Inadequate postoperative pain control still hinders recovery, fuels opioid dependence, and promotes chronic pain. Although perioperative systemic dexamethasone offers anti-inflammatory and opioid-sparing benefits, its clinical success is unpredictable, and concerns over systemic adverse events persist. To address these limitations, dexamethasone palmitate-a novel lipophilic prodrug engineered as a nanoparticle emulsion-utilizes enhanced permeability and retention (EPR) effects to concentrate selectively at inflammatory sites, promising superior local anti-inflammatory and analgesic properties with minimized systemic toxicity. Consequently, this clinical trial is designed to investigate the safety and efficacy of preoperatively administering intravenous dexamethasone palmitate for the prevention of acute postoperative pain.

Opioids are commonly prescribed as standards of care for various types of pain. Multiple pathways can impact pain response, and understanding medication metabolism is imperative to achieving optimal analgesic response. Pharmacogenomics (PGx) can assist with understanding interindividual variability and aid in safe medication prescribing. Genetic variants in pharmacokinetic and pharmacodynamic genes have been evaluated, and literature generally favors use of pharmacokinetic associations in clinical practice. Tramadol and codeine have the most literature to support integration of PGx into routine prescribing practices. Hydrocodone and oxycodone have theoretical implications; however, data have been inconsistent. Clinical decision support has been the mainstay of integration of PGx results into routine clinical practice. Future research should focus on additional pathways implicated in opioid metabolism and response to further guide effective pain management with opioids.

Opioid withdrawal is associated with heightened pain sensitivity, including allodynia. Although opioid-induced allodynia is well-documented in humans and animal models, the relationship between the severity of opioid withdrawal-induced allodynia and individual addiction-like behaviors remains poorly understood. To address this gap, Heterogeneous Stock rats underwent long access (12 hours/day) intravenous oxycodone or saline self-administration, followed by measurement of mechanical sensitivity at six timepoints across three weeks of abstinence. Oxycodone self-administering rats were stratified by an Addiction Index derived from individual differences in the escalation of oxycodone intake, motivation to consume oxycodone, tolerance to oxycodone's analgesic effects, and acute opioid withdrawal-induced mechanical pain sensitivity. Here, we show that High Addiction Index rats developed significantly more intense and longer-lasting allodynia than Low Addiction Index rats, identifying High Addiction Index status as a distinct, severe phenotype within the oxycodone self-administering population. Saline self-administering rats developed allodynia comparable in magnitude to Low Addiction Index rats, further distinguishing the severe phenotype of High Addiction Index rats. Results remained consistent even when excluding allodynia from the Addiction Index, highlighting the robustness of the association between addiction-like severity and protracted allodynia. These findings demonstrate that severe addiction-like behavior, rather than opioid exposure alone, is associated with protracted abstinence-associated allodynia and identify High Addiction Index status as a distinguishing feature of vulnerability to prolonged pain during abstinence. supporting mechanical allodynia as a marker of addiction-like severity. These results motivate future work to define the mechanisms linking addiction-like severity to protracted opioid withdrawal-induced pain, with the goal of informing targeted clinical interventions for patients most susceptible to severe opioid withdrawal-induced allodynia.

Sickle cell disease (SCD) is a debilitating hereditary hematologic disorder characterized by severe physical complications, including painful vaso-occlusive crises, chronic pain, multi-organ damage, and reduced life expectancy. Diverse medications are prescribed to treat SCD or manage its associated complications. However, no comprehensive resource for concomitant medication and drug-drug interaction (DDI) risk exists for people living with SCD. Here, we utilized real-world claims data from the Merative Commercial MarketScan Research Database to identify the 100 most prescribed drugs for adolescents and adults living with SCD in the United States with commercial health insurance. DDI risks were assessed by leveraging the CERTARA Drug Interaction Database. In total, 43/100 drugs on the list were associated with DDI risks. Inhibitors were more frequently represented than inducers, suggesting that interaction risk in this population may be driven primarily by inhibition-mediated mechanisms. CYP3A4 accounted for the largest proportion of identified interactions. The high prescription rates of the CYP3A4 substrates oxycodone (40%) and fentanyl (18.5%), associated with potentially serious clinical consequences due to DDIs, highlight the importance of considering CYP3A4 interaction risk during development of novel therapies for SCD. Overall, this analysis provides a population-level insight into prescription patterns and subsequent DDI risks for people living with SCD. We expect these findings to (1) create clinical DDI risk awareness for this population and (2) inform strategic planning of DDI assessments during development of novel therapies indicated for SCD.

Endometriosis is a chronic gynecological disorder characterized by persistent pain and impaired quality of life, with limited effective treatment options. Emerging evidence indicates that cannabinoids may provide analgesic and symptom-relieving effects in chronic pain conditions. This prospective single-center cohort study investigated the effects of standardized oral cannabis extracts (cannabinoid-based medicinal products, CBMPs) on pain and quality of life in women with endometriosis. Thirty premenopausal women aged 18-45 years with confirmed endometriosis and chronic pelvic pain were enrolled; 27 completed the 3-month treatment period. Participants received oral CBMPs containing a balanced THC: CBD ratio. Pain intensity, frequency of pain episodes, analgesic use, fatigue, anxiety, central sensitization, disability, and quality of life were assessed using validated questionnaires (VAS, EHP-30, PDI, CFS, GAD-7, CSI). Significant improvements were observed after one month of treatment, with continued benefit over three months. Pain intensity decreased markedly (p = 0.0004), accompanied by reductions in the number of pain days and analgesic use, including both NSAIDs (e.g., ibuprofen, diclofenac) and opioid analgesics (e.g., tramadol, tilidin, oxycodone) (p < 0.001). Fatigue (p = 0.0013), anxiety (p < 0.0001), central sensitization (p < 0.0001), disability (p < 0.0001), and overall quality of life (EHP-30) improved significantly. Treatment was well tolerated; side effects were predominantly mild (severity score 1 on a 0-3 scale) and transient, occurring mainly during the titration phase and declining thereafter. Although limited by its single-center design, lack of placebo control, and short follow-up, this study provides preliminary evidence that oral CBMPs may represent a safe and effective adjunct therapy for managing pain and related symptoms in women with endometriosis. Larger randomized controlled trials are warranted to confirm these findings and establish optimal dosing strategies.

Interleukin 1β (IL-1β) is a proinflammatory cytokine that binds to two receptors, IL-1R1 and IL-1R2. IL-1R1 activation initiates neuroinflammation, and IL-1R2 is a decoy receptor that reduces IL-1R1 signaling by sequestering IL-1β. Emerging evidence links IL-1β to substance use disorders. Methamphetamine and ethanol increase IL-1β levels in the brain, and antagonism of IL-1β signaling reduces negative affective behaviors caused by methamphetamine and ethanol. However, effects of chronic opioid exposure on the IL-1β system in the brain and blocking IL-1β signaling on rewarding effects of opioids are unknown. We determined if oxycodone self-administration (SA) causes brain-region specific changes in IL-1β, IL-1R1, and IL-1R2 levels (mRNA and protein) and if antagonizing IL-1β signaling affects oxycodone SA behaviors. Following 14 days of oxycodone SA (0.056 mg/kg/inf), IL-1R2 mRNA levels were increased in the basolateral amygdala (BLA) and IL-1R1 mRNA levels in the BLA were decreased. For IL-1β itself, oxycodone SA did not affect mRNA levels. Oxycodone SA also did not alter protein levels of IL-1R2, IL-1R1, pro-IL-1β, mature-IL-1β, or the relative expression ratios between pro- and mature-IL-1β. Systemic administration of anakinra, an IL-1R1 antagonist, did not block acquisition of oxycodone SA. Intracerebroventricular (ICV) administration of anakinra following oxycodone acquisition did not reduce oxycodone SA and infusions. Our results show that oxycodone SA induces notable changes in IL-1 receptor mRNA in the BLA but is not affected by pharmacological antagonism of IL-1β signaling.

Since the introduction of the tamper-resistant oral formulation of modified-release oxycodone (OxyContin®), cases of thrombotic microangiopathy (TMA) have been reported following intravenous injection of the drug. Previous reports have suggested that withdrawal of the offending agent alone may be sufficient to reverse the condition; however, the associated acute kidney injury (AKI) in these cases was only mild to moderate in severity. We report the first case of OxyContin®-associated TMA presenting with anuric AKI requiring dialysis, followed by complete renal recovery after cessation of intravenous OxyContin® use. This case demonstrates that withdrawal of the causative agent may be sufficient to achieve resolution of TMA even in severe presentations. Accordingly, supportive management without the need for invasive and costly interventions may be appropriate in selected cases. Awareness of the association between intravenous OxyContin® use and TMA is essential for timely diagnosis, as identification often depends on direct inquiry regarding drug exposure.

Opioid Use Disorder (OUD) remains a prominent threat to global health. Genetic background influences the susceptibility of developing OUD, although specific genetic factors remain elusive. Rodent models that differ in susceptibility to escalation and dysregulation of opioid use are valuable tools to facilitate discovery of genetic pathways.

Opioids are often administered before anesthesia to reduce stress/discomfort or enhance well-being, despite limited supporting evidence. This double-blind, randomized controlled trial investigates the acute subjective effects of intravenous morphine (10 mg), oxycodone (5 mg), and fentanyl (0.1 mg) in 199 adults undergoing elective surgery (ASA physical status I-II). All patients received a standardized multimodal preoperative medication. Patients rated their experiences on 0-10 verbal numerical rating scales immediately before and 3 min after opioid administration. The most prominent drug effects were undesirable (intoxication, sedation, and dizziness). Fentanyl produced higher ratings of intoxication, sedation, dizziness, and euphoria than morphine, with oxycodone generally showing intermediate effects. Substantial interindividual variability was observed across all treatment groups. Desirable effects (reduced anxiety and increased relaxation) were modest, and only 23% of patients reported feeling better. Notably, 96% reported feeling intoxicated. These results challenge the use of preoperative opioids to improve patient comfort. EudraCT: 2020-004920-40.

Characterizing the affective processes parents experience following a child's surgery and how these processes might predict their perceptions of children's pain and postoperative medication administration is critical for refining interventions to improve children's pain management. This study evaluated concurrent and lagged associations among parent affect (pain catastrophizing, negative affect, and positive affect), perceived child pain intensity, and opioid administration in the 7 days after tonsillectomy in a sample of youth ages 7 to 12 years (n = 138). Parents of potentially eligible patients were recruited before surgery and completed electronic diaries through a smartphone application 3 times daily for 7 days after surgery. Opioid administration was evaluated in the context of routine clinical care. Patients were generally prescribed a 3-day supply of liquid oxycodone for parents to administer if pain was uncontrolled by acetaminophen and ibuprofen. Of the 138 parents who completed ≥1 diary, 90 parents reported administering an opioid during the diary period (65.2%) and were included in opioid analyses. In multilevel models, both average and momentary levels of parent affect predicted parents' perceptions of their child's pain intensity, whereas only average negative affect and momentary levels of parent affect predicted odds of opioid administration. Parent pain catastrophizing had a bidirectional relation with perceived child pain in lagged analyses, with higher parent pain catastrophizing predicting higher perceived pain intensity at subsequent timepoints and vice versa. Assessing momentary levels of parent affect may be particularly important for capturing dynamic shifts that predict escalations in children's pain and opioid administration.