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10 Articles in Volume 8, Issue #2
Anticephalgic Photoprotective Premedicated Mask
Culture and the Ethics of Patient-Centered Pain Care
Interpreting the Clinical Significance of Pain Questionnaires
Intrathecal Therapy Trials with Ziconotide
Iontophoresis in Pain Management
Maximizing Tertiary Effects of Low Level Laser Therapy
Platelet Rich Plasma (PRP): A Primer
Protecting Pain Physicians from Legal Challenges: Part 1
Right Unilateral Electroconvulsive Therapy Treatment for CRPS
Temporomandibular Dysfunction and Migraine

Intrathecal Therapy Trials with Ziconotide

A trialing protocol before initiation of long-term ziconotide intrathecal therapy is presented.

The 2007 Polyanalgesic Consensus Panel recommends ziconotide as one of three options for first-line intrathecal (IT) monotherapy. As we all know, Medicare and most insurance companies require a trial of IT therapy before one can proceed with implantation of a delivery system. Unlike opioids, which produce their effect within hours of administration, ziconotide may require several days of administration to demonstrate effectiveness. Ziconotide trials may require more rapid titration than would otherwise be used for chronic administration. Unfortunately, rapid administration of IT ziconotide can produce therapy-limiting side effects. The following article by Caraway et al provides us with a practical way to address the trialing requirement for ziconotide. Until the requirement for trialing is changed or eliminated, this guide should be very helpful to those who want to use ziconotide as monotherapy.

Intrathecal (IT) therapy is a well-established technique for the management of chronic, severe pain. Intrathecal therapy trials provide an opportunity to assess both the positive and negative aspects of a patient’s experience with IT therapy before committing to long-term treatment with a fully implanted infusion system. Numerous protocols have been used for trials of IT medications, and no protocol can be considered superior based on the available literature. The choice of a trialing protocol is dependent on many factors including (but not limited to) patient condition, available facilities and resources, and practice environment.1,2 Ultimately, the protocol choice is determined by the physician’s standard of care and comfort with the procedure,3 but insurance companies may require specific trialing criteria for reimbursement. In the United States, Medicare requires that a preliminary trial “be undertaken with a temporary intrathecal/epidural catheter to substantiate adequately acceptable pain relief and degree of side effects (including effects on the activities of daily living) and patient acceptance.”4

In 2004, ziconotide became the first non-opioid IT analgesic agent approved by the U.S. Food and Drug Administration for treatment of severe chronic pain. Ziconotide is the synthetic equivalent of a neuroactive peptide isolated from the venom of the fish-eating marine snail, Conus magus. Ziconotide can be considered for treatment of patients who are intolerant of, or refractory to, systemic analgesics and adjunctive therapies or who are intolerant of, or refractory to, other IT therapies such as IT morphine.5,6

Ziconotide has been evaluated for treatment of chronic pain caused by malignant or nonmalignant conditions in three randomized, double-blind, placebo-controlled clinical studies.7-9 In the two earlier studies,8,9 ziconotide administration began with a dose of 9.6 mcg/d and titration occurred as often as twice daily. To mitigate the frequency and severity of adverse events observed during the earlier studies, the starting dose was lowered to 2.4 mcg/d while the studies were ongoing. In the more recent study,7 ziconotide was initiated at 2.4 mcg/d with 1.2- to 2.4-mcg/d increases occurring no more than once during a 24-hour period.

Ziconotide administration was associated with significant pain relief in all three clinical studies, but improvement in Visual Analog Scale of Pain Intensity scores was more pronounced for patients in the first two studies that used faster titration schedules.8,9 However, the slower titration schedule used in the third study was associated with lower incidences of both treatment discontinuation and serious adverse events.7

Because of the unique therapeutic profile of ziconotide, an effective IT ziconotide trial must balance the need to quickly assess efficacy against the adverse events associated with rapid titration. This article describes some points to consider when trialing IT ziconotide and can help guide physicians through the development of an effective IT ziconotide trial protocol.

Considerations for IT Ziconotide Trials

Method of Administration. Unlike opioids, which can be trialed either IT or epidurally, ziconotide is indicated for IT administration only. In an early Phase I/II pharmacokinetic study, fewer than half of patients who received epidural injections of ziconotide had measurable ziconotide concentrations in their cerebrospinal fluid (Elan Pharmaceuticals, Inc., South San Francisco, Calif., written communication, January 2007). The hydrophilicity and large molecular size of ziconotide (a 25–amino-acid polypeptide) likely inhibits transportation of the molecule into the IT space after epidural administration.

Results from two studies—published nearly a decade apart— reveal a trend in physician preference toward the use of continuous IT infusion during IT therapy trials. In a 1996 review, 6.4 percent of patients under consideration for long-term IT therapy were trialed with continuous IT infusion,10 but nearly half (45 percent) of respondents to a 2005 physician survey preferred continuous IT infusion trials.11 For 99 percent of survey respondents, the most important advantage associated with continuous IT infusion was that the technique closely simulates infusion via an indwelling pump. However, there is evidence to suggest that continuous infusion trials may be no more predictive of long-term patient response to IT opioid therapy than are trials that use bolus injections.12

While studies investigating the utility of bolus IT ziconotide injections are ongoing, clinical experience from the ziconotide trials suggests that continuous IT infusion is the preferred trialing method. Ziconotide infusion can be safely initiated using routine clinical practice procedures for accessing the IT space and infusing IT drugs.

Inpatient Versus Outpatient Settings. There are advantages associated with both inpatient and outpatient protocols (see Table 1). When selecting a trialing environment, factors to consider include the patient’s support system (e.g., whether or not the patient lives alone) and the ability of the patient or caregiver to maintain an external infusion system and to recognize symptoms of a potentially serious complication (e.g., meningitis). A national survey indicated that only 8 percent of physicians who prefer continuous IT infusion trials perform them on an outpatient basis,11 while many clinics will perform only inpatient continuous IT infusion trials because of patient safety concerns. However, IT therapy trials performed in an outpatient setting were considered reasonable in a 1996 expert review article.13

During inpatient IT infusion trialing, it is imperative that patients be monitored in an adequately equipped facility for sufficient time to ensure that they do not experience dangerous or life-threatening side effects. Nine patient deaths that occurred after the initiation or reinitiation of chronic IT opioid therapy were reported within a four-month period;14 seven of the nine patients were observed for less than 24 hours before release from the hospital. Therefore, hospitalization for at least 24 hours is strongly recommended. Although these deaths occurred during IT opioid treatment, similar concerns exist during an IT ziconotide trial. Furthermore, because the effects of ziconotide administration are sometimes slow to develop, physicians may choose to extend the duration of inpatient monitoring during an IT ziconotide trial.

Meningitis. Meningitis is a potentially serious complication of IT therapy. There is no evidence to suggest that ziconotide is associated with an increased risk of meningitis; rather, the risk is associated with the therapeutic technique and is likely to increase with the duration of exposure to an external system. Meningitis has been reported to occur in anywhere from zero to nine percent of patients receiving long-term spinal analgesia, with a greater rate of occurrence in patients using external devices.15-19 The meningitis rate during ziconotide clinical trials was 3 percent (41 cases in 1,254 patients), and 93 percent of those cases (38 of 41) occurred in patients infused from an external pump.5 Because continuous IT infusion trials use external systems, the surgical techniques, prophylactic antibiotic use, patient surveillance protocols, and trial duration should be clearly defined and modified as necessary to minimize meningitis risk. There are no established standards for these parameters, so physicians must use their own clinical judgment. In addition, special consideration should be given to patients with other predisposing factors for meningitis (e.g., patients with diabetes, severe rheumatological diseases, malignancies, or potentially altered immune states).20-22

Table 1. Advantages of Inpatient Versus
Outpatient Trials
Trial Type Advantages
Inpatient
  • Closer monitoring may enhance safety2
  • Closer monitoring enables faster titration
  • Easier patient observation2
  • Improved sterility2
Outpatient
  • More accurately simulates normal patient activity2
  • Longer trial duration is possible2
  • More opportunity for dose titration or adjustment2
  • Greater flexibility
  • Less expensive on a per-day basis2

Recommended Titration Schedule for a Three-Day IT Ziconotide Trial. Based on clinical study results and physician experience, an initial ziconotide dose of 1.2 mcg/d with dose increases of 1.2 mcg/d occurring every 12 to 24 hours is considered an acceptable titration schedule for a three-day IT ziconotide trial. When this schedule is used, the maximum dose that can be reached in three days is approximately 8 mcg/d, which exceeds the mean final dose achieved in the third clinical study (6.96 mcg/d).7 Many patients will respond within this dose range, and the trial can be ended early if analgesia is demonstrated at a lower dose. However, a growing body of clinical experience suggests that patients respond to ziconotide over a wide range of doses, and some patients may require ziconotide infusion rates that are substantially higher than 8 mcg/d to achieve pain relief. Hence, if adequate analgesia is not evident after the third day of the trial and adverse events remain absent or tolerable, extension of the trial and additional dose increases should be considered. The trial should be terminated immediately if intolerable adverse events develop. Termination of ziconotide infusion is not associated with withdrawal symptoms, so an IT ziconotide trial can be ended abruptly.

It is crucial to recognize that this titration scheme is suggested for external IT trials only. Titration with a permanently implanted IT system should proceed at a much slower rate.

Adverse Events. Because the titration schedule recommended for an external IT ziconotide trial is accelerated, the frequency and severity of adverse events are likely to be higher than during slow titration or chronic infusion. Unlike opioids, ziconotide is associated with a number of adverse events that appear to evolve from impaired cerebellar and/or cortical function (see Table 2). These symptoms can be subtle and difficult to recognize with standard observation techniques. It is critical that an individual familiar with the assessment of these adverse events be available to interview and evaluate patients undergoing an IT ziconotide trial.

Table 2. Ziconotide Adverse Events
of Special Interest*
Adverse Event Incidence During Clinical Studies,
n (%) (N=1202)
Nausea (including vomiting or nausea and vomiting) 659 (54.8)
Dizziness 620 (51.6)
Confusion 380 (31.6)
Abnormal gait (including ataxia) 356 (29.6)
Asthenia (including myasthenia) 342 (28.5)
Nystagmus 327 (27.2)
Somnolence 327 (27.2)
Memory impairment or amnesia 263 (21.9)
Aphasia or speech disorder 258 (21.5)
Amblyopia (including abnormal vision) 229 (19.1)
Hypotension (including postural hypotension) 170 (14.1)
Urinary retention 166 (13.8)
Abnormal thinking (including difficulty concentrating and mental slowing) 162 (13.5)
* Data on file, Elan Pharmaceuticals, Inc. (Elan Pharmaceuticals, Inc., South San Francisco, Calif.)
Table 3. Sample Ziconotide Dose Calculations
Desired Dose mcg/d Flow Rate
mL/d
Concentration mcg/mL
0.5 0.048* 10.4†
1.2 0.048* 25‡
2 0.08 25‡
* Minimum possible flow rate for SynchroMed® pumps (Medtronic, Inc.)26,27
† Requires dilution of the commercial ziconotide solution.
‡ Minimum ziconotide concentration available in commercial formulations.
Dose delivered = concentration × flow rate
Concentration = dose delivered/flow rate

Ziconotide Dosing After a Successful Trial

Titration Schedule for Initiation of Long-term Ziconotide Therapy. After successful completion of an external IT ziconotide trial and implantation of a long-term infusion system, ziconotide administration should not begin at the final dose reached with the titration schedule recommended above. The analgesia (as well as the adverse events) associated with ziconotide often has a delayed onset and may not fully develop during a three-day IT ziconotide trial. Ziconotide should be reinitiated at a very low dose (0.5-2.4 mcg/d), and each dose level should be maintained long enough to enable accurate assessment of both analgesia and adverse events before the dose is increased; weekly or less frequent dose adjustments are adequate to achieve this goal. The ziconotide prescribing information specifies that titration begin with an initial dose no greater than 2.4 mcg/d and that dose increases occur no more frequently than two to three times per week in increments of 2.4 mcg/d or less.5 A slower titration schedule has been recommended by some experts.23

Wide variability in effective, long-term doses has been observed among ziconotide-treated patients. The maximum recommended ziconotide dose is 19.2 mcg/d,5 although some patients have received safe, long-term treatment with higher doses.24,25

Dose Calculation. Ziconotide is supplied as a 25-mcg/mL solution in a single-use 20-mL glass vial and as a 100-mcg/mL solution in single-use glass vials containing 1 or 5 mL of solution.5 The minimum flow rate for the approved implantable infusion system (SynchroMed®, Medtronic, Inc.) is 0.048 mL/d, so the lowest ziconotide dose that can be delivered with a commercial ziconotide formulation is 1.2 mcg/d (see Table 3). If a lower IT ziconotide dose is desired, the commercial formulation can be diluted with preservative-free 0.9% sodium chloride under strict aseptic conditions.

Conclusions

This article is intended to serve as a guide for conducting IT therapy trials with ziconotide. The therapeutic profile of ziconotide is unique, and physicians must balance the need to evaluate patient response quickly against the adverse events associated with rapid titration. Short-term (e.g., three-day) IT ziconotide trials may require more aggressive dosing and titration than is recommended for the initiation of long-term ziconotide therapy. Clinicians must be able to recognize the sometimes subtle clinical signs that may signal the development of ziconotide-related adverse events. After successful completion of an IT ziconotide trial, patients should not begin long-term infusion at the final trial dose; instead, ziconotide should be reinitiated at a very low dose and titrated slowly to enable accurate assessments of analgesia and adverse events between dose increases. When performed judiciously, temporary IT infusion of ziconotide from an external pump may be a valuable option for trialing IT therapy before implantation of a permanent IT infusion system.

Disclosure and Acknowledgment

Financial support for this article was provided by Elan Pharmaceuticals, Inc., and MedLogix Communications, LLC, contributed to the development of the manuscript.

Last updated on: February 28, 2011
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