Intrathecal Therapy Trials with Ziconotide
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.