Subcutaneous ω-Conotoxins Alleviate Mechanical Pain in Rodent Models of Acute Peripheral Neuropathy.

The peripheral effects of ω-conotoxins, selective blockers of N-type voltage-gated calcium channels (CaV2.2), have not been characterised across different clinically relevant pain models. This study examines the effects of locally administered ω-conotoxin MVIIA, GVIA, and CVIF on mechanical and thermal paw withdrawal threshold (PWT) in postsurgical pain (PSP), cisplatin-induced neuropathy (CisIPN), and oxaliplatin-induced neuropathy (OIPN) rodent models. Intraplantar injection of 300, 100 and 30 nM MVIIA significantly (p < 0.0001, p < 0.0001, and p < 0.05, respectively) alleviated mechanical allodynia of mice in PSP model compared to vehicle control group. Similarly, intraplantar injection of 300, 100, and 30 nM MVIIA (p < 0.0001, p < 0.01, and p < 0.05, respectively), and 300 nM and 100 nM GVIA (p < 0.0001 and p < 0.05, respectively) significantly increased mechanical thresholds of mice in OIPN model. The ED50 of GVIA and MVIIA in OIPN was found to be 1.8 pmol/paw and 0.8 pmol/paw, respectively. However, none of the ω-conotoxins were effective in a mouse model of CisIPN. The intraplantar administration of 300 nM GVIA, MVIIA, and CVIF did not cause any locomotor side effects. The intraplantar administration of MVIIA can alleviate incision-induced mechanical allodynia, and GVIA and MVIIA effectively reduce OIPN associated mechanical pain, without locomotor side effects, in rodent models. In contrast, CVIF was inactive in these pain models, suggesting it is unable to block a subset of N-type voltage-gated calcium channels associated with nociceptors in the skin.

Intracerebroventricular administration of N-type calcium channel blocker ziconotide displays anticonvulsant, anxiolytic, and sedative effects in rats: A preclinical and pilot study.

OBJECTIVE: Ziconotide (ω-conotoxin MVIIA peptide) is a novel analgesic agent acting on voltage-gated calcium channels and is administered intrathecally for neuropathic pain. While antiepileptic activities of other types of calcium channel blockers (T- or L-type) are well established, there is no information regarding the effect of ziconotide as an N-type calcium channel antagonist in pentylenetetrazol-induced seizures or its anxiolytic and sedative activities. The present study is the first to report on these effects. METHODS: To evaluate the anticonvulsant activity of ziconotide in the pentylenetetrazol (60 mg/kg) seizure model, ziconotide was administered intracerebroventricular (i.c.v.) as a single dose (1 µg/rat) or repeatedly (chronic administration: 0.1, 0.3, or 1 µg/rat once a day for seven days). The anxiolytic and sedative actions of ziconotide were evaluated with the elevated plus maze, light/dark (LD) box, and pentobarbital-induced sleep tests. Immediately after behavioral testing, the amygdala was completely removed bilaterally to determine corticosterone levels by immunoassay. RESULTS: In all dosing regimens, ziconotide significantly decreased the seizure frequency and also delayed the latency period compared with control. Chronic administration affected the percentage of mortality protection, while a single dose of ziconotide did not. In behavioral tests, ziconotide significantly increased both the number of entries and the percentage of time spent in the open arms of the elevated plus maze. Furthermore, ziconotide significantly increased the latency period and the number of entries into the light compartment during the LD box examination. Chronic administration of ziconotide significantly reduced the latency to sleep and increased sleeping time, whereas these parameters were not affected by a single dose. Additionally, amygdala corticosterone levels were significantly decreased in rats treated with ziconotide compared with control. CONCLUSION: Ziconotide displays beneficial neurobehavioral effects in a model of epilepsy with anxiety as its comorbid event. It seems that at least one of the mechanisms involved in these effects is associated with a decrease in brain corticosterone levels. The main advantage of ziconotide over benzodiazepines (routine anxiolytic and sedative drugs) is that it does not cause tolerance, dependency, and addiction. Therefore, more than ever, it is necessary to improve the convenience of drug delivery protocols and attenuate the adverse effects associated with ziconotide-based therapies.

Intrathecal Therapy for Chronic Pain: A Review of Morphine and Ziconotide as Firstline Options.

OBJECTIVES: To evaluate the evidence for morphine and ziconotide as firstline intrathecal (IT) analgesia agents for patients with chronic pain. METHODS: Medline was searched (through July 2017) for "ziconotide" or "morphine" AND "intrathecal" AND "chronic pain," with results limited to studies in human populations. RESULTS: The literature supports the use of morphine (based primarily on noncontrolled, prospective, and retrospective studies) and ziconotide (based on randomized controlled trials and prospective observational studies) as first-choice IT therapies. The 2016 Polyanalgesic Consensus Conference (PACC) guidelines recommended both morphine and ziconotide as firstline IT monotherapy for localized and diffuse chronic pain of cancer-related and non-cancer-related etiologies; however, one consensus point emphasized ziconotide use, unless contraindicated, as firstline IT therapy in patients with chronic non-cancer-related pain. Initial IT therapy choice should take into consideration individual patient characteristics (e.g., pain location, response to previous therapies, comorbid medical conditions, psychiatric history). Trialing is recommended to assess medication efficacy and tolerability. For both morphine and ziconotide, the PACC guidelines recommend conservative initial dosing strategies. Due to its narrow therapeutic window, ziconotide requires careful dose titration. Ziconotide is contraindicated in patients with a history of psychosis. IT morphine administration may be associated with serious side effects (e.g., respiratory depression, catheter tip granuloma), require dose increases, and cause dependence over time. CONCLUSION: Based on the available evidence, morphine and ziconotide are recommended as firstline IT monotherapy for cancer-related and non-cancer-related pain. The choice of first-in-pump therapy should take into consideration patient characteristics and the advantages and disadvantages of each medication.

TAT-Modified ω-Conotoxin MVIIA for Crossing the Blood-Brain Barrier.

As the first in a new class of non-opioid drugs, ω-Conotoxin MVIIA was approved for the management of severe chronic pains in patients who are unresponsive to opioid therapy. Unfortunately, clinical application of MVIIA is severely limited due to its poor ability to penetrate the blood-brain barrier (BBB), reaching the central nervous system (CNS). In the present study, we have attempted to increase MVIIA's ability to cross the BBB via a fusion protein strategy. Our results showed that when the TAT-transducing domain was fused to the MVIIA C-terminal with a linker of varied numbers of glycine, the MVIIA-TAT fusion peptide exhibited remarkable ability to cross the bio-membranes. Most importantly, both intravenous and intranasal administrations of MVIIA-TAT in vivo showed therapeutic efficacy of analgesia. Compared to the analgesic effects of intracerebral administration of the nascent MVIIA, these systemic administrations of MVIIA-TAT require higher doses, but have much prolonged effects. Taken together, our results showed that TAT conjugation of MVIIA not only enables its peripheral administration, but also maintains its analgesic efficiency with a prolonged effective time window. Intranasal administration also rendered the MVIIA-TAT advantages of easy applications with potentially reduced side effects. Our results may present an alternative strategy to improve the CNS accessibility for neural active peptides.

Intrathecal Drug Delivery and Spinal Cord Stimulation for the Treatment of Cancer Pain.

PURPOSE OF REVIEW: The purpose of the present investigation is to summarize the body and quality of evidence including the most recent studies in support of intrathecal drug delivery systems and spinal cord stimulation for the treatment of cancer-related pain. RECENT FINDINGS: In the past 3 years, a number of prospective studies have been published supporting intrathecal drug delivery systems for cancer pain. Additional investigation with adjuvants to morphine-based analgesia including dexmedetomidine and ziconotide support drug-induced benefits of patient-controlled intrathecal analgesia. A study has also been recently published regarding cost-savings for intrathecal drug delivery system compared to pharmacologic management, but an analysis in the Ontario, Canada healthcare system projects additional financial costs. Finally, the Polyanalgesic Consensus Committee has updated its recommendations regarding clinical guidelines for intrathecal drug delivery systems to include new information on dosing, trialing, safety, and systemic opioid reduction. There is still a paucity of clinical evidence for spinal cord stimulation in the treatment of cancer pain. There are new intrathecal drugs under investigation including various conopeptides and AYX1. Large, prospective, modern, randomized controlled studies are still needed to support the use of both intrathecal drug delivery systems as well as spinal cord stimulation for cancer pain populations. There are multiple prospective and small randomized controlled studies that highlight a potential promising future for these interventional modalities. Related to the challenge and urgency of cancer pain, the pain practitioner community is moving toward a multimodal approach that includes discussions regarding the role of intrathecal therapies and spinal cord stimulation to the individualized treatment of patients.

Effectiveness and Safety of Intrathecal Ziconotide: Interim Analysis of the Patient Registry of Intrathecal Ziconotide Management (PRIZM).

BACKGROUND: The Patient Registry of Intrathecal Ziconotide Management (PRIZM) evaluated long-term effectiveness, safety, and tolerability of intrathecal ziconotide treatment in clinical practice. METHODS: Patient Registry of Intrathecal Ziconotide Management was an open-label, long-term, multicenter, observational study of adult patients with severe chronic pain. This interim analysis (data through July 10, 2015) of ziconotide as the first vs. not first intrathecal agent in pump included change from baseline in the Numeric Pain Rating Scale (NPRS; primary efficacy measure) and Patient Global Impression of Change (PGIC) scores. RESULTS: Enrollment closed at 93 patients; data collection was ongoing at the time of this interim analysis. Fifty-one patients (54.8%) received ziconotide as the first agent in pump (FIP+), whereas 42 (45.2%) did not (FIP-). Mean (SD) baseline NPRS scores were 7.4 (1.9) and 7.9 (1.6) in FIP+ and FIP- patients, respectively. Mean (SEM) percentage changes in NPRS scores were -29.4% (5.5%) in FIP+ patients (n = 26) and +6.4% (7.7%) in FIP- patients (n = 17) at month 6 and -34.4% (9.1%) in FIP+ patients (n = 14) and -3.4% (10.2%) in FIP- patients (n = 9) at month 12. Improvement from baseline, measured by PGIC score, was reported in 69.2% of FIP+ (n = 26) and 35.7% of FIP- (n = 14) patients at month 6 and 85.7% of FIP+ (n = 7) and 71.4% of FIP- (n = 7) patients at month 12. The most common adverse events (≥ 10% of patients overall as of the data cut) were nausea (19.6% vs. 7.1% of FIP+ vs. FIP- patients, respectively), confusional state (9.8% vs. 11.9%), and dizziness (13.7% vs. 7.1%). CONCLUSIONS: Greater improvements in efficacy outcomes were observed when ziconotide was initiated as first-line intrathecal therapy vs. not first intrathecal agent in pump. The adverse event profile was consistent with the ziconotide prescribing information.

Use of Low Dose Ziconotide as First-Line Intrathecal Monotherapy.

BACKGROUND: Ziconotide use in intrathecal drug therapy (IDT) has been limited by dosing related side effects. We examine our experience with ziconotide as a first line IDT monotherapy in patients with chronic pain and present our low and slow dosing algorithm aimed at reducing these patient experienced side effects while adequately managing pain. METHODS: We retrospectively reviewed demographics, dosing, and outcomes of 15 consecutive patients with complete three-month data sets implanted with intrathecal pain pumps more than three years utilizing ziconotide as a first-line monotherapy. RESULTS: Ziconotide response was assessed at visit 5 (69 ± 10 days) and responders were characterized by having 30% or greater improvement in numerical rating scale scores (n = 7), or activities of daily living (ADL) (n = 7). Eight of our patients had a response in at least one measure (53%). In our eight responders, NRS score decreased from 8.4 ± 0.7 at baseline (consult visit) to 2.4 ± 1.0 at 2.6 months and 4.0 ± 1.3 at most recent follow-up, mean of 12.9 months after implant. We noted that our responders tended to have neuropathic pain with an objective etiology. Initial dosing in 12 patients was 1.2 mcg/day (range for the other three patients was 0.6-1.4). Following initial dosing, visits were at 2-4 week intervals with mean titration doses between 1.1 and 2.8 mcg/day. Slight dizziness in two patients and transient urinary retention in one patient occurred, all resolving with dose reduction. No patients had discontinued use at three-month follow-up. DISCUSSION: We present our experience with low and slow ziconotide IDT as a first-line monotherapy, which showed no side effects resulting in discontinuation of the medication at three-month follow-up. Using a conservative dosing strategy, we were able to effectively treat 53% of patients.

Neuraxial drug delivery for the management of cancer pain: cost, updates, and society guidelines.

PURPOSE OF REVIEW: The present study discusses the utilization of neuraxial drug delivery (NDD) for the management of cancer pain, based on recent trials, reviews, and guidelines with a focus on cost analysis. RECENT FINDINGS: Almost all recent publications suggest that more stringent research is needed to improve evidence on NDD, particularly as conflicting reports exist regarding cost effectiveness of drug delivery systems. The combination of local anesthetics and opioids, with or without clonidine, continues to be reported as beneficial with the utilization of patient controlled systems providing an advantage over continuous ones. Interestingly, the use of opioids as an adjunct to local anesthetics may not enhance analgesia but the addition of dexamethasone is useful for incident cancer-related bone pain. Ziconitide remains supported as first-line therapy in districts where it is available - United States and Europe. Although new targeted drugs are being designed for cancer pain management, none have seen human clinical trials in the last year. SUMMARY: The ability to demonstrate cost effectiveness of NDD is variable from region to region. Less expensive externalized systems may pose a viable alternative. With the exception of dexamethasone, no new drugs have been shown to provide any benefit to conventional medications.

Intrathecal Ziconotide: Dosing and Administration Strategies in Patients With Refractory Chronic Pain.

INTRODUCTION: Ziconotide is a non-opioid analgesic for intrathecal (IT) administration. The aim of this review is to provide a comprehensive and clinically relevant summary of the literature on dosing and administration with IT ziconotide in the management of refractory chronic pain, and to describe novel dosing strategies intended to improve clinical outcomes. MATERIALS AND METHODS: A Medline search was conducted for "ziconotide," supplemented by manual searching of published bibliographies and abstracts from conferences. RESULTS: Early experience with IT ziconotide in clinical trials combined with improved understanding of drug pharmacokinetics in the cerebrospinal fluid have led to a reappraisal of approaches to trialing and initiation of continuous-infusion therapy in an effort to improve tolerability. The traditional paradigm of trialing by inpatient continuous infusion may be shifting toward outpatient trialing by IT bolus, although definitions of success and specific protocols remain to be agreed upon. Expert consensus on IT continuous infusion with ziconotide suggests a starting dose of 0.5 to 1.2 mcg/day followed by dose titration of ≤0.5 mcg/day on a no more than weekly basis, according to individual patients' pain reductions and regimen tolerability. DISCUSSION: Newer modalities that include patient-controlled analgesia and nocturnal flex dosing have been shown to hold promise of further improvements in ziconotide efficacy and tolerability. CONCLUSIONS: Clinical trials and experience confirm the feasibility and usefulness of IT ziconotide in the management of refractory chronic pain. Emerging evidence suggests that additional IT delivery options may further expand the usefulness and benefits of ziconotide.

The Relationship Between the Mechanisms of Action and Safety Profiles of Intrathecal Morphine and Ziconotide: A Review of the Literature.

OBJECTIVE: To better characterize safety profiles associated with the intrathecal (IT) administration of morphine and ziconotide and discuss how they relate to mechanisms of action. METHODS: Published data were evaluated to identify potential relationships between safety profiles of IT morphine and IT ziconotide and their mechanisms of action. RESULTS: Potentially severe and clinically relevant adverse events (AEs) associated with IT morphine include respiratory depression, tolerance, and granuloma formulation, whereas IT ziconotide is associated with neuropsychiatric AEs, such as cognitive impairment, hallucinations, and changes in mood or consciousness, particularly with high doses and rapid titration. AEs associated with these IT therapies may result from spread of the medication out of the IT space into areas of the central and peripheral nervous systems and systemic circulation. AEs that occur usually can be managed and, in some cases, prevented. To mitigate risk, patients' histories should be reviewed to identify potential complicating factors (e.g., obesity or other risk factors for respiratory dysfunction in patients receiving IT morphine; a history of psychosis in patients receiving IT ziconotide). Also, treatment should be initiated at a low dose, titrated slowly, and patients should be closely monitored during treatment. CONCLUSIONS: IT morphine and IT ziconotide are approved by the US Food and Drug Administration for patients who do not respond to less invasive treatments, but the safety profiles of each may make them more or less appropriate for certain patient populations.

Ziconotide Trialing by Intrathecal Bolus Injections: An Open-Label Non-Randomized Clinical Trial in Postoperative/Posttraumatic Neuropathic Pain Patients Refractory to Conventional Treatment.

OBJECTIVES: The aim of this open-label, non-randomized, clinical trial was to evaluate the feasibility of trialing ziconotide by intrathecal bolus injections. MATERIAL AND METHODS: Twenty-three patients, who had peripheral neuropathic pain refractory to pharmacological treatment and were under consideration for Spinal Cord Stimulation, received up to three ziconotide bolus injections according to a comprehensive algorithm. After a first injection of 2.5 µg, the patients progressed in the algorithm depending on the presence or absence of pain reduction and significant adverse events. A patient was considered a "responder" if experiencing pain reduction and no significant adverse event on two consecutive occasions at the same dosage. RESULTS: We found a low proportion of responders (13%). However 30% of patients experienced ≥30% pain reduction on a least one injection, yielding a number needed to treat of ∼3 for clinically significant pain relief. Pain intensity changed significantly over time (0-6 h) (p = 0.047) after a mean ziconotide dose of 2.75 µg. Adverse events were as expected, and no serious adverse event occurred. We did not find any statistical association between response to Spinal Cord Stimulation and response to ziconotide. CONCLUSIONS: Ziconotide bolus injection trialing seems feasible, but the proportion of responders in the present study was low. Adverse events were as expected, and no serious adverse event occurred. The predictive power of ziconotide bolus trialing remains unclear, and the pharmacological profile of ziconotide (slow tissue penetration due to high hydrophilicity) calls the rationale for bolus trialing into question.

Intrathecal Pharmacology Update: Novel Dosing Strategy for Intrathecal Monotherapy Ziconotide on Efficacy and Sustainability.

INTRODUCTION: Intrathecal drug delivery is a well-defined strategy to treat malignant and nonmalignant pain. Ziconotide is a well-studied intrathecal medicine option that has many attractive qualities, as it is non-granulomagenic, overdose or underdose is not associated with cardiopulmonary compromise or death, and is a non-opoid analgesic. However, it has had slow adoption into pain care algorithms because it has been historically plagued with the connotation of having a narrow therapeutic window and a low sustainability rate. We introduce a novel dosing strategy to improve patient outcomes and sustainability. METHODS: Patients were identified as being an intrathecal candidate and trialed with ziconotide based on the current standard of care. Patient demographics, diagnosis, previous treatment failures, and pre-implant visual analog scale (VAS) scores were recorded. Once the trial was deemed successful, based on the dual bolusing strategy, the patient underwent device implantation. Consecutive patients were prospectively followed. Ziconotide was then initiated with a flex dosing strategy, weighted during nocturnal dosing. Outcome endpoints included: reduction in VAS, side effects, durability of therapy, and systemic opioid use prior to implant and at last visit were noted (calculated to daily morphine equivalents). Primary endpoint was tolerability of ziconotide at three months following new dosing strategy. No industry support or funding was obtained for this project. RESULTS: All enrolled patients met the endpoint of the study of tolerability of ziconotide at three months. Numbers declined to 75% of patients at four months, and 70% of patients at six months. The discontinuing side-effects were most commonly urinary retention and visual hallucinations. There were no serious adverse events and no unresolved complications reported. Numerical rating scale (NRS) decreased on average from 9.06 to 1.8. Opioid reduction in morphine equivalents averaged 91.5% DISCUSSION: The efficacy and tolerability of monotherapy ziconotide may be improved by using a weighted bolus flex dosing strategy as compared with slow continuous infusions. CONCLUSION: We present a novel strategy to deliver ziconotide using a unique continuous infusion flex dosing strategy. Further randomized, prospective, higher-powered studies are needed to critically evaluate the conclusions suggested by this limited prospective case series.

Aseptic arachnoiditis in a patient treated with intrathecal morphine infusion: symptom resolution on switch to ziconotide.

INTRODUCTION: Since 1980, about 95,000 intrathecal (IT) drug delivery pumps have been implanted for the administration of a variety of opioid and non-opioid agents for neuropathic and nociceptive pain patients. IT granuloma in chronic opioid infusion is becoming less rare as an adverse effect of IT therapy and has been associated with many analgesic infusion agents. MATERIALS AND METHODS: After thymectomy, upper left lobectomy, and pericardial resection, our patient developed a left hemithorax nociceptive pain. An IT catheter and infusion pump were implanted, providing adequate analgesia. After eight months, the patient developed pain in the lower extremities without neurological impairment and an urge to move the legs without meningeal signs (3.2 mg morphine/day). A lumbar puncture revealed an inflammatory reaction in the cerebrospinal fluid (CSF); neuroimaging results were negative for granuloma. Reduction in morphine dose and a switch to ziconotide infusion were carried out. Nine months after the switch, CSF test values were in normal ranges. The patient described ongoing benefit in terms of pain and walking ability. RESULTS: The patient reported restless legs and leg pain, causing insomnia and necessitating an increase in IT opioid dose. After the switch to ziconotide and morphine discontinuation, inflammatory reactions and symptoms in the CSF abated. CONCLUSIONS: CSF analysis should be performed in patients chronically treated by IT infusion who develop a rapid increase in pain with or without neurological deficits. A switch to ziconotide can be an option in patients without neurological signs. Further studies are needed to determine the relationship between granuloma formation and CSF reaction.

In vitro stability of low-concentration ziconotide alone or in admixtures in intrathecal pumps.

OBJECTIVES: Ziconotide is often administered in combination with other analgesics via an intrathecal pump. Studies have established that ziconotide is stable when delivered alone in high concentrations. No stability data are available, however, for ziconotide given in low concentrations and/or with other analgesics as usually occurs in clinical oncology practice. The objective of this study was to assess the in vitro stability of ziconotide alone and combined with other analgesics in intrathecal pumps at 37 °C, as well as in syringes at 5 °C, to evaluate conditions for storing and transporting preparations. MATERIALS AND METHODS: Various ziconotide concentrations (0.1, 0.25, 0.5, and 0.75 µg/mL) were combined with an admixture of ropivacaine (7.5 mg/mL), morphine (7.5 mg/mL), and clonidine (15 µg/mL) in 20-mL intrathecal pumps at 37 °C and in syringes at 5 °C. Solutions of ziconotide alone in concentrations of 0.25, 0.5, 0.75, and 1 µg/mL were introduced into pumps at 37 °C and syringes at 5 °C. Assays were performed using ultra high pressure liquid chromatography. RESULTS: In admixtures, mean ziconotide concentrations decreased linearly to 53.4% (± 3.33%) of baseline after 35 days. When ziconotide was introduced alone in pumps at 37 °C, the residual concentration on day 31 was 35.54% (± 0.04%) with 0.25 µg/mL, 39.37% (± 0.15%) with 0.5 µg/mL, and 44.49% (± 0.18%) with 1 µg/mL. Ziconotide alone or combined with the other analgesics was stable in syringes stored at 5 °C. The preparations complied with the prescriptions, with a mean error of less than 10%, except with the lowest ziconotide concentration (0.1 µg/mL). CONCLUSIONS: At the low ziconotide concentrations studied, the degradation of ziconotide admixed with other drugs was linear and only weakly influenced by the baseline concentration. Linear regression with intrapolation to 30 days showed that the degradation of ziconotide admixed with other drugs was consistent with previously published data.

Intrathecal ziconotide for the treatment of chronic pain: a collection of clinical experiences and literature review.

OBJECTIVE: 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. CASE SERIES: Collected clinical experiences suggested that the use of IT ziconotide represents a valuable option, particularly in cases where other treatments have been ineffective or poorly tolerated. Ziconotide was shown to not cause severe side effects in the long-term treatment, leading to a constant pain relief effect at stable doses, without adverse events that caused therapy interruption. The overall constant ziconotide dosages also suggest the absence of a tolerance effect. In parallel, the evidence in the literature aligns with real-world evidence and further supports the use of IT ziconotide as an important option for the management of chronic pain. CONCLUSIONS: IT ziconotide represents a valuable addition to the armamentarium of pain management strategies, offering hope for improved quality of life for patients suffering from chronic, treatment-resistant pain. Continued research and clinical experience will further elucidate its optimal use and role in comprehensive pain care.

An orally available Cav2.2 calcium channel inhibitor for the treatment of neuropathic pain.

BACKGROUND AND PURPOSE: Neuropathic pain affects up to 10% of the global population and is caused by an injury or a disease affecting the somatosensory, peripheral, or central nervous system. NP is characterized by chronic, severe and opioid-resistant properties. Therefore, its clinical management remains very challenging. The N-type voltage-gated calcium channel, Cav2.2, is a validated target for therapeutic intervention in chronic and neuropathic pain. The conotoxin ziconotide (Prialt®) is an FDA-approved drug that blocks Cav2.2 channel but needs to be administered intrathecally. Thus, although being principally efficient, the required application route is very much in disfavour. EXPERIMENTAL APPROACH AND KEY RESULTS: Here, we describe an orally available drug candidate, RD2, which competes with ziconotide binding to Cav2.2 at nanomolar concentrations and inhibits Cav2.2 almost completely reversible. Other voltage-gated calcium channel subtypes, like Cav1.2 and Cav3.2, were affected by RD2 only at concentrations higher than 10 µM. Data from sciatic inflammatory neuritis rat model demonstrated the in vivo proof of concept, as low-dose RD2 (5 mg·kg-1) administered orally alleviated neuropathic pain compared with vehicle controls. High-dose RD2 (50 mg·kg-1) was necessary to reduce pain sensation in acute thermal response assessed by the tail flick test. CONCLUSIONS AND IMPLICATIONS: Taken together, these results demonstrate that RD2 has antiallodynic properties. RD2 is orally available, which is the most convenient application form for patients and caregivers. The surprising and novel result from standard receptor screens opens the room for further optimization into new promising drug candidates, which address an unmet medical need.

SPIDOL study protocol for the assessment of intrathecal ziconotide antalgic efficacy for severe refractory neuropathic pain due to spinal cord lesions.

RATIONALE: Central neuropathic pain resulting from spinal cord injury is notoriously debilitating and difficult to treat with few currently available treatments. A novel molecule with intrathecal administration: Ziconotide has been approved for treatment of refractory neuropathic pain in general. It acts as a presynaptic calcium channel blocker. A pilot study has shown its potential in SCI neuropathic pain patients. OBJECTIVE: The aim of this study is to determine the long-term (6 months) efficacy of chronic intrathecal ziconotide for the treatment of neuropathic SCI pain. STUDY DESIGN: Multicenter, Randomized, Comparative, Placebo controlled, Double blind clinical trial, with a crossover of random alternated periods of 6 months (placebo or ITZ) for a total of 15 months including a total of 44 patients. STUDY POPULATION: • Patients with SCI of various etiologies exhibiting neuropathic pain refractory to non-invasive treatments. • > 18 years. INTERVENTION: Intrathecal administration of ziconotide via an implanted pump. STUDY OUTCOMES: Primary study outcome Difference in pain intensity for all patients between effective treatment and placebo periods. Secondary study outcomes 1. Continuous evaluation of pain intensity. 2. Percentage of patients with at least 30% of pain reduction. 3. Satisfaction level of the patient pain relief. 4. Declarations of serious adverse events. 5. Duration and intensity of spontaneous and provoked pain. 6. Quality of life. 7. Patient global impression of change. 8. Quantification of daily dosages of analgesic drug intake. 9. Long term memory and neurocognitive effects. 10. Assessment of the patient's physical and emotional distress. NATURE AND EXTENT OF THE BURDEN AND RISKS ASSOCIATED WITH PARTICIPATION, BENEFIT, AND GROUP RELATEDNESS: Participation in this study is in accordance with current treatment protocols for SCI neuropathic pain in France therefore it proposes a treatment that would currently be considered regular practice even though no RCT evidence is yet available. The study gives patients the advantage of directly testing versus placebo a treatment that otherwise entails significant constraints. A Data Safety Monitoring board (DSMB) will be created for continuous safety analysis. Furthermore, patients will be followed in specialized pain centers offering the possibility of continuing their treatment after the study period.

Novel ω-conotoxins from C. catus reverse signs of mouse inflammatory pain after systemic administration.

BACKGROUND: Antagonists of N-type voltage-gated calcium channels (VGCC), Ca(v)2.2, can manage severe chronic pain with intrathecal use and may be effective systemically. A series of novel ω-conotoxins that selectively inhibit N-type VGCCs was isolated from Conus catus. In the present study, the potency and reversibility of ω-conotoxins CVID, CVIE and CVIF to inhibit N-type calcium currents were investigated in mouse isolated dorsal root ganglion (DRG) neurons. The systemic potency of each ω-conotoxin to reverse signs of mouse chronic inflammatory pain was also compared. RESULTS: In DRG neurons, the rank order of potency to inhibit N-type calcium currents was CVIE > CVIF > CVID. After subcutaneous administration, CVID and CVIE, but not CVIF, partially reversed impaired weight bearing in mice injected with Freund's complete adjuvant (CFA) three days prior to testing. No side-effects associated with systemic administration of ω-conotoxins were observed. CONCLUSIONS: The present study indicates a potential for CVID and CVIE to be developed as systemically active analgesics with no accompanying neurological side-effects.

Administering ziconotide and monitoring patients treated with ziconotide: expert opinions.

Some patients with chronic pain who are intolerant of or refractory to treatment with systemic analgesics may benefit from intrathecal therapy. Ziconotide is the first nonopioid analgesic approved by the United States Food and Drug Administration for intrathecal administration. Several randomized, double-blind, placebo-controlled clinical trials have demonstrated the efficacy and safety of ziconotide. However, the maximum recommended dosing and titration schedule provided in the prescribing information may be too aggressive for some patients, and experience has demonstrated that ziconotide is better tolerated with slower titration to a lower maximum dose. Efficacy can be assessed by an evaluation of changes in pain, functionality, and quality of life. Cognitive adverse events may be subtle; therefore, it is important that health care professionals not only monitor patients for signs and symptoms of cognitive adverse events, but also teach family members how to do the same. Careful patient assessment and monitoring can help optimize the potential benefit from treatment with ziconotide.