a minimal clinically important difference of 1. Results: All patients completed the study (median age, 64 years; 65% male) and had adequate postoperative pain control. The mean (SD) 24-h TWA of visceral pain at rest was 1.40 (0.77) in the oxycodone group vs 2.00 (0.98) in the sufentanil group (mean difference=-0.60, 95% CI, -1.16 to -0.03; 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).

Two Weeks of Continuous Opioid Treatment in an Adenine-Induced Mouse Model of Chronic Kidney Disease Exacerbates the Bone Inflammatory State and Increases Osteoclasts.

Patients with chronic kidney disease (CKD) report high pain levels, but reduced renal clearance eliminates many analgesic options; therefore, 30-50% of CKD patients have chronic opioid prescriptions. Opioid use in CKD is associated with higher fracture rates. Opioids may directly alter bone turnover directly through effects on bone cells and indirectly via increasing inflammation. We hypothesized that continuous opioid exposure would exacerbate the high bone turnover state of CKD and be associated with elevated measures of inflammation. Male C57Bl/6J mice after 8 weeks of adenine-induced CKD (AD) and non-AD controls (CON) had 14-day osmotic pumps (0.25-µL/hr release) containing either saline or 50-mg/mL oxycodone (OXY) surgically implanted in the subscapular region. After 2 weeks, all AD mice had elevated blood urea nitrogen, parathyroid hormone, and serum markers of bone turnover compared to controls with no effect of OXY. Immunohistochemical staining of the distal femur showed increased numbers of osteocytes positive for the mu opioid and for toll-like receptor 4 (TLR4) due to OXY. Osteocyte protein expression of tumor necrosis factor-α (TNF-α) and RANKL were higher due to both AD and OXY so that AD + OXY mice had the highest values. Trabecular osteoclast-covered surfaces were also significantly higher due to both AD and OXY, resulting in AD + OXY mice having 4.5-fold higher osteoclast-covered surfaces than untreated CON. These data demonstrate that opioids are associated with a pro-inflammatory state in osteocytes which increases the pro-resorptive state of CKD.

Cannabidiol Protects against the Reinstatement of Oxycodone-Induced Conditioned Place Preference in Adolescent Male but Not Female Rats: The Role of MOR and CB1R.

Cannabidiol (CBD), a phytocannabinoid, appeared to satisfy several criteria for a safe approach to preventing drug-taking behavior, including opioids. However, most successful preclinical and clinical results come from studies in adult males. We examined whether systemic injections of CBD (10 mg/kg, i.p.) during extinction of oxycodone (OXY, 3 mg/kg, i.p.) induced conditioned place preference (CPP) could attenuate the reinstatement of CPP brought about by OXY (1.5 mg/kg, i.p.) priming in adolescent rats of both sexes, and whether this effect is sex dependent. Accordingly, a priming dose of OXY produced reinstatement of the previously extinguished CPP in males and females. In both sexes, this effect was linked to locomotor sensitization that was blunted by CBD pretreatments. However, CBD was able to prevent the reinstatement of OXY-induced CPP only in adolescent males and this outcome was associated with an increased cannabinoid 1 receptor (CB1R) and a decreased mu opioid receptor (MOR) expression in the prefrontal cortex (PFC). The reinstatement of CCP in females was associated with a decreased MOR expression, but no changes were detected in CB1R in the hippocampus (HIP). Moreover, CBD administration during extinction significantly potentialized the reduced MOR expression in the PFC of males and showed a tendency to potentiate the reduced MOR in the HIP of females. Additionally, CBD reversed OXY-induced deficits of recognition memory only in males. These results suggest that CBD could reduce reinstatement to OXY seeking after a period of abstinence in adolescent male but not female rats. However, more investigation is required.

ABCB1 genetic polymorphisms affect opioid requirement by altering function of the intestinal P-glycoprotein.

The association between polymorphisms of the human ATP binding cassette subfamily B member 1 (ABCB1) gene and opioid response has attracted intense attention recently. As the ABCB1 gene encodes for the transporter P-glycoprotein in the brain and intestine involved in the pharmacokinetics of opioids, we investigated the effects of ABCB1 genetic polymorphisms on doses of opioids for pain relief and determined which pharmacokinetic process was affected in cancer pain patients. Sixty-eight cancer pain patients admitted for intrathecal therapy (ITT) were included. The association between ABCB1 genetic polymorphisms (C3435T, C1236T, G2677T/A and A61G) and systemic doses of opioids before ITT were investigated. Concentrations of oxycodone in plasma and cerebrospinal fluid (CSF) were determined by HPLC-MS/MS in 17 patients treated with oral oxycodone before ITT, and the influences of ABCB1 genetic polymorphisms on plasma-concentration to oral-dose ratios and CSF-concentration to plasma-concentration ratios of oral oxycodone were further analyzed. ABCB1 C3435T and G2677T/A polymorphisms were significantly associated with systemic doses of opioids before ITT, which coincided with the influences of ABCB1 C3435T and G2677T/A polymorphisms on the ratios of plasma-concentration to oral-dose. However, no significant difference was found in ratios of CSF-concentration to plasma-concentration among ABCB1 SNP genotypes. The present study provided the first evidence that ABCB1 C3435T and G2677T/A polymorphisms affect opioid requirement in cancer pain patients via altering transportation function of P-glycoprotein in the intestine, which will further expand our knowledge about pharmacokinetics of opioids and could contribute to the individualization of opioids use.

The epigenetically regulated PP1α expression by KDM1A may contribute to oxycodone conditioned place preference in mice.

The lysine-specific demethylase 1 (KDM1A) is reported to be a regulator in learning and memory. However, the effect of KDM1A in oxycodone rewarding memory has yet to be studied. In our study, rewarding memory was assessed by using conditioned place preference (CPP) in male mice. Next generation sequencing and chromatin immunoprecipitation-PCR were used to explore the molecular mechanisms. Oxycodone significantly decreased PP1α mRNA and protein levels in hippocampal neurons. Oxycodone significantly increased KDM1A and H3K4me1 levels, while significantly decreased H3K4me2 levels in a time- and dose-dependent manner. Behavioral data demonstrated that intraperitoneal injection of ORY-1001 (KDM1A inhibitor) or intra-hippocampal injection of KDM1A siRNA/shRNA blocked the acquisition and expression of oxycodone CPP and facilitated the extinction of oxycodone CPP. The decrease of PP1α was markedly blocked by the injection of ORY-1001 or KDM1A siRNA/shRNA. Oxycodone-induced enhanced binding of CoRest with KDM1A and binding of CoRest with the PP1α promoter was blocked by ORY-1001. The level of H3K4me2 demethylation was also decreased by the treatment. The results suggest that oxycodone-induced upregulation of KDM1A via demethylation of H3K4me2 promotes the binding of CoRest with the PP1α promoter, and the subsequent decrease in PP1α expression in hippocampal neurons may contribute to oxycodone reward.

The persistent benefits of decreasing default pill counts for postoperative narcotic prescriptions.

BACKGROUND: In 2017, a university-based academic healthcare system changed the opioid default pill count from 30 to 12 pills. Modifying the electronic default pill count influences short-term clinician prescribing practices. We sought to understand the long-term impact on postoperative opioid prescribing habits after an opioid default pill count reduction. MATERIALS AND METHODS: A retrospective electronic medical record system (EMRS) review was conducted in a healthcare system comprised of seven affiliated hospitals. Patients who underwent a surgical procedure and were prescribed an opioid on discharge between 2017-2021 were evaluated. All prescriptions were converted into morphine equivalents (MME). Analyses were performed with the chi-square test and Bonferonni adjusted t-test. RESULTS: 191,379 surgical procedures were studied. The average quantity of opioids prescribed decreased from 32 oxycodone 5 mg tablets in 2017 to 21 oxycodone 5 mg tablets in 2021 (236 MME to 154 MME, p<0.001). The percentage of patients obtaining a refill within 90 days of surgery varied between 18.3% and 19.9% (p<0.001). Patients with a pre-existing opioid prescription and opioid-naïve patients both had significant reductions in prescription quantities above the default MME (79.7% to 60.6% vs. 65.3% to 36.9%, p<0.001). There was no significant change in refills for both groups (pre-existing 36.7% to 38.3% (p = 0.1) vs naïve 15.0% to 15.3% (p = 0.29)). CONCLUSIONS: The benefits of decreasing the default opioid pill count continue to accumulate long after the original change. Physician uptake of small changes to default EMRS practices represents a sustainable and effective intervention to reduce the quantities of postoperative opioids prescribed without deleterious effects on outpatient opiate requirements.

Neurobehavioral Characterization of Perinatal Oxycodone-Exposed Offspring in Early Adolescence.

The opioid epidemic has received considerable attention, but the impact on perinatal opioid-exposed (POE) offspring remains underexplored. This study addresses the emerging public health challenge of understanding and treating POE children. We examined two scenarios using preclinical models: offspring exposed to oxycodone (OXY) in utero (IUO) and acute postnatal OXY (PNO). We hypothesized exposure to OXY during pregnancy primes offspring for neurodevelopmental deficits and severity of deficits is dependent on timing of exposure. Notable findings include reduced head size and brain weight in offspring. Molecular analyses revealed significantly lower levels of inflammasome-specific genes in the prefrontal cortex (PFC). Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) highlighted the enrichment of genes associated with mitochondrial and synapse dysfunction in POE offspring. Western blot analysis validated IPA predictions of mitochondrial dysfunction in PFC-derived synaptosomes. Behavioral studies identified significant social deficits in POE offspring. This study presents the first comparative analysis of acute PNO- and IUO-offspring during early adolescence finding acute PNO-offspring have considerably greater deficits. The striking difference in deficit severity in acute PNO-offspring suggests that exposure to opioids in late pregnancy pose the greatest risk for offspring well-being.

A master regulator of opioid reward in the ventral prefrontal cortex.

In addition to their intrinsic rewarding properties, opioids can also evoke aversive reactions that protect against misuse. Cellular mechanisms that govern the interplay between opioid reward and aversion are poorly understood. We used whole-brain activity mapping in mice to show that neurons in the dorsal peduncular nucleus (DPn) are highly responsive to the opioid oxycodone. Connectomic profiling revealed that DPn neurons innervate the parabrachial nucleus (PBn). Spatial and single-nuclei transcriptomics resolved a population of PBn-projecting pyramidal neurons in the DPn that express µ-opioid receptors (µORs). Disrupting µOR signaling in the DPn switched oxycodone from rewarding to aversive and exacerbated the severity of opioid withdrawal. These findings identify the DPn as a key substrate for the abuse liability of opioids.

Postoperative opioids administered to inpatients with major or orthopaedic surgery: A retrospective cohort study using data from hospital electronic prescribing systems.

BACKGROUND: Opioids administered in hospital during the immediate postoperative period are likely to influence post-surgical outcomes, but inpatient prescribing during the admission is challenging to access. Modified-release(MR) preparations have been especially associated with harm, whilst certain populations such as the elderly or those with renal impairment may be vulnerable to complications. This study aimed to assess postoperative opioid utilisation patterns during hospital stay for people admitted for major/orthopaedic surgery. METHODS: Patients admitted to a teaching hospital in the North-West of England between 2010-2021 for major/orthopaedic surgery with an admission for ≥1 day were included. We examined opioid administrations in the first seven days post-surgery in hospital, and "first 48 hours" were defined as the initial period. Proportions of MR opioids, initial immediate-release(IR) oxycodone and initial morphine milligram equivalents (MME)/day were calculated and summarised by calendar year. We also assessed the proportion of patients prescribed an opioid at discharge. RESULTS: Among patients admitted for major/orthopaedic surgery, 71.1% of patients administered opioids during their hospitalisation. In total 50,496 patients with 60,167 hospital admissions were evaluated. Between 2010-2017 MR opioids increased from 8.7% to 16.1% and dropped to 11.6% in 2021. Initial use of oxycodone IR among younger patients (≤70 years) rose from 8.3% to 25.5% (2010-2017) and dropped to 17.2% in 2021. The proportion of patients on ≥50MME/day ranged from 13% (2021) to 22.9% (2010). Of the patients administered an opioid in hospital, 26,920 (53.3%) patients were discharged on an opioid. CONCLUSIONS: In patients hospitalised with major/orthopaedic surgery, 4 in 6 patients were administered an opioid. We observed a high frequency of administered MR opioids in adult patients and initial oxycodone IR in the ≤70 age group. Patients prescribed with ≥50MME/day ranged between 13-22.9%. This is the first published study evaluating UK inpatient opioid use, which highlights opportunities for improving safer prescribing in line with latest recommendations.

The effect of pre-emptive oral pregabalin on opioid consumption in patients undergoing laparoscopic sleeve gastrectomy with an analysis of intraoperative hemodynamic stability and quality of recovery: study protocol for a randomized, prospective, double-blind study.

BACKGROUND: Obese patients undergoing laparoscopic sleeve gastrectomy (LSG) are particularly at risk of opioid-related side effects. To reduce patient exposure to opioids, multimodal analgesia, which involves the use of drugs of different classes, may be utilized. One of the drugs under consideration is pregabalin. Despite an opioid-sparing potential, few studies assess the role of pregabalin as an element of multimodal analgesia in LSG. Considering the limited number and inconsistent results of available studies, we decided to conduct a randomized, prospective study on the effect of preemptive pregabalin administration in obese patients on opioid consumption, pain scores, the incidence of opioid side effects, and hemodynamical stability. METHODS: The study is designed as a prospective randomized controlled trial with double-blinding. Randomization will be performed in a block with a parallel 1:1 allocation. The intervention will involve receiving a pregabalin 150 mg capsule 1-2 h before the surgery, whereas the control group will receive an identically looking placebo. The primary outcome measure will be total oxycodone consumption in the first 24 h following surgery. Secondary outcome measures will be pain severity assessed using the Numerical Rating Scale (NRS) 1, 6, 12, and 24 h after surgery, postoperative sedation on the Ramsay scale, PONV impact scale, the incidence of desaturation episodes < 94%, and episodes of blurred vision at 1, 6, 12, and 24 h after surgery, intraoperative hemodynamic parameters such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure (MBP), total fluid volume, and total ephedrine dose. Patient comfort will be additionally assessed using the QoR-40 questionnaire at discharge. DISCUSSION: The study will explore the efficacy and safety of preemptive pregabalin in a dose of 150 mg as a co-analgesic used in multimodal analgesia for LSG. As studies on opioid-sparing regimes concern the safety of obese patients, we aim to contribute objective data with a relatively large study sample size. The result of the present clinical trial may support the reassessment of recommendations to use pregabalin in the studied population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05804591. Registered on 07.04.2023.

Patient-reported pain, satisfaction, adverse effects, and deviations from ambulatory surgery pain medication.

OBJECTIVES: Addressing the challenges of ambulatory surgery involves balancing effective pain relief with minimizing the side effects of pain medication. Due to the heightened risk of opioid abuse, Helsinki University Hospital (Finland) has had a stringent oxycodone prescription policy. This policy prompts an exploration into whether ambulatory surgery patients experience severe post-surgical pain and whether an increase in prescribed opioids would cause elevation in adverse effects. METHODS: This prospective cohort study, with a 1-week follow-up, included 111 adult ambulatory surgery patients (orthopaedics, urology). The patients documented their pain levels within the first postoperative week (using a numerical rating scale [NRS] of 0-10) and pain medication intake up to two days postoperatively. Furthermore, they completed a questionnaire assessing their satisfaction with pain relief, medication-related adverse effects, and adherence to instructions. Medication intake was cross-referenced with the provided instructions and prescriptions. RESULTS: A notable 56% of patients reported experiencing intense pain (NRS ≥5) within a week following surgery. Of these, 52% received a single dose of slow-release oxycodone (5-20 mg) at discharge for use on the night of surgery. Predominantly prescribed pain medications included a combination of paracetamol and codeine (64%) or ibuprofen (62%). Satisfaction rates were high, with 87% expressing satisfaction with pain medication given at hospital discharge and 90% expressing contentment with the prescribed medication. The most common adverse effects were tiredness/grogginess (45%), sleep disturbances (38%), nausea (37%), and constipation (27%). Also, 24% of patients self-reported deviations from medication instructions. A comparison of self-reported and instructed medications revealed that 14% exceeded prescribed dosages, and 28% opted for preparations different from those prescribed. Notably, patients who self-reported deviations from instructions differed from those objectively deviating from instructions. CONCLUSIONS: Although 56% of patients had intense pain, the majority expressed satisfaction with the provided pain relief. Instances of non-adherence to medication instructions were prevalent, often going unnoticed by the patients themselves.

Comparing withdrawal- and anxiety-like behaviors following oral and subcutaneous oxycodone administration in C57BL/6 mice.

Excessive prescribing and misuse of prescription opioids, such as oxycodone, significantly contributed to the current opioid crisis. Although oxycodone is typically consumed orally by humans, parenteral routes of administration have primarily been used in preclinical models of oxycodone dependence. To address this issue, more recent studies have used oral self-administration procedures to study oxycodone seeking and withdrawal in rodents. Behavioral differences, however, following oral oxycodone intake versus parenteral oxycodone administration remain unclear. Thus, the goal of the current studies was to compare anxiety- and withdrawal-like behaviors using established opioid dependence models of either home cage oral intake of oxycodone (0.5 mg/ml) or repeated subcutaneous (s.c.) injections of oxycodone (10 mg/kg) in male and female mice. Here, mice received 10 days of oral or s.c. oxycodone administration, and following 72 h of forced abstinence, anxiety- and withdrawal-like behaviors were measured using elevated zero maze, open field, and naloxone-induced precipitated withdrawal procedures. Global withdrawal scores were increased to a similar degree following oral and s.c. oxycodone use, while both routes of oxycodone administration had minimal effects on anxiety-like behaviors. When examining individual withdrawal-like behaviors, mice receiving s.c. oxycodone exhibited more paw tremors and jumps during naloxone-induced precipitated withdrawal compared with oral oxycodone mice. These results indicate that both models of oxycodone administration are sufficient to elevate global withdrawal scores, but, when compared with oral consumption, s.c. oxycodone injections yielded more pronounced effects on some withdrawal-like behaviors.

Pharmacologic profile of ITI-333: a novel molecule for treatment of substance use disorders.

RATIONALE: Medications are urgently needed to treat symptoms of drug withdrawal and mitigate dysphoria and psychiatric comorbidities that drive opioid abuse and relapse. ITI-333 is a novel molecule in development for treatment of substance use disorders, psychiatric comorbidities, and pain. OBJECTIVE: Characterize the preclinical profile of ITI-333 using pharmacological, behavioral, and physiological assays. METHODS: Cell-based assays were used to measure receptor binding and intrinsic efficacy of ITI-333; animal models were employed to assess effects on opioid reinstatement, precipitated oxycodone withdrawal, and drug abuse liability. RESULTS: In vitro, ITI-333 is a potent 5-HT2A receptor antagonist (Ki = 8 nM) and a biased, partial agonist at µ-opioid (MOP) receptors (Ki = 11 nM; lacking ß-arrestin agonism) with lesser antagonist activity at adrenergic α1A (Ki = 28 nM) and dopamine D1 (Ki = 50 nM) receptors. In vivo, ITI-333 blocks 5-HT2A receptor-mediated head twitch and MOP receptor-mediated effects on motor hyperactivity in mice. ITI-333 alone is a naloxone-sensitive analgesic (mice) which suppresses somatic signs of naloxone-precipitated oxycodone withdrawal (mice) and heroin cue-induced reinstatement responding without apparent tolerance or physical dependence after chronic dosing (rats). ITI-333 did not acutely impair gastrointestinal or pulmonary function (rats) and was not intravenously self-administered by heroin-maintained rats or rhesus monkeys. CONCLUSIONS: ITI-333 acts as a potent 5-HT2A receptor antagonist, as well a biased MOP receptor partial agonist with low intrinsic efficacy. ITI-333 mitigates opioid withdrawal/reinstatement, supporting its potential utility as a treatment for OUD.

Neuroplasticity-related genes correlate with individual differences in distinct phases of oxycodone self-administration in male rats.

Opioid use disorder (OUD) is a chronic condition associated with long-lasting molecular and behavioral changes. Animals with prolonged access to opioids develop behaviors similar to human OUD. Identifying associated molecular changes can provide insight to underpinnings that lead to or maintain OUD. In pilot studies, we identified several miRNA targets that are altered by the administration of oxycodone. We selected mir182 for follow up as it was recently shown to be dysregulated in plasma of men administered oxycodone. In addition, mir182 is increased in reward-related brain regions of male rats following exposure to various addictive substances. The present study utilizes a long-access oxycodone self-administration paradigm to examine changes in mir182 and its mRNA targets associated with neuroplasticity, which may be involved in the maintenance of OUD-like phenotype in rats. Male rats were trained to self-administer oxycodone (0.1 mg/kg/infusion, i. v.) for 6 h daily sessions for 12 days. Each animal had a yoked saline control that received matched saline infusions. Animals were then tested on a progressive ratio schedule to measure motivation to obtain a single infusion of oxycodone. Drug seeking was measured following 28 days of forced abstinence using a 90-min cued/test. RTqPCR was utilized to measure mir182 and mRNA targets related to neuroplasticity (wnt3, plppr4, pou3f3, tle4, cacna2d, and bdnf) from the nucleus accumbens. Data revealed that animals responded on a continuum for oxycodone. When divided into two groups termed high- and low responders, animals diverged during self-administration acquisition and maintained differences in behavior and gene expression throughout the study. mir182 was upregulated in the nucleus accumbens of both high and low responders and negatively correlated with tle4, which showed a strong negative correlation with reinstatement behavior. mRNA target levels were correlated with behaviors associated with increased severity of OUD behavior in male rats.

The impact of more restrictive hydrocodone rescheduling on unintentional pediatric opioid exposures.

PURPOSE: To evaluate the impact of rescheduling hydrocodone combination products (HCPs) from schedule III of the Controlled Substances Act to the more restrictive schedule II on unintentional pediatric exposures (≤5 years old). METHODS: Using U.S. data on outpatient retail pharmacy dispensing, emergency department (ED) visits, and poison center (PC) exposure cases, we assessed trends in prescriptions dispensed and unintentional pediatric exposure cases involving hydrocodone (rescheduled from III to II) compared to oxycodone (schedule II) and codeine (schedule III for combination products) using descriptive and interrupted time-series (ITS) analyses during the 16 quarters before and after the October 2014 rescheduling of HCPs. RESULTS: Dispensing of hydrocodone products was declining before rescheduling but declined more steeply post-rescheduling. In ITS analyses, both hydrocodone and oxycodone had significant slope decreases in PC case rates in the post versus pre-period that was larger for hydrocodone, while codeine had a small but significant slope increase in PC case rates. An estimated 4202 ED visits for pediatric hydrocodone exposures occurred in the pre-period and 2090 visits occurred in the post-period, a significant decrease of 50.3%. Oxycodone exposures showed no significant decrease. CONCLUSIONS: Pediatric hydrocodone unintentional exposure ED visits and PC cases decreased after HCP rescheduling more than would be expected had the pre-rescheduling trend continued; the acceleration in the decrease in hydrocodone PC cases was partially offset by a slowing in the decrease in codeine-involved cases. The trend changes were likely due to multiple factors, including changes in dispensing that followed the rescheduling. Unintentional pediatric medication exposures and poisonings remain a public health concern requiring ongoing, multifaceted mitigation efforts.

Tramadol-paracetamol for postoperative pain after spine surgery - A randomized, double-blind, placebo-controlled study.

OBJECTIVES: Multimodal pain management is one component in enhanced recovery after surgery protocol. Here we evaluate the efficacy of tramadol-paracetamol in acute postoperative pain and pain outcome at 12 months after spine surgery in randomized, double-blind, placebo-controlled trial. METHODS: We randomized 120 patients undergoing spine surgery to receive, for add-on pain management, two tramadol-paracetamol 37.5 mg/325 mg (n = 61) or placebo tablets (n = 59) twice a day for 5 postoperative days. In the hospital, multimodal pain management consisted of dexketoprofen and oxycodone. After discharge, patients were prescribed ibuprofen 200 mg, maximum 1,200 mg/day. Pain, analgesic use, and satisfaction with pain medication were followed up with the Brief Pain Inventory questionnaire before surgery and at 1 and 52 weeks after surgery. The primary outcome was patients' satisfaction with pain medication 1 week after surgery. RESULTS: At 1 week after surgery, patients' satisfaction with pain medication was similarly high in the two groups, 75% [interquartile range, 30%] in the placebo group and 70% [40%] in the tramadol-paracetamol group (p = 0.949) on a scale: 0% = not satisfied, 100% = totally satisfied. At 1 week, ibuprofen dose was lower in the placebo group 200 mg [1,000] compared to the tramadol-paracetamol group, 800 mg [1,600] (p = 0.016). There was no difference in the need for rescue oxycodone. Patients in the tramadol-paracetamol group had more adverse events associated with analgesics during the first postoperative week (relative risk = 1.8, 95% confidence interval, 1.2-2.6). CONCLUSION: Add-on pain treatment with tramadol-paracetamol did not enhance patients' satisfaction with early pain management after back surgery.

A rapid and sensitive LC-MS/MS method for quantifying oxycodone, noroxycodone, oxymorphone and noroxymorphone in human plasma to support pharmacokinetic drug interaction studies of oxycodone.

A sensitive and reliable LC-MS/MS method was developed and validated for the quantification of oxycodone and metabolites in human plasma. The method has a runtime of 6 min and a sensitivity of 0.1 µg/L for all analytes. Sample preparation consisted of protein precipitation. Separation was performed on a Kinetix biphenyl column (2.1 × 100 mm, 1.7 µm), using ammonium formate 5 mm in 0.1% aqueous formic acid and methanol LC-MS grade 100% in gradient elution at a flow rate of 0.4 ml/min. Detection was performed in multiple reaction monitoring mode using positive electrospray ionization. The method was linear over the calibration range of 0.1-25.0 µg/L for oxycodone, noroxycodone and noroxymorphone and 0.1-5.0 µg/L for oxymorphone. The method demonstrated good performance in terms of intra- and interday accuracy (86.5-110.3%) and precision (CV 1.7-9.3%). The criteria for the matrix effect were met (CV < 15%) except for noroxymorphone, for which an additional method was applied to compensate for the matrix effect. Whole blood samples were stable for 4 h at room temperature. Plasma samples were stable for 24 h at room temperature and 3 months at -20°C. Furthermore, the method was successfully applied in a pharmacokinetic drug interaction study of oxycodone and enzalutamide in patients with prostate cancer.