Search Results (2,784)

Purpose: Whether medical cannabis reduces opioid use during early chemotherapy remains unclear. We examined cannabinoid and opioid prescribing among patients with GI cancers initiating chemotherapy. Methods: Patients with GI cancers initiating chemotherapy (2016–2025) were identified from the Epic COSMOS database. Cannabis exposure was defined as prescriptions for FDA-approved cannabinoids recorded in the EHR; non-prescription cannabis obtained through dispensaries were not captured. Patients with any cannabis or opioid use in the prior year or death within 90 days were excluded. Multivariable logistic regression evaluated factors associated with cannabinoid use. Results: Among 144,981 patients, 2.4% received cannabinoids within 90 days of chemotherapy initiation. Cannabinoid recipients were more likely to receive opioids than nonrecipients (60.6% vs. 31.1%, p < 0.01). In adjusted analyses, cannabinoid prescribing was more common among Black patients (aOR 1.45; 95%CI 1.30–1.61), women (aOR 1.11; 95%CI 1.03–1.19), and individuals with pancreatic cancer (aOR 3.26; 95%CI 2.97–3.58). Prescribing varied by region and declined over time, relative to 2017. Conclusions: Early cannabinoid prescribing was not associated with reduced opioid use. Use was more common among patients with pancreatic cancer and among Black patients, highlighting clinical and structural variation in supportive-care practices. Full article

Background: Neuropathic pain remains a major unmet clinical challenge. Growing evidence identifies sigma receptors (σRs) as pivotal intracellular modulators of maladaptive stress signaling, positioning them as promising non-opioid targets for chronic pain management. Notably, despite the pleiotropic nature of σRs in regulating diverse cellular pathways—which might theoretically suggest a high risk of off-target effects—current selective antagonists have demonstrated remarkable safety and tolerability profiles. Sigma-1 and sigma-2 receptors (σ1R and σ2R) are molecularly and functionally distinct proteins that regulate neuronal excitability, proteostasis, and neuroimmune communication, all mechanisms that characterize neuronal excitability and cellular stress adaptation. σ1R acts as a ligand-operated molecular chaperone at the mitochondria-associated endoplasmic reticulum membrane. Extensive preclinical data demonstrate that σ1R antagonism attenuates peripheral and central sensitization, suppresses neuroinflammation, and restores opioid analgesic efficacy. These findings are supported by the advanced clinical candidate E-52862, which has shown efficacy and a favorable safety profile in neuropathic pain conditions. σ2R, identified as transmembrane protein 97 (σ2R/TMEM97), functions as a regulator of cholesterol trafficking, lysosomal integrity, and integrated stress response (ISR). σ2R modulation alleviates neuropathic pain by restoring proteostatic balance and reducing ISR-driven neuronal vulnerability rather than directly suppressing excitability. Emerging σ2R ligands such as FEM-1689, UKH-1114, and CM-398 provide compelling proof-of-concept for durable, disease-modifying analgesia. Methods: A structured literature search was conducted using PubMed, Scopus, and Web of Science to identify studies published within the last decade describing σ1R and σ2R/TMEM97 biology, ligand development, and their preclinical or clinical evaluation in neuropathic pain. Reference lists were manually screened to ensure comprehensive coverage. Conclusions: This review synthesizes pharmacology, ligand development, and translational evidence supporting σRs as next-generation targets for neuropathic pain therapy, highlighting convergent roles of σ1R and σ2R in pain chronification and outlining future directions for structure-guided therapeutic strategies. Full article

Background/Objectives: Gabapentinoids are first-line treatments for neuropathic pain (NP); however, real-world evidence regarding their safety and effectiveness in complex clinical populations remains limited. This study aimed to evaluate the effectiveness and safety profile of gabapentinoid therapy in patients managed within a specialized pain relief institution. Methods: A retrospective cohort study (n = 109) was conducted (January 2024 to December 2024). Effectiveness was assessed via DN4 and VAS over one year. Time to improvement was analyzed using Kaplan–Meier curves. Results: The cohort (mean age 66.2 ± 15.3 years) presented 100% comorbidity and polypharmacy (66.1% opioids; 67.9% antidepressants). Although all patients showed improvement, only 35.8% achieved “maximal improvement.” Pregabalin demonstrated faster VAS reduction than gabapentin (p = 0.029), though long-term success was comparable (p = 0.30). Significantly, 100% of patients reported at least one adverse drug event (ADE), primarily somnolence (66.1%), though no serious ADEs occurred. Lower baseline pain scores were significant predictors of therapeutic success. Conclusions: Gabapentinoids are effective for long-term NP management; however, their use is consistently associated with non-serious ADEs. In specialized settings characterized by extensive CNS-active polypharmacy, proactive pharmacovigilance and multidisciplinary oversight are essential to balance analgesic effectiveness with medication safety. Full article

Fentanyl is a potent analgesic widely used in clinical practice. Fentanyl and its analogues are seriously abused and are emerging in the illegal drug market, leading to numerous intoxication cases. However, assessment of the potency of the pharmacological effect of these novel fentanyl analogues remains limited and inconsistent across studies. The development of novel analgesics has largely relied on the assessment of mu opioid receptor (MOR) binding affinity, with insufficient verification through the assessment of antinociceptive effects. This study evaluated the antinociceptive effects of 25 fentanyl analogues to investigate the relationship between chemical structure and antinociceptive effect. In this study, hot plate tests were conducted in mice to generate time–effect and dose–effect curves for the evaluation of the antinociceptive effect of fentanyl and its analogues. The results demonstrated that the antinociceptive effects of fentanyl analogues were dose- and time-dependent. The potency of the antinociceptive effect observed in this study generally aligned with the corresponding MOR binding affinities reported in the literature, although several analogues exhibited discrepancies. Structural modifications in different regions of the fentanyl scaffold affect the antinociceptive potency to different degrees, and the duration of action also varied across fentanyl analogues. Furthermore, opioid-induced hyperalgesia (OIH) was observed following administration of several fentanyl analogues, raising potential concerns regarding their abuse liability and development for analgesic purposes. Taken together, this study systematically evaluated and compared the antinociceptive effects of fentanyl analogues. The findings clarify the relationship between chemical structure and the antinociceptive effect, providing valuable insights for drug regulation and the development of novel analgesics. Full article

Volatile anesthetics have steadily become more popular in intensive care units for sedation for reasons related to their beneficial pharmacokinetic and pharmacodynamic properties. Common anesthetics such as isoflurane and sevoflurane rapidly reach sedative levels in the body, but they are also rapidly eliminated, allowing for quick recovery. These agents have minimal impact on the liver and kidneys, which makes them attractive options when compared to other agents including opioids, benzodiazepines, ketamine, and propofol. Use of delivery systems like AnaConDa^® (Anaesthetic Conserving Device; Sedana Medical AB, Danderyd, Sweden) has enabled providers to easily use these agents in the Intensive Care Unit (ICU). In this regard, they have recently provided additional beneficial consideration during intravenous drug shortages seen during the COVID-19 pandemic and at other times. These agents have shown organ-protective effects in the kidneys and lungs, which may even reduce the total time spent in the ICU. Pharmacodynamically, these anesthetics mediate their effects through central nervous system ion channels to exert analgesic and anxiolytic actions, thereby minimizing effects in the kidneys and lungs. These agents are primarily eliminated via exhalation, which makes them potential options for those with liver or kidney failure. This narrative review examines current efficacy and risks of using volatile anesthetics for sedation in the ICU setting and clinical roles for the future. Full article

Background: Polysubstance use, particularly the combination of opioids and stimulants, represents a growing public health concern due to its high risk of severe multisystem complications and mortality. Here, we present a case illustrating the lethal synergy of opioid–stimulant co-use. Methods: A 37-year-old male with chronic Hepatitis C and documented polysubstance use reported recent use of fentanyl, cocaine, methamphetamine, and cannabis. He presented with generalized weakness, left lower limb pain, tense edema, and anuria. Clinical assessment included monitoring of vital signs, physical examination, capillary blood gas analysis, extended laboratory panels (muscle and cardiac enzymes, electrolytes, and coagulation parameters), urinalysis, and Doppler imaging. Management over five days included intravenous hydration, diuretics, urinary alkalinization, electrolyte correction, anticoagulation, metabolic and vitamin therapy, hemodialysis, and comprehensive supportive care. Results: Laboratory evaluation revealed massive rhabdomyolysis (peak CK 161,050 U/L), severe hyperkalemia (K⁺ 8.4 mmol/L), metabolic acidosis, acute kidney injury with oligoanuria, and left-sided deep vein thrombosis. Despite intensive multidisciplinary interventions, the patient’s repeated refusal of ongoing treatment critically contributed to a fatal outcome. Conclusions: This case underscores the high mortality risk associated with opioid–stimulant co-use and the crucial impact of treatment refusal. Clinicians and public health stakeholders should recognize the rapid progression of multisystem dysfunction in polysubstance users and prioritize early, aggressive interventions combined with patient engagement strategies to mitigate fatal outcomes. Full article

Purpose: Opioids are widely used for pain management but are associated with adverse events that may differ between women and men. However, post-marketing safety data are rarely examined at the individual level to characterize these sex differences. This study aimed to identify sex disparities in opioid-associated adverse events using the FDA Adverse Event Reporting System (FAERS) to inform safer opioid selection for women. Methods: Opioid drugs were identified using the FDA’s Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) list and official drug labeling. Relevant FAERS reports were extracted, and adverse events were classified into 27 System Organ Classes (SOCs) based on the Medical Dictionary for Regulatory Activities (MedDRA). Sex-specific signals of disproportionate reporting were evaluated using proportional reporting ratios and reporting odds ratios for drug–SOC pairs. Results: Across most opioid drugs and SOCs, adverse events were reported more frequently in women than in men. The largest sex disparities were observed for codeine, fentanyl, tapentadol, hydrocodone, and sufentanil, with significantly higher disproportionate reporting rates among women. These findings indicate pronounced sex-specific differences in the post-marketing safety profiles of several commonly used opioids. Conclusions: Women demonstrate higher disproportionate reporting of adverse events for certain opioid medications, particularly codeine and fentanyl. These results suggest the need for increased awareness of sex-specific safety differences and support sex-informed prescribing and monitoring strategies to improve opioid safety in women. Since pharmacists are medication experts and play a key role in promoting rational and safe use, our findings may further support pharmacists counseling patients and monitoring for opioid-related adverse events. Full article

This study seeks to inform emergency preparedness efforts by summarizing the pandemic’s impacts on access to opioid use disorder (OUD) recovery support as reported by women in recovery. In-depth interviews were completed with adult women in recovery from OUD. We used a primarily deductive approach to coding and analysis. Two coders analyzed transcripts; discrepancies were resolved through discussion. Seventeen women completed interviews from June to October 2020. Pandemic impacts primarily focused on engagement in care and retention at community and interpersonal levels. Community-level barriers to engagement included facilities’ halting intake of patients and fear of COVID-19 infection in treatment settings. Interpersonal barriers to engagement included loss of childcare support and the sudden transition to virtual services. Community-level retention barriers included perception of facility staff’s lack of adherence to infection prevention protocols and strict enforcement of infection prevention protocols on residents within facilities. Interpersonal barriers to retention included reduced availability of mutual aid meetings. Participants also highlighted how the pandemic worsened the addiction crisis and increased women’s caretaking burden. Leaders and administrators must be prepared to simultaneously balance responses for two public health crises: a novel infectious disease and addiction. Lessons learned from the pandemic can mitigate barriers to care and recovery when future emergencies arise. Full article

Background: Mitragynine pseudoindoxyl (MP) is a semi-synthetic kratom metabolite increasingly sold online and over-the-counter, marketed misleadingly as “kratom” or “7-OH,” despite lacking FDA approval and safety data in humans. Methods: This case report describes a 44-year-old male with polysubstance use history who developed opioid withdrawal symptoms after regular MP use (400 mg daily for pain management following neck injury). Vital signs, alcohol and opioid withdrawal scores and clinical outcomes were recorded. Results: The patient presented exhibiting symptoms of moderate opioid withdrawal in the absence of other opioid use. A buprenorphine macro-induction protocol was initiated. Following pre-treatment using chlorpromazine as an anti-emetic and diazepam to treat concomitant alcohol withdrawal, 32 mg buprenorphine were provided (16 mg × 2) on day one, with subsequent maintenance dosing and adjunctive medications. The patient demonstrated significant symptomatic improvement with decreased COWS scores and expressed interest in long-acting injectable buprenorphine maintenance therapy. Discussion: This represents the first documented case of suspected MP withdrawal successfully managed with buprenorphine macro-induction, demonstrating the potential efficacy of this approach for novel semi-synthetic kratom metabolites when standard withdrawal management protocols are insufficient. Further studies should evaluate long term outcomes and validate findings. Full article

Background/Objectives: Postoperative pain pharmacology is complex. We investigated the sensitivity of analgesic-like effects induced by morphine, ibuprofen, and their combination to peripheral opioid antagonism in a mouse laparotomy model. Methods: Mechanical hypersensitivity was assessed using von Frey filaments, and ongoing pain (abdominal licking and facial expressions) was evaluated using artificial intelligence algorithms. We tested the sensitivity of the analgesic treatments to the opioid antagonist naloxone or its peripherally restricted analog, naloxone methiodide. We also tested the effects of neutrophil depletion using an anti-Ly6G antibody. Gastrointestinal transit and pupillary diameter were measured to assess non-analgesic opioid effects. Results: Morphine reversed all pain-related behaviors; its effect on mechanical hypersensitivity was reversed by peripheral opioid antagonism, whereas its effects on ongoing pain were not. Ibuprofen reduced mechanical hypersensitivity and facial expressions but failed to alter licking. Interestingly, the ibuprofen effect on mechanical hypersensitivity depended on peripheral opioid receptors and neutrophils at the injury site. The morphine–ibuprofen combination produced synergistic analgesia across all endpoints without enhancing opioid-induced gastrointestinal inhibition or mydriasis. Peripheral opioid antagonism reversed the effect of the combination on mechanical hypersensitivity and facial expressions but not on licking. Conclusions: Our results replicate the key clinical phenomena relevant to the postoperative pain context, including the potentiation of morphine analgesia by ibuprofen without the exacerbation of adverse effects. Our results suggest that drug effects on different postoperative pain measures rely on distinct neurobiological mechanisms and are not interchangeable. Therefore, the use of a battery of complementary pain endpoints in preclinical pharmacology studies is advisable. Full article

Major depressive disorder (MDD) is a highly prevalent psychiatric illness for which rapid-acting antidepressants such as ketamine provide only transient benefit. Because κ-opioid receptor (KOR) signaling contributes to stress-related dysphoria and impaired neuroplasticity, we examined whether KOR antagonism could prolong ketamine’s antidepressant-like effects in a mouse model of adolescent chronic unpredictable stress (CUS). Male C57BL/6J mice (n = 10 per group for behavioral analyses) were exposed to CUS during adolescence and developed persistent depression-like behavior in adulthood. Mice with depressive-like behavior received a single injection of ketamine, the selective KOR antagonist norbinaltorphimine (nBNI), or their combination. Behavioral testing showed that all treatments reduced immobility in the tail suspension test (TST) 24 h post-administration; however, only the combined ketamine/nBNI treatment maintained antidepressant-like effects one week post-treatment. Molecular analyses (n = 4–8 per group) were conducted at this single time point, one week post-treatment, to characterize region-specific signaling states in the prefrontal cortex, hippocampus, and striatum, focusing on ERK, AKT, JNK, mTOR, and BDNF pathways. These molecular findings represent correlates of sustained behavioral effects rather than evidence of causal mechanisms. Together, the data indicate that concurrent KOR antagonism is associated with prolonged antidepressant response to ketamine in stress-exposed male mice and with distinct region-dependent signaling profiles at one week post-treatment. Further studies are needed to establish mechanistic causality and confirm the possible applicability of these findings. Full article

Background/Objectives: Opioid-induced constipation (OIC) is a frequent adverse effect of opioid therapy. In contrast to other opioid-related side effects, OIC usually does not improve over time and significantly impairs the quality of life of affected patients. Despite its high prevalence, OIC remains underdiagnosed and undertreated in clinical practice, which has been demonstrated in several European countries. Healthcare data indicates that approximately 2.3 million people in Germany received potentially OIC-inducing opioids in 2023, the majority being patients with chronic non-cancer pain. Methods: An interdisciplinary board of experts in gastroenterology, pain medicine, neurology, oncology, and palliative care developed consensus-based recommendations to improve the diagnosis and management of OIC. Fifteen statements were drafted according to current national German and international guidelines and literature and subsequently discussed. Out of the fifteen statements, twelve statements remained, which achieved consensus with at least 90% agreement. Results: The consensus statements address key aspects of OIC management, including pathophysiology, patient education, diagnosis, prevention, treatment and structured follow-up. Following the statements, a practical treatment algorithm was developed to facilitate clinical implementation. Use of validated tools such as the Bowel Function Index (BFI) for diagnosis and monitoring, early initiation of laxative therapy and timely escalation to mechanism-oriented therapy with peripherally acting μ-opioid receptor antagonists (PAMORAs) in cases of inadequate response have been recommended by the panel. Accordingly, treatment should follow an approach with the following steps: (1) Laxative, (2) switch to PAMORA, (3) rotation of PAMORA, and (4) combination of PAMORA with laxative. In Europe, the PAMORAs methylnaltrexone, naloxegol and naldemedine are approved for the treatment of OIC. Conclusions: This consensus paper provides both evidence-based and practice-oriented recommendations for the systematic management of OIC. By promoting patient education, early recognition, structured evaluation and stepwise treatment escalation, the presented statements and algorithm aim to improve patient outcomes and quality of life under opioid therapy including better adherence to opioid therapy. Full article

This study investigated temporal group-level changes in gut microbiome composition and fecal metabolic markers in Wistar rats following a 10-day administration of morphine. Fecal samples were collected at predefined post-discontinuation time points and analyzed using 16S rRNA gene sequencing and GC×GC-TOF/MS-based metabolomics, with a focus on short-chain fatty acids (SCFAs). Morphine exposure was associated with transient alterations in gut microbiome structure at early post-treatment time points, including changes in alpha diversity and shifts in the relative abundance of major bacterial taxa. Unsupervised multivariate analysis of fecal metabolomic profiles revealed substantial inter-individual variability without persistent global separation between control and morphine-treated groups. Targeted analysis identified transient reductions in the relative signal intensities of selected SCFAs shortly after morphine withdrawal, while no significant differences were observed at later time points. These findings suggest that morphine-associated perturbations of the gut microbiome and fecal metabolome are predominantly time-dependent and tend to diminish during extended post-discontinuation phases. Full article

Effective pain management during labor must balance adequate maternal pain relief with preservation of maternal participation and fetal safety. Epidural anesthesia remains the gold standard for labor analgesia. However, commonly used local anesthetics and opioid adjuvants are associated with adverse effects that include nausea, pruritus, urinary retention, and prolonged labor. Dexmedetomidine, a highly selective α₂ agonist, does not carry the same risks for misuse and abuse as opioids do and may be a promising non-opioid adjuvant for epidural labor analgesia due to its analgesic, anxiolytic, and opioid-sparing properties. Furthermore, dexmedetomidine has unique pharmacodynamic effects, including preserving maternal consciousness while providing adequate analgesia. This combination of consciousness preservation and sufficient analgesia suggests dexmedetomidine may be a promising pharmaceutic for epidural anesthesia. In addition to preserving maternal consciousness, dexmedetomidine does not appear to cause a clinically significant increase in the motor blockade. Although epidural analgesia is known to prolong labor in nulliparous and multiparous patients, the use of dexmedetomidine as an epidural adjuvant does not have a significant effect on labor duration in available trials. Across studies, dexmedetomidine does not have deleterious outcomes for neonates, measured using the neonatal Apgar score. Although dexmedetomidine is not currently FDA-approved for epidural labor analgesia, existing evidence from available trials suggests its safety and efficacy as an opioid-sparing adjuvant. This narrative review aims to highlight the current state of knowledge of dexmedetomidine’s pharmacology, efficacy, analgesic ability, and side effects. Full article

Background: Opioid dependence treated with buprenorphine/naloxone is associated with increased cardiovascular risk; however, data regarding aortic elasticity and cardiac electrophysiological balance during long-term maintenance therapy remain limited. This study investigated aortic stiffness and distensibility in individuals receiving buprenorphine/naloxone (Suboxone), and examined their associations with echocardiographic and electrocardiographic parameters, including the index of cardiac electrophysiological balance (iCEB and iCEBc). Methods: A retrospective cohort analysis was conducted, including 130 intravenous opioid users receiving Suboxone and 150 age- and sex-matched healthy controls. All participants underwent clinical evaluation, transthoracic echocardiography, resting 12-lead electrocardiography, and 24-h ambulatory blood pressure monitoring. Results: Compared to controls, opioid users demonstrated significantly higher aortic distensibility (median 0.019 vs. 0.015, p < 0.001) and lower aortic stiffness (median 52.31 vs. 64.66, p < 0.001). Patients receiving Suboxone for more than 18 months exhibited higher diastolic blood pressure (p = 0.044), mean arterial pressure (p = 0.046), and pulmonary artery pressure (p = 0.022). Aortic elasticity indices showed strong correlations with blood pressure and echocardiographic parameters. In the overall cohort, Suboxone use duration was not significantly correlated with aortic stiffness or distensibility parameters, while a weak negative correlation was observed with ferritin levels (r = −0.231, p = 0.008). In subgroup analysis of long-term users (>18 months), a moderate positive correlation was observed between therapy duration and iCEB values (r = 0.367, p = 0.001). Conclusions: Chronic buprenorphine/naloxone therapy appears to be associated with changes in aortic elasticity, blood pressure, and mild electrophysiological alterations. These results support the use of non-invasive vascular and electrocardiographic evaluations for cardiovascular risk monitoring and stratification among patients receiving opioid maintenance therapy. Full article