Intrathecal drug delivery (IDD) is an established therapy for patients with refractory pain across cancer and non-cancer populations. By enabling targeted spinal drug delivery, IDD can provide durable symptom control at substantially lower doses than systemic therapy, often reducing systemic medication burden and treatment-limiting adverse effects. Despite decades of clinical experience and supportive evidence, IDD remains underutilized and largely concentrated in high-volume centers, reflecting persistent uncertainty related to patient selection, trialing, device planning, long-term management, limited evidence, and complication mitigation.This practical guide synthesizes current evidence, consensus recommendations, and collective international clinical experience to provide a structured approach to short-term and long-term management of implantable IDD systems. Shared principles applicable across indications are emphasized, while cancer-specific considerations are addressed separately, including prognosis, coordination with oncologic therapies, evolving spinal anatomy, and compressed treatment horizons. Key topics include preimplant evaluation and risk mitigation, trialing strategies and their limitations, pump and catheter selection, perioperative management, early post-implant troubleshooting, long-term maintenance, and surveillance for device-related, biological, and operational complications. Intrathecal pharmacologic strategies for pain are examined, including opioids, local anesthetics, ziconotide, clonidine, and baclofen, with attention to indication-specific dosing, titration, and safety considerations.Clinical outcomes are framed beyond pain intensity alone, emphasizing functional improvement, quality of life, and reduction in systemic medication use as clinically meaningful endpoints. Differences in therapeutic goals, time horizons, and risk tolerance between cancer and non-cancer populations are integrated into a practical decision framework aligned with real-world pain practice. International and regional practice variations are also discussed to contextualize differences in drug availability, compounding practices, and reimbursement. By consolidating pragmatic guidance across the full lifecycle of intrathecal therapy, this guide aims to support consistent, safe, and effective use of IDD for complex pain management in contemporary practice.

Disulfide-rich peptide therapeutics often exhibit compact cystine knot-like architectures that endow them with high conformational rigidity, proteolytic stability, and target specificity. Yet their intrinsic polymorphism and structural heterogeneity are difficult to resolve with conventional analytical methods, which lack sufficient power to distinguish subtle structural variants within highly constrained peptide frameworks. Here, cyclic ion mobility-mass spectrometry (cIM-MS), combined with accelerated thermal stress testing, was applied to a manufacturing batch of ziconotide and linaclotide under native and thermally stressed conditions. Pronounced conformational heterogeneity was observed for both drugs even under native conditions. Upon thermal stress, notable degradation and structural reorganization occurred, revealing conformational changes that were not adequately captured by conventional methods. The high-resolution separation achieved by cIM-MS enabled detailed mapping of coexisting conformers and their stress-induced transitions. These results demonstrate that cIM-MS provides a spatially resolved analytical platform for interrogating higher-order structural heterogeneity in disulfide-rich peptide therapeutics, extending the capabilities of conventional mass spectrometry and offering a generalizable approach for structural characterization and quality assessment.

The clinical case of a young patient with intractable residual limb pain is presented. Following the initial administration of opioids and subsequent overuse, the patient was switched to intrathecal (IT) ziconotide infusion with complete opioid withdrawal. After 15 years of treatment with ziconotide infusion, the patient achieved sustained analgesic control and excellent functional recovery. IT ziconotide showed good long-term tolerability and safety.

N-type voltage-gated calcium channels (Cav2.2) are validated targets for chronic pain management. Although ziconotide is clinically effective, its use is hampered by a narrow therapeutic window and severe side effects. This review examines the subunit structure of Cav2.2 and its fundamental role in nociceptive signaling. We focus on emerging therapeutic strategies developed in recent years, including the optimization of direct blockade, the inhibition of channel trafficking, the modulation of signaling pathways, and targeted channel depletion. These advancements provide a deeper understanding of calcium channel regulation and identify promising targets for safer, more effective, and precision-based pain management.

Peptide therapeutics have emerged as a versatile class of biomolecules bridging the gap between small-molecule drugs and large biologics. Advantages of such molecules include high target specificity, potent bioactivity and reduced off-target toxicity. Despite these, broader clinical translation remains constrained by inherent limitations like poor metabolic stability, rapid renal clearance, limited membrane permeability and scalable synthesis. This review aims to systematically integrate advances in peptide science across natural discovery, synthetic methodologies, structural engineering, and translational delivery systems, while identifying critical research gaps hindering clinical adoption. We highlight diverse natural sources of bioactive peptides, including plant- (lunasin), animal- (Val-Pro-Pro (VPP) and Ile-Pro-Pro (IPP)), microbial- (nisin and cyclosporine), marine- (dolastatins) and venom-derived (chlorotoxin and ω-conotoxin MVIIA (ziconotide)) agents. Advances in solid-phase peptide synthesis (SPPS), green chemistry, and catalytic strategies are discussed alongside emerging in silico approaches, including artificial intelligence-driven sequence design and molecular modeling. Structural modifications such as cyclization, hydrocarbon stapling, PEGylation, and lipidation are critically evaluated for their role in enhancing pharmacokinetic and pharmacodynamic properties. Furthermore, nanoformulation strategies, including self-assembling peptides and cell-penetrating systems, are examined for their potential to overcome biological barriers. Importantly, this review identifies key unresolved challenges, including the lack of predictive models for peptide delivery systems, safety concerns associated with long-term modifications, and limited in vivo validation of naturally derived peptides. Addressing these gaps through integrated computational and experimental approaches will be essential for advancing next-generation peptide therapeutics. Collectively, this work provides a comprehensive framework for the rational design and translation of peptide-based precision medicines.

Conotoxins, isolated from the venom produced by marine snails of the Conus genus, are a range of bioactive, disulfide-rich peptides. However, their narrow therapeutic window and significant interindividual variability make the efficient and accurate detection of their concentration in biological fluids a "lifeline" for ensuring safe and effective clinical use. In this work, we employed α-conotoxin ImI (α-ImI) and ziconotide as model peptides. Inspired by the mechanisms through which these two peptides exert bioactivity, we fabricated and characterized porous polystyrene-based magnetic microspheres grafted with a terpolymer, poly (divinylbenzene-co-N-vinylpyrrolidone-co-vinylphosphonic acid), DVB-co-NVP-co-VPA, for the efficient capture of α-ImI and ziconotide from biofluid samples. The results implied that the modified DVB-co-NVP-co-VPA enhanced the selectivity and adsorption capability for α-ImI and ziconotide. The established method was characterized by good linearity (R[2] above 0.9993), acceptable sensitivity (LODs below 0.03 μg mL[-1]), high accuracy (recoveries ranging from 85.3% to 92.9%) and excellent repeatability (RSDs varied from 1.3% to 2.8%). Furthermore, the adsorbent maintained good reusability over six adsorption-desorption cycles, indicating its potential as an efficient candidate for pharmacokinetic studies of conotoxins.

Determining disulfide bridge connectivity in disulfide rich peptides presents significant analytical challenges, primarily due to the presence of isobaric species that cannot be distinguished by intact mass analysis alone. This study describes a targeted approach based on controlled partial reduction followed by cyanylation for the reliable assignment of disulfide linkages. The method was evaluated using representative approved cyclic peptide therapeutics, specifically Linaclotide, Plecanatide, and Ziconotide. These peptides were selected as model due to their clinical relevance, well-defined and diverse disulfide bond architectures, and their status as benchmark examples of disulfide-rich therapeutics. Partial reduction was optimized to generate mono-reduced intermediates, which were subsequently derivatized through cyanylation. This modification enabled selective cleavage at cysteine residues, producing structurally informative fragments after final reduction. These fragments were characterized using high-resolution mass spectrometry (HRMS), facilitating clear identification of disulfide connectivity. The proposed workflow demonstrates high reproducibility and analytical consistency, with excellent mass accuracy and enhanced structural resolution relative to conventional methodologies. Notably, it enables reliable differentiation of disulfide isomers that are otherwise indistinguishable using routine analytical techniques. Overall, this study establishes a practical and robust method for disulfide bond mapping in cyclic peptides, with broad applicability for structural characterization and quality assessment and don't require enzymatic digestion or specialized instrumentation.The methodology was successfully validated using Linaclotide, Plecanatide, and Ziconotide, which contain three, two, and three disulfide bridges, respectively.

Traditional analgesics, including Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and strong opioid analgesics, remain foundational in managing diverse pain conditions, especially chronic pain. However, their clinical utility is frequently hampered by inadequate efficacy and significant adverse effects, such as gastrointestinal complications from NSAIDs and addiction risks from opioids, prompting an urgent need for safer and more effective alternatives. Consequently, substantial efforts have been directed toward discovering more effective pain therapeutics through the development of novel administration routes, analgesic targets, and drugs, aiming to broaden options for pain management. Ion channel modulators have emerged as particularly promising candidates, leveraging the essential functions of ion channels in pain signaling pathways. Key channels involved include voltage-gated calcium (VGCCs), sodium (VGSCs), and potassium channels (VGKCs), alongside Transient Receptor Potentials (TRPs), nicotinic acetylcholine receptors (nAChRs), P2X receptors, and Acid-Sensing Ion Channels (ASICs). These channels regulate neuronal excitability, neurotransmitter release, and nociceptive transduction, making their modulation a strategic approach for pain intervention. This review comprehensively examines the clinical development landscape of ion channel modulators for pain relief. It systematically discusses each aforementioned channel class, including VGCCs, VGSCs, VGKCs, TRPs, nAChRs, P2X, and ASICs, highlighting breakthrough drugs (e.g., ziconotide for VGCCs) and summarizing recent advances in clinical trials for emerging candidates. By elucidating both the successes and challenges in translating ion channel-targeted therapies, this review underscores their potential to overcome the limitations of conventional analgesics. This study aims to inform future research directions and accelerate the development of optimized, mechanism-based pain therapeutics.

Marine organisms have proven to be excellent sources of bioactive natural products with potential therapeutic applications. To date, seventeen marine-derived molecules are on the market for the treatment of human diseases, mainly cancer. While multiple bioactivities of marine compounds have been consecutively reported, peptides represent promising candidates for these applications. This review focuses on peptides from marine organisms living in extreme marine environments, such as the deep ocean, polar regions, and tropical ecosystems. These are particularly promising for further bioprospecting, since their distinctive conditions have driven the evolution of unique biomolecules, as well as unique stability profile that can improve efficacy, shelf life, and performance under a wide range of industrial conditions. Ziconotide (Prialt), a neurotoxic peptide derived from the venom of a marine snail (Conus sp.) found at depths greater than 1000 m, is already commercially available for the treatment of severe pain. Recent technologies and computational tools are speeding up the discovery of new peptides and enzymes (very few from extreme environments). Overall, the review reports about eight peptides with anticancer properties from deep environments, nine, two and seven from polar habitats with antioxidants, anti-inflammatory and anticancer properties, respectively, and approximately ninety peptides from tropical waters (five antioxidant, thirty-five anti-inflammatory and fifty-four anticancer peptides). However, future studies in extreme environments will need to develop and apply sampling technologies, cultivation systems, as well as methods to assess efficacy, side effects and mechanisms of action, in vitro and in vivo.

Marine metabolites and sea-based biomaterials derived from diverse oceanic organisms have emerged as a rich source of bioactive compounds with significant therapeutic potential for human diseases. This review explores their applications in cardiovascular disorders, cancer therapy, neurodegenerative diseases, and metabolic syndromes, emphasizing their unique molecular architectures and underlying mechanisms of action. Importantly, several value-added marine-derived products are obtained from waste generated by fishing and aquaculture industries, reinforcing their relevance within a sustainable and circular bioeconomy framework. Representative case studies, including ziconotide for pain management and trabectedin for cancer treatment, highlight the successful translation of marine metabolites from discovery to clinical use. Despite their promise, challenges such as regulatory constraints, limited natural availability, and batch-to-batch variability associated with isolation-based production remain significant barriers. In this context, the integration of alternative synthetic and semi-synthetic approaches, alongside advances in biotechnology and chemical synthesis, offers viable strategies to enhance reproducibility, quality control, and scalability. Furthermore, emerging applications of marine-derived biomolecules in regenerative medicine and tissue engineering underscore their expanding therapeutic relevance. Looking ahead, the impact of climate change on marine biodiversity poses additional challenges to the availability and compositional consistency of marine resources, necessitating adaptive and sustainable sourcing strategies. Overall, this review underscores the critical importance of continued and responsible exploration of marine biodiversity to support innovative and effective therapeutic solutions for human health.

Ziconotide is a selective, potent, and reversible blocker of neuronal N-type voltage-gated calcium channels (VGCCs). Neuropeptide FF (NPFF) belongs to the opioid-modulating peptide family and plays a vital role in pain control through interactions with the opioid system. NPFF receptor agonists inhibit N-type VGCCs via G-protein coupling mechanism. This study focuses on whether intrathecal administration of NPFF influences ziconotide-induced antinociception. The effects of NPFF and related peptides on the antinociceptive activities of ziconotide were examined in male Kunming mice. Results showed that NPFF significantly enhanced ziconotid-induced analgesia in a dose-dependent manner in both the mouse tail-flick test and the visceral pain model. Additionally, treatment with the NPFF receptor selective antagonist RF9 markedly reduced the ziconotide-modulating effects of NPFF and related peptides in the pain models, whereas treatment with the opioid receptors antagonist naloxone had no effect. Co-administration of ziconotide with NPFF and related peptides from day 1 to day 8 produced insignificant differences in analgesic sensitivity, indicating that NPFF and related peptides did not induce tolerance to ziconotide following chronic co-treatment. These data provide the first in vivo evidence of a functional interaction between the NPFF system and N-type VGCCs, demonstrating that spinal NPFF receptor activation interferes with ziconotide-mediated antinociception. Thus, combining ziconotide with NPFF agonists may represent a valuable strategy for pain management.

Cone snails (Conus spp.) biosynthesize a highly specialized venom comprising a vast arsenal of neurotoxic peptides, termed conotoxins. These peptides exhibit exceptional structural and functional diversity, characterized by unique disulfide-bond architectures, highly variable amino acid sequences, and precise interactions with defined molecular targets. This review presents a comprehensive synthesis of current knowledge on conotoxin biology, beginning with evolutionary origin and proceeding through the classification systems used to define their gene superfamilies and pharmacological families. Advances in discovery methodologies are also examined, with particular emphasis on the transformative role of high-throughput multi-omics in expanding conotoxin identification and characterization. Furthermore, this review analyzes the pharmacological properties of representative conotoxins acting on key ion channels and receptors and evaluates the structure-activity relationships that determine their potency, selectivity, and functional profile. Mechanistic insights derived from these studies have established conotoxins as powerful neuropharmacological tools and a rich reservoir for drug discovery. Their significant therapeutic potential is underscored by efficacy in chronic pain management, exemplified by the US FDA-approved drug ziconotide, and by growing evidence supporting applications in neuroprotection in disorders such as Alzheimer's disease and Parkinson's disease, as well as in selected cardiovascular conditions. Future perspectives are also discussed, with progress likely dependent on the integration of computational design, peptide engineering, and bioengineering platforms to accelerate the translation of these marine peptides into next-generation clinical therapeutics.