Ziconotide: a clinical update and pharmacologic review

Pope, Jason E.; Deer, Timothy R.

doi:10.1517/14656566.2013.784269

Cited by 125 publications

(119 citation statements)

References 51 publications

(66 reference statements)

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“…However, the poor pharmacokinetic properties of peptides, particularly inefficient transport across the blood-brain barrier, limit their usefulness to target CNS disorders. However, peptide NOP agonists may be useful after intrathecal administration, a treatment that is becoming more popular for patients with intractable pain (Kress et al, 2009) Currently, only two drugs are approved for this indication, morphine and the N-type calcium channel blocker, v-conotoxin analog, ziconotide (Pope and Deer, 2013). However, neither of these is ideal because ziconotide is poorly tolerated, whereas the analgesic effect of morphine displays considerable tolerance liability.…”

Section: A Nociceptin/orphanin Fq Related Peptidesmentioning

confidence: 99%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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The NOP receptor (nociceptin/orphanin FQ opioid peptide receptor) is the most recently discovered member of the opioid receptor family and, together with its endogenous ligand, N/OFQ, make up the fourth members of the opioid receptor and opioid peptide family. Because of its more recent discovery, an understanding of the cellular and behavioral actions induced by NOP receptor activation are less well developed than for the other members of the opioid receptor family. All of these factors are important because NOP receptor activation has a clear modulatory role on mu opioid receptor-mediated actions and thereby affects opioid analgesia, tolerance development, and reward. In addition to opioid modulatory actions, NOP receptor activation has important effects on motor function and other physiologic processes. This review discusses how NOP pharmacology intersects, contrasts, and interacts with the mu opioid receptor in terms of tertiary structure and mechanism of receptor activation; location of receptors in the central nervous system; mechanisms of desensitization and downregulation; cellular actions; intracellular signal transduction pathways; and behavioral actions with respect to analgesia, tolerance, dependence, and reward. This is followed by a discussion of the agonists and antagonists that have most contributed to our current knowledge. Because NOP receptors are highly expressed in brain and spinal cord and NOP receptor activation sometimes synergizes with mu receptor-mediated actions and sometimes opposes them, an understanding of NOP receptor pharmacology in the context of these interactions with the opioid receptors will be crucial to the development of novel therapeutics that engage the NOP receptor

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Section: A Nociceptin/orphanin Fq Related Peptidesmentioning

confidence: 99%

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

et al. 2016

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“…Ziconotide, the synthetic version of the venom peptide MVIIA from Conus magus,w a s approved by the FDA in 2004 for treating patients with intractable pain. The compound selectively blocks N-type calcium ion channels (Ca v 2.2); when administered intrathecally, it can reduce pain transmission in the spinal cord (Pope and Deer, 2013).…”

Section: More Recent Successesmentioning

confidence: 99%

Toxins and Drug Discovery

Cruz¹,

Luo²

2017

Toxinology

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Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process.

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“…It is a polypeptide consisting of 25 amino acids, has a molecular weight of 2639 Da, and acts as a presynaptic N-type voltage-sensitive calcium channel antagonist in the Rexed lamina I and II of the spinal cord dorsal horn ( Figure 8 and Figure 9) [158,189,223].…”

Section: Ziconotidementioning

confidence: 99%

“…Typical opioid adverse events (AEs) such as respiratory depression, tolerance or dependence have not been described for ziconotide [215]. However, ziconotide has a narrow therapeutic window [189,215] and several neurological AEs have been reported, e.g. dizziness, ataxia, abnormal gait, nystagmus, or nausea.…”

Section: Ziconotidementioning

confidence: 99%

“…dizziness, ataxia, abnormal gait, nystagmus, or nausea. Ziconotide AEs tend to occur more commonly at higher doses [213,223,257], and a slow-titration strategy is recommended [189,257]. Due to the risk of severe psychiatric AEs, patients with a history of psychosis should not be treated with ziconotide, and all patients have to be closely monitored for cognitive impairment, psychosis or changes in mood [174,189,213,247].…”

Section: Ziconotidementioning

confidence: 99%

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The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects

Bäckryd¹

2015

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The treatment of both cancer pain and non-cancer chronic pain is still suboptimal. The overall aim of this PhD thesis was to conduct translational pain research at the interface between clinical pain medicine and the field of human proteomics, using the practice of intrathecal analgesia at our institution as a starting point. Hence, the cerebrospinal fluid (CSF) is at the centre of the present dissertation, both as a target for infusing analgesics (Papers I and II – clinical and pharmacological aspects) and as an important biofluid for human biomarker studies (Papers III and IV – proteomic aspects). In Paper I, 28 cases of intrathecal analgesia in cancer patients were prospectively followed. Movement-evoked breakthrough pain remained a major clinical problem throughout the study month despite otherwise successful intrathecal analgesia (defined as good control of spontaneous resting pain paralleled by a marked decrease of concomitant systemic opioid doses). This study therefore illustrates the importance of considering not only spontaneous resting pain but also movement-evoked breakthrough pain. In Paper II, an expert-based algorithm for trialing the intrathecal analgesic ziconotide by bolus injections was evaluated in an open-label study of 23 patients with chronic neuropathic pain. We found few responders (13%) according to the strict criteria of the algorithm, but ziconotide bolus injection trialing seems feasible. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (with very slow tissue penetration due to high hydrophilicity) calls the rationale for ziconotide bolus trialing into question. In Paper III, we found low levels of beta-endorphin in the CSF of chronic neuropathic pain patients (n=15) compared to healthy controls (n=19). We speculate that this might indicate dysfunctional top-down control of nociception. Substance P levels in the CSF did not differ by univariate statistics. In Paper IV, the CSF proteome of 11 patients with chronic neuropathic pain and 11 healthy controls was exploratively studied, combining gel-based proteomics with multivariate data analysis. After eliminating four proteins associated with age, 32 proteins were found to highly discriminate between groups. Among these, the seven proteins having the highest discriminatory power between patients and controls were: one isoform of angiotensinogen, two isoforms of alpha-1-antitrypsin, three isoforms of haptoglobin, and one isoform of pigment epithelium-derived factor. In conclusion, this PhD thesis demonstrates the fruitfulness of studying the CSF, both as a target for infusing analgesics and as a potential mirror of the neurobiological processes involved in pathological pain conditions. The thesis points to the need for more research into the mechanisms of different pain conditions, in order to hopefully achieve the vision of mechanism-based pain diagnoses

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Ziconotide: a clinical update and pharmacologic review

Cited by 125 publications

References 51 publications

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Nociceptin/Orphanin FQ Receptor Structure, Signaling, Ligands, Functions, and Interactions with Opioid Systems

Toxins and Drug Discovery

The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects

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