morphine (Intramorph / Duramorph / Epimorph)

Zonisamide attenuates morphine tolerance in association with reduced spinal TLR4/p38 MAPK signaling.

Gei Li-Ba LB, Liu Ying-Hua YH, Guo Hong H, Zhao Xin X et al.

Morphine tolerance limits its long-term clinical utility, and neuroinflammation is a key underlying mechanism. This study investigated whether zonisamide, an antiepileptic drug with anti-inflammatory properties, attenuates morphine-induced neuroinflammation and morphine tolerance. In vitro, BV-2 microglial cells were treated with morphine (200 μM) with or without zonisamide (10 μM). Quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA), and Western blot analysis were used to assess inflammatory mediators and signaling pathways. In vivo, male C57BL/6 mice received repeated morphine injections (10 mg/kg, s.c., twice daily) for 9 days to induce tolerance, with or without zonisamide (30 mg/kg, i.p.). Behavioral tests (hot plate and tail flick) were performed to evaluate analgesic tolerance. Immunofluorescence was performed to assess microglial activation (Iba1), and Western blot analyses were conducted to evaluate TLR4 expression, p38 phosphorylation, and pro-inflammatory cytokine protein levels. Pharmacological inhibition of TLR4 with TAK-242 was used to verify the involvement of TLR4 signaling. In vitro, zonisamide suppressed morphine-induced upregulation of interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and Toll-like receptor 4 (TLR4) mRNA, reduced morphine-induced secretion of IL-1β, IL-6, and TNF-α at the protein level, and inhibited morphine-induced p38 mitogen-activated protein kinase (MAPK) phosphorylation. In vivo, zonisamide did not affect acute morphine analgesia but significantly attenuated the development of chronic morphine tolerance. Spinal cord analyses revealed that zonisamide reduced microglial activation (Iba1), TLR4 expression, p38 phosphorylation, and pro-inflammatory cytokine (IL-1β, TNF-α) protein levels. Pharmacological inhibition of TLR4 with TAK-242 produced a behavioral effect similar to that of zonisamide, and combined treatment did not provide additional benefit, suggesting overlapping signaling effects. These findings indicate that zonisamide attenuates morphine tolerance in association with reduced spinal TLR4/p38 MAPK signaling and neuroinflammation. This study provides a mechanistic rationale for repurposing zonisamide as an adjunct therapy to improve long-term pain management and mitigate opioid-related adverse effects.

Morphine versus hydromorphone pharmacokinetic vs. pharmacodynamic variabilities.

Meissner Konrad K, Olofsen Erik E, Dahan Albert A, Kharasch Evan D ED

Intraoperative Methadone for Postoperative Pain Control in Living Donor Hepatectomy.

Seibert Adam A, Puri Devika D, Whong Zachary Z, Kim Beomchang B et al.

Postoperative pain control is often suboptimal, with many patients experiencing inadequate relief or side effects. Methadone, a long-acting μ-opioid agonist and NMDA antagonist, provides stable analgesia and reduces postoperative opioid requirements when administered as a single intraoperative dose. However, its use has not been studied in living donor hepatectomy patients. We conducted a retrospective review of a quality improvement initiative involving 50 living donor hepatectomy patients treated from 2023 to 2025. 32 received usual opioid care and 18 received methadone, stratified into high-dose (≥ 0.2 mg/kg lean body weight) and low-dose (< 0.2 mg/kg) groups. The primary outcome was postoperative morphine milligram equivalents (MMEs) consumed during the hospital stay. Secondary outcomes included intraoperative MME, total MME, ICU and hospital length of stay, bowel recovery, and safety events. Mean age was 39.4 years, 70% female and 72% white. Most patients (66%) underwent a minimally invasive, robotic surgical approach. Methadone was administered to 36%. Intraoperative opioid exposure was significantly higher in methadone groups compared with usual care (p < 0.0001), but postoperative opioid requirements did not increase. There was a trend toward lower postoperative morphine equivalents in patients receiving higher methadone doses (156.7 ± 152.8 vs. 260.4 ± 112.3, p = 0.09). No adverse events occurred; length of stay and bowel recovery were similar across groups. Intraoperative methadone administration in living donor hepatectomy appears safe and demonstrated a trend toward reduced postoperative MME use at higher doses of ≥ 0.2 mg/kg lean body weight. These findings warrant further prospective evaluation.

Correlative Spectroscopic and Structural Imaging for Resin-Embedded Extended-Release Morphine Sulfate Pellets.

Zaker Yeakub Y, Ahmed Snober S, Tian Li L, Yilmaz Huzeyfe H et al.

Correlative spectroscopic and structural imaging provides a powerful approach for characterizing the microstructure of complex pharmaceutical formulations. Laser direct infrared (LDIR) spectroscopy is an emerging, rapid spectroscopic imaging technique that complements traditional approaches by enabling non-destructive chemical and morphological analysis over large sample surfaces within minutes. In this study, the capabilities of LDIR imaging were evaluated alongside Raman mapping, SEM-EDS, laser microscopy, and micro-CT as part of a correlative workflow to characterize the microstructure and chemical composition of pharmaceutical pellets. Resin embedding enabled consistent handling and structural preservation of extended-release pharmaceutical pellets across all imaging modalities. Two commercially available morphine sulfate ER pellets (ER-1 and ER-2) with different excipient compositions were used as model systems. Laser microscopy revealed distinct differences in surface topography, while micro-CT performed before milling confirmed inherent structural features. ER-1 displayed a smooth, intact core, whereas ER-2 exhibited internal cracks and cavities. Hyperspectral LDIR imaging successfully identified major components in both formulations (hit-quality index, HQI ≥ 0.83) with strong concordance to Raman mapping (HQI ≥ 0.85). The spatial distribution of the active pharmaceutical ingredient (API) revealed a layered structure in ER-1 and a homogeneous core in ER-2. This correlative workflow, combining resin embedding with multiple imaging modalities, underscores the value of LDIR and complementary techniques for comprehensive physicochemical characterization of complex drug products. These findings highlight the utility of correlative imaging for regulatory assessment and quality control of complex extended-release formulations.