Continuous Intrathecal Infusion of Ziconotide for Treatment of Chronic Malignant and Nonmalignant Pain Over 12 Months: A Prospective,Open‐label Study

Objectives. This study aims to assess the safety and efficacy of long‐term intrathecal (IT) ziconotide infusion. Materials and Methods. In this prospective study, 155 patients with severe chronic pain (48 with malignant pain, 107 with nonmalignant pain) who had been responsive to short‐term IT ziconotide in a double‐blind, placebo‐controlled study received long‐term, open‐label IT ziconotide monotherapy. Efficacy assessments included the mean percentage change on the visual analog scale of pain intensity from baseline in the study of origin; safety was monitored by adverse event (AE) reports, periodic laboratory tests, and vital sign measurements. Results. At the last available observation, the visual analog scale of pain intensity scores had decreased by a mean of 36.9% from baseline in the short‐term trial (N = 144; 95% CI: 30.1–43.7%; p < 0.0001). The mean IT ziconotide dose remained stable over 12 months in the 31 patients who participated in the study for ≥ one year. Ziconotide‐related AEs were reported in 147 out of 155 patients (94.8%); 39.4% of patients discontinued treatment because of AEs, the majority of which were considered ziconotide related. Conclusions. Ziconotide IT monotherapy provided patients with analgesia for 12 months in this open‐label study, with an acceptable benefit/risk profile and no evidence of tolerance.     

Intrathecal Ziconotide in the Treatment of Chronic Nonmalignant Pain: A Randomized,Double‐Blind,Placebo‐Controlled Clinical Trial

Objective. The safety and efficacy of intrathecal (IT) ziconotide was studied in a randomized, double‐blind, placebo‐controlled trial. Materials and Methods. Patients (169 ziconotide, 86 placebo) with severe chronic nonmalignant pain unresponsive to conventional therapy and a visual analog scale of pain intensity (VASPI score) ≥ 50 mm were treated over a 6‐day period in an inpatient hospital setting. Initial starting dose was 0.4 µg/hour and was titrated to analgesia or intolerance (maximum dose 7.0 µg/hour). The starting and maximum doses were reduced to 0.1 µg/hour and 2.4 µg/hour, respectively, due to adverse events (AEs). Results. The mean percent reduction in VASPI score from baseline was 31.2% and 6.0% for ziconotide‐ and placebo‐treated patients, respectively (p ≤ 0.001). During the initial titration phase, a significantly greater percentage of patients in the ziconotide group compared to the placebo group reported AEs, including abnormal gait, amblyopia, dizziness, nausea, nystagmus, pain, urinary retention, and vomiting. Conclusion. Ziconotide provided significant analgesia in patients for whom conventional therapy failed. However, there was a considerable incidence of ziconotide‐associated AEs due to the rapid titration and high doses administered.     

Chemical Stability of Admixtures Combining Ziconotide With Baclofen During Simulated Intrathecal Administration

Objective. To determine the stability of admixtures combining ziconotide with commercially formulated or powdered baclofen during simulated intrathecal infusion under laboratory conditions at 37°. Materials and Methods. Admixtures of ziconotide (25 µg/mL) with commercially formulated (1.5 mg/mL) or powdered (2.0 mg/mL) baclofen were stored in implantable intrathecal pumps at 37°. Drug concentrations were determined with high‐performance liquid chromatography, and the length of time that the concentrations of both drugs remained ≥90% and ≥80% of initial (ie, the 90% and 80% stability, respectively) was estimated based on lower 95% confidence bounds obtained via linear regression. Results. Baclofen was stable in both admixtures. In the commercially formulated baclofen admixture, the mean ziconotide concentration declined to 82.2% of initial in 30 days; the estimates for 90% and 80% stability were 12 and 29 days, respectively. In the powdered baclofen admixture, the mean ziconotide concentration declined to 87.4% of initial in 30 days; the estimates for 90% and 80% stability were 20 and 41 days, respectively. Conclusion. Ziconotide–baclofen admixtures were more stable when prepared using powdered baclofen rather than a commercial baclofen formulation.     

Ziconotide for the Management of Cancer Pain: A Budget Impact Analysis

ObjectivesRecent 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 MethodsAn 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.ResultsZiconotide 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.ConclusionsThe 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.     

Long‐Term Intrathecal Ziconotide Therapy: A Case Study and Discussion

This case study describes the therapeutic result of intrathecal administration of ziconotide, a new synthetic neurotoxin derived from the venom of the Philippine marine snail, Conus Magus, to a 48‐year‐old male with chronic, and previously untreatable, neuropathic pain of an undeterminable etiology. The patient suffered tactile allodynia and reported his baseline pain intensity to be 80 mm on the 100 mm Visual Analog Scale for Pain Intensity. After responding affirmatively to treatment in a blinded placebo‐controlled trial, the patient enrolled in a long‐term, open‐label trial. Currently, the patient rates his pain at 16 mm and enjoys an improved quality of life. This result suggests that treatment with ziconotide may provide outstanding relief to patients with chronic pain while sparing them the unpleasant side effects associated with other treatments.     

A Prospective,Open‐label Study of Long‐term Intrathecal Ziconotide for Chronic Nonmalignant Back Pain: A Case Report

Ziconotide is an N‐type calcium channel (NCC) blocking conopeptide, acting primarily at the NCC‐rich dorsal horn. Reported here is an early experience with intrathecal ziconotide in a 55‐year‐old man with chronic pain resulting from failed back surgery. All conservative and surgical treatments, in addition to IT morphine, failed prior to enrollment in a short‐term, placebo‐controlled trial testing ziconotide efficacy and safety. Following successful short‐term treatment, the patient was enrolled in a long‐term follow‐up study. The dosing regimen, onset and resolution of adverse events, and improvement on the primary efficacy measure, the Visual Analog Scale of Pain Intensity, are discussed. Overall, the patient responded positively to ziconotide.     

Intrathecal Administration of Different Drugs by Programmable Infusion Device in Chronic Pain. A Case Report.

Objective and Importance . The subarachnoid infusion of narcotics by programmable devices in patients with chronic non-malignant pain can be a useful therapeutic method. However, certain side-effects, opioid tolerance or changes in the nature of the pain can lead to failure of the therapy. Clinical Presentation . We present a case report of a woman with both chronic perineal pain and sciatic pain with radiation to her lower limbs caused by failed back surgery syndrome. The pain proved to be resistant to common medical therapy and to spinal cord stimulation. Technique . After surgical implantation of a programmable infusion pump, the patient's leg pain improved with an intrathecal infusion of morphine and bupivacaine. The perineal pain was treated with an infusion of clonidine. The patient therefore needed alternative infusions of both drugs with changes of infusional parameters. Conclusion . The possibility of varying the infusion method of mixed drugs or alternating the drugs is fundamental for successful therapy since neuropathic pain must be considered a dynamic state.     

Symptomatic Intrathecal Catheter Tip Granuloma Formation With Ultralow-Dose and Low-Concentration Morphine Infusion: A Case Report and Review of Literature

ObjectivesThis study aimed to describe catheter tip granuloma (CTG) formation in a patient on ultralow-dose, low-concentration morphine via intrathecal (IT) drug delivery system (IDDS) and to review literature for reports of IT granuloma formation and association with drug type, drug dose, and drug concentration.Materials and MethodsThis review describes diagnosis and management of a patient with CTG on ultralow-dose, low-concentration morphine. PubMed data base search was conducted from January 1990 to July 2021 for original articles on CTG formation in humans getting intrathecal analgesics. Data were extracted on indications for IDDS, time to detect CTG, and type of drug/s with drug doses and concentrations. Percentages and average with range for age, sex, duration of infusion, drug doses, and drug concentrations were calculated.ResultsWe describe CTG formation and spinal cord compression with worsening of sensorimotor deficits in a patient receiving intrathecal morphine at ultralow dose (0.6 mg/d) and low concentration (1.2 mg/mL), which is the lowest reported morphine dose associated with CTG in the literature. Our literature review shows all IT drugs have the potential for granuloma formation, and there is no drug with granuloma-inhibiting effect.ConclusionsThere is no drug, dose, or concentration that has granuloma-sparing effect. It is imperative to maintain vigilance for potential CTG in all patients with IDDS. Routine monitoring and prompt evaluation for any unexplained symptoms or change in neurologic status from baseline is critical in early detection and treatment of CTG.     

An Open‐Label,Multicenter Study of the Safety and Efficacy of Intrathecal Ziconotide for Severe Chronic Pain When Delivered via an External Pump

Objectives. The study aims to assess the safety and efficacy of intrathecal (IT) ziconotide when delivered via an external infusion system. Materials and Methods. Patients with severe chronic pain were implanted with an external infusion system, and IT ziconotide was titrated over one to four weeks. Safety was evaluated via adverse event (AE) reports, and efficacy measures included the visual analog scale of pain intensity (VASPI), categorical pain relief scale (CPRS), and clinical global impression (CGI). Results. Sixty‐four of the 71 patients (90.1%) experienced an AE during titration; five patients developed meningitis after completing at least two weeks of therapy. A significant (p ≤ 0.005) median percentage improvement in VASPI scores was seen at week 1 and maintained through week 4 (range: 11.0–32.6%); 53.6% of patients reported good to excellent pain control on the CGI and 52.2% of patients reported moderate to complete pain relief on the CPRS. Conclusions. The study results suggest that a short‐term trial of IT ziconotide using an external infusion system may be sufficient to assess patient response. High rates of AEs were noted; however, ziconotide‐related AEs were consistent with those reported in previous trials.