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ANALGESIA

Intrathecal Ziconotide for Severe Chronic Pain: Safety and Tolerability Results of an Open-Label, Long-Term Trial

Mark S. Wallace, MD^*, Richard Rauck, MD, Robert Fisher, MD, Steven G. Charapata, MD, David Ellis, MD, PhD^||, Sanjeeva Dissanayake, MBBS, MRCP^¶ For the Ziconotide 98-022 Study Group

From the *Center for Pain Medicine, University of California, San Diego, La Jolla, California; Center for Clinical Research, Winston-Salem, North Carolina; RC Goodman Institute for Pain Management, Sparks Regional Medical Center, Fort Smith, Arkansas; Pain Management Associates, Kansas City, Missouri; ||Elan Pharmaceuticals, Inc., San Diego, California; and ¶Elan Pharma, Ltd., Stevenage, UK.

Address correspondence and reprint requests to Mark S. Wallace, MD, University of CA, San Diego, Medical Center, 9500 Gilman Dr., Ste. 0924, La Jolla, CA 92093. Address e-mail to mswallace{at}ucsd.edu.

Abstract

BACKGROUND: Ziconotide is a non-opioid drug indicated for management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of or refractory to other treatments.

METHODS: Six-hundred and forty-four patients with severe chronic pain participated in this open-label, multicenter study. Ziconotide titration was followed by long-term infusion. Efficacy assessments included the Visual Analog Scale of Pain Intensity. Safety was assessed via adverse events (AEs), vital signs, and routine laboratory values.

RESULTS: One-hundred and nineteen patients received ziconotide for 360 days; total exposure was 350.9 patient years. Median duration of ziconotide therapy was 67.5 days (range, 1.2–1215.5 days); mean dose at last infusion was 8.4 µg/d (range, 0.048–240.0 µg/d). Median Visual Analog Scale of Pain Intensity scores at baseline, month 1, and the last available observation up to month 2 were 76 mm (range, 4–100 mm), 68 mm (range, 0–100 mm), and 73 mm (range, 0–100 mm), respectively. Most patients (99.7%) experienced 1 AE. Most AEs were of mild (43.5%) or moderate (42.3%) severity; 58.6% of AEs were considered unrelated to ziconotide. The most commonly reported AEs (25% of patients) included nausea, dizziness, headache, confusion, pain, somnolence, and memory impairment. Clinically significant abnormalities (>3 times the upper limit of normal) in creatine kinase levels were reported in 0.9% of patients at baseline, 5.7% at month 1, and 3.4% at ziconotide discontinuation. No drug-related deaths, IT granulomas, or permanent adverse sequelae occurred with ziconotide therapy.

CONCLUSION: We conclude that long-term IT ziconotide is an option for patients with severe, refractory chronic pain.

Ziconotide is the synthetic form of -conopeptide MVIIA, a conopeptide isolated from the venom of the marine snail Conus magus.1–3 This non-opioid drug was approved in the United States in 2004 for the management of severe chronic pain in patients for whom intrathecal (IT) therapy is warranted and who are intolerant of or refractory to other treatments such as systemic analgesics, adjunctive therapies, or IT morphine. In 2005, ziconotide was approved in the European Union for the treatment of severe chronic pain in patients who require IT analgesia. Ziconotide exerts antinociceptive effects through blockade of N-type voltage-sensitive calcium channels, inhibiting depolarization-induced calcium influx and reducing neurotransmitter release from nociceptive afferents.1,4 No development of tolerance has been seen in animal model studies of IT ziconotide infusion.5

The efficacy and safety of ziconotide have been studied in three randomized, double-blind, placebo-controlled trials.6–8 In the first two trials, 111 patients with refractory cancer-related or acquired immunodeficiency syndrome-related pain7 and 257 patients with inadequately managed nonmalignant pain8 were continuously infused with IT ziconotide or placebo for 5–6 days. Ziconotide was associated with statistically significant pain relief, as measured by the percent reduction in Visual Analog Scale of Pain Intensity (VASPI) scores from baseline, in patients with malignant pain (53%, ziconotide versus 18%, placebo; P < 0.001) and nonmalignant pain (31%, ziconotide versus 6%, placebo; P < 0.001). Some adverse events (AEs), such as dizziness and nystagmus, were observed with a 15% difference in incidence between the ziconotide and placebo groups. The third trial included 220 patients and used a lower-dose, slower-titration regimen than that used in the previous studies.6 After 3 wk of treatment, mean percentage improvement in VASPI score from baseline was significantly greater in the ziconotide-treated group (14.7%) than in the placebo group (7.2%, P = 0.0360). Although the degree of pain relief in this study was less than that seen in the previous trials, the low-dose, slow-titration regimen resulted in a lower incidence of serious AEs and a smaller proportion of discontinuations for AEs than did the higher-dose, faster-titration regimen used in the previous studies.

The primary objective of the current study was to investigate the safety and tolerability of long-term ziconotide therapy using a slow-titration regimen.

METHODS

Study Design
This open-label, multicenter, long-term, outpatient study evaluated the efficacy, safety, and tolerability of IT ziconotide in patients with severe chronic pain, with a primary focus on safety and tolerability. The study had no predetermined duration, and the length of treatment was open-ended. Patients wishing to continue ziconotide therapy at the end of this study were allowed to enroll in a new study. The study protocol was approved by appropriate IRBs before the study was initiated. Before the performance of any study-specific procedures, all patients provided written informed consent. The clinical investigators conducted the trial under grants from Elan Pharmaceuticals, Inc. The investigators or the institutions by which they were employed were reimbursed for clinical assessments and case report form completion on a per-visit basis.

Eligible patients were at least 18-yr-of-age (or at least 10-yr-of-age with parental consent) with severe chronic pain attributable to cancer, acquired immune deficiency syndrome, or the treatment thereof, or a nonmalignant etiology with a demonstrable neurological basis. Only patients for whom IT therapy was recommended as the next clinically indicated treatment or who had an unsatisfactory response to IT opioids alone or in combination with adjunctive drugs such as clonidine and bupivacaine could participate. No minimum VASPI score was required for study participation. Each patient was required to have prior IT medications tapered and discontinued and to be stabilized on a systemic analgesic regimen for at least 7 days before beginning ziconotide therapy. Patients were excluded if they were pregnant or lactating; showed signs of sepsis or inadequately treated infection; had uncontrolled heart failure or second- or third-degree heart block; had a history of dementia, delirium, somatization disorder, hypochondriasis, hysteria, or Munchausen syndrome; or had an untreated or inadequately treated affective disorder. Patients were excluded if they had been exposed to an investigational drug other than ziconotide <30 days before initiation of ziconotide, had a nonpatent spinal canal, or were unable to comply with the study protocol.

Patient Visits and Safety Measurements
Patients underwent an initial screening visit, followed by scheduled visits (twice weekly for 4 wk, monthly thereafter). Within 7 days before ziconotide initiation, a complete physical examination was performed, a medical and pain management history was obtained, and baseline pain was assessed using the VASPI. Function level and pain impact were assessed using the Function Level Assessment Test (a scale developed by the study sponsor, Appendix: Table A1). The purpose of the Function Level Assessment Test was to determine patients' functionality via a series of questions regarding ambulation (from walking normally to being bedridden), sleep pattern (amount of uninterrupted sleep per night), work (from full-time employment to not working), driving (from no restrictions to not driving), and pain impact on daily life (from mild to dominating). In addition, vital signs, routine laboratory tests (i.e., chemistry, hematology, and urinalysis), and a 12-lead electrocardiogram (ECG) were obtained. Cognitive function was also evaluated at screening through administration of the Wechsler Memory Scale-Revised (WMS-R)9 story memory subtest and the Trail-Making Test (parts A and B).10,11

Vital signs were measured at twice weekly visits during the first 4 wk of the study and monthly thereafter. Laboratory tests were assessed at each monthly visit and on discontinuation of therapy. A 12-lead ECG was obtained at screening, month 1, and the time of ziconotide discontinuation. A 12-lead ECG was also repeated for any patient who restarted ziconotide therapy after an interruption of more than 2 wk. The WMS-R story memory subtest was administered at month 2, ziconotide discontinuation, and 4 wk after ziconotide discontinuation. The Trail-Making Test (parts A and B) was administered at month 1, monthly thereafter, and at ziconotide discontinuation/ study termination.

Two and 4 wk after discontinuing ziconotide, patients returned for follow-up visits conducted by the investigator. At these visits, vital signs were measured and AEs (including follow-up of any unresolved AEs or unresolved clinically significant laboratory evaluations) were assessed.

Drug Administration
Ziconotide is approved by the United States Food and Drug Administration for the management of severe chronic pain in patients for whom IT therapy is warranted and who are intolerant of or refractory to other treatment such as systemic analgesics, adjunctive therapies, or IT morphine. Ziconotide was continuously infused via an IT catheter and infusion pump. If an enrolled patient did not have an implanted SynchroMed® Infusion System (Medtronic, Inc., 710 Medtronic Parkway, Minneapolis, MN), a temporary IT catheter was inserted and a CADD-Micro® ambulatory infusion pump (SIMS Deltec, Inc., 1265 Gray Fox Road, St. Paul, MN) was used to deliver the medication. Patients were not trialed with ziconotide before study participation. Treatment consisted of a ziconotide titration/stabilization period with an initial dose of 2.4 µg/d, followed by long-term ziconotide infusion. Dose adjustments were made by the investigator at both scheduled and unscheduled study visits. Dose increases were not to exceed 2.4 µg/d at any adjustment and were not permitted more than once every 24 h. No maximum dose limit was defined. The dose could be decreased by any amount at any time, and a single voluntary discontinuation of ziconotide infusion for up to 30 days was permitted (i.e., drug holiday). This temporary discontinuation of ziconotide therapy was permitted based on previous experience in clinical trials in which patients discontinued treatment and later requested re-entry into the trial.

Statistical Analysis
Statistical analyses were performed using SAS version 6.12 and above (SAS Institute Inc., Cary, NC). Median VASPI scores at baseline, month 1, and the last available observation up to month 2 were calculated for patients who had scores at both baseline and at least one follow-up visit. The proportion of patients with a 30% improvement in VASPI score at month 1 was calculated for patients with VASPI scores 50 mm and <50 mm at baseline. For the Function Level Assessment Test, patients with data at both baseline and month 2 were evaluated, and results were summarized via descriptive statistics. Tests for marginal homogeneity were performed to compare frequency distributions at baseline and at month 2 for ambulation, sleep pattern, work, driving, and pain impact on daily life.

All patients who received any amount of ziconotide were included in the safety analysis. To increase the statistical power of the study to detect less common AEs, an amendment to the original protocol increased the target for enrollment from 400 to up to 700 patients. This increase would allow for the detection, with 95% confidence, of AEs at a 0.43% occurrence rate in the study population. All AEs were coded with the Coding Symbols for Thesaurus of Adverse Reaction Terms, and all reasons for study discontinuation were recorded. Changes from baseline for vital signs and ECG readings were analyzed with paired t-tests. All tests were two-tailed with an level <0.05 considered statistically significant; data from all sites were pooled for each analysis. Results of the laboratory tests, WMS-R story memory subtest, and Trail-Making Test (parts A and B) were summarized using descriptive statistics.

RESULTS

The study was conducted at 68 study centers between October 28, 1998, and August 13, 2002. The flow of patients through the trial is illustrated in Figure 1. Six-hundred and forty-four patients received treatment and were included in the safety analysis (Table 1); the mean number of patients treated at each study center was 9.5 (range, 1–53 patients). At screening, patients exhibited a variety of physical and neurological abnormalities including musculoskeletal (n = 389, 60.4%), sensory system (n = 317, 49.2%), gait (n = 311, 48.3%), reflex (n = 268, 41.6%), and motor system (n = 249, 38.7%). At screening, Function Level Assessment Test data were available for 643 patients. Of these patients, only 132 patients (20.5%) could walk normally, 63 patients (9.8%) got more than 6 h of uninterrupted sleep per night, 554 patients (86.2%) were not working, 172 patients (26.7%) did not drive, and 364 patients (56.6%) indicated that pain dominated their lives. All 644 patients used at least one concomitant medication during the study, and the vast majority of patients (90.1%) used strong analgesics (e.g., opioids) (Table 2). The primary reasons for permanent discontinuation from the study included AE occurrence (48.9%), lack of efficacy (29.7%), and rollover into a new ziconotide study (10.6%). Enrolled patients received therapy with ziconotide for a median of 67.5 days (range, 1.2–1215.5 days); 119 patients (18.5%) received ziconotide for 360 days. In 36.6% of patients, treatment was temporarily interrupted without termination from the trial. The total exposure to ziconotide during the study was 350.9 patient years. The mean ziconotide dose at the last infusion was 8.4 µg/d (range, 0.048–240.0 µg/d).

View larger version (12K): [in this window] [in a new window]   Figure 1. Flow of patients through the study.

The median VASPI scores at baseline, month 1, and the last available observation up to month 2 were 76 mm (range, 4–100 mm; sd, 20.3 mm; n = 643), 68 mm (range, 0–100 mm; sd, 27.7 mm; n = 453), and 73 mm (range, 0–100 mm; sd, 25.4 mm; n = 643), respectively. At baseline, 85.2% of patients (548 of 643) had VASPI scores 50 mm and 14.8% (95 of 643) had VASPI scores <50 mm. Among patients with VASPI scores 50 mm at baseline who completed 1 mo of therapy, 129 of 394 patients (32.7%) had a 30% improvement in VASPI score at month 1. Nine of 59 patients (15.3%) who had baseline VASPI scores <50 mm and completed 1 mo of therapy had a 30% improvement in VASPI score at month 1.

Three-hundred and thirty-nine patients were included in the change-from-baseline analyses for the Function Level Assessment Test (i.e., those with data on the parameters at both baseline and month 2). The distribution of scores for pain impact on daily life differed significantly between baseline and month 2 (P < 0.001); 119 patients (35.1%) noted improvement from baseline at month 2, and only 36 patients (10.6%) noted worsening from baseline at month 2. Distributions for work and driving differed significantly (P = 0.0340 and 0.0004, respectively) between baseline and month 2; more patients worsened than improved on these variables. Distributions for ambulation and sleep pattern between baseline and month 2 were not significantly different.

At least one AE was reported by nearly every study participant (99.7%). Most patients (587 of 644; 91.1%) first reported AEs during the first 14 days of the study. The AEs experienced by 25% of patients included nausea (52.6%), dizziness (51.6%), headache (40.1%), confusion (35.1%), pain (32.0%), somnolence (29.3%), and memory impairment (27.8%). Most reported AEs were described as either mild (43.5%) or moderate (42.3%), and more than half (58.6%) were considered unrelated to ziconotide. Those AEs considered ziconotide-related with the highest incidence were dizziness, nausea, confusion, memory impairment, and nystagmus (Table 3). Men and women exhibited similar AE profiles, with the exception of urinary tract infection, which was reported more frequently in women (16.7%) than in men (5.1%). AEs observed more frequently (5% difference in incidence) in older patients (60 yr) than in younger patients (<60 yr) included confusion (40.7% vs 32.7%), constipation (24.9% vs 17.1%), and peripheral edema (24.3% vs 17.1%).

View this table: [in this window] [in a new window]   Table 3. Reported Adverse Events by Relationship to Ziconotide (Difference in Incidence 5% Related Minus Unrelated) (n = 644)

A detailed evaluation was performed for 14 AEs (i.e., abnormal gait, asthenia, blurred vision, confusion, difficulty concentrating, dizziness, hypotension, impaired verbal expression, memory impairment, mental slowing, nausea, nystagmus, somnolence, and urinary retention) that were commonly reported in short-term ziconotide efficacy trials.6–8 Onset of nausea and dizziness occurred at the lowest median doses (3.6 and 4.1 µg/d, respectively) and were reported earliest (median, 4.4 and 5.5 days, respectively). Mental slowing, confusion, difficulty concentrating, memory impairment, and impaired verbal expression (i.e., primarily cognitive events) were associated with the highest median ziconotide doses at onset (5.0–5.8 µg/d) and generally had the longest median times to onset (23.3–36.2 days). For patients with 90 days of ziconotide exposure, evaluation of AE occurrence versus time revealed no increase in AE onset over time that was suggestive of a cumulative toxic effect with prolonged ziconotide exposure.

The time to resolution of continuing AEs after ziconotide discontinuation was evaluated for 12 treatment-related AEs (i.e., abnormal gait, ataxia, confusion, difficulty concentrating, dizziness, impaired verbal expression, memory impairment, mental slowing, nausea, nausea and vomiting, somnolence, and vomiting) that were often identified as the reason for ziconotide discontinuation, some of which were reported as serious AEs (Table 4). The AEs related to cognition (i.e., confusion, difficulty concentrating, impaired verbal expression, memory impairment, and mental slowing) typically resolved within approximately 2 wk of ziconotide discontinuation, with the median time to resolution ranging from 10.5 to 15.0 days for these events. A reversal of other nervous system-related AEs (i.e., abnormal gait, ataxia, dizziness, and somnolence) was seen, with the median time to reversal ranging from 8.0 to 14.0 days. The occurrence of nausea, vomiting, or nausea and vomiting resolved within 5.0–8.0 days (median) after discontinuation of ziconotide.

The presence of an external infusion device was associated with a higher incidence of device-related AEs than was use of an internal infusion device. Of the 242 patients with an external device, 68.2% experienced a device-related AE, compared with 29.1% of 532 patients with an implanted infusion system (130 patients switched from an external to an internal infusion system during the study). The most commonly reported AEs related to the infusion device (5% of patients) included headache (15.4%), catheter complications (13.8%), abnormal cerebrospinal fluid (11.0%), pump complications (9.3%), pump site edema (7.8%), pump site pain (5.3%), and pain (5.0%).

Meningitis was reported in 20 patients (3.1%) and was a serious AE in 19 of these patients. Of the 20 patients with meningitis, 19 had external infusion systems, and most of the reported cases of meningitis were considered to be related to the infusion device (95%) and not to ziconotide. One case of meningitis (5.0%) was considered to be ziconotide-related and was described by the investigator as "chemical meningitis." Nineteen of the 20 patients recovered without sequelae. One patient died from end-stage cardiac disease while concurrently having meningitis. The patient's death and meningitis were considered not related to ziconotide.

Two-hundred and thirty-three patients (36.2%) experienced at least one serious AE during the study, and of these patients, 56 (8.7% of the total study cohort) experienced at least one serious AE that was considered to be related to ziconotide. The most commonly reported (>0.5% of patients) ziconotide-related serious AEs were confusion (2.5%), mental slowing (1.1%), stupor (0.9%), and delirium (0.8%) (Table 4).

Temporary or permanent discontinuation of ziconotide therapy because of an AE occurred in 12.1% and 48.9% of patients, respectively. Study discontinuation for AEs occurred most often within the first 3 mo of the study (Fig. 2). The AEs that most frequently resulted in discontinuation of ziconotide were neurological in nature and included impaired cognitive function (i.e., confusion, mental slowing, impaired verbal expression, and memory impairment) and psychiatric events (i.e., depression, anxiety, and hallucinations). Other AEs that commonly led to discontinuation of ziconotide included nausea, headache, and catheter complications.

View larger version (10K): [in this window] [in a new window]   Figure 2. Permanent study discontinuations for adverse events over time. Duration of study participation refers to the number of days a patient was actively participating in the study, not counting time for temporary discontinuation of ziconotide. The n's denote the number of patients receiving study drug at the beginning of each specified time period.

Twenty-three patients enrolled in the study died; five of these deaths occurred more than 30 days after ziconotide discontinuation. The most common causes of death were cardiovascular disease (n = 6), cancer (n = 3), suicide (n = 3), and opioid overdose (n = 2). None of the deaths was considered by the investigators to be related to ziconotide or to the infusion device. For one of the cases of suicide, an alternative etiology of situational depression was offered by the investigator. In another case, no alternative etiology was offered, but the suicide occurred 24 days after the patient had discontinued ziconotide. In the third case, no alternative etiology was provided; however, the patient had a history of depression.

Ziconotide did not cause any substantial changes in arterial blood pressure, heart rate, or respiration rate. There was no evidence to suggest that IT ziconotide prolonged the QTc interval or otherwise affected patient ECGs.

Generally, the median serum chemistry and hematology values showed no clinically important changes over time. The only serum chemistry value that showed a substantial and consistent increase during ziconotide treatment was creatine kinase (CK). Median total CK levels were increased from baseline at a number of study visits (Fig. 3). At baseline, 11.7% of patients had abnormally high CK values. This proportion was increased to 29.6% at month 1, 24.1% at month 2, and 26.0% at final ziconotide discontinuation. The proportions of patients having shifts from normal CK levels at baseline to high levels at month 1, month 2, and final ziconotide discontinuation were 21.2%, 17.1%, and 17.5%, respectively.

View larger version (10K): [in this window] [in a new window]   Figure 3. Median creatine kinase (CK) levels by study visit. Isoenzyme determinations were performed only when total CK was elevated. Creatine kinase I (brain) values were zero at all visits where they were collected, except for one sample from one patient at one visit (month 6). The value recorded at that visit was 8 U/L. Numbers of patients evaluated at each time point for total CK were n = 633 (baseline), n = 439 (month 1), n = 315 (month 2), n = 253 (month 3), n = 216 (month 4), n = 198 (month 5), n = 169 (month 6), n = 130 (month 9), n = 100 (month 12), n = 86 (month 15), n = 71 (month 18), n = 57 (month 21), n = 56 (month 24), n = 46 (month 27), n = 29 (month 30), n = 25 (month 33), n = 12 (month 36), n = 9 (month 39), n = 1 (month 42), n = 549 (last available follow-up), and n = 377 (final study drug discontinuation). Numbers of patients evaluated at each time point for total CKMB and CKMM were n = 89 (baseline), n = 120 (month 1), n = 66 (month 2), n = 53 (month 3), n = 40 (month 4), n = 38 (month 5), n = 37 (month 6), n = 27 (month 9), n = 21 (month 12), n = 14 (month 15), n = 13 (month 18), n = 7 (month 21), n = 9 (month 24), n = 10 (month 27), n = 4 (months 30, 33, and 36), n = 2 (month 39), n = 122 (last available follow-up), and n = 84 (final study drug discontinuation). CKMB indicates creatine kinase (myocardium isoenzyme); CKMM, creatine kinase (skeletal muscle isoenzyme). aX-axis of figure represents study visits, with unequal time intervals between visits.

Clinically significant abnormalities (i.e., >3 times the upper limit of normal) in CK values were reported in 0.9% of patients at baseline, 5.7% at month 1, and 3.4% at the time of ziconotide discontinuation. For patients with elevated total CK levels, isoenzyme analysis revealed that most CK was of skeletal muscle origin (Fig. 3). Among patients with nonzero values for CK of myocardial origin (CKMB), there was a single case of myocardial infarction 2 wk after the patient had a CKMB value of 12 IU/L. This event was thought to be related to the patient's history of type 2 diabetes mellitus, hypertension, cerebrovascular accident, hyperlipidemia, and possible infarct not apparent on screening ECG. There were no other cardiovascular AEs that were suggestive of myocardial injury among patients with nonzero values for CKMB.

Most patients with elevated CK levels did not report AEs suggestive of muscle injury or myopathy. However, some reports of serious AEs also included CK elevations, including a case of myositis (peak CK, 2101 IU/L), a case of purported malignant hyperthermia (peak CK, 924 IU/L), and a case of hypotension and acute tubular necrosis as a complication of rhabdomyolysis and myoglobulinuria (CK >16,000 IU/L). The case of myositis was considered ziconotide-related and resolved within 3 days of ziconotide discontinuation. The purported malignant hyperthermia was also considered ziconotide-related and resolved with treatment. The patient with rhabdomyolysis and myoglobulinuria had a history of parenteral opioid abuse with an episode of prolonged stupor and immobility. This patient's AEs were not thought to be ziconotide-related. The rhabdomyolysis was thought to be ischemic in origin, due to muscle compression and damage after the patient had lain in an unresponsive state for a prolonged period.

Objective measurements of cognitive function were not affected by study drug administration, as evaluated by the WMS-R story memory subtest (Table 5). For the Trail-Making Test, the median time to complete the trail at baseline was 38.0 s (range, 14.0–350.0 s) for part A and 88.0 s (range, 30.0–630.0 s) for part B. At no time point during the study was the mean or median time to complete the trail (part A or B) increased relative to baseline. The proportion of patients who completed part A of the test at baseline but did not complete it at a given postbaseline assessment differed little from month to month (range, 0% at months 10 and 12 to 4.0% at last available follow-up). For part B, the proportion of patients who completed the test at baseline, but not at a given postbaseline assessment, had a wider range: 3.0% at month 9 to 12.0% at last available follow-up.

DISCUSSION

This open-label, multicenter study evaluated the safety and tolerability of IT ziconotide in patients with chronic severe pain in the largest clinical trial of long-term IT therapy. These patients had many physical and neurological abnormalities and uncontrolled pain, despite taking a variety of concomitant medications. Pain and other underlying medical conditions affected ambulation, sleep, work, and driving for many patients, and the majority of patients indicated that pain dominated their lives.

Because the primary objective of this study was to evaluate the safety of ziconotide, no minimum VASPI score was required for study participation. Several patients (14.8%) had baseline VASPI scores below 50 mm (the lowest baseline score was only 4 mm). The potential for absolute or percentage reductions in VASPI scores in these patients was limited. Furthermore, since pain levels typically fluctuate and the VASPI captures a patient's pain state at a single point in time, these low values were most likely not representative of the patient's chronic pain state and, in fact, most subsequent values were much higher. This on-treatment increase in pain level in a subgroup of the study population confounds interpretation of VASPI data. It would be unlikely that patients would continue in an open-label clinical trial if they were not maintaining some benefit. Notably, for patients with VASPI scores 50 mm at baseline, 32.7% had 30% improvement in VASPI score from baseline at month 1, which is comparable to the results of another double-blind, placebo-controlled trial of ziconotide in which 33.7% of ziconotide-treated patients had 30% improvement in VASPI score from baseline (along with no increase in concomitant opioid use and no change in the type of opioid used).8 Additionally, despite somewhat modest improvements in VASPI scores, a significant difference from baseline was seen in the distribution of pain impact on daily life scores, with 35.1% of patients noting improvement at month 2. Considering the refractory nature of the patients' pain in the present study, the patients' responses to ziconotide treatment can be considered a therapeutic success.

Considering the high incidence of physical and neurological abnormalities and concomitant medication use in this cohort, the fact that most patients in the present study reported AEs is not surprising. The most commonly reported ziconotide-related AEs included dizziness, nausea, confusion, memory impairment, and nystagmus, which were generally consistent with both the observed AE profile in the double-blind, placebo-controlled trials6–8 and the pharmacodynamic effects of ziconotide.4 However, no occurrences of respiratory depression, drug dependence, or withdrawal symptoms (potential hazards of opioid administration) were reported during this study, and there was no evidence of tolerance to ziconotide or of granuloma formation at the tip of the IT catheter (as is observed rarely during IT opioid treatment in association with neurological sequelae).

Most of the AEs reported in the study (58.6%) were considered unrelated to ziconotide. Because the relatedness of AEs to ziconotide therapy was based solely on investigator judgment, the possibility that more than 41.4% of AEs were attributable to ziconotide cannot be excluded, and further postmarketing studies are needed to investigate the relationship between ziconotide and various AEs. However, it should be noted that, by the time this trial was conducted, the AE profile of ziconotide had been well established in clinical trials, and a summary of this profile was available to investigators in the present study. Therefore, investigator assessment of the relatedness of AEs to ziconotide therapy was expected to be reasonably accurate. Additionally, 61.0% of patients in the present study discontinued ziconotide, either temporarily or permanently, because of AEs. This finding is in stark contrast to results from a previous short-term (3-wk treatment period) study of ziconotide in which the discontinuation rate for AEs in ziconotide-treated patients was low (5.4%) and comparable to that of the placebo group (4.6%).6 Likely, the much longer duration of the present study contributed to the larger percentage of patients discontinuing ziconotide therapy for AEs. Notably, the AEs that most frequently led to ziconotide discontinuation were neurological in nature, including impaired cognitive function and psychiatric AEs. The prescribing information for ziconotide contains a boxed warning regarding severe psychiatric symptoms and neurological impairment associated with ziconotide.12 Patients with a history of psychosis should not be treated with ziconotide. All patients should be monitored frequently for severe cognitive or psychiatric AEs, and ziconotide therapy should be discontinued if such AEs occur.

Elevations in CK levels were observed with ziconotide therapy, starting at 1 mo of treatment (Fig. 3). There was no consistent pattern of AEs or symptoms associated with elevated CK levels. Although these elevations in CK levels may be, in part, attributable to ziconotide therapy, other disease processes and/or concomitant medications may also contribute to increased CK levels. However, it is recommended that physicians periodically (e.g., every other week for the first month and monthly as appropriate thereafter) monitor serum CK values in patients undergoing ziconotide treatment.12

Another important aspect of this study was that patients were permitted to temporarily discontinue ziconotide therapy and later restart it, which allowed for evaluation of anaphylaxis. Among patients who temporarily discontinued ziconotide therapy during the study, no evidence of hypersensitivity or anaphylaxis was noted. Additionally, the allowance for temporary ziconotide discontinuation in this study further demonstrated that ziconotide therapy can be interrupted or discontinued without evidence of withdrawal effects.

Overall, the results of this study suggest that long-term IT ziconotide therapy is an option for patients with severe, refractory chronic pain. Efficacy data from this study should be interpreted with caution, as there was no comparator group in the study. An important limitation of this study is that it is unlikely that rare AEs would have been detected. The detection of such AEs typically requires patient exposure well beyond that achieved in this study.13 Additionally, it has been suggested that long-term, open-label trials are not ideal for detecting and assessing the risk for rare AEs because of lack of a control group and the potential for under-reporting of treatment-emergent AEs.13 Thus far, AEs that have been commonly associated with ziconotide are generally not life-threatening and typically resolve upon discontinuation of therapy. In the case of a serious AE, ziconotide therapy can be abruptly interrupted or discontinued without concern regarding withdrawal effects.

ACKNOWLEDGMENTS

The authors gratefully acknowledge the contributions of the following investigators to this study: Charles Argoff, MD, Bethpage, NY; David Bryce, MD, Madison, WI; Daniel Buffington, PharmD, MBA, Tampa, FL; John Buonocore, DO, West Babylon, NY; Maia Chakerian, MD, Los Gatos, CA; Iva T. Chapple, MD, West Columbia, SC; Jayant Damle, Fargo, ND; Michael J. Drass, MD, Altoona, PA; Stuart DuPen, MD, Bremerton, WA; Theresa Ferrer-Brechner, MD, Bakersfield, CA; Kenneth A. Follett, MD, PhD, Omaha, NE; Stuart Fox, MD, Morristown, NJ; Veronica Garcia, MD, Waterford, MI; Brad Goodman, MD, Birmingham, AL; J. Thomas Grissom, MD, DABA, Lewiston, ID; Gene W. Grove, MD, Elkhart, IN; Robert Henderson, MD, Dallas, TX; Nathaniel Katz, MD, Boston, MA; Joel Kent, MD, Baltimore, MD; David Kloth, MD, Danbury, CT; Lyal Leibrock, MD, Omaha, NE; Todd Lininger, MD, Waterford, MI; Steven Litman, MD, Bay Shore, NY; Y. Eugene Mironer, MD, Spartanburg, SC; Barry M. Miskin, MD, West Palm Beach, FL; Osmin Morales, MD, Miami, FL; Bruce Nicholson, MD, Allentown, PA; Michael O'Connell, MD, Somersworth, NH; Joe Ordia, MD, FACS, Randolph, MA; Winston Parris, MD, Tampa, FL; Joshua P. Prager, MD, MS, Los Angeles, CA; Robert W. Presley, MD, Colorado Springs, CO; Lowell Reynolds, MD, Loma Linda, CA; Stuart Rosenblum, MD, PhD, Portland, OR; Mike Royal, MD, JD, Malvern, PA; Morris Scherlis, MD, Huntsville, AL; Jan Slezak, MD, Rochester, NH; Daneshvari Solanki, MD, Galveston, TX; Michael Solomon, MD, Clearwater, FL; Brett Stacey, Portland, OR; Mark Stuckey, Minneapolis, MN; Nolan Tzou, MD, Huntington, NY; Clayton A. Varga, MD, Pasadena, CA; Lynn R. Webster, MD, Salt Lake City, UT; Kent Weinmeister, MD, Scottsdale, AZ.

The authors acknowledge the contributions that Robert Presley, MD, made to this study and to the development of ziconotide before his death.

The authors acknowledge Tonya Marmon, DrPH (Elan Pharmaceuticals, Inc., employee), and Elizabeth Ludington, PhD (former Elan Pharmaceuticals, Inc., employee), for their critical reviews and statistical support in the analyses of the data from this study. We acknowledge Ronald Kartzinel, MD, PhD (former Elan Pharmaceuticals, Inc., employee), Graham McLennan (Elan Pharmaceuticals, Inc., employee), and George Miljanich, PhD (former Elan Pharmaceuticals, Inc., employee), for their critical review and comments on the manuscript. Additionally, we acknowledge Elizabeth Barton, MS, for her technical writing contributions to the manuscript.

Appendix 1

Footnotes

Accepted for publication October 19, 2007.

Supported by Elan Pharmaceuticals, Inc.

Mark S. Wallace has received research funding from and has acted as a speaker for Elan Pharmaceuticals, Inc. Richard Rauck has acted as a speaker for Elan Pharmaceuticals, Inc., and Advanced Bionics Corporation and has received research funding from Medtronic, Inc. Robert Fisher has received research funding from and acted as a speaker for Elan Pharmaceuticals, Inc. Steven Charapata has received research funding from and has acted as a speaker for Elan Pharmaceuticals, Inc. David Ellis is a former employee of Elan Pharmaceuticals, Inc. Sanjeeva Dissanayake is a former employee of Elan Pharma, Ltd.

David Ellis, MD, PhD, is currently at Aryx Therapeutics, Inc., Fremont, California.

Sanjeeva Dissanayake, MBBS, MRCP, is currently at Medicines and Healthcare Products Regulatory Agency, London, UK.

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