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Journal of Clinical Medicine Mar 2024Ziconotide is an intrathecal drug administered for the treatment of chronic pain. The current literature lacks an exhaustive benefit/risk assessment on this drug. We... (Review)
Review
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.
PubMed: 38541869
DOI: 10.3390/jcm13061644 -
Advances in Therapy May 2020This is a comprehensive review of the current literature on central neuropathic pain mechanisms that is secondary to spinal cord injury. It reviews recent and seminal... (Review)
Review
PURPOSE
This is a comprehensive review of the current literature on central neuropathic pain mechanisms that is secondary to spinal cord injury. It reviews recent and seminal findings on the pathophysiology, diagnosis, and treatment and compares treatment options and recommendations.
RECENT FINDINGS
Neuropathic pain (NP) is a common complication of spinal cord injury (SCI). Chronicity of NP is attributed to increased abundance of inflammatory mediators and ion channel dysfunction leading to afferent nerve sensitization; nerve damage and nerve-glia cross talk have also been implicated. Conventional treatment is medical and has had limited success. Recent studies have made headway in identifying novel biomarkers, including microRNA and psychosocial attributes that can predict progress from SCI to chronic NP (CNP). Recent advances have provided evidence of efficacy for two promising drugs. Baclofen was able to provide good, long-lasting pain relief. Ziconotide, a voltage-gated calcium channel blocker, was studied in a small trial and was able to provide good analgesia in most participants. However, several participants had to be withdrawn because of worrisome creatine phosphokinase (CPK) elevations, and further studies are required to define its safety profile. Non-medical interventions include brain sensitization and biofeedback techniques. These methods have recently had encouraging results, albeit preliminary. Case reports of non-conventional techniques, such as hypnosis, were also reported. CNP is a common complication of SCI and is a prevalent disorder with significant morbidity and disability. Conventional medical treatment is limited in efficacy. Recent studies identified baclofen and ziconotide as possible new therapies, alongside non-medical interventions. Further research into the pathophysiology is required to identify further therapy candidates. A multidisciplinary approach, including psychosocial support, medical and non-medical interventions, is likely needed to achieve therapeutic effects in this difficult to treat syndrome.
Topics: Analgesics; Calcium Channel Blockers; Humans; Neuralgia; Neuroglia; Pain Management; Spinal Cord Injuries; omega-Conotoxins
PubMed: 32291648
DOI: 10.1007/s12325-020-01334-w -
Neurology and Therapy Dec 2015Studies have shown that, at low doses and with careful titration, combination therapy with intrathecal ziconotide and morphine results in rapid control of...
INTRODUCTION
Studies have shown that, at low doses and with careful titration, combination therapy with intrathecal ziconotide and morphine results in rapid control of opioid-refractory cancer pain. However, there is a lack of published data regarding the efficacy and safety of intrathecal ziconotide specifically for the treatment of neuropathic cancer pain.
CASE SERIES
Case reports of ziconotide intrathecal infusion in eight patients (age 45-71 years; 75% male) with chronic, uncontrolled cancer pain during therapy with intrathecal morphine plus bupivacaine were reviewed. Neuropathic pain was confirmed in five patients. Treatment was initiated with adjunctive ziconotide when pain ≥5 on a visual analog scale persisted in spite of 3 successive 20% dose increases of intrathecal morphine. Ziconotide was initiated at 0.5-1.0 µg/day, with mean increases of 0.5 µg every 4-7 days if required (maximum dose 10 µg/day; mean dose 4.9 µg/day). Pain intensity was reduced in all patients after 3-5 days. Of the eight patients, three died for reasons unrelated to ziconotide, three discontinued treatment due to adverse effects (predominantly psychoneurological disorders), and one patient is still receiving treatment. One patient discontinued ziconotide due to confusion and delirium. Due to continued lack of pain control with intrathecal morphine, intrathecal fentanyl was initiated; however, effective pain relief was not achieved with 1500 µg/day. Ziconotide was restarted and the patient then achieved pain control.
CONCLUSION
On the basis of our clinical experience, we recommend adding ziconotide to intrathecal opioid-based therapy in cancer patients with neuropathic pain inadequately controlled by intrathecal morphine alone.
FUNDING
Eisai, Spain.
PubMed: 26563119
DOI: 10.1007/s40120-015-0035-z -
Journal of Controlled Release :... Feb 2016The purpose of the current study was to investigate the plausibility of delivery of ziconotide to the cerebrospinal fluid (CSF) via intranasal administration. Ziconotide...
The purpose of the current study was to investigate the plausibility of delivery of ziconotide to the cerebrospinal fluid (CSF) via intranasal administration. Ziconotide was administered either in the form of solution or Kolliphor P 407 gels (KP 407) intranasally in Sprague-Dawley rats. The effect of incorporation of chitosan in the formulation was also investigated. Time course of drug in the CSF was investigated by collecting CSF from cisterna magna. Pharmacokinetics of ziconotide in CSF following intrathecal and intravenous (i.v.) administration of ziconotide was investigated. Upon intrathecal administration the elimination rate constant of ziconotide in CSF was found to be 1.01±0.34h(-1). The Cmax and Tmax of ziconotide in CSF following intravenous administration were found to be 37.78±6.8ng/mL and ~2h respectively. The time required to attain maximum concentration (Tmax) in CSF was less upon intranasal administration (15min) compared to i.v. administration (120min). Presence of chitosan enhanced the overall bioavailability of ziconotide from intranasal solution and gel formulations. The elimination rate constant of ziconotide in CSF following intranasal and intravenous administration of ziconotide solution was found to be 0.54±0.08h(-1) and 0.42±0.10h(-1) respectively. Whereas, intranasal administration of ziconotide in the form of in situ forming gel lowered the elimination rate significantly. These results suggest that intranasal administration could be a potential noninvasive and patient compliant method of delivering ziconotide to CSF to treat chronic pain.
Topics: Administration, Intranasal; Administration, Intravenous; Analgesics; Animals; Biological Availability; Chronic Pain; Drug Delivery Systems; Gels; Injections, Spinal; Male; Olfactory Mucosa; Pharmaceutical Solutions; Rats; Rats, Sprague-Dawley; Viscosity; omega-Conotoxins
PubMed: 26732557
DOI: 10.1016/j.jconrel.2015.12.044 -
Pain Physician 2009Intrathecal ziconotide is used to manage severe chronic pain. Although ziconotide is approved by the US Food and Drug Administration for monotherapy, it is sometimes... (Clinical Trial)
Clinical Trial
BACKGROUND
Intrathecal ziconotide is used to manage severe chronic pain. Although ziconotide is approved by the US Food and Drug Administration for monotherapy, it is sometimes used in combination with other intrathecal drugs for the management of intractable pain conditions in clinical practice.
OBJECTIVES
Evaluate the safety and tolerability of ziconotide combination therapy.
STUDY DESIGN
A retrospective, observational study.
SETTING
A single center.
METHODS
Patients with severe chronic pain of noncancer origin who were receiving inadequate analgesia with intrathecal opioid therapy (with or without intrathecal adjuvants) and who had ziconotide added to their intrathecal regimens were included. Patient characteristics, intrathecal ziconotide doses, concomitant intrathecal and systemic drug use, visual analog scale pain scores, Oswestry Disability Index scores, mini-mental status examination scores, neurological examination results, clinical observations (including adverse event reports), and equipment complications were reviewed for 12 weeks after ziconotide initiation.
RESULTS
Sixteen patients were identified. Ziconotide was initiated at a dose of 0.5 mcg/d and titrated to a mean dose of 2.64 mcg/d at week 12. Intrathecal opioids were hydromorphone (n=7), morphine (n=5), fentanyl (n=3), and sufentanil (n=1). Adverse events were noted in one patient, who reported increased depression and pain during combination therapy; ziconotide treatment was discontinued, and all adverse events resolved over a 4-week period. Substantial pain relief (> or =4-point decrease in visual analog scale score) was reported in 3 of 15 patients (20.0%) and increased functional capacity was evident in 3 of 15 patients (20.0%).
LIMITATIONS
A retrospective study with a limited number of patients from a single center.
CONCLUSION
Results from this observational study suggest that combination intrathecal ziconotide and opioid therapy may be a safe and potentially effective treatment option for patients with refractory chronic pain. Controlled, prospective clinical trials to evaluate ziconotide combination therapy are needed.
Topics: Analgesics, Non-Narcotic; Analgesics, Opioid; Drug Therapy, Combination; Female; Humans; Injections, Spinal; Male; Observation; Pain; Pain Measurement; Retrospective Studies; omega-Conotoxins
PubMed: 19668287
DOI: No ID Found -
Journal of Pharmacy & Bioallied Sciences 2016Disease ailments are changing the patterns, and the new diseases are emerging due to changing environments. The enormous growth of world population has overburdened the... (Review)
Review
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.
PubMed: 27134458
DOI: 10.4103/0975-7406.171700 -
Proceedings of the National Academy of... Nov 2023Transmembrane Ca2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Ca2.2...
Transmembrane Ca2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Ca2.2 (e.g., with Prialt/Ziconotide) or indirect modulation [e.g., with gabapentinoids such as Gabapentin (GBP)] mitigates chronic pain but is encumbered by side effects and abuse liability. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Ca2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Ca2.2-CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the dipeptide in CBD3 as the anchoring Ca2.2 motif and designed pharmacophore models to screen 27 million compounds on the open-access server ZincPharmer. Of 200 curated hits, 77 compounds were assessed using depolarization-evoked calcium influx in rat dorsal root ganglion neurons. Nine small molecules were tested electrophysiologically, while one (CBD3063) was also evaluated biochemically and behaviorally. CBD3063 uncoupled Ca2.2 from CRMP2, reduced membrane Ca2.2 expression and Ca currents, decreased neurotransmission, reduced fiber photometry-based calcium responses in response to mechanical stimulation, and reversed neuropathic and inflammatory pain across sexes in two different species without changes in sensory, sedative, depressive, and cognitive behaviors. CBD3063 is a selective, first-in-class, CRMP2-based peptidomimetic small molecule, which allosterically regulates Ca2.2 to achieve analgesia and pain relief without negative side effect profiles. In summary, CBD3063 could potentially be a more effective alternative to GBP for pain relief.
Topics: Rats; Animals; Chronic Pain; Rats, Sprague-Dawley; Peptidomimetics; Calcium; Calcium Channels, N-Type; Sensory Receptor Cells; Ganglia, Spinal
PubMed: 37972067
DOI: 10.1073/pnas.2305215120 -
European Journal of Pain (London,... Aug 2018Ziconotide is a selective and potent blocker of N-type voltage-gated calcium channels. It was approved by the Food and Drug Administration in 2004 and by the European... (Review)
Review
Ziconotide is a selective and potent blocker of N-type voltage-gated calcium channels. It was approved by the Food and Drug Administration in 2004 and by the European Medicines Agency in 2005 for the treatment of severe chronic pain in patients needing intrathecal analgesia (ITA). The aim of this paper is to provide a practitioner-oriented, educational, narrative, up-to-date review on the use of ziconotide in clinical pain medicine. Of special concern regarding safety is the partial incongruity between dosing statements in the Summary of Product Characteristics and novel low-dosage, slow uptitration recommendations. Even though ziconotide has obvious advantages compared to opioids, pain practitioners pondering the use of ziconotide nonetheless have to balance its proved potential analgesic effect against its neurological side effects, with special consideration being given to dosing and neuropsychiatric dangers. Using a seesaw analogy, the paper discusses what factors pain physicians should weigh in when considering ziconotide as ITA drug, the non-opioid advantages of ziconotide being counterbalanced by its potential psychiatric side effects. Ziconotide is an important part of the armamentarium of modern interventional pain medicine. If ITA is deemed necessary, ziconotide is a rational alternative, at least in chronic (neuropathic) non-cancer pain. However, in many European countries, ziconotide treatment is only available in a few (if any) centres. The safety profile of ziconotide is not fundamentally more worrying than that of opioids or cannabinoids; it is just different. This paper provides a concise, up-to-date and clinically-oriented summary of the use of ziconotide in clinical practice, not least concerning safety and dosage issues.
Topics: Analgesics, Non-Narcotic; Chronic Pain; Europe; Humans; Practice Patterns, Physicians'; Risk Assessment; omega-Conotoxins
PubMed: 29635804
DOI: 10.1002/ejp.1229 -
Tremor and Other Hyperkinetic Movements... Oct 2020Ziconotide (ZCN), a nonopioid analgesic, is first-line intrathecal therapy for patients with severe chronic pain refractory to other management options. We describe...
BACKGROUND
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.
CASES
Case one is a 64-year-old woman who presented with oro-lingual (OL) dyskinesia with dysesthesias and bilateral upper extremity kinetic tremor. Case two is a 43-year-old man with a 20-month history of ZCN treatment who developed OL dyskinesia with dysesthesias, involuntary left hand and neck movements, hallucinations, dysesthesias on his feet, and gait imbalance. Case three is a 70-year-old man with a 4-month history of ZCN use who developed OL dyskinesia with dysesthesias.
CONCLUSIONS
Intrathecal treatment of pain with ZCN may be complicated by a drug-induced movement disorder where OL dyskinesia is characteristic. The movement disorder is likely to be dose related and reversible with ZCN discontinuation, but a chronic movement disorder is also possible.
Topics: Adult; Aged; Analgesics, Non-Narcotic; Chronic Pain; Dyskinesia, Drug-Induced; Female; Humans; Male; Middle Aged; omega-Conotoxins
PubMed: 33101763
DOI: 10.5334/tohm.431 -
Future Medicinal Chemistry May 2010An accelerated rate of natural-product discovery is critical for the future of ion channel pharmacology. For the full potential of natural products to be realized, an... (Review)
Review
An accelerated rate of natural-product discovery is critical for the future of ion channel pharmacology. For the full potential of natural products to be realized, an interdisciplinary initiative is required that combines chemical ecology and ion channel physiology. A prime source of future drug leads targeted to ion channels is the vast assortment of compounds that mediate biotic interactions in the marine environment. Many animals have evolved a chemical strategy to change the behavior of their prey, predators or competitors, which appears to require a large set of ion channel-targeted compounds acting in concert. Some of these compounds (e.g., ziconotide [Prialt(®)]) have already found important biomedical applications. The elucidation of molecular mechanisms mediating biotic interactions should yield a rich stream of potent and selective natural products for the drug pipeline.
Topics: Amino Acid Sequence; Animals; Biological Products; Drug Discovery; Humans; Ion Channels; Models, Molecular; Molecular Sequence Data
PubMed: 21426200
DOI: 10.4155/fmc.10.31