Search Results (103)

Introduction: During pharmaceutical care, community pharmacists play a crucial role by carrying out interventions aimed at preventing, detecting, and resolving drug-related problems (DRPs) and negative outcomes associated with medication (NOM), simultaneously enhancing patients’ knowledge about their treatments. The chronic use of Benzodiazepines (BZDs) is known to be associated with risks such as tolerance, dependence, and cognitive impairment. Furthermore, the combined use of BZDs with other medications or alcohol may expose patients to significant drug interactions. Objectives: This study aimed to characterize and describe the clinical profile of patients using BZDs, to evaluate the extent of polypharmacy and potential drug interactions, to investigate their level of knowledge regarding BZD treatment, and ultimately, to propose evidence-based interventions from the community pharmacy to contribute to improving patient safety and minimizing risks associated with BZD use. Method: A cross-sectional, descriptive study was conducted in a single community pharmacy in Gran Canaria (Canary Islands, Spain). The study population comprised 125 adult patients with active BZD prescriptions. Data collection was performed through pharmacist–patient structured interviews using a questionnaire that included sociodemographic, clinical, and BZD knowledge variables. Results: Lormetazepam and alprazolam were the BZDs most frequently prescribed and dispensed. Potential drug interactions with other medications were detected in 38.4% of BZD users. Notably, 61.5% of patients using BZDs also reported the concurrent use of opioid analgesics, with tramadol being the most common opioid (48.1% of BZD users were also treated with tramadol). Statistically significant differences were observed between patients with and without BZD and other drug interactions in several adverse outcome variables, including the risk of falls (p = 0.003), cognitive impairment (p = 0.047), and urinary incontinence (p = 0.016). Existing BZD dependence is detected in 25% and 22.1% of cases, respectively. Patients’ knowledge of their BZD treatment revealed critical gaps, which are identified as a challenge and a clear opportunity for intervention through pharmaceutical care services. Conclusions: The findings underscore the essential and proactive role of community pharmacists in identifying and managing drug interactions, as well as in supporting deprescribing strategies through collaborative and interprofessional care models. Full article

Background/Objectives: Lumbar degenerative disease drives numerous elective spine surgeries, and anesthetic choice significantly influences airway risk, hemodynamics, analgesia, mobilization, and recovery. Interest in awake lumbar surgery, typically using spinal anesthesia (SA) with light sedation, has grown as comparative studies suggest comparable safety to general anesthesia (GA) with potential reductions in opioid use, nausea, time to ambulation, and efficiency metrics. However, these benefits may be context-dependent under standardized perioperative care. Therefore, the aim of this umbrella review is to synthesize previously published meta-analyses that compare postoperative outcomes between SA and GA in patients undergoing lumbar spine surgery. Methods: A systematic literature search was executed with defined criteria across PubMed, Embase, and Web of Science. Data analysis was performed using the metaumbrella R package to report equivalent Hedges’ g values. Each meta-analysis was evaluated with the AMSTAR2 tool, and the credibility of the evidence was determined with Ioannidis criteria. Results: Seven meta-analyses were included. Pooled data showed that SA was associated with shorter operative time, reduced length of stay, and lower intraoperative blood loss, supported by class III credibility for operative time and length of stay and class IV for blood loss in the setting of high between study heterogeneity. SA was also associated with lower odds of postoperative nausea and vomiting and reduced postoperative analgesic requirements, both graded as class IV with prediction intervals that encompassed the null. Intraoperative hypotension and bradycardia did not differ significantly between SA and GA, and postoperative pain scores and overall complication rates were similarly neutral. Conclusions: This umbrella review identifies potential advantages of SA in lumbar spine surgery, including shorter operative time, reduced length of stay, lower intraoperative blood loss, and lower postoperative nausea and analgesic requirements, while finding no consistent differences in hemodynamic events or overall complications. These findings suggest SA as an alternative pathway to general anesthesia for selected lumbar procedures but highlight substantial heterogeneity and low-to-intermediate credibility for several endpoints, underscoring the need for additional high-quality, protocolized comparative studies to refine effect sizes and define optimal patient and procedural selection. Full article

Blarina paralytic peptides (BPPs), neurotoxins from shrew saliva that paralyze mealworms, share high sequence similarity with human synenkephalin [1–53] (hSYN), a peptide released from proenkephalin together with opioid peptides that mediate analgesic and antidepressant effects in the brain. Both synthetic BPP2 and hSYN induce a hyperpolarizing shift in the human T-type voltage-gated calcium channel (hCa_v3.2) at sub-micromolar concentrations, although only BPP2 causes paralysis in insects. To gain insight into the functions of these insectivorous animal-specific neurotoxins and the largely uncharacterized brain peptides, we investigated the structure prediction of BPPs and SYNs and their interactions with hCa_v3.2. AlphaFold 3 modeling complemented available cryo-EM data and accurately reproduced the overall channel architecture; however, this inactivated-state model proved unsuitable for predicting agonistic binding of BPPs and SYNs. In contrast, docking simulations using an activated-state hCa_v3.2 homology model revealed distinct ligand-dependent differences in binding energies, affinity, and conformational flexibility. Notably, the C-terminal tail of BPPs—particularly its variable length and flexibility—was identified as a key determinant for the interactions with the S4 voltage-sensing domain of the channel. These findings provide new insights into the evolutionary adaptation of venom peptides in mammals and into potential therapeutic strategies targeting neurological disorders. Full article

Pain management remains a major clinical challenge, as conventional opioids and local anesthetics suffer from short analgesic duration, systemic toxicity, and dependence risks. Advanced drug delivery systems, particularly hydrogels and liposomal bupivacaine, have emerged as promising solutions to address these limitations. Hydrogels, composed of cross-linked hydrophilic polymer networks, enable biocompatible, biodegradable, and sustained drug release, while liposomal bupivacaine encapsulates the anesthetic within lipid vesicles to prolong local analgesia and minimize systemic toxicity. The combination of these systems offers synergistic benefits, including extended drug retention, enhanced efficacy, and reduced opioid reliance. However, clinical translation remains constrained by formulation instability, high production costs, variable patient responses, and stringent regulatory requirements. This review provides a comprehensive overview of current advances in hydrogel and liposomal bupivacaine technologies, highlighting their clinical potential, ongoing challenges, and future directions toward safer, more effective, and personalized pain management strategies. Full article

The ongoing opioid epidemic in the United States highlights the need for novel analgesics with reduced risk of misuse, dependence, and adverse central nervous system effects. Suzetrigine (trade name Journavx), a first-in-class selective Nav1.8 (a sodium channel expressed in peripheral nociceptors) inhibitor, was approved by the FDA in early 2025 and marketed as the first non-opioid analgesic in over two decades. Current studies have shown that suzetrigine has potential in treating acute pain perioperatively for minimally to moderately painful ambulatory procedures. However, suzetrigine appears less potent than hydrocodone-acetaminophen in this context, and it remains unclear how effective suzetrigine is in treating more severe postoperative pain. Notably, all current studies are limited to short durations of treatment; further studies will be required to delineate suzetrigine’s long-term efficacy, safety, and addiction potential to be utilized in the management of chronic pain patients. This article provides a review of the current literature available on the use of suzetrigine in treating acute pain. Full article

Objective: Morphine is a widely used analgesic for severe pain, but tolerance is a major challenge in long-term pain management. This study examined the potential of Daflon^® to enhance morphine’s pain-relieving effects and to reduce tolerance in a rat model with neuropathic pain induced by partial sciatic nerve transection (PSNT). Methods: Male Wistar rats were divided into five groups: (1) Sham + Saline, (2) PSNT + Saline, (3) PSNT + morphine, (4) PSNT + Daflon, and (5) PSNT + morphine + Daflon. Morphine tolerance was induced through continuous intrathecal infusion (15 µg/µL/h, i.t.) for 7 days, starting on day 7 post-PSNT, while Daflon was administered orally (50 mg/kg/day, oral) for 7 days. Pain relief was assessed using tail-flick and paw withdrawal on days 1, 4, and 7 after osmotic pump implantation. Spinal cords were collected for immunohistochemistry to analyze glial expression, and serum biomarkers (TNF-α, IL-1β, IL-6, and IL-10) were measured to evaluate neuroinflammation. Results: The results showed that oral Daflon significantly enhanced morphine’s analgesic effects, evidenced by improved pain thresholds in all behavioral tests. Moreover, Daflon reduced morphine tolerance. Mechanistically, Daflon upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and activated heme oxygenase-1 (HO-1), reducing oxidative stress and modulating neuroinflammation through glial regulation. Combining morphine and Daflon reduces pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and enhances anti-inflammatory IL-10 serum level, showing a synergistic effect in managing neuropathic pain with greater efficacy and lower drug dependence. Histology and immunohistochemistry evaluations further confirmed that morphine and Daflon co-treatment substantially reduced mononuclear cell infiltration, astrocyte activation (as indicated by GFAP expression), and microglial activation (as indicated by Iba-1 expression) compared to single treatment. Conclusions: Our findings suggest that dual therapy synergistically targets both oxidative stress and inflammatory pathways, leading to stronger neuroprotection and pain relief. Importantly, the combination approach may allow for lower opioid dosages, minimizing the risks of opioid-related side effects. Overall, morphine and Daflon co-administration offers a promising and safer strategy for managing neuropathic pain and preserving spinal cord integrity. Full article

The neuropeptide’s multifaceted involvement in various components of neural homeostasis impacts pain and behavioral regulation. One of the highly potent neuropeptides is dermorphin, extracted from the skin of the Amazon frog (Phyllomedusa sauvagei). The unique feature of dermorphin is the D-Ala residue in its sequence, which has inspired researchers to search for dermorphin analogs for use as pharmaceuticals. The primary objective of this study is to synthesize several new linear and cyclic dermorphin analogs and evaluate them as potential non-invasive analgesics. By exploring our method for converting linear peptides into 2,5-diketopiperazine(2,5-DKP) derivatives, which stabilize peptide structures, we synthesize several new dermorphin linear peptides and chimeric cyclopeptidomimetics. These compounds were tested in vitro and in vivo to determine their biological activities and potential applicability as pharmaceuticals. For the evaluation of in vitro opioid activity, the “Guinea Pig Ileum” (GPI) test was used. D2 showed the highest activity, and cyclopeptides D3 and D4 showed high activity. We can assume that dermorphin analogues D2, D3, and D4 are potent agonists of µ-type opioid receptors and have high opioid activity. However, this needs to be verified using molecular modeling methods in further research. The analgesic effects of dermorphins have been evaluated in the “Hot-Plate” and “Tail-Flick” tests. In rats, D2 dermorphin analogues demonstrated dose-dependent analgesic effect in the “Water Tail-Flick” test after intranasal administration. A smaller dose of 0.5 µg/kg resulted in 40% analgesia and a short-term state of stupor. The maximum long-lasting analgesia was observed at a dose of 1.0 µg/kg, which induced complete stupor. The analgesic effect of peptide D2 after intraperitoneal administration at a 5.0 mg/kg dose was over 50%. The “Open-Field” test demonstrated a dose-dependent (15, 50, 150 μg/kg) peptide D2 suppression effect on behavioural reactions in rats following intranasal administration. A new modification of linear peptides, combined with a 2,5-DKP scaffold (D3 and D4), proved promising for oral use based on the results of analgesic effect evaluation in mice following intragastric administration. Full article

Remifentanil is a potent opioid characterized by a unique pharmacokinetic profile that makes it well-suited for analgesia in obstetrics. When administered in a patient-controlled analgesia (PCA) modality, remifentanil has become a recognized and versatile alternative for labor pain relief in cases where epidural analgesia is contraindicated or is declined by the parturient. It offers mild to moderate pain relief, effectively decreasing pain from severe levels to a more manageable, moderate intensity. Remifentanil can be administered promptly and acts quickly, making it particularly useful in rapidly progressing or advanced labor. It can also benefit women with anxiety or tokophobia, as its sedative, anxiolytic, and euphoric effects help reduce pain perception and facilitate coping during labor. While it is not superior to epidural analgesia in terms of analgesic efficacy, remifentanil-PCA has obtained a role as a complementary pain-relieving option in several obstetric situations. Remifentanil-PCA is associated with high patient satisfaction, which is closely linked to realistic counseling and proper expectation management. The safety profile for both mother and neonate has been established; however, safety depends on cautious incremental dosing tailored to sedation levels, the use of supplemental oxygen, rigorous monitoring, and avoiding background infusion. Vigilant supervision by healthcare providers is essential, ideally supported by the continuous presence of an anesthesia team in the labor ward. Full article

Opioids are among the most effective drugs for treating moderate to severe pain. Unfortunately, opioid use, even short-term, can lead to addiction, tolerance, overdose, and respiratory depression. Therefore, efforts to design and develop novel compounds that would retain analgesic activity while reducing side effects continue unabated. The present study was designed to investigate the respiratory and cardiovascular effects of the hybrid peptide LENART01, which has evidenced potent antinociceptive and antimicrobial activity. This hybrid peptide, composed of N-terminally located dermorphin and C-terminal modified ranatensin pharmacophore, was tested in vivo in anesthetized rats. The main effect of LENART01 was apnea in 70% of examined animals, sighing, and a significant increase in blood pressure. Interestingly, the hybrid induced sighs less frequently than ranatensin, and apnea dependent on vagus nerve mu opioid receptor activation much less frequently and less intensely than dermorphin itself. This shows that LENART01 is a safer opioid system-related agent as compared to dermorphin for its prospective use in the treatment of pain. Full article

Neuropeptide FF (NPFF) receptor antagonists prevent morphine-mediated antinociceptive tolerance, and compounds with dual mu opioid receptor (MOR) agonist and NPFF antagonist activity produce antinociception without tolerance. Compounds synthesized showed affinities in radioligand competition binding assays in the nM and µM range at the opioid and NPFF receptors, respectively, and displayed substitution-dependent functional profiles in the [³⁵S]GTPγS functional assay. From six compounds screened in vivo for antinociception and ability to prevent NPFF-induced hyperalgesia in mouse warm water tail withdrawal tests, compound 22b produced dose-dependent MOR-mediated antinociception with an ED₅₀ value (and 95% confidence interval) of 6.88 (4.71–9.47) nmol, i.c.v., and also prevented NPFF-induced hyperalgesia. Meanwhile, 22b did not demonstrate the respiratory depression, hyperlocomotion, or impaired intestinal transit of morphine. Moreover, repeated treatment with 22b produced a 1.6-fold rightward shift in antinociceptive dose response, significantly less acute antinociceptive tolerance than morphine. Evaluated for microsomal stability in vitro and in vivo pharmacokinetic profile, 22b showed suitable microsomal stability paired in vivo with a large apparent volume of distribution and a clearance smaller than the hepatic flow in rats, suggesting no extra-hepatic metabolism. In conclusion, the present study confirms that dual-action opioid–NPFF ligands may offer therapeutic promise as analgesics with fewer liabilities of use. Full article

Background/Objectives: Sepsis remains one of the most serious and possibly fatal complications encountered in intensive care units. Considering the frequent use of narcotic analgesics in this setting, we investigated whether the cardiovascular and peripheral and central inflammatory features of sepsis could be modified by morphine. Methods: Rats were instrumented with femoral and intracisternal (i.c.) indwelling catheters and sepsis was induced by cecal ligation and puncture (CLP). Results: The i.v. administration of morphine (3 and 10 mg/kg) significantly and dose-dependently aggravated septic manifestations of hypotension and impaired cardiac autonomic activity, as reflected by the reductions in indices of heart rate variability (HRV). Cardiac contractility (dP/dtmax) was also reduced by morphine in septic rats. The morphine effects were mostly eliminated following (i) blockade of μ-opioid receptors by i.v. naloxone and (ii) inhibition of central PI3K, MAPK-ERK, MAPK-JNK, NADPH oxidase (NADPHox), or Rho-kinase (ROCK) by i.c. wortmannin, PD98059, SP600125, diphenyleneiodonium, and fasudil, respectively. Further, these pharmacologic interventions significantly reduced the heightened protein expression of toll-like receptor 4 (TLR4) and monocyte chemoattractant protein-1 (MCP1) in brainstem rostral ventrolateral medullary (RVLM), but not cardiac, tissues of CLP/morphine-treated rats. Conclusions: Morphine worsens cardiovascular and autonomic disturbances caused by sepsis through a mechanism mediated via μ-opioid receptors and upregulated central inflammatory, chemotactic, and oxidative signals. Clinical studies are warranted to re-affirm the adverse cardiovascular interaction between opioids and the septic challenge. Full article

Recently, an old drug, disulfiram, has been shown to reduce cocaine intake by inhibiting dopamine beta (β)-hydroxylase. Its effectiveness was also reported in opioid treatment, as disulfiram attenuated morphine-induced tolerance and dependence. A similar mechanism of action was evident in a selective inhibitor of DβH, nepicastat, particularly in the aspect of cocaine-seeking behavior. Hence, the objective of this study was to verify whether or not nepicastat reproduces disulfiram activity in pain reduction. Moreover, determination of its likely biological effects resulting from interactions with targets other than DβH has been given, in particular acetylcholinesterase. As was found, nepicastat was characterized by the absence of desired antinociceptive activity, though its co-administration with morphine resulted in a dose- and time-dependent enhancement of morphine-induced analgesic effect and attenuation of tolerance. Similarly, nepicastat was found to manifest antimicrobial potency against selected bacterial strains, although the effect was found to be weak. Intriguingly, this compound interacted with acetylcholinesterase through inhibition of its activity. These results clearly indicate nepicastat as a potent molecule that exhibits various biological effects. This, in turn, suggests its possible application in pathological conditions that still require effective treatment. Full article

Tramadol, a widely used analgesic, has recently been explored for its potential anti-cancer effects. However, the antitumor dosage of tramadol is over its current clinical application. Its primary metabolite, O-desmethyltramadol, has greater μ-opioid receptor affinity and stronger pharmacological activity. Hence, we sought to examine whether the cytotoxic effect of O-desmethyltramadol was better than tramadol on breast cancer cells. Our results showed that O-desmethyltramadol significantly reduced cell viability in breast cancer cells, with IC50 values of 64.2 μg/mL (MDA-MB-231) and 96.7 μg/mL (MCF-7), demonstrating over ten-fold greater potency than tramadol. The presence of a μ-opioid receptor antagonist Alvimopan did not alter the cytotoxic effects of tramadol and O-desmethyltramadol, indicating a non-opioid receptor-mediated mechanism. Compared with antitumor activity of tramadol mediated through ER stress, we confirmed that O-desmethyltramadol induced ER stress proteins, including the p-eIF2α/eIF2α ratio, ATF4, and CHOP. In MDA-MB-231 cells, O-desmethyltramadol treatment elevated mRNA expression levels of ATF4, CHAC1, and DDIT3 by approximately 2-fold. In MCF-7 cells, the induction was even more pronounced, with ATF4 increased 1.7-fold, CHAC1 12-fold, and DDIT3 9-fold. Beyond the opioid receptor-mediated pathway, we further analyzed the differential functions of O-desmethyltramadol than tramadol using the RNA-seq analysis. The pathway enrichment analyses revealed that O-desmethyltramadol influenced immune and inflammatory pathways, such as TNF and IL-6/JAK/STAT3 signaling in MDA-MB-231 cells, while in MCF-7 cells, it affected metabolic and transcriptional pathways, including mTOR and MAPK signaling. Gene Set Enrichment Analysis further highlighted O-desmethyltramadol’s role in interferon response and tumor microenvironment modulation. Four upregulated genes and five downregulated genes were modulated by O-desmethyltramadol in MDA-MB-231 and MCF-7 cells. Overall, our findings indicated that O-desmethyltramadol exerted potent anti-cancer effects through multiple non-opioid mechanisms, with distinct response from tramadol depending on breast cancer subtype. These findings not only highlight the therapeutic potential of O-desmethyltramadol as a novel adjunct in breast cancer treatment, but also emphasize the need for further investigation into its safety and clinical applicability in oncology. Full article

The adaptation of the body when exposed to a lower-than-usual temperature is a challenge that involves neuro-endocrine–immune mechanisms and affects the pharmacokinetics and/or pharmacodynamics of drugs taken before or after cold exposure. The experiments presented in this study clearly show differences in the analgesic effect of an exogenously introduced model substance (C-terminal fragment of calcium-binding protein, spermatid-specific 1) before and after cold exposure compared to its effect at an ambient temperature. The model substance used for the experiments is an octapeptide, TDIFELLK, which was synthesized via standard solid-phase peptide synthesis. Preliminary studies proved TDIFELLK’s analgesic activity. The ANOVA analysis performed showed statistically significant differences in the pain thresholds, measured by a paw pressure test, in 109 rats distributed among 14 groups and subjected to cold exposure according to different set-ups. Cold exposure immediately after TDIFELLK administration appears to enhance its analgesic effect, while cold exposure before administration reduces the effect. In some of the set-ups, antagonists of the most significant for analgesia receptors, i.e., opioid, cannabinoid, and serotonergic, were also introduced. The results showed that cold exposure had a modulating influence on the effect of the exogenously administered substances. The modulating effect was manifested differently depending on whether the intake occurred before or after cold exposure. The results also showed that the interaction with individual mediator systems was also subjected to differences depending on intake occurring before and after cold exposure. Full article

Laparoscopic surgery reduces tissue trauma and accelerates recovery, but postoperative pain remains a concern. Opioids are effective but have adverse effects, highlighting the need for multimodal analgesia. Nefopam, a non-opioid analgesic, provides pain relief without respiratory depression or dependence. This study aims to investigate the efficacy of intravenous nefopam combined with a transversus abdominis plane (TAP) block in living liver donors undergoing laparoscopic hepatectomy. This retrospective cohort analysis was conducted on 452 adult living donors who underwent laparoscopic hepatectomy with a TAP block between August 2013 and August 2018 at a single tertiary medical center. After propensity score matching, 296 patients were included, with 148 in the nefopam group and 148 in the non-nefopam group. The primary outcomes assessed were pain scores using the Numeric Rating Scale (NRS) at 1, 4, 8, 12, and 24 h postoperatively, opioid consumption, postoperative nausea and vomiting, and nefopam-related adverse effects. Nefopam significantly reduced NRS at 1, 4, and 8 h postoperatively (p < 0.001) and decreased fentanyl use in the post-anesthesia care unit (26.0 ± 32.2 μg vs. 60.5 ± 37.9 μg, p < 0.001) and total intravenous patient-controlled analgesia volume (p < 0.001). The incidence of postoperative nausea and vomiting and severe opioid-related complications did not differ between groups. Nefopam-related side effects were mild and self-limiting. Nefopam combined with a TAP block effectively reduces postoperative pain and opioid consumption in living liver donors, supporting its role in multimodal analgesia. Further research is needed to explore its broader applications. Full article