Search

OBJECTIVE: Despite the wide use of ziconotide in the USA for treating refractory cancer- and noncancer-related pain, this agent is little used in Europe, even if licensed by the European Medicines Agency (EMA). The reason could be attributed to the high, fixed starting dose required for ziconotide, as stated in the EMA Summary of Product Characteristics (SmPC). This dosage recommendation is based on the results of pivotal clinical studies of ziconotide, which utilized aggressive titration schedules. Thus, a reappraisal of the available evidence, as well as a reflection on real-life clinical experiences, might be useful to identify practice adjustments to improve the clinical application of ziconotide in the European scenario. In line with this need, this paper reports some clinical experiences of patients with chronic pain treated with ziconotide intrathecal (IT) therapy in Italy, particularly focusing on long-term treatment to further characterize and improve the use of this agent in real practice. Moreover, a literature review of the available data on the effectiveness and safety of IT ziconotide is provided. CASE SERIES: Collected clinical experiences suggested that the use of IT ziconotide represents a valuable option, particularly in cases where other treatments have been ineffective or poorly tolerated. Ziconotide was shown to not cause severe side effects in the long-term treatment, leading to a constant pain relief effect at stable doses, without adverse events that caused therapy interruption. The overall constant ziconotide dosages also suggest the absence of a tolerance effect. In parallel, the evidence in the literature aligns with real-world evidence and further supports the use of IT ziconotide as an important option for the management of chronic pain. CONCLUSIONS: IT ziconotide represents a valuable addition to the armamentarium of pain management strategies, offering hope for improved quality of life for patients suffering from chronic, treatment-resistant pain. Continued research and clinical experience will further elucidate its optimal use and role in comprehensive pain care. [ABSTRACT FROM AUTHOR]

Background and Purpose: Neuropathic pain affects up to 10% of the global population and is caused by an injury or a disease affecting the somatosensory, peripheral, or central nervous system. NP is characterized by chronic, severe and opioid‐resistant properties. Therefore, its clinical management remains very challenging. The N‐type voltage‐gated calcium channel, Cav2.2, is a validated target for therapeutic intervention in chronic and neuropathic pain. The conotoxin ziconotide (Prialt®) is an FDA‐approved drug that blocks Cav2.2 channel but needs to be administered intrathecally. Thus, although being principally efficient, the required application route is very much in disfavour. Experimental Approach and Key Results: Here, we describe an orally available drug candidate, RD2, which competes with ziconotide binding to Cav2.2 at nanomolar concentrations and inhibits Cav2.2 almost completely reversible. Other voltage‐gated calcium channel subtypes, like Cav1.2 and Cav3.2, were affected by RD2 only at concentrations higher than 10 μM. Data from sciatic inflammatory neuritis rat model demonstrated the in vivo proof of concept, as low‐dose RD2 (5 mg·kg‐1) administered orally alleviated neuropathic pain compared with vehicle controls. High‐dose RD2 (50 mg·kg‐1) was necessary to reduce pain sensation in acute thermal response assessed by the tail flick test. Conclusions and Implications: Taken together, these results demonstrate that RD2 has antiallodynic properties. RD2 is orally available, which is the most convenient application form for patients and caregivers. The surprising and novel result from standard receptor screens opens the room for further optimization into new promising drug candidates, which address an unmet medical need. [ABSTRACT FROM AUTHOR]

Background: Ziconotide is an intrathecal drug administered for the treatment of chronic pain. The current literature lacks an exhaustive benefit/risk assessment on this drug. We herein focus on Ziconotide's pharmacology and clinical applications. Methods: Literature research was conducted to identify studies on Ziconotide administration for the treatment of chronic pain, published between January 1990 and March 2023 and located via PubMed, Embase, Medline, Cinahl, and Web of Science, using the following keywords: Ziconotide, Omega conotoxin, Prialt, SNX-111, intrathecal therapy, and neuropathic pain. Only publications written in English were selected. Results: Among the 86 selected studies, we found 4 Randomized Controlled Trials (RCTs) and 3 prospective long-term studies concerning the intrathecal use of Ziconotide as a monotherapy in chronic pain. Other studies described the intrathecal infusion of Ziconotide combined with other drugs. Overall, Ziconotide has been proved to have strong efficacy for relieving chronic pain, although patients with co-morbid psychiatric disorders require a careful monitoring when treated with Ziconotide. Conclusions: Overall, the use of Ziconotide, as a monotherapy or in conjunction with other therapies for the treatment of chronic pain, was reported to be efficacious. Overall, its use in patients with chronic pain refractory to other pharmacologic agents outweighs the possible adverse consequences, thus resulting in a favorable benefit/risk assessment. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NP) remains maltreated for a wide number of patients by the currently available treatments and little research has been done in finding new drugs for treating NP. Ziconotide (PrialtTM) had been developed as the new drug, which belongs to the class of ω-conotoxin MVIIA. It inhibits N-type calcium channels. Ziconotide is under the last phase of the clinical trial, a new non-narcotic drug for the management of NP. Synthetically it has shown the similarities with ω-conotoxin MVIIA, a constituent of poison found in fish hunting snails (Conus magus). Ziconotide acts by selectively blocking neural N-type voltage-sensitized Ca2+ channels (NVSCCs). Certain herbal drugs also have been studied but no clinical result is there and the study is only limited to preclinical data. This review emphasizes the N-type calcium channel inhibitors, and their mechanisms for blocking calcium channels with their remedial prospects for treating chronic NP.

Background: Ziconotide is an intrathecal drug administered for the treatment of chronic pain. The current literature lacks an exhaustive benefit/risk assessment on this drug. We herein focus on Ziconotide’s pharmacology and clinical applications. Methods: Literature research was conducted to identify studies on Ziconotide administration for the treatment of chronic pain, published between January 1990 and March 2023 and located via PubMed, Embase, Medline, Cinahl, and Web of Science, using the following keywords: Ziconotide, Omega conotoxin, Prialt, SNX-111, intrathecal therapy, and neuropathic pain. Only publications written in English were selected. Results: Among the 86 selected studies, we found 4 Randomized Controlled Trials (RCTs) and 3 prospective long-term studies concerning the intrathecal use of Ziconotide as a monotherapy in chronic pain. Other studies described the intrathecal infusion of Ziconotide combined with other drugs. Overall, Ziconotide has been proved to have strong efficacy for relieving chronic pain, although patients with co-morbid psychiatric disorders require a careful monitoring when treated with Ziconotide. Conclusions: Overall, the use of Ziconotide, as a monotherapy or in conjunction with other therapies for the treatment of chronic pain, was reported to be efficacious. Overall, its use in patients with chronic pain refractory to other pharmacologic agents outweighs the possible adverse consequences, thus resulting in a favorable benefit/risk assessment.

Targeted intrathecal drug delivery (TIDD) has the objective of bringing the drug(s) close to the receptors influencing pain modulation, and thus reducing the dose and the side effects. Intrathecal drug delivery knew its real start with the development of permanent implantation of intrathecal and epidural catheters, combined with internal or external ports, reservoirs, and programmable pumps. TIDD is a valuable treatment for patients with cancer suffering refractory pain. Patients suffering noncancer-related pain should only be considered for TIDD when all other options have been tested, including spinal cord stimulation. Only two drugs are approved by the US Food and Drug Administration for TIDD administration for chronic pain: morphine and ziconotide as monotherapy. In pain management, off-label use of medication and combination therapy is often reported. The specific action of the intrathecal drugs, the efficacy and safety, is described, as well as the modalities for trialing intrathecal drug delivery and the implantation methods. [ABSTRACT FROM AUTHOR]

Ziconotide is a non-opioid intrathecal drug considered, along with morphine, the first line of intrathecal treatment for cancer related chronic pain and non-oncological chronic pain. Even though it is a safe and effective drug, it is not exempt from adverse reactions. Among the most feared are those related to neuropsychiatric disorders such as anxiety, depression, or psychosis. We present the case of a 62-yearold man diagnosed with a chromophobe renal cell carcinoma with a neoplastic recurrence at the left lower back that causes nociceptive pain not controlled with systemic medication. An intrathecal pump containing morphine, ziconotide and bupivacaine was implanted. Afterwards, the patient began to manifest existential suffering and have thoughts of death. Suspecting that it could be an adverse effect of ziconotide, the infusion dose was reduced, achieving the disappearance of the neuropsychiatric symptoms with an optimal pain control. [ABSTRACT FROM AUTHOR]

A 60-year-old patient diagnosed with persistent pain after back surgery, with symptoms of severe lumbosciatic pain refractory to treatment. It was decided to place an intrathecal device with administration of morphine, presenting improvement. Later progressive increase in pain despite dose adjustment, so ziconotide is started with satisfactory results. After one year of treatment, he was admitted due to acute confusional syndrome, presuming an adverse effect of ziconotide, which is why it was terminated. During admission he presented desaturation and dyspnea. A computed tomography revealed condensation compatible with bilateral pneumonia plus catheter migration. It is treated with oxygen therapy and antibiotics. When faced with a patient under treatment with ziconotide who presents symptoms of confusion, we must rule out an adverse effect as a cause. However, we must always perform a differential diagnosis. In the case presented, it was probably secondary to pneumonia, since once resolved the patient presented clinical improvement. [ABSTRACT FROM AUTHOR]

Ziconotide (ZIC) is an N-type calcium channel antagonist for treating severe chronic pain that is intolerable, or responds poorly to the administration of other drugs, such as intrathecal morphine and systemic analgesics. As it can only work in the brain and cerebrospinal fluid, intrathecal injection is the only administration route for ZIC. In this study, borneol (BOR)-modified liposomes (LIPs) were fused with exosomes from mesenchymal stem cells (MSCs) and loaded with ZIC to prepare microneedles (MNs) to improve the efficiency of ZIC across the blood-brain barrier. To evaluate local analgesic effects of MNs, the sensitivity of behavioral pain to thermal and mechanical stimuli was tested in animal models of peripheral nerve injury, diabetes-induced neuropathy pain, chemotherapy-induced pain, and ultraviolet-B (UV-B) radiation-induced neurogenic inflammatory pain. BOR-modified LIPs loaded with ZIC were spherical or nearly spherical, with a particle size of about 95 nm and a Zeta potential of −7.8 mV. After fusion with MSC exosomes, the particle sizes of LIPs increased to 175 nm, and their Zeta potential increased to −3.8 mV. The nano-MNs constructed based on BOR-modified LIPs had good mechanical properties and could effectively penetrate the skin to release drugs. The results of analgesic experiments showed that ZIC had a significant analgesic effect in different pain models. In conclusion, the BOR-modified LIP membrane-fused exosome MNs constructed in this study for delivering ZIC provide a safe and effective administration for chronic pain treatment, as well as great potential for clinical application of ZIC. [Display omitted] • To provide a transdermal delivery system for the delivery of ziconotide. • ZIC@MSCEXO/LIP-BOR can improve the ability of crossing the BBB effectively. • ZIC@MSCEXO/LIP-BOR have the characteristics of liposomes and exosomes. • Various pain models were established to evaluate the analgesic effect. • MN#ZIC@MSCEXO/LIP-BOR has high biocompatibility and analgesic effect. [ABSTRACT FROM AUTHOR]

The venom of marine cone snails is mainly composed of peptide toxins called conopeptides, among which conotoxins represent those that are disulfide-rich. Publications on conopeptides frequently state that conopeptides attract considerable interest for their potent and selective activity, but there has been no analysis yet that formally quantifies the popularity of the field. We fill this gap here by providing a bibliometric analysis of the literature on cone snail toxins from 2000 to 2022. Our analysis of 3028 research articles and 393 reviews revealed that research in the conopeptide field is indeed prolific, with an average of 130 research articles per year. The data show that the research is typically carried out collaboratively and worldwide, and that discoveries are truly a community-based effort. An analysis of the keywords provided with each article revealed research trends, their evolution over the studied period, and important milestones. The most employed keywords are related to pharmacology and medicinal chemistry. In 2004, the trend in keywords changed, with the pivotal event of that year being the approval by the FDA of the first peptide toxin drug, ziconotide, a conopeptide, for the treatment of intractable pain. The corresponding research article is among the top ten most cited articles in the conopeptide literature. From the time of that article, medicinal chemistry aiming at engineering conopeptides to treat neuropathic pain ramped up, as seen by an increased focus on topological modifications (e.g., cyclization), electrophysiology, and structural biology. [ABSTRACT FROM AUTHOR]

Sea snails of the genus Conus produce toxins that have been the subjects of numerous studies, projects, publications, and patents over the years. Since Conus toxins were discovered in the 1960s, their biological activity has been thought to have high pharmaceutical potential that could be explored beyond the limits of academic laboratories. We reviewed 224 patent documents related to conotoxins and conopeptides globally to determine the course that innovation and development has taken over the years, their primary applications, the technological trends over the last six years, and the leaders in the field, since the only previous patent review was performed in 2015 and focused in USA valid patents. In addition, we explored which countries/territories protect their inventions and patents and the most relevant collaborations among assignees. We also evaluated whether academia or pharmaceutical companies are the future of conotoxin research. We concluded that the 224 conotoxin patents reviewed in this study have more academic value than industrial value, which was noted by the number of active patents that have not yet been licensed and the contributions to medical research, especially as tools to study neuropathic pain, inflammation, immunology, drug design, receptor binding sites, cancer, neurotransmission, epilepsy, peptide biosynthesis, and depression. The aim of this review is to provide an overview of the current state of conotoxin patents, their main applications, and success based on the number of licensing and products in the market. [ABSTRACT FROM AUTHOR]

The venom of marine cone snails is mainly composed of peptide toxins called conopeptides, among which conotoxins represent those that are disulfide-rich. Publications on conopeptides frequently state that conopeptides attract considerable interest for their potent and selective activity, but there has been no analysis yet that formally quantifies the popularity of the field. We fill this gap here by providing a bibliometric analysis of the literature on cone snail toxins from 2000 to 2022. Our analysis of 3028 research articles and 393 reviews revealed that research in the conopeptide field is indeed prolific, with an average of 130 research articles per year. The data show that the research is typically carried out collaboratively and worldwide, and that discoveries are truly a community-based effort. An analysis of the keywords provided with each article revealed research trends, their evolution over the studied period, and important milestones. The most employed keywords are related to pharmacology and medicinal chemistry. In 2004, the trend in keywords changed, with the pivotal event of that year being the approval by the FDA of the first peptide toxin drug, ziconotide, a conopeptide, for the treatment of intractable pain. The corresponding research article is among the top ten most cited articles in the conopeptide literature. From the time of that article, medicinal chemistry aiming at engineering conopeptides to treat neuropathic pain ramped up, as seen by an increased focus on topological modifications (e.g., cyclization), electrophysiology, and structural biology.

Oncologic pain is a particularly important entity within hospital clinical care. It may take different presentation forms such assomatic, visceral and/or neuropathic. All of them pose a challenge forclinical doctors. We present a case study of a patient with oncologic pain of mixed nature: somatic and neuropathic. This pain is caused by multiple metastatic lesions on the spinal cord. Given the complexity of the case, diverse types of analgesic treatments are considered: an interventional treatment with radiofrequency, intrathecal therapy, and intravenous methadone. Then, a detailed discussion takes place with regards the selection of the chosen treatment. Considering the complexity of oncologic pain, it is of the utmost importance to accurately assess the features of the pain referred by the patient. This will allow us to choose an adequate treatment depending on the available options and according to the patient’s needs. [ABSTRACT FROM AUTHOR]

Copyright of Der Schmerz is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: N-type voltage-gated calcium (CaV) channels mediate Ca2+ influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of the human CaV2.2 complex in apo, ziconotide-bound, and two CaV2.2-specific pore blockers-bound states. The second voltage-sensing domain (VSD) is captured in a resting-state conformation, trapped by a phosphatidylinositol 4,5-bisphosphate (PIP2) molecule, which is distinct from the other three VSDs of CaV2.2, as well as activated VSDs observed in previous structures of CaV channels. This structure reveals the molecular basis for the unique inactivation process of CaV2.2 channels, in which the intracellular gate formed by S6 helices is closed and a W-helix from the domain II–III linker stabilizes closed-state inactivation. The structures of this inactivated, drug-bound complex lay a solid foundation for developing new state-dependent blockers for treatment of chronic pain.

Background and Purpose: Neuropathic pain affects up to 10% of the global population and is caused by an injury or a disease affecting the somatosensory, peripheral, or central nervous system. NP is characterized by chronic, severe and opioid-resistant properties. Therefore, its clinical management remains very challenging. The N-type voltage-gated calcium channel, Ca v 2.2, is a validated target for therapeutic intervention in chronic and neuropathic pain. The conotoxin ziconotide (Prialt®) is an FDA-approved drug that blocks Ca v 2.2 channel but needs to be administered intrathecally. Thus, although being principally efficient, the required application route is very much in disfavour., Experimental Approach and Key Results: Here, we describe an orally available drug candidate, RD2, which competes with ziconotide binding to Ca v 2.2 at nanomolar concentrations and inhibits Ca v 2.2 almost completely reversible. Other voltage-gated calcium channel subtypes, like Ca v 1.2 and Ca v 3.2, were affected by RD2 only at concentrations higher than 10 μM. Data from sciatic inflammatory neuritis rat model demonstrated the in vivo proof of concept, as low-dose RD2 (5 mg·kg -1 ) administered orally alleviated neuropathic pain compared with vehicle controls. High-dose RD2 (50 mg·kg -1 ) was necessary to reduce pain sensation in acute thermal response assessed by the tail flick test., Conclusions and Implications: Taken together, these results demonstrate that RD2 has antiallodynic properties. RD2 is orally available, which is the most convenient application form for patients and caregivers. The surprising and novel result from standard receptor screens opens the room for further optimization into new promising drug candidates, which address an unmet medical need., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

To develop an efficient synthesis for target peptide 1, systematic optimization studies were performed on solid‐phase peptide synthesis (SPPS) of precursor peptide 2 (linear 25‐mer) and its aqueous phase folding process. A combination of DIC/HOBt (16‐25‐mer) and HBTU/NMM (1‐15‐mer) in DMF proved the best coupling strategy to deliver linear precursor peptide 2 with enhanced purity in crude (81.3%) and purified (99.4%) forms, in addition to improved yield (35.5%). For precursor 2, a modified cystine‐cysteine redox system with short‐chain organic co‐solvents such as 20% EtOH or MeOH promoted native folding, whereas surfactants, chaotropic agents, and other additives were not obligatory. Notably, folding efficiency was dramatically elevated at a concentration of 1 mg/20 mL (18.9 μM) over a period of 24 hours. However, prolonging the reaction time did not further improve the isomerization of misfolded products to their precisely folded counterparts. Adopting the amended oxidative conditions, scale‐up studies were successfully carried out. Purification by preparative HPLC and lyophilization afforded a spongy white solid with 98.3% purity. Solution state structural information derived from nuclear magnetic resonance spectroscopy was consistent with literature reports, and confirmed that our synthetically derived Ziconotide (1) possesses the correct disulfide connectivity and three‐dimensional conformation. [ABSTRACT FROM AUTHOR]

Abstract This article summarizes recommendations made by six pain specialists who discussed the rationale for ziconotide intrathecal analgesia (ITA) and the requirement for evidence‐based guidance on its use, from a European perspective. Riemser Pharma GmbH (Greifswald, Germany), which holds the European marketing authorization for ziconotide, hosted the meeting. The group agreed that ITA is under‐used in Europe, adding that ziconotide ITA has potential to be a first‐line alternative to morphine; both are already first‐line options in the USA. Ziconotide ITA (initiated using a low‐dose, slow‐titration approach) is suitable for many patients with noncancer‐ or cancer‐related chronic refractory pain and no history of psychosis. Adopting ziconotide as first‐line ITA could reduce opioid usage in these patient populations. The group advocated a risk‐reduction strategy for all candidate patients, including compulsory prescreening for neuropsychosis, and requested US–European alignment of the licensed starting dose for ziconotide: the low‐and‐slow approach practiced in the USA has a better tolerability profile than the fixed high starting dose licensed in Europe. Of note, an update to the European Summary of Product Characteristics is anticipated in early 2021. The group acknowledged that the Polyanalgesic Consensus Conference (PACC) treatment algorithms for ziconotide ITA provide useful guidance, but recommendations tailored specifically for European settings are required. Before a consensus process can formally begin, the group called for additional European prospective studies to investigate ziconotide in low‐and‐slow dosing strategies, in different patient settings. Such data would enable European guidance to have the most appropriate evidence at its core.

This article summarizes recommendations made by six pain specialists who discussed the rationale for ziconotide intrathecal analgesia (ITA) and the requirement for evidence‐based guidance on its use, from a European perspective. Riemser Pharma GmbH (Greifswald, Germany), which holds the European marketing authorization for ziconotide, hosted the meeting. The group agreed that ITA is under‐used in Europe, adding that ziconotide ITA has potential to be a first‐line alternative to morphine; both are already first‐line options in the USA. Ziconotide ITA (initiated using a low‐dose, slow‐titration approach) is suitable for many patients with noncancer‐ or cancer‐related chronic refractory pain and no history of psychosis. Adopting ziconotide as first‐line ITA could reduce opioid usage in these patient populations. The group advocated a risk‐reduction strategy for all candidate patients, including compulsory prescreening for neuropsychosis, and requested US–European alignment of the licensed starting dose for ziconotide: the low‐and‐slow approach practiced in the USA has a better tolerability profile than the fixed high starting dose licensed in Europe. Of note, an update to the European Summary of Product Characteristics is anticipated in early 2021. The group acknowledged that the Polyanalgesic Consensus Conference (PACC) treatment algorithms for ziconotide ITA provide useful guidance, but recommendations tailored specifically for European settings are required. Before a consensus process can formally begin, the group called for additional European prospective studies to investigate ziconotide in low‐and‐slow dosing strategies, in different patient settings. Such data would enable European guidance to have the most appropriate evidence at its core. [ABSTRACT FROM AUTHOR]

Previous studies have shown decreased pain scores with ziconotide as a first-line agent for intrathecal drug therapy (IDT). Subset analysis suggests that patients with neuropathic pain have greater improvement. We prospectively examine the role of first-line ziconotide IDT on the tridimensional pain experience in ziconotide IDT-naive patients with neuropathic pain. We included patients who underwent a successful ziconotide trial and were scheduled for standard-of-care IDT pump placement. Scores were collected at baseline and latest follow-up for the following measures: Short-Form 36 (SF-36), Oswestry Disability Index (ODI), Beck Depression Inventory, and Pain Catastrophizing Scale (PCS). Numeric rating scale (NRS) scores were also collected at each follow-up visit to monitor patients' pain levels and to guide ziconotide dose titration. Responders were identified as patients who had a previously established minimum clinically important difference of a ≥1.2-point reduction in NRS current scores. Eleven of 14 patients completed long-term follow-up. There were 7 responders based on NRS minimum clinically important difference. At a mean (±standard error of the mean) follow-up of 10.91 ± 0.70 months, SF-36 emotional well-being (P = 0.04), SF-36 pain (P = 0.02), and ODI (P = 0.03) significantly improved for the entire cohort and in responders (SF-36 emotional well-being, P = 0.01; SF-36 pain, P = 0.04; ODI, P = 0.02). PCS-Rumination (P = 0.02), PCS-Helplessness (P = 0.02), and PCS-Total (P = 0.003) scores improved significantly for responders only. We show that ziconotide IDT improves pain as well as emotional components and function. Our study adds prospective evidence to the literature on IDT for neuropathic pain, specifically its role in improving disability, emotional well-being, and catastrophizing. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this review provide support for further development of voltage gated calcium channel (VGCC) antagonists as potential therapeutic agents. Following TBI, neurons and astrocytes experience a rapid and sometimes enduring increase in intracellular calcium ([Ca2+]i). These fluxes in [Ca2+]i drive not only apoptotic and necrotic cell death, but also can lead to long-term cell dysfunction in surviving cells. In a limited number of in vitro experiments, both L-type and N-type VGCC antagonists successfully reduced calcium loads as well as neuronal and astrocytic cell death following mechanical injury. In rodent models of TBI, administration of VGCC antagonists reduced cell death and improved cognitive function. It is clear that there is a critical need to find effective therapeutics and rational drug delivery strategies for the management and treatment of TBI, and we believe that further investigation of VGCC antagonists should be pursued before ruling out the possibility of successful translation to the clinic.

Objective: The aim of this study was to investigate the physicochemical stability of morphine-bupivacaine-ziconotide mixtures used in intrathecal analgesia in polypropylene syringes and intrathecal pumps., Materials and Methods: The stability study method was conceived according to International Council for Harmonisation guidelines. For propylene syringes, six different mixtures of morphine-bupivacaine and ziconotide were assessed over seven days. Two storage temperatures were tested (5 °C ± 3 °C and 25 °C ± 2 °C). For implantable pumps, nine different mixtures were assessed over 60 days and stored at 37 °C. Assays were performed using ultrahigh-pressure liquid chromatography. Turbidity and pH also were measured throughout the study., Results: Results confirmed excellent physicochemical stability for morphine and bupivacaine in the study for all conditions investigated (pumps at 37 °C, polypropylene syringes at 5 °C ± 3 °C and 25 °C ± 2 °C). Concerning ziconotide, after seven days, our study showed that every 95% confidence interval calculated had lower bounds >90% for all mixtures stored in polypropylene syringes. In implantable pumps, a decrease of the concentration was observed in all the mixtures studied. Moreover, the appearance of a degradation product confirmed the ziconotide degradation., Conclusion: All results are in favor with a physicochemical stable preparation for six mixture profiles when stored in polypropylene syringes at 5 °C ± 3 °C and 25 °C ± 2 °C. For mixtures stored in implantable pumps, the efficacy should decrease over time owing to the degradation of ziconotide. A trade-off between high morphine concentration and increased refill interval will need to be found by clinicians., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Introduction: In cancer-related pain refractory to systemic opioids, intrathecal (IT) administration of morphine can be a useful strategy. In clinical practice, IT morphine is usually combined with other drugs with different mechanisms of action, in order to obtain a synergistic analgesic effect. However, the discussion on efficacy and safety of IT combination therapy is still ongoing. The aim of this observational study was to report the effects of an IT combination of low doses of ziconotide, morphine, and levobupivacaine in end-stage cancer refractory pain. Methods: Sixty adult patients, 21 females and 39 males, were enrolled to an IT device implant. The mean visual analogue scale of pain intensity (VASPI) score was 88 ± 20 mm. All patients started with a triple combination therapy: the initial IT dose of morphine was calculated for each patient based on the equivalent daily dose of morphine; an oral/IT ratio of 400/1 was used. For ziconotide, a standard slow titration schedule was started at 1.2 μg/day and the initial dose of levobupivacaine was 3 mg/day. Results: The initial IT mean doses of morphine, ziconotide, and levobupivacaine were 0.8 ± 0.3 mg/day, 1.2 mcg/day and 3 mg/day, respectively. At day 2, a significant reduction in VASPI score was registered (49 ± 17, p < 0.001), and this significant reduction persisted at 56 days (mean VASPI score 44 ± 9, p < 0.001), with mean doses of morphine 2 ± 1 mg/day, ziconotide 2.8 ± 1 mcg/day, and levobupivacaine 3.8 ± 2 mg/day. Very few adverse effects (AEs) were observed. Patients' satisfaction was very high during the entire study period. Conclusions: Our results, within the limit of the study design, suggest that the IT combination of ziconotide, morphine, and levobupivacaine, at low doses, allows safe and rapid control of refractory cancer pain, with high levels of patient satisfaction. [ABSTRACT FROM AUTHOR]

ɷ-Conotoxin MVIIA (ziconotide or SNX-111) is an atypical analgesic drug with the water-soluble formulation and routinely is injected into the brain and spinal regions in human and animal model studies. The aim of the current study was to investigate the neurobehavioral protection of this agent as a selective N-type calcium channels antagonist following spontaneous morphine withdrawal in rats. Male rats were administered morphine (10–50 mg/kg) intraperitoneal (IP) twice daily for 7 days. Ziconotide was injected intrathecal (IT) either in chronic form (0.1, 0.3 and 1 µg/rat) concurrent with daily doses of morphine or it was injected as a single dose (1 µg/rat) on the last day. Novel object recognition task (NOR) and radial arm maze (RAM) were used in order to evaluation of the recognition and spatial working/reference memory performances, respectively. The amount of N-methyl-D-aspartate (NMDA) receptor subunits including NR2A and NR2B in the hippocampus and prefrontal cortex were determined by western blotting. We observed that abrupt cessation after chronic exposure to morphine led to decrease in both recognition and working/reference memory performances (p <.01). Spontaneous withdrawal also significantly suppressed the amount of NR2A and NR2B. This impairment was attenuated by single and chronic doses of ziconotide (p <.05). Also, expression of NR2A and NR2B were significantly increased during both drug delivery protocols. Our findings suggest that ziconotide prevents morphine withdrawal-induced memory deficits through alteration in glutamatergic transmission and regulation of NMDA receptors (NMDARs). [ABSTRACT FROM AUTHOR]