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Ziconotide is a non-opioid analgesic that acts on N-type voltage-gated calcium channels. Despite its proven effectiveness in pain treatment, it can induce neuropsychiatric symptoms. The aim of this article is to present a case of psychosis secondary to ziconotide and to explore the variety of neuropsychiatric symptoms it produces, exploring the relationship between these symptoms and the mechanism of action of ziconotide. For this purpose, a clinical case is presented as well as a scoping review of other cases published in the scientific literature. A search on Web of Science, Pubmed and Embase databases was performed on December 11, 2023, following the criteria of the PRISMA-ScR Statement. The clinical case presented shows the variety of neuropsychiatric symptomatology that ziconotide can cause in the same patient. On the other hand, 13 papers were retrieved from the scoping review (9 case reports, 4 case series), which included 21 cases of patients treated with ziconotide who presented adverse effects ranging from psychotic symptoms to delirium. In conclusion, the variety of neuropsychiatric symptoms derived from ziconotide could be related to the blockade of N-type voltage-gated calcium channels in glutamatergic and GABAergic neurons, in turn affecting dopaminergic pathways. [ABSTRACT FROM AUTHOR]

Background: Intrathecal drug delivery (IDD) is part of the fourth analgesic step. Evidence on the quality of life of patients with refractory chronic non-cancer pain (CNCP) using these devices and their long-term outcomes is scarce. This study aims to evaluate patients with IDD to assess their HRQoL. Additionally, the study seeks to understand the patients' satisfaction with the treatment and changes in pain magnitude over time. Methods: Adult patients with CNCP and intrathecal drug delivery systems (IDDS) were included. The study population was divided into two groups: less than and more than 15 years of treatment. HRQoL was analyzed using validated questionnaires. Pain reduction was assessed using the visual analog scale (VAS), and treatment satisfaction was evaluated using the Patient Global Impression of Improvement scale. Results: The results indicate a poor HRQoL in IDD patients, with better scores in the group with ≥15 years of treatment. Pain reduction was similar in both groups, and patients reported a positive satisfaction level with the treatment. Conclusions: HRQoL in CNCP patients is severely affected. Long-term IDD patients have a similar or even better HRQoL in some respects compared to those with shorter follow-ups. IDD patients experienced pain reduction, with most feeling better or much better. [ABSTRACT FROM AUTHOR]

Ziconotide is a non-opioid analgesic that acts on N-type voltage-gated calcium channels. Despite its proven effectiveness in pain treatment, it can induce neuropsychiatric symptoms. The aim of this article is to present a case of psychosis secondary to ziconotide and to explore the variety of neuropsychiatric symptoms it produces, exploring the relationship between these symptoms and the mechanism of action of ziconotide. For this purpose, a clinical case is presented as well as a scoping review of other cases published in the scientific literature. A search on Web of Science, Pubmed and Embase databases was performed on December 11, 2023, following the criteria of the PRISMA-ScR Statement. The clinical case presented shows the variety of neuropsychiatric symptomatology that ziconotide can cause in the same patient. On the other hand, 13 papers were retrieved from the scoping review (9 case reports, 4 case series), which included 21 cases of patients treated with ziconotide who presented adverse effects ranging from psychotic symptoms to delirium. In conclusion, the variety of neuropsychiatric symptoms derived from ziconotide could be related to the blockade of N-type voltage-gated calcium channels in glutamatergic and GABAergic neurons, in turn affecting dopaminergic pathways.

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.

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.

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.

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]

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.

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]

Since the late 1980s, intrathecal (IT) analgesic therapy has improved, and implantable IT drug delivery devices have become increasingly sophisticated. Physicians and patients now have myriad more options for agents and their combination, as well as for refining their delivery. As recently as 2007, The Polyanalgesic Consensus Conference of expert panelists updated its algorithm for drug selection in IT polyanalgesia. We review this algorithm and the emerging therapy included. This article provides an update on newly approved as well as emerging IT agents and the advances in technology for their delivery.

Background and Objectives The Patient Registry of Intrathecal Ziconotide Management evaluated the long-term effectiveness and safety of intrathecal ziconotide. Methods The study was a prospective, multicenter observational study of intrathecal ziconotide in US clinical practice. Patients were adults with severe chronic pain that warranted intrathecal therapy. Ziconotide was initiated as the single agent in the pump; however, other intrathecal medications were permitted. The primary efficacy outcome was ≥30% reduction in numeric pain rating scale score from baseline at week 12. A secondary outcome was patient global impression of change. Adverse events were solicited at each visit. Results The registry enrolled 93 patients. Seventy-four and 28 patients completed 12 weeks and 18 months of treatment, respectively. In the overall patient population, 17.4% had ≥30% pain reduction from baseline at week 12, with a mean reduction in pain of 10.9%. At month 18, 38.5% of patients had ≥30% pain reduction from baseline, with a mean pain reduction of 24.7%. Patient-rated improvement was reported in 67% of patients at week 12 and 71% at month 18. Almost all patients experienced adverse events, the most common of which were nausea (25.8%), confusional state (22.6%), and dizziness (20.4%). Conclusions Final study analyses showed that intrathecal ziconotide provided clinically meaningful pain relief in 17.4% and 38.5% of patients at week 12 and month 18, respectively. At these same time points, patient-rated improvement was reported in at least two-thirds of patients. The safety profile was consistent with that listed in the ziconotide prescribing information. [ABSTRACT FROM AUTHOR]

Jeremy A Adler,1 Neona M Lotz2 1Pacific Pain Medicine Consultants, Encinitas, 2Cypress Ambulatory Surgery Center, Santa Maria, CA, USA Objective: Physician assistants (PAs), nurse practitioners (NPs), and registered nurses (RNs) provide professional services on pain management teams. This review provides an overview of the practical management of chronic pain with intrathecal (IT) therapy using an interprofessional approach (eg, physicians and other health care professionals), with a focus on the contributions of PAs, NPs, and RNs.Methods: Narrative review based on literature searches of the Medline database and treatment guidelines on the use of IT therapy in the management of patients with chronic pain.Results: The specific roles and responsibilities of PAs, NPs, and RNs in the management of patients receiving IT therapy vary by practice. In many pain treatment centers, PAs, NPs, and RNs are responsible for patient education, postimplant maintenance, and ongoing supportive care of patients receiving IT therapy. Topics that we address include patient selection, patient expectations and goal setting, medication selection, outcome assessment, and treatment adjustment. Currently, morphine and ziconotide (a nonopioid, selective N-type calcium channel blocker) are the only agents approved by the US Food and Drug Administration for IT analgesia. We provide relevant information on the dosing, titration, and adverse effect management of these medications for PAs, NPs, and RNs responsible for administering IT therapy.Conclusion: PAs, NPs, and RNs are valuable members of IT pain management teams. Treatment success requires ongoing monitoring of efficacy and adverse effects, with corresponding adjustments to medication selection and dosing, in addition to good communication among the health care professionals involved in patient care. Keywords: chronic pain, implantable drug delivery system, morphine, patient education, ziconotide

Intrathecal analgesia has increased over the past two decades based on high level proof of efficacy in patients with cancer. Morphine and Ziconotide remains the reference. Polyanalgesic Consensus Conference IT treatment algorithm recommends as the second line therapy opioids/ziconotide combination. Sufentanil and ziconotide combination can be used. The implantable pumps development helped to improve the comfort of the patient. The refills were prepared under a laminar airflow hood under strictly aseptic conditions, by the hospital pharmacist. In order to secure the process, a new analytical method by simple liquid chromatography ultraviolet spectrometry method was developed for the simultaneous quantification of two analgesic drugs (sufentanil, ziconotide). The method was validated according to the recommendation of the US Food and Drug Administration (FDA). The method was linear between 0.1 to 4 μg/mL for ziconotide and 3.125 to 50 µg/mL for sufentanil. This routine quality control analysis secures the production process.

Objectives To evaluate the evidence for morphine and ziconotide as firstline intrathecal (IT) analgesia agents for patients with chronic pain. Methods Medline was searched (through July 2017) for "ziconotide" or "morphine" AND "intrathecal" AND "chronic pain," with results limited to studies in human populations. Results The literature supports the use of morphine (based primarily on noncontrolled, prospective, and retrospective studies) and ziconotide (based on randomized controlled trials and prospective observational studies) as first-choice IT therapies. The 2016 Polyanalgesic Consensus Conference (PACC) guidelines recommended both morphine and ziconotide as firstline IT monotherapy for localized and diffuse chronic pain of cancer-related and non–cancer-related etiologies; however, one consensus point emphasized ziconotide use, unless contraindicated, as firstline IT therapy in patients with chronic non–cancer-related pain. Initial IT therapy choice should take into consideration individual patient characteristics (e.g. pain location, response to previous therapies, comorbid medical conditions, psychiatric history). Trialing is recommended to assess medication efficacy and tolerability. For both morphine and ziconotide, the PACC guidelines recommend conservative initial dosing strategies. Due to its narrow therapeutic window, ziconotide requires careful dose titration. Ziconotide is contraindicated in patients with a history of psychosis. IT morphine administration may be associated with serious side effects (e.g. respiratory depression, catheter tip granuloma), require dose increases, and cause dependence over time. Conclusion Based on the available evidence, morphine and ziconotide are recommended as firstline IT monotherapy for cancer-related and non–cancer-related pain. The choice of first-in-pump therapy should take into consideration patient characteristics and the advantages and disadvantages of each medication. [ABSTRACT FROM AUTHOR]

Disease ailments are changing the patterns, and the new diseases are emerging due to changing environments. The enormous growth of world population has overburdened the existing resources for the drugs. And hence, the drug manufacturers are always on the lookout for new resources to develop effective and safe drugs for the increasing demands of the world population. Seventy-five percentage of earth's surface is covered by water but research into the pharmacology of marine organisms is limited, and most of it still remains unexplored. Marine environment represents countless and diverse resource for new drugs to combat major diseases such as cancer or malaria. It also offers an ecological resource comprising a variety of aquatic plants and animals. These aquatic organisms are screened for antibacterial, immunomodulator, anti-fungal, anti-inflammatory, anticancer, antimicrobial, neuroprotective, analgesic, and antimalarial properties. They are used for new drug developments extensively across the world. Marine pharmacology offers the scope for research on these drugs of marine origin. Few institutes in India offer such opportunities which can help us in the quest for new drugs. This is an extensive review of the drugs developed and the potential new drug candidates from marine origin along with the opportunities for research on marine derived products. It also gives the information about the institutes in India which offer marine pharmacology related courses.

N-type calcium channels (Neuronal-type Calcium channel, Cav2.2) is a member of high voltage activated calcium channels. There are two native small peptides for N-type calcium channels (NTCC) directly which are derived from cone snail, ω-conotoxin-GVIA isolated from Conus geographus and ω-conotoxin-MVIIA (SNX-111, Ziconotide, PrialtTM), from Conus magus which both directly block the α1-ion conducting pore. NTCCs, have been shown to play a key role in nociceptive transmission due to their strategic location, presynaptically in afferent C & Aᵹ fiber terminals and postsynaptically in descending neuron. NTCCs, which are highly expressed at the pre-synaptic terminals of nociceptive neurons in dorsal horn of the spinal cord regulate release of the key pro-nociceptive neurotransmitters such as glutamate, substance P, neurokinin A, and CGRP. There have been many preclinical studies demonstrating the effect of different NTCC blockers in various acute, inflammatory and neuropathic animal pain models. In 2004 ziconotide has been approved in US and Europe to be used in clinical practice. Furthermore, many clinical trials have been performed in more than 1000 patients studying the efficacy and safety of ziconotide. IT administrated of ziconotide showed significant decrease in pain scores in patients with malignant and nonmalignant pain which are practically in neuropathic pain characteristic and resistant to IT opioids.

Byline: Arif. Ahmed, Raghu. Thota, Aparna. Chatterjee, Parmanand. Jain, Raghavendra. Ramanjulu, Sushma. Bhatnagar, Naveen. Salins, Dipasri. Bhattacharya The Indian Society for Study of Pain (ISSP), Cancer Pain Special Interest Group [...]

The authors describe the clinical case of a patient suffering from severe cervico-facial pain syndrome with great incident component from inoperable pharynx cancer. The patient that was poorly responding to systemic therapy with high doses of opioids, benefi ted from intrathecal administration of ziconotide in combination with morphine and bupivacaine. After a long period of effectiveness (16 months), the patient complained of pain recurrence.The increase of ziconotide dose caused a serious adverse effect (psychosis), which led to the suspension of the drug. After four weeks washout, lower doses of the drug (1/4) administered at cervical segmental level; the patient achieved again a good pain relief.

As the first in a new class of non-opioid drugs, ω-Conotoxin MVIIA was approved for the management of severe chronic pains in patients who are unresponsive to opioid therapy. Unfortunately, clinical application of MVIIA is severely limited due to its poor ability to penetrate the blood-brain barrier (BBB), reaching the central nervous system (CNS). In the present study, we have attempted to increase MVIIA’s ability to cross the BBB via a fusion protein strategy. Our results showed that when the TAT-transducing domain was fused to the MVIIA C-terminal with a linker of varied numbers of glycine, the MVIIA-TAT fusion peptide exhibited remarkable ability to cross the bio-membranes. Most importantly, both intravenous and intranasal administrations of MVIIA-TAT in vivo showed therapeutic efficacy of analgesia. Compared to the analgesic effects of intracerebral administration of the nascent MVIIA, these systemic administrations of MVIIA-TAT require higher doses, but have much prolonged effects. Taken together, our results showed that TAT conjugation of MVIIA not only enables its peripheral administration, but also maintains its analgesic efficiency with a prolonged effective time window. Intranasal administration also rendered the MVIIA-TAT advantages of easy applications with potentially reduced side effects. Our results may present an alternative strategy to improve the CNS accessibility for neural active peptides.

Objective: Physician assistants (PAs), nurse practitioners (NPs) and registered nurses (RNs) provide professional services on pain management teams. This review provides an overview of the practical management of chronic pain with intrathecal (IT) therapy using an interprofessional approach (eg, physicians and other health care professionals), with a focus on the contributions of PAs, NPs and RNs. Methods: Narrative review based on literature searches of the Medline database and treatment guidelines on the use of IT therapy in the management of patients with chronic pain. Results: The specific roles and responsibilities of PAs, NPs and RNs in the management of patients receiving IT therapy vary by practice. In many pain treatment centers, PAs, NPs and RNs are responsible for patient education, postimplant maintenance and ongoing supportive care of patients receiving IT therapy. Topics that we address include patient selection, patient expectations and goal setting, medication selection, outcome assessment and treatment adjustment. Currently, morphine and ziconotide (a nonopioid, selective N-type calcium channel blocker) are the only agents approved by the US Food and Drug Administration for IT analgesia. We provide relevant information on the dosing, titration and adverse effect management of these medications for PAs, NPs and RNs responsible for administering IT therapy. Conclusion: PAs, NPs and RNs are valuable members of IT pain management teams. Treatment success requires ongoing monitoring of efficacy and adverse effects, with corresponding adjustments to medication selection and dosing, in addition to good communication among the health care professionals involved in patient care. [ABSTRACT FROM AUTHOR]

Objective. The increasing incidence of cancer survivorship has shifted treatment of cancer-related pain from short-term analgesia to long-term chronic pain management. As a result, alternatives to oral analgesics, such as intrathecal therapy, may be beneficial for patients with cancer-related pain. The authors review the use of intrathecal therapy in the management of cancer-related pain. Methods. The Medline database was searched for English-language articles that included "ziconotide" or "morphine" AND ("cancer" OR "malignant") AND "intrathecal" in title or abstract. Available abstracts from scientific congresses in the areas of neuromodulation and oncology were also reviewed. Results. Intrathecal therapy provides pain relief with reduced systemic concerns in patients with cancer-related pain. Patients should undergo multidisciplinary evaluation and, in most cases, drug trialing before intrathecal pump implantation. Morphine, an opioid (m-opioid receptor antagonist), and ziconotide, a nonopioid (selective N-type calcium channel inhibitor), are both approved for intrathecal analgesia; however, tolerance and safety concerns may deter the use of intrathecal morphine. Ziconotide has also shown efficacy for reduction of cancer-related pain; however, proper dosing and titration must be used to prevent adverse events. There is little information available on use of intrathecal therapies specifically in cancer survivors. Conclusions. Treatment of cancer-related pain has shifted toward chronic pain management strategies, especially among cancer survivors. Intrathecal therapy provides an alternate route of administration of chronic pain medications (e.g., morphine and ziconotide) for cancer patients with and without active disease, although additional research is needed to support effectiveness in cancer survivors. [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.

Neuropathic pain afflicts a large percentage of the global population. This form of chronic, intractable pain arises when the peripheral or central nervous systems are damaged, either directly by lesion or indirectly through disease. The comorbidity of neuropathic pain with other diseases, including diabetes, cancer, and AIDS, contributes to a complex pathogenesis and symptom profile. Because most patients present with neuropathic pain refractory to current first-line therapeutics, pharmaceuticals with greater efficacy in pain management are highly desired. In this review we discuss the growing application of ω-conotoxins, small peptides isolated from Conus species, in the management of neuropathic pain. These toxins are synthesized by predatory cone snails as a component of paralytic venoms. The potency and selectivity with which ω-conotoxins inhibit their molecular targets, voltage-gated Ca2+ channels, is advantageous in the treatment of neuropathic pain states, in which Ca2+ channel activity is characteristically aberrant. Although ω-conotoxins demonstrate analgesic efficacy in animal models of neuropathic pain and in human clinical trials, there remains a critical need to improve the convenience of peptide drug delivery methods, and reduce the number and severity of adverse effects associated with ω-conotoxin-based therapies.

Introduction and objective: ziconotide is the first-in-class drug of selective N-type voltage-sensitive calcium-channel blockers used to control severe chronic pain. The present study is developed in order to analyze clinical and economical outcomes of spinal neuromodulation with ziconotide continuous infusion in cancer pain in a real clinical practice. Methods: costs and effects of ziconotide are compared with those of traditional neuromodulation with morphine and adjuvant drugs, administered by intrathecal infusion. Effectiveness and resources consumption data were retrospectively collected in 22 patients with severe complex cancer pain followed by one Italian centre from the day of port implantation to drop-out , due to death or consent withdrawal. 11 patients received morphine regimens and the other 11 were treated with ziconotide. The evaluation of the number of days with controlled pain (i.e., with an at least 30% reduction on the Numeric Rating Scale-Pain Intensity, NRSPI) is the primary outcome of the analysis. The evaluated consumed health resources include drugs, visits, port maintenance, and pump recharge and amortization. Current Italian prices, real practice acquisition and remuneration costs borne by the third payer are applied. Results: patients receiving ziconotide lived significantly more days with controlled pain (78% vs 40%; p < 0.05). Average weekly cost is about 232 € for ziconotide and 120 € for morphine; the main driver being the pharmaceutical cost (respectively 81% and 65% of the total). Higher ziconotide acquisition costs are partially offset by minor expenses for adjuvant therapies, as ziconotide-treated patients on average receive a lower number of drugs than those receiving a traditional regimen. The incremental cost for one further day with controlled pain resulted of 42,30 €. Conclusions: ziconotide permits effective treatment of extremely difficult-to-manage pain, with a mild increment of cost, as compared to intrathecal morphine-based therapy.

The aim of this report is to describe the emission of a erious painful symptomatology in a 57 years patient that suffered from low back pain and pain to the inferior limbs for several years. The pain was a result of surgical treatment (Failed Back Surgery Syndrome, FBSS) and the gravity of the symptoms had negatively influenced the patient’s quality of life. The pain, nociceptive and neuropathic,was resistant to several therapeutic approaches (pharmacological or not). Also a period of test with dorsal spinal cord stimulation (SCS) was ineffective. After careful analysis, the patient has been submitted to period of test with ziconotide intrathecally administered. The result that surpassed all one’s expectations, was a remarkable reduction of the pain. Such reduction allowed the patient to totally recover its autonomy and clearly improve the quality of life.

Disease ailments are changing the patterns, and the new diseases are emerging due to changing environments. The enormous growth of world population has overburdened the existing resources for the drugs. And hence, the drug manufacturers are always on the lookout for new resources to develop effective and safe drugs for the increasing demands of the world population. Seventy-five percentage of earth's surface is covered by water but research into the pharmacology of marine organisms is limited, and most of it still remains unexplored. Marine environment represents countless and diverse resource for new drugs to combat major diseases such as cancer or malaria. It also offers an ecological resource comprising a variety of aquatic plants and animals. These aquatic organisms are screened for antibacterial, immunomodulator, anti-fungal, anti-inflammatory, anticancer, antimicrobial, neuroprotective, analgesic, and antimalarial properties. They are used for new drug developments extensively across the world. Marine pharmacology offers the scope for research on these drugs of marine origin. Few institutes in India offer such opportunities which can help us in the quest for new drugs. This is an extensive review of the drugs developed and the potential new drug candidates from marine origin along with the opportunities for research on marine derived products. It also gives the information about the institutes in India which offer marine pharmacology related courses. [ABSTRACT FROM AUTHOR]