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Targeted intrathecal drug delivery (TIDD) has the objective of bringing the drug(s) close to the receptors influencing pain modulation, and thus reducing the dose and the side effects. Intrathecal drug delivery knew its real start with the development of permanent implantation of intrathecal and epidural catheters, combined with internal or external ports, reservoirs, and programmable pumps. TIDD is a valuable treatment for patients with cancer suffering refractory pain. Patients suffering noncancer-related pain should only be considered for TIDD when all other options have been tested, including spinal cord stimulation. Only two drugs are approved by the US Food and Drug Administration for TIDD administration for chronic pain: morphine and ziconotide as monotherapy. In pain management, off-label use of medication and combination therapy is often reported. The specific action of the intrathecal drugs, the efficacy and safety, is described, as well as the modalities for trialing intrathecal drug delivery and the implantation methods. [ABSTRACT FROM AUTHOR]

Ziconotide (ZIC) is an N-type calcium channel antagonist for treating severe chronic pain that is intolerable, or responds poorly to the administration of other drugs, such as intrathecal morphine and systemic analgesics. As it can only work in the brain and cerebrospinal fluid, intrathecal injection is the only administration route for ZIC. In this study, borneol (BOR)-modified liposomes (LIPs) were fused with exosomes from mesenchymal stem cells (MSCs) and loaded with ZIC to prepare microneedles (MNs) to improve the efficiency of ZIC across the blood-brain barrier. To evaluate local analgesic effects of MNs, the sensitivity of behavioral pain to thermal and mechanical stimuli was tested in animal models of peripheral nerve injury, diabetes-induced neuropathy pain, chemotherapy-induced pain, and ultraviolet-B (UV-B) radiation-induced neurogenic inflammatory pain. BOR-modified LIPs loaded with ZIC were spherical or nearly spherical, with a particle size of about 95 nm and a Zeta potential of −7.8 mV. After fusion with MSC exosomes, the particle sizes of LIPs increased to 175 nm, and their Zeta potential increased to −3.8 mV. The nano-MNs constructed based on BOR-modified LIPs had good mechanical properties and could effectively penetrate the skin to release drugs. The results of analgesic experiments showed that ZIC had a significant analgesic effect in different pain models. In conclusion, the BOR-modified LIP membrane-fused exosome MNs constructed in this study for delivering ZIC provide a safe and effective administration for chronic pain treatment, as well as great potential for clinical application of ZIC. [Display omitted] • To provide a transdermal delivery system for the delivery of ziconotide. • ZIC@MSCEXO/LIP-BOR can improve the ability of crossing the BBB effectively. • ZIC@MSCEXO/LIP-BOR have the characteristics of liposomes and exosomes. • Various pain models were established to evaluate the analgesic effect. • MN#ZIC@MSCEXO/LIP-BOR has high biocompatibility and analgesic effect. [ABSTRACT FROM AUTHOR]

Previous studies have shown decreased pain scores with ziconotide as a first-line agent for intrathecal drug therapy (IDT). Subset analysis suggests that patients with neuropathic pain have greater improvement. We prospectively examine the role of first-line ziconotide IDT on the tridimensional pain experience in ziconotide IDT-naive patients with neuropathic pain. We included patients who underwent a successful ziconotide trial and were scheduled for standard-of-care IDT pump placement. Scores were collected at baseline and latest follow-up for the following measures: Short-Form 36 (SF-36), Oswestry Disability Index (ODI), Beck Depression Inventory, and Pain Catastrophizing Scale (PCS). Numeric rating scale (NRS) scores were also collected at each follow-up visit to monitor patients' pain levels and to guide ziconotide dose titration. Responders were identified as patients who had a previously established minimum clinically important difference of a ≥1.2-point reduction in NRS current scores. Eleven of 14 patients completed long-term follow-up. There were 7 responders based on NRS minimum clinically important difference. At a mean (±standard error of the mean) follow-up of 10.91 ± 0.70 months, SF-36 emotional well-being (P = 0.04), SF-36 pain (P = 0.02), and ODI (P = 0.03) significantly improved for the entire cohort and in responders (SF-36 emotional well-being, P = 0.01; SF-36 pain, P = 0.04; ODI, P = 0.02). PCS-Rumination (P = 0.02), PCS-Helplessness (P = 0.02), and PCS-Total (P = 0.003) scores improved significantly for responders only. We show that ziconotide IDT improves pain as well as emotional components and function. Our study adds prospective evidence to the literature on IDT for neuropathic pain, specifically its role in improving disability, emotional well-being, and catastrophizing. [ABSTRACT FROM AUTHOR]

Some patients with chronic pain and implanted spinal cord stimulators or intrathecal (IT) pumps fail to obtain significant pain relief. The use of dual modality treatment with both therapies is understudied. This study evaluated comprehensive outcomes in this patient population and reported outcomes primarily using IT ziconotide. We retrospectively analyzed 11 patients with chronic pain treated with both spinal cord stimulation and IT therapy. When a primary treatment failed to achieve significant pain relief, a secondary device was trialed and implanted. Pain severity (measured by a numeric rating scale) was assessed by the change from baseline to after the first and second intervention. In a subset of patients (n = 6), quality-of-life metrics were also assessed. Outcome measures were analyzed closest to the 1-year follow-up date after implantation of the first modality and then at the most recent follow-up after implantation of the second modality. Spinal cord stimulation leads were percutaneous (n = 2) or paddles (n = 9) and commonly covered T8-10. IT medication included ziconotide (n = 8), baclofen (n = 1), hydromorphone (n = 1), and morphine/clonidine (n = 1). There was a mean of 19.64 ± 3.17 months between primary and secondary intervention. There was a significant improvement in pain severity from baseline to implantation of the second modality (P = 0.032) at a mean follow-up of 50.18 ± 11.83 months. Dual modality therapy is a potential treatment option in patients who have lost efficacy with a single neuromodulation modality. Further study is required to identify potential responders and nonresponders. [ABSTRACT FROM AUTHOR]

Abstract There have been numerous attempts to develop non-opioid drugs for severe pain, but the vast majority of these efforts have failed. A notable exception is Ziconotide (Prialt®), approved by the FDA in 2004. In this review, we summarize the present status of Ziconotide as a therapeutic drug and introduce a wider framework: the potential of venom peptides from cone snails as a resource providing a continuous pipeline for the discovery of non-opioid pain therapeutics. An auxiliary theme that we hope to develop is that these venoms, already a validated starting point for non-opioid drug leads, should also provide an opportunity for identifying novel molecular targets for future pain drugs. This review comprises several sections: the first focuses on Ziconotide as a therapeutic (including a historical retrospective and a clinical perspective); followed by sections on other promising Conus venom peptides that are either in clinical or pre-clinical development. We conclude with a discussion on why the outlook for discovery appears exceptionally promising. The combination of new technologies in diverse fields, including the development of novel high-content assays and revolutionary advancements in transcriptomics and proteomics, puts us at the cusp of providing a continuous pipeline of non-opioid drug innovations for pain. Significance The current opioid epidemic is the deadliest drug crisis in American history. Thus, this review on the discovery of non-opioid pain therapeutics and pathways from cone snail venoms is significant and timely. [ABSTRACT FROM AUTHOR]

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 ± 0.34 h − 1 . The C max and T max of ziconotide in CSF following intravenous administration were found to be 37.78 ± 6.8 ng/mL and ~ 2 h respectively. The time required to attain maximum concentration (T max ) in CSF was less upon intranasal administration (15 min) compared to i.v. administration (120 min). 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 ± 0.08 h − 1 and 0.42 ± 0.10 h − 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. [ABSTRACT FROM AUTHOR]

Purpose The aim of our study was to investigate the influence of pH and temperature on the stability of ziconotide in analgesic admixtures containing morphine and ropivacaine. Methods All admixtures were combined using a wide range of concentrations, in implantable pumps and syringes, using temperatures from 4 °C to 37 °C. Quantification was made thanks to a specific chromatographic technique. pH has also been measured throughout the study. Results Admixtures confirm excellent stability for morphine and ropivacaine. Concerning ziconotide, an acid hydrolysis has been observed, reducing the time of use of our admixtures in a significant way, but producing non-toxic degradation products. The degradation was linear in all conditions. Inside the implantable pumps at body temperature turned out to be the best conditions for lower protein breakdown. Finally the degradation process showed a high correlation with the pH and the morphine concentration with a median loss of concentration delay due to degradation of 3.5 days [3; 5] when pH < 4.5 and 13 days [13; 24] when pH ≥ 4.5. Conclusion Our admixtures showed different stability depending on the drug concentrations, pH and temperature. The great majority of mixtures in real life in our institution have stability highly compatible with our practice and with the delay between two pump refilling. [ABSTRACT FROM AUTHOR]

This review describes the state of the art for the use of laboratory testing in myasthenia gravis. The review brings a detailed description of the different clinical forms of auto-immune myasthenia and of the Lambert Eaton Myasthenic Syndrome (LEMS). The stress the differences between the different forms of acquired (auto-immune) myasthenia. Then they present a summary of the different antibodies found in the disease. They insist on the advantage of the RIPA assay to measure antibodies to the acetylcholine receptor. They stress the different types of contribution of each of these antibodies to the clinical diagnosis. They also describe the methods to measure each of the specific antibodies that have recently permitted to split the diagnosis: Abs to omega-conotoxin receptor in Lambert Eaton Myasthenic Syndrome (LEMS), abs to the acetylcholine receptor (AchR) in MG, Abs to muscle specific tyrosine kinase (MuSK) in Ab negative MG, and Abs to low molecular weight receptor related low-density lipo protein-4 (LRP-4). They also broach over the striated antibodies, less frequent and clinically less useful such as anti-titin, -ryanodine, -agrin and -rapsyn. This represent a 360° view of the field as presented in Toronto in October 2014. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: In the nineties, spinal analgesia has been described as an useful means to control pain in advanced cancer patients. The aim of this review was to update this information with a systematic analysis of studies performed in the last 10 years. 27 papers pertinent with the topic selected for review were collected according to selection criteria. Few studies added further information on spinal analgesia in last decade. Despite a lack of a clinical evidence, spinal analgesia with a combination of opioids, principally morphine, and local anesthetics may allow to achieve analgesia in patients who had been intensively treated unsuccessfully with different trials of opioids. Some adjuvant drugs such as clonidine, ketamine, betamethasone, meperidine, and ziconotide may be promising agents, but several problems have to be solved before they can be used in the daily practice. In complex pain situations, spinal analgesia should not be negated to cancer patients, and oncologists should address this group of patients to other specialists. [Copyright &y& Elsevier]

Abstract: The Irukandji syndrome is caused by the sting of some small jellyfish species. The syndrome has severe life-threatening consequences. The exacerbating pain and cardiovascular symptoms (tachycardia and hypertension) are hard to control in many cases. We suggest a way to experiment a new possible therapy with an FDA approved analgesic, ziconotide, a synthetic derivative from a marine cone snail (Conus magus) venom component, which is administrated intravenously. The proposed experimental plasma concentration of ziconotide for rats is in the range of 0–6μgml−1. Based on a molecular biological scenario of the venom action mechanism at cellular level, we suggest that the proposed method should be functional in re-establishing the normal cardiovascular parameters of the experimental animals and concomitantly it should abolish the severe pain caused by envenomation. We expect that positive experimental results in agreement with our theory will lead to the possibility of a new therapy for the Irukandji syndrome and possibly for other envenomations with similar ethyology. [Copyright &y& Elsevier]

Abstract: This open-label multicenter study evaluated the long-term safety and efficacy of intrathecal ziconotide and included 78 patients with chronic pain who had completed one of two previous ziconotide clinical trials. Each patient''s initial ziconotide dose was based on his or her dose from the study of origin and was adjusted as necessary on the basis of adverse events and analgesic effect. The median ziconotide dose was 6.48mcg/day (range, 0.00–120.00mcg/day) at the Initial Visit and ranged from 5.52 to 7.20mcg/day across all study visits. The most commonly reported new adverse events that were considered ziconotide related were memory impairment (11.3%); dizziness, nystagmus, and speech disorder (8.5% each); nervousness and somnolence (7.0% each); and abnormal gait (5.6%). There was no evidence of increased adverse event incidence at higher cumulative ziconotide doses. Elevations in creatine kinase were noted, but the proportion of patients with creatine kinase elevations did not change from the Initial Visit to the Termination Visit (4.1% each). Stable mean Visual Analog Scale of Pain Intensity scores during the three years of the study suggested no evidence of increased pain intensity with increased duration of ziconotide exposure. Long-term treatment with ziconotide appeared to be well tolerated and effective in patients whose response to ziconotide and ability to tolerate the drug had been previously demonstrated. [Copyright &y& Elsevier]

Abstract: There are a number of neurologically active ion channel blocking peptides derived from cone snail venom, such as conantokin-G and ω-conotoxin MVIIA. Conantokin-G inhibits NMDA receptors containing the NR2B subunit whereas ω-conotoxin MVIIA blocks N-type Ca2+ channels. Separately, these peptides induce antinociceptive effects in pre-clinical pain models following intrathecal injection. In the current study, the efficacies of these peptides were determined separately and in combination by intrathecal injection into rats with a spinal nerve ligation, in rats with a spinal cord compression injury and in the formalin test. Separately, both conantokin-G and ω-conotoxin MVIIA dose-dependently attenuated nociceptive responses in all of these models. However, at high antinociceptive doses for both formalin and nerve injury models, ω-conotoxin MVIIA evoked untoward side effects. Using isobolographic analysis, the combination of sub-antinociceptive doses of peptides demonstrated additive antinociception in rats with a nerve ligation and in the formalin test, without apparent adverse side effects. In a model of neuropathic spinal cord injury pain, which is clinically difficult to treat, the combination of conantokin-G and ω-conotoxin MVIIA resulted in robust synergistic antinociception. These data suggest that a combination of these peptides may be analgesic across diverse clinical pains with limited untoward side effects, and particularly potent for reducing spinal cord injury pain. [Copyright &y& Elsevier]

Abstract: Safety and efficacy data from a study of slow intrathecal (IT) ziconotide titration for the management of severe chronic pain are presented. Patients randomized to ziconotide (n =112) or placebo (n =108) started IT infusion at 0.1μg/hour (2.4μg/day), increasing gradually (0.05–0.1μg/hour increments) over 3 weeks. The ziconotide mean dose at termination was 0.29μg/hour (6.96μg/day). Patients'' baseline Visual Analogue Scale of Pain Intensity (VASPI) score was 80.7 (SD 15). Statistical significance was noted for VASPI mean percentage improvement, baseline to Week 3 (ziconotide [14.7%] vs. placebo [7.2%; P =0.036]) and many of the secondary efficacy outcomes measures. Significant adverse events (AEs) reported in the ziconotide group were dizziness, confusion, ataxia, abnormal gait, and memory impairment. Discontinuation rates for AEs and serious AEs were comparable for both groups. Slow titration of ziconotide, a nonopioid analgesic, to a low maximum dose resulted in significant improvement in pain and was better tolerated than in two previous controlled trials that used a faster titration to a higher mean dose. [Copyright &y& Elsevier]

N-type voltage-gated calcium (Ca V) 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 Ca V 2.2 complex in apo, ziconotide-bound, and two Ca V 2.2-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 (PIP 2) molecule, which is distinct from the other three VSDs of Ca V 2.2, as well as activated VSDs observed in previous structures of Ca V channels. This structure reveals the molecular basis for the unique inactivation process of Ca V 2.2 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. [Display omitted] • W768 on W-helix is a structural determinant for CSI of Ca V 2.2 channel • Voltage-sensing domain II was trapped in the resting state by a PIP 2 molecule • Ziconotide is located on the top of the selectivity filter blocking ion influx • Small molecules, PD173212 and Ca V 2.2 blocker 1, occupy the D III –D IV fenestration site Dong et al. report the cryo-EM structures of Ca V 2.2 complexes in apo state and ligand-bound states. A six-turn helix (W-helix) is determined underneath the pore domain, which contributes to the closed-state inactivation mechanism of Ca V 2.2 channel. The pore-blocking mechanisms of ziconotide, PD173212 and Ca V 2.2 blocker-1, are unraveled. [ABSTRACT FROM AUTHOR]

The lack of oral or injectable formulations of ziconotide (ω-conotoxin peptide), a novel analgesic agent, limits research on potential neurobehavioral protective properties of this substance, including antidepressant-like effects. Here we expose rats to a stress paradigm that induces depression and memory impairment to assess the effects of ziconotide treatment. Ziconotide was administered intracerebroventricular (i.c.v.) to rats undergoing stereotaxic surgery at a single dose (1 μg/rat) or in repeated long-term applications (dosage groups: 0.1, 0.3, and 1 μg/rat). The antidepressant activity and memory-enhancing effects of ziconotide were examined via the forced swimming test, the Morris water maze test, and the passive avoidance learning test. Behavioral results showed that long-term i.c.v. ziconotide administration significantly decreased the immobility time and delayed the latency period to immobility in a dose-dependent manner compared to controls. In the passive avoidance learning test, the latency period increased, and in the Morris water maze test, the platform location latency time decreased. A single dose of ziconotide (1 μg/rat) did not show a significant effect on memory function or depression parameters during the same tests. Animals were sacrificed immediately after behavioral testing, and both hippocampi were removed and prepared for BDNF evaluation. Hippocampal BDNF levels were significantly increased in rats receiving long-term i.c.v. ziconotide compared to controls. Our results suggest that long-term consumption of ziconotide may attenuate the severity of depression-like behavior and could be useful for preventing memory impairments in various learning models by elevating BDNF levels. [ABSTRACT FROM AUTHOR]

Introduction/Background The goal of this study was to evaluate the efficacy and safety of ITZ in patients with harmful refractory neuropathic pain following spinal cord lesions. Material and method This study was designed as a prospective cohort of twenty patients with pain following spinal cord injury (SCI) of various etiologies (post-traumatic, postsurgical, ischemic syringomyelia). Primary endpoint is the number of patients responders to the ITZ tests. Secondary endpoints is the assessment of long-term efficacy and study of impact on different features of pain and changes in antalgic medications. The efficacy of the drug was tested initially by lumbar bolus injection (1 to 2.5 mcg) and/or continuous lumbar infusion using external pump (increased progressively max 10 mcg/d). Patients were considered responders if > 40% reduction from baseline visual analogic scale (VAS) was observed without side effects. Pump placement with continuous intrathecal infusion was then proposed. Detailed analyses of test failures were performed in order to identify reasons for lack of efficacy. Results Overall out of twenty patients tested, fourteen were considered responders to test (70%). Only eleven of them (55%) benefited from a permanent pump implantation without any side effects. Pump were followed up on average for 3.59 years (± 1.94). The absolute value of pain on VAS significantly decreased between baseline and last follow-up from 7.91 to 4.31 with an average decrease of more than 3 points (45.5% P = 0.02 Wilcoxon rank sum test). After pump implantation, minor increases in CPK levels have been noted in three patients. Conclusion This pilot study shows significant decrease of pain after ITZ for well selected patients with SCI in whom other antalgic options are not available. This study includes a short population but is encouraging as facing with one of the most difficult to treat neuropathic pain. Further study with randomized controlled design is ongoing. [ABSTRACT FROM AUTHOR]

Ziconotide is used intrathecally in the management of severe chronic pain that contains a warning against neuropsychiatric adverse events. The definition of psychiatric events is broad and management strategies are vague. This case report describesa 49-year-old female who was admitted to the acute psychiatric unit to address auditory hallucinations and paranoid ideation persisting for 3 weeks. Approximately 3 months ago, an intrathecal pump with ziconotide was implanted to treat pain. Upon hospital admission, the pump was infusing at a rate of 4.9 mcg/24 hours. Because the drug could not be immediately discontinued, risperidone 0.5 mg nightly was initiated and subsequently, the pump was drained of ziconotide, rinsed, and refilled with normal saline. The patient reported no hallucinations or apparent delusions several hours later and was eventually discharged with resolution of psychotic symptoms and continuation of risperidone for 10 days. Despite the identification of neuropsychiatric effects, limited information is available to characterize the presentation and guide specific management aside from recommendations to discontinue the infusion and possible use of psychotropic medications or necessity for hospitalization. This case report characterizes one presentation of hallucinations and paranoia associated with ziconotide intrathecal infusion. Clinicians should be aware of the management strategies to mediate these adverse effects, including expected time to adverse effect resolution, removal of ziconotide from the pump, and role for short-term use of antipsychotics. [ABSTRACT FROM AUTHOR]