Ziconotide Research & Studies

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.

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.

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.

Ziconotide (ZCN), a nonopioid analgesic, is first-line intrathecal therapy for patients with severe chronic pain refractory to other management options. We describe three cases of ZCN-induced movement disorders.

Central neuropathic pain related to spinal cord injury is notoriously difficult to treat. So far most pharmacological and surgical options have shown but poor results. Recently ziconotide has been approved for use both neuropathic and non-neuropathic pain. In this cohort study, we assessed responder rate and long-term efficacy of intrathecal ziconotide in patients with pain related to spinal cord injury.

Chronic neuropathic pain is difficult to treat and is often refractory to most modalities of treatment. Ziconotide is a novel, potent, non-opioid, calcium channel blocking agent which has been shown in clinical trials to be effective in treating chronic neuropathic pain.

Ziconotide (Prialt(®)) is a synthetic conopeptide analgesic that acts by selectively antagonizing N-type voltage-gated calcium channels. Intrathecal ziconotide is the only non-opioid intrathecal analgesic that is FDA-approved for use in patients with treatment-refractory, chronic pain. The efficacy of intrathecal ziconotide was demonstrated in randomized, double-blind, placebo-controlled trials in patients with treatment-refractory noncancer-related pain or cancer- or AIDS-related pain. Across trials, ziconotide recipients had significantly greater reductions in pain intensity during ziconotide treatment than those receiving placebo (primary endpoint). At the end of the titration period, approximately one-sixth to one-third of patients with noncancer chronic pain and one-half with cancer- or AIDS-related pain who received ziconotide reached a pain response threshold (≥30 % reduction in the pain intensity score). In ziconotide responders, analgesic effects were enduring, with some patients continuing treatment over extended periods. Across trials, the chief tolerability concerns in ziconotide recipients during the titration phase and during extended treatment were related to CNS adverse events. These were mostly of mild to moderate intensity, although serious adverse events were commonly attributed to ziconotide treatment, especially in trials with rapid ziconotide titration and that permitted higher dosages. In general, clinically important non-CNS adverse events were infrequent, and during the ziconotide titration phase, relatively few patients discontinued treatment because of adverse events. Ongoing research will assess various strategies for selecting patients for ziconotide treatment and for enhancing its efficacy and tolerability. At the present time, intrathecal ziconotide provides a treatment option for patients with severe, unremitting pain who have failed to respond to other intensive analgesic regimens.

Ziconotide is a nonopioid intrathecal analgesic used to manage moderate to severe chronic pain. Although ziconotide is approved in the United States for intrathecal monotherapy only, it is often used in combination with other intrathecal drugs in clinical practice.

Neuropathic pain is a considerable burden that affects activities of daily living. The management of neuropathic pain can be challenging because of multiple etiologies and complex manifestations. Ziconotide is a nonopioid intrathecal (IT) analgesic option for patients with neuropathic pain refractory to conventional treatments. The objective of this article is to review the published literature on ziconotide for the treatment of neuropathic pain. Relevant publications were identified through searches of all years of 6 databases, which included PubMed, EMBASE, and CINAHL. Search terms used were ziconotide, SNX-111, MVIIA, Prialt, and neuropathic pain. Publications were included if ziconotide was intrathecally administered (either alone or in combination with other IT agents) to treat neuropathic pain of any etiology and if pain assessment was an outcome measure. Data extracted included study design, IT drug doses, pain outcome measures, and adverse events (AEs). Twenty-eight articles met the inclusion criteria: 5 were preclinical studies and 23 were clinical studies. In the preclinical studies, ziconotide demonstrated antiallodynic effects on neuropathic pain. Data from double-blind, placebo-controlled (DBPC) trials indicated that patients with neuropathic pain reported a mean percent improvement in pain score with ziconotide monotherapy that ranged from 15.7% to 31.6%. A low starting dose and slow titration of ziconotide resulted in an improved safety profile in the aforementioned trials. Common AEs associated with ziconotide include nausea and/or vomiting, dizziness, confusion, urinary retention, and somnolence. Evidence from DBPC trials, open-label studies, case series, and case studies suggests that ziconotide, as either monotherapy or in combination with other IT drugs, is a potential therapeutic option for patients with refractory neuropathic pain. Additional studies are needed to establish the long-term efficacy and safety of ziconotide for neuropathic pain.

Ziconotide is the only N-type calcium channel blocker approved by the US FDA for the treatment of chronic pain. The approved indication is for the management of severe chronic pain in patients for whom intrathecal therapy is warranted and who are intolerant of or refractory to other treatments such as systemic analgesics, adjunctive therapies or intrathecal morphine.

Worldwide a large number of patients suffer from severe chronic pain even after treatment with opioids following the 3-step analgesic ladder developed by the WHO. Intraspinal agents, including morphine, have been tried as a fourth step. However, approximately 20% of cases remain refractory. Ziconotide, an intrathecal analgesic with orphan drug status, is a novel alternative for the management of chronic intractable pain. Ziconotide is a synthetic peptide based on the toxin of the fish-hunting marine snail, Conus magus. It is the first therapeutic agent in a new pharmacological class of "topically" active analgesics that selectively target neuron-specific (N-type), voltage-gated calcium channels. Ziconotide produces potent analgesia by interruption of Ca-dependent primary afferent transmission of pain signals in the spinal cord. Ziconotide was significantly more effective than placebo in the treatment of chronic malignant (p < 0.001) and non-malignant pain (p < 0.001). In several clinical studies morphine dosages could be substituted by ziconotide. The drug has a lag-time for the onset and offset of analgesia and adverse effects. Initial doses should therefore be low (2.4 microg/day) and titrated slowly (increasing up to a maximum of 21.6 microg/day in increases of 2.4 microg/day no more than twice weekly). The gradual increase in dose helps to reduce the incidence and severity of adverse events which affect primarily the central nervous system (e.g. dizziness, nausea, confusion). Ziconotide maintains its analgesic efficacy over months and does not cause tolerance, dependence or respiratory depression. Following intrathecal infusion ziconotide is distributed within the cerebral spinal fluid (CSF) where its clearance (0.38 ml/min) corresponds to the rate of turnover of the CSF. Negligible amounts of ziconotide are present in the systemic circulation where it is rapidly degraded by proteolysis. In conclusion, ziconotide is a new and valuable alternative analgesic for the acute and long-term treatment of severe pain, especially in patients refractory to opioids.

To describe the pharmacology, efficacy, and safety of ziconotide for treatment of severe chronic pain in patients who are candidates for intrathecal therapy.

For cancer and AIDS patients, 10-30% of pain is refractory to strong opioids, requiring intraspinal administration for pain management. Ziconotide is a selective N-type calcium channel blocker, which inhibits neurotransmitter release, and following intrathecal administration will affect primary nociceptive afferents. In 108 patients with previously unmanaged refractory pain despite the use of systemic or intrathecal opioids, in the initial titration phase, the mean Visual Analogue Scale of Pain Intensity scores improved more in the ziconotide group (53%) than the placebo group (18%). Serious adverse effects were more common in the ziconotide group (31%) than placebo group (10%) in the initial titration phase. In the 48 patients receiving ziconotide, who proceeded to the maintenance phase, the benefit of ziconotide was continued. Until a new approach with a better effectiveness/adverse effects profile than ziconotide for refractory pain emerges, further optimisation of ziconotide for use in the treatment of refractory pain should be undertaken.

Ziconotide (PRIALT) is a neuroactive peptide in the final stages of clinical development as a novel non-opioid treatment for severe chronic pain. It is the synthetic equivalent of omega-MVIIA, a component of the venom of the marine snail, Conus magus. The mechanism of action underlying ziconotide's therapeutic profile derives from its potent and selective blockade of neuronal N-type voltage-sensitive calcium channels (N-VSCCs). Direct blockade of N-VSCCs inhibits the activity of a subset of neurons, including pain-sensing primary nociceptors. This mechanism of action distinguishes ziconotide from all other analgesics, including opioid analgesics. In fact, ziconotide is potently anti-nociceptive in animal models of pain in which morphine exhibits poor anti-nociceptive activity. Moreover, in contrast to opiates, tolerance to ziconotide is not observed. Clinical studies of ziconotide in more than 2,000 patients reveal important correlations to ziconotide's non-clinical pharmacology. For example, ziconotide provides significant pain relief to severe chronic pain sufferers who have failed to obtain relief from opiate therapy and no evidence of tolerance to ziconotide is seen in these patients. Contingent on regulatory approval, ziconotide will be the first in a new class of neurological drugs: the N-type calcium channel blockers, or NCCBs. Its novel mechanism of action as a non-opioid analgesic suggests ziconotide has the potential to play a valuable role in treatment regimens for severe chronic pain. If approved for clinical use, ziconotide will further validate the neuroactive venom peptides as a source of new and useful medicines.