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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., Competing Interests: Conflict of Interest The authors reported no conflict of interest., (Copyright © 2023 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aimed to investigate the physicochemical stability of morphine-ropivacaine-ziconotide mixtures used in intrathecal analgesia., Materials and Methods: Eight mixtures were studied to assess their stability profiles according to the initial drug concentrations used. The solutions obtained were put in implantable pumps and stored at 37 °C over a period of 60 days. Assays were performed using ultra high-pressure liquid chromatography. Turbidity and pH were also measured throughout the study., Results: Results confirmed excellent physicochemical stability for morphine and ropivacaine. Concerning ziconotide, three of the eight mixtures did not show any sign of chemical instability: average concentrations remained constant throughout the 60 days. A decrease of the concentration was observed for the five other mixtures. Moreover, the appearance of a degradation product linked to oxidation confirmed the ziconotide degradation., Conclusions: All these results are in favor of a physicochemical stable preparation for three of the mixture profiles when stored in implantable pumps at 37 °C up to 60 days. For the five others, the efficacy should decrease over time owing to the degradation of ziconotide. The decrease in kinetics of the ziconotide concentration depends on the mixing profile. One possibility is to adapt the filling intervals according to the profile of the mixture. Finally, the results show the period of stability ensuring maximum analgesic efficacy for the eight mixture profiles studied., (Copyright © 2021 International Neuromodulation Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Recent recommendations on starting dose, smaller dose increments, and longer intervals between dose increase have the potential to increase the safety of ziconotide administration in addition to improving its value for money. Ziconotide is not routinely commissioned in England, with one of the concerns being whether it represents the best use of resources. The aim of this project is to conduct a budget impact analysis to estimate the costs or savings associated with the changes in ziconotide dosage in addition to its use in combination with morphine for the management of cancer pain., Materials and Methods: An open, Markov-like cohort decision analytic model was developed to estimate the budget impact of ziconotide in combination with morphine (ziconotide combination therapy) vs morphine monotherapy through intrathecal drug delivery (ITDD) for the management of cancer pain. The perspective adopted was that of the UK National Health Service, with a five-year time horizon. Sensitivity analyses were conducted to evaluate different scenarios., Results: Ziconotide combination therapy was more expensive than treatment with morphine monotherapy. The total costs of ziconotide combination therapy and morphine monotherapy for the first year were £395,748 and £136,628 respectively. The estimated five-year cumulative budget impact of treatment with ziconotide combination therapy for the five-year time horizon was £2,487,539, whereas that of morphine monotherapy was £913,804. The additional costs in any of the first five years are below the resource impact significance level of £1 million for medical technologies in England., Conclusions: The results of this budget impact analysis suggest that although a combination of intrathecal ziconotide in combination with morphine is associated with higher costs to the health care system in England, the incremental costs are not significant. Routine commissioning of ziconotide alone or in combination with morphine would provide an alternative for a population with limited ITDD treatment options., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The association of morphine ziconotide or sufentanil ziconotide was used to manage cancer pain. Moving these patients is sometimes difficult. In order to transport these syringes for pump refilling, it could be interesting to demonstrate the stability of the mixture and so to be able to ensure the best transport conditions of syringes., Materials and Methods: A stability indicating UPLC-DAD method was developed and validated according to the ICH guidelines. Fur mixtures of each association have been stored in 5 ± 3°C and 25 ± 2°C and were evaluated for seven days and compared to the initial observed concentrations., Results: The stability of these associations was demonstrated at 5°C for seven days thanks to relative concentrations (95% confidence intervals of the mean of three samples) systematically positioned between 95% and 105%. No degradation product was observed during the stability study., Conclusion: This study shows the stability of these association morphine ziconotide or sufentanil ziconotide at 5°C for seven days in polypropylen syringes. This result will allow the transport of the preparation under optimal conditions. Advance preparations for intrathecal pump refills could also be feasible., (© 2020 International Neuromodulation Society.)

Background and Objectives: There have been numerous recommendations for a starting dose of intrathecal ziconotide. The therapy remains underutilized partially due to reports of inefficacy and/or intolerance. This study describes short-term outcomes of a high-volume, low-concentration bolus (HVLC-B) ziconotide starting dose technique for patients with chronic spine pain. Intrathecal pumps are available with a Patient Therapy Manager (PTM), or patient-controlled intrathecal bolus device. Commonly published recommendations for a bolus dose has been 10% of the daily dose. This article describes an inversion of the traditional 10% rule-of-thumb. This article describes using the basal rate at a lowest programmable dose and utilizing the bolus for the majority of the medication delivery. Such an inversion may be considered a high volume bolus. The lowest commercially available concentration of ziconotide from the manufacturer is 25 mcg/mL. Pope and Deer (Neuromodulation, 18, 414-420 [2015]) described use of a dilution down to 5 mcg/mL. For purposes of this article, such dilutions to one-fifth of the commercially available solution are considered sufficiently dilute to qualify for the term "low concentration." Furthermore, the patients in this analysis received dilutions down to one-fiftieth of the lowest commercially available solution., Materials and Methods: A case series of patients with chronic spine pain with or without radicular pain received a starting dose intrathecal ziconotide regimen based on a specific HVLC-B technique. Efficacy, tolerability, and pump settings are reported and analyzed., Results: In total, 17 patients were identified who started ziconotide with the specified HVLC-B starting regimen. One of the 17 patients reported side effects that led to discontinuation of the therapy, although the side effect was not typical of ziconotide but rather likely attributable to other medications the patient was taking. Fifteen of the 17 reported improved pain control with intrathecal ziconotide. Sixteen of the 17 patients remained on intrathecal ziconotide throughout the 4.7-month average follow-up period. One patient who failed to obtain pain relief chose to remain on the therapy because of reported resolution of lower limb numbness., Conclusions: The HVLC-B starting regimen was effective and well tolerated in this short-term study of patients with chronic spine pain. More studies are needed to better elucidate long-term outcomes in larger patient populations., (© 2021 The Author. Neuromodulation: Technology at the Neural Interface published by Wiley Periodicals LLC on behalf of International Neuromodulation Society.)

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., (© 2020 International Neuromodulation Society.)

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., (© 2016 International Neuromodulation Society.)

Introduction: Intrathecal therapy is an important part of the pain treatment algorithm for chronic disease states. The use of this option is a viable treatment strategy, but it is inherent for pain physicians to understand risk assessment and mitigation. In this manuscript, we explore evidence and mitigating strategies to improve safety with intrathecal therapy., Methods: A robust literature search was performed covering January 2011 to October 9, 2016, in PubMed, Embase, MEDLINE, Biomed Central, Google Scholar, Current Contents Connect, and International Pharmaceutical Abstracts. The information was cross-referenced and compiled for evidence, analysis, and consensus review, with the intent to offer weighted recommendations and consensus statements on safety for targeted intrathecal therapy delivery., Results: The Polyanalgesic Consensus Conference has made several best practice recommendations to improve care and reduce morbidity and mortality associated with intrathecal therapy through all phases of management. The United States Prevention Service Task Force evidence level and consensus strength assessments are offered for each recommendation., Conclusion: Intrathecal therapy is a viable and relatively safe option for the treatment of cancer- and noncancer-related pain. Continued research and expert opinion are required to improve our current pharmacokinetic and pharmacodynamic model of intrathecal drug delivery, as this will undoubtedly improve safety and efficacy., (© 2017 International Neuromodulation Society.)

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., (© 2016 The Authors. Neuromodulation: Technology at the Neural Interface.)

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., (© 2015 International Neuromodulation Society.)

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., (© 2015 International Neuromodulation Society.)

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., (© 2015 International Neuromodulation Society.)

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., (© 2014 International Neuromodulation Society.)

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., (© 2014 International Neuromodulation Society.)

Objective: The objective of this study was to identify best practices and provide guidance to clinicians to ensure safety and optimize intrathecal drug delivery for chronic intractable pain., Methods: Twelve experienced pain medicine practitioners-eight anesthesiologists, one neurosurgeon, one physiatrist, one clinical psychologist, and one advanced practice registered nurse-from the United States, Australia, and Europe gathered to identify and publish consensus on best practices in three areas related to safe intrathecal therapy for pain: safety and monitoring, patient and device management, and patient selection and trialing., Conclusions: Intrathecal drug delivery is a valuable alternative drug delivery system for many patients with severe chronic or end-of-life pain. While device-related complications (mostly with catheters) and surgical-site infections can occur, the main therapy-related safety issues associated with intrathecal drug delivery arise primarily with inadequate patient monitoring (e.g., respiratory depression), inflammatory mass (e.g., high doses and concentrations of opioids), wound healing, dosing errors (e.g., medication concentration and pump programming), pump fills or refills (e.g., pocket fills), and interaction with concomitant systemic medications (e.g., opioids and benzodiazepines). Many of the reported adverse events and complications of intrathecal drug delivery can be prevented by adequate clinician training, implementation of best practices, and experience. In adopting the therapy, patients must be apprised of its risks and benefits. Physicians and patients must partner to achieve both safety and effectiveness., (© 2014 International Neuromodulation Society.)

Objectives: This study evaluated efficacy and safety of bolus doses of ziconotide (Prialt®, Eisai Limited, Hertfordshire, UK) to assess the option of continuous administration of this drug via an implanted intrathecal drug delivery system., Materials and Methods: Twenty adults with severe chronic pain who were under consideration for intrathecal (IT) therapy were enrolled in this open label, nonrandomized, pilot study. Informed consent was obtained. Demographics, medical/pain history, pain scores, and concomitant medications were recorded. A physical examination was performed. Creatine kinase was measured. Initial visual analog scale (VAS), blood pressure, heart rate, and respiratory rate were recorded. All patients received an initial bolus dose of 2.5 mcg ziconotide; the dose in the subsequent visits was modified according to response. Subsequent doses were 2.5 mcg, 1.2 mcg, or 3.75 mcg as per protocol. A good response (≥30% reduction in baseline pain VAS) with no side-effects on two occasions was considered a successful trial. Data were analyzed using a generalized estimating equations model, with pain VAS as the outcome and time (seven time points; preinjection and one to six hours postinjection) as the predictor., Results: Generalized estimating equations analysis of summary measures showed a mean reduction of pain VAS of approximately 25% at the group level; of 11 responders, seven underwent pump implantation procedure, two withdrew because of adverse effects, one refused an implant, and one could not have an implant (lack of funding from the Primary Care Trust)., Conclusions: Our data demonstrated that mean VAS was reduced by approximately 25% at the group level after IT ziconotide bolus. Treatment efficacy did not vary with sex, center, age, or pain etiology. Ziconotide bolus was generally well tolerated. Larger studies are needed to determine if bolus dosing with ziconotide is a good predictor of response to continuous IT ziconotide via an intrathecal drug delivery system., (© 2012 International Neuromodulation Society.)