Effective ropivacaine delivery using lipid nanoparticles enables simultaneous cancer therapy and pain control.

Pain affects 70-80% of patients with pancreatic adenocarcinoma and remains inadequately controlled in more than half of cases. Beyond its impact on quality of life, pain is now recognized as an independent prognostic factor, reflecting the unique neurobiological features of this malignancy. Perineural invasion drives a bidirectional dialogue between cancer cells and the peripheral nervous system, in which neurotrophic factors, neuropeptides, and immune mediators fuel both nociception and tumour progression. Current pain management relies on the WHO analgesic ladder supplemented by adjuvant agents (gabapentinoids, duloxetine, corticosteroids) and interventional procedures including celiac plexus neurolysis, intrathecal opioid delivery, and palliative radiotherapy. Recent advances, notably celiac plexus radiosurgery and evidence favouring early neurolysis, challenge the prevailing reactive approach. This review examines the pathophysiology of pancreatic cancer pain, critically appraises available treatments, identifies gaps in current evidence, and argues for a proactive, multimodal strategy initiated at diagnosis rather than reserved for refractory disease.

Metabolic-epigenetic regulation of TRPM3 via H3K18 lactylation in dorsal root ganglia mediates bone cancer pain and its attenuation by microwave ablation.

DEL-1 relieves bone cancer pain by targeting IL-17-triggered ferroptosis and astrocyte activation in the spinal cord.

Chronic pain syndromes represent amajor medical and socioeconomic burden. In both cancer-related and noncancer pain, pharmacological treatment alone is often insufficient or limited by adverse effects, particularly during long-term opioid therapy. Image-guided interventional procedures are therefore increasingly relevant as targeted, opioid-sparing components of multimodal pain management. This narrative review summarizes diagnostic blocks, therapeutic injections, and neurolytic procedures targeting sympathetic plexuses and peripheral nerves. It outlines the principal imaging modalities (computed tomography, fluoroscopy, ultrasound), common indications, and the distinction between diagnostic/prognostic, pharmacological, and definitive neurolytic techniques. Available evidence demonstrates clinically meaningful pain reduction, functional improvement, and opioid-sparing effects in selected indications. The strongest evidence exists for visceral cancer pain, particularly for celiac plexus and splanchnic nerve interventions, and for chronic musculoskeletal pain such as genicular nerve procedures. Image-guided nerve and plexus interventions are effective components of multimodal pain management and can be integrated into interdisciplinary care pathways. Their clinical value depends on careful patient selection, precise anatomical targeting, standardized procedural quality, and structured outcome assessment; they should be considered early rather than only as alast-line option.

To explore the feasibility and mechanism of CPBMP among patients with oral cancer in China. We conducted a mixed methods study that included a single-center, randomized controlled trial to determine the effect of CPBMP on pain in patients with oral cancer and a semistructured interview to explore the mechanism of action of CPBMP and factors influencing its implementation. A total of 76 individuals participated in the RCT. Patients were randomized to receive a standard recovery protocol (control group) or the CPBMP (intervention group). The outcomes included pain, pain catastrophizing, fear of pain, self-efficacy, and quality of life. Saliva samples of cortisol were collected from 12 randomly selected participants in each group. From the intervention arm, 10 participants were randomly selected for interviews in this study. The semistructured questions were analyzed using content analysis. There was a significant difference in pain intensity, fear of pain, pain catastrophizing, pain self-efficacy, and quality of life (all p < 0.001) between the intervention and control groups. There was a significant difference over time in pain intensity, fear of pain, pain catastrophizing, pain self-efficacy, and quality of life (all p < 0.05). The interaction effects were significant for pain intensity, fear of pain, pain catastrophizing, pain self-efficacy, and quality of life (all p < 0.001). There was a significant difference in the morning (p = 0.028) and at 17:00 (p = 0.036) salivary cortisol level between the experimental group and the control group within 24h before the beginning of radiotherapy. There was no significant difference in salivary cortisol slopes between the intervention and control groups (p > 0.05). The interview results included two parts: "psychological mechanism of CPBMP" and "implementation of CPBMP, situational factors, and feedback." The former extracted four themes: "effects of emotion regulation on pain," "changes in pain cognition," "impact of self-efficacy on pain," and "improvement of pain coping skills," and five subthemes. The latter extracted three themes: "implementation of CPBMP (acceptability)," "situational factors," and "feedback and improvement," and eight subthemes. The CPBMP showed a positive effect on promoting patients' pain intensity, fear of pain, pain catastrophizing, pain self-efficacy, and quality of life, which effect is affected by individual characteristics. And CPBMP improves pain-related outcomes through psychological adjustment and regulation of HPA axis activity.

To determine the prevalence and pattern of endocrinopathy in patients with cancer pain receiving long-term opioid therapy and evaluate the associated temporal hormonal changes. This prospective, hospital-based observational study was conducted in a tertiary care centre in India and included 175 patients with histologically confirmed cancer (≥18 years) receiving oral daily morphine of ≥25 mg for at least 3 months. Serum levels of testosterone, thyroid-stimulating hormone (TSH), thyroxine, adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinising hormone (LH), growth hormone (GH), estradiol and prolactin were assessed at baseline and week 12. Data were analysed using repeated-measures analysis of variance with Bonferroni post hoc correction. Most participants were middle-aged males (mean age, 46.96±9.30 years) with advanced-stage cancer (64.6%). Significant hormonal alterations were observed over the 12-week period (p<0.001). Mean testosterone levels decreased from 2.49±1.76 ng/mL at baseline to 2.01±1.42 ng/mL at week 12, T4 declined from 1.30 ± 0.24 to 1.05 ± 0.19 pg/mL, ACTH from 31.41 ± 18.58 to 25.36 ± 15.01 pg/mL and prolactin rose from 11.06 ± 4.22 to 13.35 ± 5.10 ng/mL. Similar downward trends were noted for FSH, LH, GH and estradiol, whereas TSH increased from 2.12 ± 1.09 to 2.57 ± 1.32 µIU/mL. Chronic opioid therapy is associated with substantial suppression of gonadal, adrenal and thyroid axes and elevation of prolactin levels, consistent with opioid-induced endocrinopathy. Regular endocrinological assessment should be integrated into palliative care to improve quality of life in patients with cancer receiving long-term opioid therapy.

Bridging the pain gaps: Opioid access for cancer pain in rural Nepal and the untapped role of pharmacists.

Pain is a common symptom for children and adolescents with treatment-refractory cancers at the end of life (EoL). Palliative radiotherapy (RT) is a noninvasive, outpatient therapy with an acceptable safety profile that helps to mitigate physical pain. It has been proven as an essential treatment modality for symptom control at EoL in the adult population. While the efficacy of palliative RT is well-established in adults, evidence in the pediatric population remains limited. This systematic review aimed to identify and evaluate the current evidence on palliative RT for the treatment of cancer pain in children and adolescents. Five databases were searched for pediatric empirical quantitative studies. Inclusion criteria include children and adolescents aged ≤21 years old with terminal cancer who received palliative RT for pain relief, single- or multicenter studies with ≥10 cases published in English. The primary outcome was pain control postpalliative RT, and secondary outcomes included reduction in opioid usage. Seven observational retrospective studies (n = 63 patients/235 metastatic sites/139 palliative RT courses), published between 2003 and 2024, were included. Palliative RT was associated with a 77.9% (95% confidence interval [CI] 71.2-84.6, p = 0.4) reduction in pain when used as an adjuvant therapy across all seven studies. A reduction in opioid use was observed in 43.2% (95% CI 31.8-54.7, p = 0.4) across two studies (n = 52 patients/17 palliative RT courses). These were not statistically significant results. The subgroup analysis showed that it was associated with 80.0% (95% CI 69.9-90.1, p = 0.9) reduction of pain in patients with bony lesions across two studies (n = 19 metastatic sites/41 courses). While our meta-analysis does not provide sufficient evidence to show that palliative RT reduced pain in children and adolescents with terminal cancer, it adds to the growing body of evidence supporting integrated approaches to symptom control in pediatric oncology. Further research is needed to substantiate its clinical benefits in augmenting and facilitating optimal EoL care in children and adolescents with advanced malignancies.

The use of opioids has expanded significantly worldwide in patients with cancer-related pain. Therefore, opioid-induced constipation (OIC) is emerging as one of the most frequent and distressing gastrointestinal side effects. Despite the high prevalence, OIC is frequently underdiagnosed and inadequately managed, with critical effects on the quality of life of patients. The present study assessed the real-life prevalence of opioid use and OIC in 316 consecutive cancer patients hospitalized in an Internal Medicine ward and evaluated the outcomes following PEG or naldemedine during hospitalization. When OIC was diagnosed (Rome IV criteria), all patients underwent polyethylene glycol (PEG). Naldemedine was subsequently administered in refractory OIC. A total of 82 patients (26% of admissions) were assuming opioids for cancer pain, with constipation diagnosed in 62% and 24% of patients with or without opioid treatment, respectively. The risk of OIC was higher during combined opioids than in monotherapy, and fentanyl was associated with the highest OIC prevalence. Among patients with OIC, 47% responded to polyethylene glycol (PEG), whereas 52.9% started naldemedine 200 micrograms/day for a refractory OIC, with subsequent improvement in 59.3% of cases. The prevalence of opioid use and OIC is relevant among hospitalized cancer patients. The systematic adoption of standardized diagnostic tools can improve recognition and the clinical management in patients with OIC, in particular in case of refractory OIC. It is essential to increase awareness on this condition and to implement management pathways based on existing guidelines.

To evaluate the efficacy and safety of a structured measurement-based care (MBC) strategy with a "Monitor-Assess-Adjust" closed-loop protocol for managing moderate-to-severe cancer pain in patients receiving intrathecal morphine patient-controlled analgesia (IT-PCA). A retrospective observational study was conducted at two pain centers, enrolling 15 patients with cancer pain (Visual Analog Scale [VAS] ≥ 7). All patients initially received intravenous patient-controlled analgesia (IV-PCA) for dose titration, followed by IT-PCA implantation. A structured MBC protocol was implemented, including three core components: (1) Multidimensional assessment: regular evaluations using the VAS, Brief Pain Inventory (BPI), and leeds assessment of neuropathic symptoms and signs (LANSS) scale; (2) Dynamic individualized titration: a standardized dosing algorithm based on pain reassessment every 15min during IT-PCA initiation, with adjustments as follows: 50-100% dose increase for unchanged/elevated VAS, 50% increase for VAS 4-6, and dose maintenance for VAS 1-3 (target: VAS < 4); (3) Systematic follow-up: assessments at baseline, post-IV-PCA, post-IT-PCA, discharge, and 1, 3, 6 months after discharge. After IT-PCA under the MBC protocol, the mean VAS score decreased significantly from 8.28 ± 0.76 at baseline to 2.14 ± 0.90, representing a 76.4% pain reduction (P < 0.05), and this effect was sustained throughout follow-up. Pain relief and quality of life (BPI scores) were significantly improved compared with baseline and post-IV-PCA stages (P < 0.01). Notably, the incidence of opioid-related adverse reactions was extremely low: only 1 patient (6.7%) experienced mild, manageable constipation, with no cases of nausea, vomiting, or respiratory depression. Implementing IT-PCA within an MBC framework enables effective, individualized analgesia, sustains long-term pain relief, and optimizes the therapeutic benefit-risk profile by minimizing adverse effects, thus improving the quality of life in cancer pain patients. This study provides evidence for a data-driven, precision medicine approach to intrathecal analgesia management.

The use of medicinal products derived from cannabis and its synthetic analogues has grown in recent years for various health conditions, which led to an increase in systematic reviews (SR) on the topic. The objective of this overview was to identify, synthesize, and critically appraise the evidence from SR on the benefits and harms of cannabis derivatives when used for therapeutic purposes in different health conditions. A comprehensive search was conducted to identify all relevant SR in Embase, Epistemonikos, MEDLINE, and Cochrane Database of Systematic Reviews. The inclusion criteria was SR assessing the effects of cannabis and its derivatives for any clinical condition that included only randomized controlled trials. A structured selection and extraction process was performed by two independent researchers. The methodological quality of the included SR was assessed using AMSTAR-2. This overview included 102 SR, 68.6% of which were of critically low quality and 17.6% were of high quality. There is low to moderate certainty of evidence of benefits from these interventions for ulcerative colitis, chronic non-cancer pain, Crohn's disease, multiple sclerosis, and post-chemotherapy nausea and vomiting. The results point to a lack of benefits for sleep disorders, chronic cancer pain refractory to opioids, pain related to radiotherapy, and pain in people receiving palliative care. For other conditions, the certainty of the evidence was very low or not assessed. This overview opens a broad and complex field for the development of primary studies to evaluate the effects of cannabinoids as primary or adjunctive therapy for different health conditions and reinforces the importance of safety assessment. Decision-makers and guideline developers can be guided by the results summarized in this overview. However, when making formal recommendations, it is essential to consider the quality of the SR and the certainty of the evidence identified for each outcome.

Tetrodotoxin (TTX) is a potent neurotoxin with therapeutic potential, particularly in the fields of analgesia, cancer pain treatment, and drug addiction therapy. However, its high toxicity and lack of antidotes limit its clinical application. This study evaluated the acute toxicity and sub-acute toxicity of TTX via intramuscular injection in Sprague-Dawley (SD) rats. The acute toxicity test employed the Bliss method to determine the median lethal dose (LD50), with 10 rats per group (sex-balanced). Rats received a single intramuscular injection at doses of 8.2-20.0μg/kg. The sub-acute toxicity study was conducted through daily intramuscular injections at doses of 1.5, 3.0, and 6.0μg/kg/day for 28 consecutive days. Parameters, including body weight, food consumption, hematology, serum biochemistry, urinalysis, and histopathology, were assessed. Acute toxicity was characterized by squinting, reduced spontaneous activity, convulsions, hind limb rigidity, limb weakness, and mortality. In the sub-acute toxicity study, no toxicity-related changes associated with TTX treatment were observed in any dose group compared to controls, including in food consumption, hematology, urinalysis, and histopathological examination. Although statistically significant differences in body weight, serum biochemical, and organ weights were noted at certain time points in individual dose groups, these were not dose-dependent and were of minimal magnitude. The LD50 of TTX administered via a single intramuscular injection in SD rats was 13.1μg/kg. In the sub-acute toxicity study, no adverse effects were observed up to the highest tested dose (6.0μg/kg/day), which was therefore considered the no observed adverse effect level (NOAEL) under the conditions.

Lysine lactylation (Kla) is a lactate-derived post-translational modification that has emerged as a critical metabolic-epigenetic regulator linking cellular metabolic states to innate immune signaling. The cGAS-STING pathway, a central cytosolic DNA-sensing mechanism essential for antiviral defense, antitumor immunity, and inflammatory regulation, is profoundly influenced by the metabolic milieu. However, the precise role of lactylation in modulating this pathway remains to be systematically synthesized. This review aims to comprehensively analyze the molecular mechanisms by which lysine lactylation regulates the cGAS-STING signaling axis, and to discuss the pathophysiological implications and therapeutic potential of targeting this modification in diseases ranging from autoimmunity and neuroinflammation to cancer. A comprehensive review of the relevant literature was conducted to summarize the biochemical basis of lactylation (including writers, erasers, and readers) and to systematically examine emerging evidence demonstrating direct and indirect regulation of cGAS-STING components by lactylation. Studies involving site-specific modifications, disease models, and therapeutic interventions were collated and analyzed. Lactylation directly targets core pathway components-cGAS at residues such as K21, K131, K156, K162, K275, and K409, and STING-altering their stability, enzymatic activity, DNA-binding capacity, phase separation, and downstream signaling outputs. Depending on context, lactylation exerts dual effects: it stabilizes cGAS and amplifies type I interferon responses in autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis) and hypoxic-ischemic encephalopathy, but promotes cGAS degradation or suppresses STING activity in cancer (lung adenocarcinoma, glioblastoma) and neuropathic pain, thereby facilitating immune evasion or pain sensitization. Indirectly, lactylation modulates cytosolic DNA ligand availability by influencing mitochondrial DNA release (via HMGB1, VDAC1, Arg1, DRP1) or DNA repair (via KU70). The discovery of specific lactyltransferases (AARS1/2, p300) and delactylases (SIRT1-3, HDAC1-3) establishes lactylation as a dynamic, enzymatically controlled process. Lactylation functions as a pivotal metabolic-immune checkpoint that fine-tunes cGAS-STING signaling in a cell-type- and disease-specific manner. Targeting the lactylation regulatory axis-by inhibiting pathogenic lactylation to restore anti-tumor immunity or enhancing it to dampen deleterious inflammation-offers a novel immunometabolic therapeutic strategy for autoimmune disorders, chronic infections, neurodegeneration, and cancer.

The central sensitization mechanism of bone cancer pain is related to neuroinflammation, glial cell activation, and an acidic environment. Among them, the NLRP3 inflammasome is involved in the occurrence of bone cancer pain. Studies have shown that an intrathecal injection of bone marrow mesenchymal stem cells (BMSCs) alleviates bone cancer pain by inhibiting microglial cell activation. Upon inflammatory stimulation, BMSCs produce increased levels of Tumor necrosis factor-α-stimulated gene 6 (TSG-6), which regulates intercellular signaling and inflammatory responses; however, whether the secretion of TSG-6 from BMSCs inhibits NLRP3-mediated microglial pyroptosis to alleviate bone cancer pain is unknown. Therefore, this study aimed to evaluate the analgesic effect of TSG-6 released by BMSCs on bone cancer pain (BCP) and explore its potential mechanisms through in vitro and in vivo experiments. In vivo, Walker 256 breast cancer cells were injected into the bone marrow cavity of the left tibia of rats to establish a BCP model. On days 7 and 14 after surgery, intrathecal injections of BMSCs or exogenous recombinant TSG-6 were administered, and the analgesic effects were observed at 2, 4, 8, 24, and 48h after administration. Spinal cord tissues were collected for Western blotting and immunofluorescence staining to assess the activation of the NLRP3 signaling pathway. In vitro, BV2 microglia were cocultured with BMSCs or recombinant TSG-6, and the same detection methods were performed to evaluate changes in the levels of proteins involved in the NLRP3 signaling pathway. BMSCs transfected with TSG-6-targeting shRNA were intrathecally injected in vivo or cocultured with microglia in vitro to investigate whether TSG-6 is involved in the inhibition of microglial pyroptosis and the inflammatory response mediated by BMSCs to alleviate BCP. BMSC transplantation or treatment with exogenous recombinant TSG-6 significantly improved BCP-related behaviors, inhibited the expression of key proteins in the NLRP3 signaling pathway in spinal dorsal horn microglia in rats, and reduced the release of inflammatory factors. Experiments revealed that coculturing BMSCs with BV2 microglia or treating BV2 cells with exogenous recombinant TSG-6 inhibited the LPS-induced activation of NLRP3 in BV2 cells and regulated microglial pyroptosis. Transfection of BMSCs with TSG-6-targeting shRNA significantly weakened the inhibitory effect on microglial pyroptosis. In vivo and in vitro experiments revealed that bone marrow mesenchymal stem cells inhibit the NLRP3 signaling pathway to regulate the pyroptosis of microglia through the secretion of TSG-6, thereby alleviating bone cancer pain.

Tumor neuron hijack is a malignant adaptive program whereby tumor cells recruit, physically engage and functionally reprogram the peripheral and central nervous system within the local microenvironment and host macroenvironment; this process not only exploits neuro-immune regulatory machineries, neural endocrine signaling, and nutrient supply for sustaining tumor growth, invasion, metastasis, immune escape and treatment resistance, but also closely involves the induction and amplification of cancer-associated pain, a common and debilitating manifestation of the host's pathological response to tumor-neural crosstalk, which further perturbs the host macroenvironment and facilitates tumor progression. Neoplastic cells employ context-dependent strategies: central nervous system tumors (e.g., gliomas) integrate into existing neuronal circuits via synaptogenesis and metabolic coupling, while peripheral solid tumors induce de novo innervation via neurotrophic factors, axon guidance cues regulating angiogenesis, and perineural invasion. Sympathetic, parasympathetic, and sensory nerves modulate tumor behavior via neurotransmitters or neuropeptides, with autonomic nerves also regulating endocrine glands to reprogram tumor metabolism. Pivotal to this regulation is the tripartite crosstalk among nerves, immune cells, and tumor cells, which establishes an immunosuppressive tumor microenvironment and drives progression from immune equilibrium to escape. These mechanisms have spurred therapeutic avenues such as neurotrophic agent repurposing, synaptic blockade, and neural-signal reprogramming, particularly in combination with immunotherapy, with promising preclinical and translational potential for precision oncology and cancer pain management.

Injectable opioid use in home palliative care requires multiprofessional coordination, but regional implementation data are limited. We conducted a pilot survey to describe experience, task sharing, difficulties, and future willingness. We performed an anonymous web-based cross-sectional survey of multidisciplinary professionals involved in community-based palliative care in a Japanese regional health care area. Among 159 respondents, 117 (73.6%) had prior opioid experience for cancer pain, and 73/117 (62.4%) had prior injectable opioid experience. Initiation was mainly attributed to hospital physicians, maintenance dose management to hospital and clinic/home care physicians, and solution or cassette exchange to nurses. Difficulties when starting or modifying injectable opioids were reported by 27/73 respondents (37.0%). Future willingness was higher with prior experience (41/72, 56.9%) than without prior experience (7/83, 8.4%). This pilot survey suggests that home injectable opioid practice is a multidisciplinary workflow with an experience-related readiness gap, supporting broader regional evaluation and implementation-focused support.

Objectives: To evaluate the clinical impact and treatment adaptations during the immediate-release oxycodone hydrochloride shortage. Methods: This retrospective, observational study was conducted during the oxycodone shortage period (May 2024-March 2025) in patients with cancer pain. Pain intensity was assessed using the Numerical Rating Scale (NRS) at baseline (prior to switching, while receiving oxycodone) and at follow-up (after switching to alternative analgesics). Changes in pain intensity were evaluated using within-patient differences (ΔNRS), with clinically meaningful worsening defined as an increase of ≥2 points. Descriptive and inferential statistics were used to summarize patient characteristics and outcomes. Results: Of 300 patients screened, 55 met inclusion criteria (mean age 65.2 ± 11.0 years; 63.6% male). Pain intensity increased significantly following treatment modification during the period of oxycodone unavailability, with mean NRS scores rising from 4.3 ± 1.7 to 5.9 ± 2.5 (p < 0.001). The mean ΔNRS was +1.56 (95% CI 0.79-2.34), with clinically meaningful worsening observed in 36 patients (65.5%). No statistically significant association was observed between substitute analgesic type and clinically meaningful worsening (p = 0.11). Conclusions: The oxycodone shortage was associated with worsened pain control and increased need for treatment modifications in cancer patients, highlighting the importance of uninterrupted access to essential opioids.

The bidirectional crosstalk between the nervous system and tumors has emerged as a transformative new frontier in both precision oncotherapy and mechanism-driven cancer pain management. Marine natural products with inherent neuroactive properties exhibit unparalleled intervention advantages for targeting this complex pathophysiological axis. Herein, we systematically and prospectively dissect the multi-layered bidirectional communication between the nervous system and malignancies, comprehensively summarize the pivotal contributions of marine-derived bioactive molecules to advances in neuroscience and antitumor therapeutics, and finally provide an outlook on and a call for integrated, interdisciplinary collaboration to enable transformative breakthroughs in the development of marine neuropharmacological agents targeting the nerve-tumor crosstalk axis.

Targeting Circadian Rhythm to Treat Cancer Pain.