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The Mental Health Clinician Sep 2018Ziconotide is an intrathecally administered medication indicated for the treatment of severe chronic pain in patients who are intolerant of or refractory to other...
Ziconotide is an intrathecally administered medication indicated for the treatment of severe chronic pain in patients who are intolerant of or refractory to other treatment options. A black box warning is included in the packaging and states ziconotide is contraindicated in patients with a preexisting history of psychosis. Patients taking ziconotide should be monitored for evidence of cognitive impairment, hallucinations, or changes in mood, and ziconotide should be discontinued if neurological or psychiatric signs and symptoms appear. We present a case of a 49-year-old white male with no previous neuropsychiatric history who received ziconotide for several years before he developed command auditory hallucinations within 24 hours of a dose increase. Upon admission to the emergency room, the patient's pain management physician was contacted and the ziconotide dose was decreased and eventually discontinued. Because of a continuation of symptoms, the patient was transferred from the emergency room to an acute care psychiatric hospital where he was started on risperidone 1 mg orally at bedtime. At discharge, the patient was noted to be in good behavioral control without any hallucinations. The patient was encouraged to follow up with his pain management physician to determine if ziconotide should be reconsidered.
PubMed: 30206508
DOI: 10.9740/mhc.2018.09.242 -
Neuromodulation : Journal of the... Oct 2020To determine the physicochemical stability of ziconotide solutions for intrathecal administration in the Medication Cassette Reservoir (MCR).
OBJECTIVE
To determine the physicochemical stability of ziconotide solutions for intrathecal administration in the Medication Cassette Reservoir (MCR).
MATERIALS AND METHODS
A stability indicating UPLC-DAD method was developed and validated according to the ICH guidelines. Two mixtures of ziconotide (0.40 μg/mL and 0.60 μg/mL) stored in MCR stored at 25 ± 2°C were evaluated for 14 days and compared to the initial observed concentrations.
RESULTS
The physicochemical stability of the two solutions was demonstrated for two days thanks to relative concentrations, pH measurement, visual inspections, and turbidity assays. A degradation product was observed and increased during the study.
CONCLUSION
This study showed a very low physicochemical stability of diluted ziconotide stored at 25 ± 2°C in the MCR. The intrathecal administration of ziconotide does not seem appropriate with this device for outpatients.
Topics: Drug Stability; Drug Storage; omega-Conotoxins
PubMed: 32743885
DOI: 10.1111/ner.13218 -
IDrugs : the Investigational Drugs... Mar 2001Elan Pharmaceuticals (formerly Neurex) is developing ziconotide, a neuron-specific N-type calcium channel blocker, for the potential treatment of severe pain and...
UNLABELLED
Elan Pharmaceuticals (formerly Neurex) is developing ziconotide, a neuron-specific N-type calcium channel blocker, for the potential treatment of severe pain and ischemia. A US NDA for the use of the compound in intractable pain is under review [351606,357600] and phase III trials for ischemia are ongoing [261455,292579]. Elan received an approvable letter from the FDA for pain in June 2000, and by October 2000, was responding to questions raised by the FDA in the letter [372580,386279]. In December 2000, DRAXIS filed an NDS for ziconotide with the Therapeutic Products Programme of Health Canada [393773]. The drug has Priority Review status in Canada [387218]. PAIN: In pivotal studies, ziconotide showed a significant reduction in pain compared to placebo. In the two trials, completed by December 1999, more than 700 patients received the drug for the treatment of intractable pain intrathecally. This included patients who had failed morphine therapy, or who had become intolerant of therapy due to side-effects. The drug was safe and well tolerated over periods as long as 3 years [351606].
ISCHEMIA
Elan and Pfizer (formerly Warner-Lambert) are also developing ziconotide for the treatment of ischemia associated with head trauma and stroke [292579]. In September 1997, Neurex and Warner-Lambert restarted a pivotal phase III head trauma study with no changes in the study design. In July 1997, patient enrollment had been halted pending analysis of clinical data from earlier studies to determine the relative risk/benefits of administering ziconotide with the current protocol [261455]. By April 1999, Parke-Davis (now Pfizer) was also working on the development of nonpeptide analogs of ziconotide, with the aim of developing an orally available agent for the treatment of chronic pain [325613,324954]. In July 2000, Merrill Lynch predicted FDA approval and launch in the third or fourth quarter of 2000 [375966], but in January 2001, the prediction of approval was revised to be in 2001 [395423].
PubMed: 16025393
DOI: No ID Found -
Neuropsychiatric Disease and Treatment Feb 2007Ziconotide is a powerful analgesic drug that has a unique mechanism of action involving potent and selective block of N-type calcium channels, which control...
Ziconotide is a powerful analgesic drug that has a unique mechanism of action involving potent and selective block of N-type calcium channels, which control neurotransmission at many synapses. The analgesic efficacy of ziconotide likely results from its ability to interrupt pain signaling at the level of the spinal cord. Ziconotide is a peptidic drug and has been approved for the treatment of severe chronic pain in patients only when administered by the intrathecal route. Importantly, prolonged administration of ziconotide does not lead to the development of addiction or tolerance. The current review discusses the various studies that have addressed the in vitro biochemical and electrophysiological actions of ziconotide as well as the numerous pre-clinical studies that were conducted to elucidate its antinociceptive mechanism of action in animals. In addition, this review considers the pivotal Phase 3 (and other) clinical trials that were conducted in support of ziconotide's approval for the treatment of severe chronic pain and tries to offer some insights regarding the future discovery and development of newer analgesic drugs that would act by a similar mechanism to ziconotide but which might offer improved safety, tolerability and ease of use.
PubMed: 19300539
DOI: 10.2147/nedt.2007.3.1.69 -
Neuromodulation : Journal of the... Jul 2015The efficacy and safety of ziconotide as a single agent has been evaluated in few short-term clinical trials and open-label studies. Ziconotide use is challenging given...
OBJECTIVES
The efficacy and safety of ziconotide as a single agent has been evaluated in few short-term clinical trials and open-label studies. Ziconotide use is challenging given its adverse effect (AE) profile. The objective of this study is to describe the long-term efficacy and AEs of ziconotide used as an adjunct to other intrathecal (IT) agents in chronic noncancer pain patients.
MATERIALS AND METHODS
A case series of chronic noncancer pain patients who had suboptimal pain control from IT therapy. Ziconotide was introduced in the IT infusion mixture after a successful ziconotide trial. Pain scores, IT doses, as well as AEs were recorded and analyzed from trial to initial ziconotide infusion and up to 24 months.
RESULTS
Fifteen patients underwent ziconotide trials. Four subjects failed the trial, and 11 proceeded to continuous ziconotide treatment. Seven out of 11 patients experienced AEs resulting in ziconotide discontinuation. Two of the seven subjects who required discontinuation of ziconotide had improved pain. Four subjects were able to continue IT ziconotide through 24 months.
CONCLUSIONS
A high incidence of AEs limits the usefulness of IT ziconotide as adjunct therapy. Our results are limited by the size of our patient population; however, they represent a long follow-up period, which is limited in most current publications on this IT peptide. While ziconotide is a needed IT agent, more studies are necessary to better understand the factors that would improve the treatment to trial ratio as well as the long-term efficacy of IT ziconotide treatment.
Topics: Analgesics, Non-Narcotic; Cohort Studies; Combined Modality Therapy; Female; Humans; Injections, Spinal; Male; Middle Aged; Pain; Pain Management; Pain Measurement; omega-Conotoxins
PubMed: 25655991
DOI: 10.1111/ner.12270 -
Pain Practice : the Official Journal of... 2009Administering drugs into the intrathecal space is becoming more popular in the treatment of patients with intractable pain or intolerable side effects of systemic... (Review)
Review
Administering drugs into the intrathecal space is becoming more popular in the treatment of patients with intractable pain or intolerable side effects of systemic analgesic treatments. Although morphine and ziconotide are the only intrathecal analgesics currently approved by regulatory authorities in the U.S. (Food and Drug Administration) and Europe (national-level approval by individual countries for morphine and European Agency for the Evaluation of Medicinal Products approval for ziconotide), a wide variety of opioid and non-opioid drugs are being used in this way. There is no official guidance concerning the selection of these drugs or their use in combinations and a paucity of efficacy and safety data from randomized controlled trials. The polyanalgesic initiative aims to summarize the current knowledge and to facilitate rational choices of intrathecal drug and drug combinations for the management of chronic pain. The most recent polyanalgesic consensus recommendations were published in 2007. In this review, we shall examine these recommendations, which are tailored toward those practicing intrathecal analgesia in the U.S., and discuss how they should be implemented in Europe, where the healthcare systems and regulations of the medical authorities are different.
Topics: Analgesics, Non-Narcotic; Humans; Injections, Spinal; Pain; omega-Conotoxins
PubMed: 19740270
DOI: 10.1111/j.1533-2500.2009.00308.x -
Indian Journal of Palliative Care 2018
PubMed: 29440821
DOI: 10.4103/IJPC.IJPC_113_17 -
Angewandte Chemie (International Ed. in... Jul 2023Ziconotide (ω-conotoxin MVIIA) is an approved analgesic for the treatment of chronic pain. However, the need for intrathecal administration and adverse effects have...
Ziconotide (ω-conotoxin MVIIA) is an approved analgesic for the treatment of chronic pain. However, the need for intrathecal administration and adverse effects have limited its widespread application. Backbone cyclization is one way to improve the pharmaceutical properties of conopeptides, but so far chemical synthesis alone has been unable to produce correctly folded and backbone cyclic analogues of MVIIA. In this study, an asparaginyl endopeptidase (AEP)-mediated cyclization was used to generate backbone cyclic analogues of MVIIA for the first time. Cyclization using six- to nine-residue linkers did not perturb the overall structure of MVIIA, and the cyclic analogues of MVIIA showed inhibition of voltage-gated calcium channels (Ca 2.2) and substantially improved stability in human serum and stimulated intestinal fluid. Our study reveals that AEP transpeptidases are capable of cyclizing structurally complex peptides that chemical synthesis cannot achieve and paves the way for further improving the therapeutic value of conotoxins.
Topics: Humans; omega-Conotoxins; Analgesics; Conotoxins; Calcium Channels; Calcium Channel Blockers
PubMed: 37148162
DOI: 10.1002/anie.202302812 -
Pain Physician 2011Ziconotide is commonly used for intrathecal (IT) therapy of chronic pain, and has been recently indicated as a first-line IT drug. It is also extremely useful for...
BACKGROUND
Ziconotide is commonly used for intrathecal (IT) therapy of chronic pain, and has been recently indicated as a first-line IT drug. It is also extremely useful for patients intolerant or refractory to the common IT drugs (such as morphine). The literature, excluding registration studies, mostly includes small samples, and gives only fragmentary evidence on the long-term risks and benefits of ziconotide.
OBJECTIVE
To collect data on safety and efficacy of long-term ziconotide IT infusion in Italian pain centers.
STUDY DESIGN
Retrospective cohort study on the use of ziconotide in Italy. The study was designed and coordinated by the Foundation ISAL (Algological Sciences Research and Training Institute). Patients treated with ziconotide from several pain therapy and neurosurgery units were included in the study, allowing the creation of the first Italian Registry of Ziconotide.
SETTING
Seventeen Italian public and private pain and neurosurgery centers.
METHODS
Patients suffering from cancer or non-cancer intractable chronic pain who had been treated with ziconotide IT infusion for at least one month. Efficacy was analyzed considering changes on the visual analog scale of pain intensity from baseline observation. Safety was assessed by monitoring the number and intensity of adverse events.
RESULTS
Currently, 104 patients are included in the Italian Registry of Ziconotide. Ziconotide was administered as the first IT drug choice to 55 patients. Seventy-two patients reported at least a 30% pain intensity reduction with a mean dose of 4.36 ug/d. The sustained analgesic effect (P < 0.001) of the ziconotide IT therapy was observed in a group of 45 patients who remained in the study over 6 months without treatment interruptions and with relatively stable doses. Sixty-six patients reported at least one side effect related to ziconotide. However, adverse events have not always been decisive for treatment interruptions.
LIMITATIONS
Data were collected retrospectively from different pain centers that used different methods for ziconotide treatment and clinical forms for its data collection; for this reason there is an absence of standardized methodologies and a placebo-controlled group, and some data were missing.
CONCLUSIONS
Ziconotide IT therapy is a treatment option commonly used for clinical practice in 17 Italian pain therapy and neurosurgery units. It might give relief to patients with refractory chronic pain, and it seems to have a safe profile. Long-term studies and controlled trials are required.
Topics: Adult; Aged; Aged, 80 and over; Analgesia; Analgesics, Non-Narcotic; Cohort Studies; Female; Humans; Longitudinal Studies; Male; Middle Aged; Pain, Intractable; Registries; Retrospective Studies; Time; Treatment Outcome; omega-Conotoxins
PubMed: 21267038
DOI: No ID Found -
Neuromodulation : Journal of the... Jan 2024The aim of this study was to investigate the physicochemical stability of morphine-bupivacaine-ziconotide mixtures used in intrathecal analgesia in polypropylene...
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.
PubMed: 38300172
DOI: 10.1016/j.neurom.2023.11.009