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Address reprint requests to: Richard L. Rauck, MD, Wake Forest University School of Medicine, The Center for Clinical Research, Carolinas Pain Institute, 145 Kimel Park Drive, Suite 330 Winston-Salem, NC 27103, USA.
Wake Forest University School of Medicine (R.L.R.), Winston-Salem, North Carolina; Center for Pain and Palliative Medicine (M.S.W.), University of California, La Jolla, California; Bay Area Pain Center (M.S.L.), Los Gatos, California; Advanced Pain Institute (M.M.), Duarte, California; Lifetree Clinical Research and Pain Clinic (L.R.W.), Salt Lake City, Utah; Pain Management Associates (S.G.C.), Research Medical Center, Pain Institute, Kansas City, Missouri; Hot Springs Pain Clinic (J.E.A.), Hot Springs, Arkansas; University of South Florida College of Medicine (D.E.B.), Tampa, Florida; and Elan Pharmaceuticals Inc. (D.E., R.K.), San Diego, California
Wake Forest University School of Medicine (R.L.R.), Winston-Salem, North Carolina; Center for Pain and Palliative Medicine (M.S.W.), University of California, La Jolla, California; Bay Area Pain Center (M.S.L.), Los Gatos, California; Advanced Pain Institute (M.M.), Duarte, California; Lifetree Clinical Research and Pain Clinic (L.R.W.), Salt Lake City, Utah; Pain Management Associates (S.G.C.), Research Medical Center, Pain Institute, Kansas City, Missouri; Hot Springs Pain Clinic (J.E.A.), Hot Springs, Arkansas; University of South Florida College of Medicine (D.E.B.), Tampa, Florida; and Elan Pharmaceuticals Inc. (D.E., R.K.), San Diego, California
Wake Forest University School of Medicine (R.L.R.), Winston-Salem, North Carolina; Center for Pain and Palliative Medicine (M.S.W.), University of California, La Jolla, California; Bay Area Pain Center (M.S.L.), Los Gatos, California; Advanced Pain Institute (M.M.), Duarte, California; Lifetree Clinical Research and Pain Clinic (L.R.W.), Salt Lake City, Utah; Pain Management Associates (S.G.C.), Research Medical Center, Pain Institute, Kansas City, Missouri; Hot Springs Pain Clinic (J.E.A.), Hot Springs, Arkansas; University of South Florida College of Medicine (D.E.B.), Tampa, Florida; and Elan Pharmaceuticals Inc. (D.E., R.K.), San Diego, California
Wake Forest University School of Medicine (R.L.R.), Winston-Salem, North Carolina; Center for Pain and Palliative Medicine (M.S.W.), University of California, La Jolla, California; Bay Area Pain Center (M.S.L.), Los Gatos, California; Advanced Pain Institute (M.M.), Duarte, California; Lifetree Clinical Research and Pain Clinic (L.R.W.), Salt Lake City, Utah; Pain Management Associates (S.G.C.), Research Medical Center, Pain Institute, Kansas City, Missouri; Hot Springs Pain Clinic (J.E.A.), Hot Springs, Arkansas; University of South Florida College of Medicine (D.E.B.), Tampa, Florida; and Elan Pharmaceuticals Inc. (D.E., R.K.), San Diego, California
Wake Forest University School of Medicine (R.L.R.), Winston-Salem, North Carolina; Center for Pain and Palliative Medicine (M.S.W.), University of California, La Jolla, California; Bay Area Pain Center (M.S.L.), Los Gatos, California; Advanced Pain Institute (M.M.), Duarte, California; Lifetree Clinical Research and Pain Clinic (L.R.W.), Salt Lake City, Utah; Pain Management Associates (S.G.C.), Research Medical Center, Pain Institute, Kansas City, Missouri; Hot Springs Pain Clinic (J.E.A.), Hot Springs, Arkansas; University of South Florida College of Medicine (D.E.B.), Tampa, Florida; and Elan Pharmaceuticals Inc. (D.E., R.K.), San Diego, California
Wake Forest University School of Medicine (R.L.R.), Winston-Salem, North Carolina; Center for Pain and Palliative Medicine (M.S.W.), University of California, La Jolla, California; Bay Area Pain Center (M.S.L.), Los Gatos, California; Advanced Pain Institute (M.M.), Duarte, California; Lifetree Clinical Research and Pain Clinic (L.R.W.), Salt Lake City, Utah; Pain Management Associates (S.G.C.), Research Medical Center, Pain Institute, Kansas City, Missouri; Hot Springs Pain Clinic (J.E.A.), Hot Springs, Arkansas; University of South Florida College of Medicine (D.E.B.), Tampa, Florida; and Elan Pharmaceuticals Inc. (D.E., R.K.), San Diego, California
Wake Forest University School of Medicine (R.L.R.), Winston-Salem, North Carolina; Center for Pain and Palliative Medicine (M.S.W.), University of California, La Jolla, California; Bay Area Pain Center (M.S.L.), Los Gatos, California; Advanced Pain Institute (M.M.), Duarte, California; Lifetree Clinical Research and Pain Clinic (L.R.W.), Salt Lake City, Utah; Pain Management Associates (S.G.C.), Research Medical Center, Pain Institute, Kansas City, Missouri; Hot Springs Pain Clinic (J.E.A.), Hot Springs, Arkansas; University of South Florida College of Medicine (D.E.B.), Tampa, Florida; and Elan Pharmaceuticals Inc. (D.E., R.K.), San Diego, California
Wake Forest University School of Medicine (R.L.R.), Winston-Salem, North Carolina; Center for Pain and Palliative Medicine (M.S.W.), University of California, La Jolla, California; Bay Area Pain Center (M.S.L.), Los Gatos, California; Advanced Pain Institute (M.M.), Duarte, California; Lifetree Clinical Research and Pain Clinic (L.R.W.), Salt Lake City, Utah; Pain Management Associates (S.G.C.), Research Medical Center, Pain Institute, Kansas City, Missouri; Hot Springs Pain Clinic (J.E.A.), Hot Springs, Arkansas; University of South Florida College of Medicine (D.E.B.), Tampa, Florida; and Elan Pharmaceuticals Inc. (D.E., R.K.), San Diego, California
Wake Forest University School of Medicine (R.L.R.), Winston-Salem, North Carolina; Center for Pain and Palliative Medicine (M.S.W.), University of California, La Jolla, California; Bay Area Pain Center (M.S.L.), Los Gatos, California; Advanced Pain Institute (M.M.), Duarte, California; Lifetree Clinical Research and Pain Clinic (L.R.W.), Salt Lake City, Utah; Pain Management Associates (S.G.C.), Research Medical Center, Pain Institute, Kansas City, Missouri; Hot Springs Pain Clinic (J.E.A.), Hot Springs, Arkansas; University of South Florida College of Medicine (D.E.B.), Tampa, Florida; and Elan Pharmaceuticals Inc. (D.E., R.K.), San Diego, California
Wake Forest University School of Medicine (R.L.R.), Winston-Salem, North Carolina; Center for Pain and Palliative Medicine (M.S.W.), University of California, La Jolla, California; Bay Area Pain Center (M.S.L.), Los Gatos, California; Advanced Pain Institute (M.M.), Duarte, California; Lifetree Clinical Research and Pain Clinic (L.R.W.), Salt Lake City, Utah; Pain Management Associates (S.G.C.), Research Medical Center, Pain Institute, Kansas City, Missouri; Hot Springs Pain Clinic (J.E.A.), Hot Springs, Arkansas; University of South Florida College of Medicine (D.E.B.), Tampa, Florida; and Elan Pharmaceuticals Inc. (D.E., R.K.), San Diego, California
Wake Forest University School of Medicine (R.L.R.), Winston-Salem, North Carolina; Center for Pain and Palliative Medicine (M.S.W.), University of California, La Jolla, California; Bay Area Pain Center (M.S.L.), Los Gatos, California; Advanced Pain Institute (M.M.), Duarte, California; Lifetree Clinical Research and Pain Clinic (L.R.W.), Salt Lake City, Utah; Pain Management Associates (S.G.C.), Research Medical Center, Pain Institute, Kansas City, Missouri; Hot Springs Pain Clinic (J.E.A.), Hot Springs, Arkansas; University of South Florida College of Medicine (D.E.B.), Tampa, Florida; and Elan Pharmaceuticals Inc. (D.E., R.K.), San Diego, California
Safety and efficacy data from a study of slow intrathecal (IT) ziconotide titration for the management of severe chronic pain are presented. Patients randomized to ziconotide (n=112) or placebo (n=108) started IT infusion at 0.1 μg/hour (2.4 μg/day), increasing gradually (0.05–0.1 μg/hour increments) over 3 weeks. The ziconotide mean dose at termination was 0.29 μg/hour (6.96 μg/day). Patients' baseline Visual Analogue Scale of Pain Intensity (VASPI) score was 80.7 (SD 15). Statistical significance was noted for VASPI mean percentage improvement, baseline to Week 3 (ziconotide [14.7%] vs. placebo [7.2%; P=0.036]) and many of the secondary efficacy outcomes measures. Significant adverse events (AEs) reported in the ziconotide group were dizziness, confusion, ataxia, abnormal gait, and memory impairment. Discontinuation rates for AEs and serious AEs were comparable for both groups. Slow titration of ziconotide, a nonopioid analgesic, to a low maximum dose resulted in significant improvement in pain and was better tolerated than in two previous controlled trials that used a faster titration to a higher mean dose.
The nonopioid analgesic ziconotide has been developed as a new treatment for patients with severe chronic pain who are intolerant of and/or refractory to other analgesic therapies. Ziconotide is the synthetic equivalent of a 25-amino-acid polybasic peptide found in the venom of the marine snail Conus magus.
Use of intrathecal SNX-11, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain.
The starting dose in these studies was 0.4 μg/hour (9.6 μg/day), which was subsequently lowered to 0.1 μg/hour (2.4 μg/day) due to unexpected intolerance. The dose was increased daily to a maximum dose of 2.4 μg/hour (57.6 μg/day) in these hospitalized patients, according to a fixed defined titration schedule, for 5 to 6 days until analgesia was obtained or intolerance developed. The mean final ziconotide dose was 0.91 μg/hour (21.8 μg/day) for the malignant pain trial and 1.02 μg/hour (24.5 μg/day) for the nonmalignant pain trial.
In both studies, the ziconotide-treated patients experienced a statistically and clinically significant reduction in pain compared to placebo patients. However, pain relief was accompanied by a high incidence of serious adverse events (SAEs) and frequent discontinuations due to AEs.
The current randomized, controlled trial was designed to evaluate the safety and efficacy of ziconotide using a slower titration schedule and lower maximum dose than was used in the two previous controlled trials. To allow a more gradual titration of ziconotide, the current double-blind study was conducted over a three-week period, with a longer time interval between dose increases, smaller dose increments, and a lower maximum dose.
Methods
Study Design
This double-blind, placebo-controlled, two-arm, randomized study consisted of an initial screening visit, a three-week weaning period from all IT drugs, a one-week stabilization period, and a three-week double-blind treatment period. During the initial screening visit, patients provided written informed consent and were evaluated for study eligibility. Eligible patients receiving IT analgesics or other IT medications at screening were gradually weaned from all IT medications over a three-week period. As IT opioids were withdrawn, they were replaced with systemic opioids for pain control before entering the stabilization period, during which only preservative-free saline was administered in the IT pump. Investigators were not provided with directions on weaning patients and used clinical judgment and experience to complete this phase of the study. Patients not taking any IT medications at screening proceeded directly to the stabilization period. All patients were stabilized on systemic analgesics and other non-IT medications for at least one week prior to administration of the study drug. At the end of the stabilization period (baseline), patients were randomized in a 1:1 ratio to receive ziconotide or placebo. The three-week, double-blind treatment period required weekly treatment visits, with interval visits (one or two times per week) as necessary, to adjust the dose based upon patient response and to evaluate safety during dose titration.
Study Participants
Patients were recruited from 39 centers in the United States. Each investigator's Institutional Review Board approved the study protocol. To be eligible for screening, patients were required to have severe chronic pain that was inadequately controlled by systemic and/or IT analgesics, a Visual Analogue Scale of Pain Intensity (VASPI)
score ≥50 mm, and pain of any etiology that warranted the use of IT therapy. Patients were also required to have a programmable SynchroMed® infusion system (Minneapolis, MN) implanted prior to study enrollment. Exclusion criteria included pregnancy or lactation, investigational drug or device use within 30 days prior to screening, known sensitivity to ziconotide, and contraindications to IT therapy. There were no exclusions for coexisting medical or psychiatric conditions, and all systemic medications, including opioids and other analgesics, were allowed.
Patients were eligible for randomization if they met the following inclusion criteria at baseline (i.e., after the screening and stabilization period): a VASPI score ≥50 mm, successful discontinuation of all IT medications, and a stabilized regimen of systemic analgesics and other necessary medications.
Drug Administration
During the three-week double-blind treatment period, patients received ziconotide at a starting dose of 0.1 μg/hour (2.4 μg/day) or placebo at the equivalent infusion rate, which was gradually titrated upward by 0.05–0.10 μg/hour (1.2–2.4 μg/day) increments until patients attained analgesia or reported intolerance. At least 24 hours were required between each dose increase but downward titration was allowed at any time to improve tolerability. The maximum allowable dose was 0.9 μg/hour (21.6 μg/day) by the end of the treatment period. Patients could receive other systemic medications, including opioids, as clinically indicated, but no IT medications other than the study drug were permitted.
Efficacy and Safety Measures
The primary efficacy outcome was the mean percentage changes in VASPI score from baseline to Week 3. The mean percentage changes in VASPI from baseline to Weeks 1 and 2 were secondary efficacy outcomes. Other secondary efficacy measurements included the Clinical Global Impression (CGI) of Patient Satisfaction and CGI Overall Pain Control,
and the percentage of treatment responders at termination. Treatment responders were defined as patients with a 30% or greater decrease in VASPI scores from baseline to the end of Week 3. All other patients, including those with data missing at Week 3, were classified as nonresponders. Other secondary efficacy measures included changes from baseline to termination on the Global McGill Pain Relief Questionnaire and the scores from subscales of the Brief Pain Inventory (BPI). Quality-of-life assessments included a sponsor-defined sleep questionnaire and the Treatment Outcomes in Pain Survey (TOPS).
To quantify concomitant opioid use, patients recorded opioid consumption in a daily diary that was converted to oral morphine equivalents using standard conversion factors. Mean weekly opioid consumption during Weeks 1, 2, and 3 was compared with that during the pretreatment stabilization period.
A complete medical history and a physical and neurological examination were performed at the screening visit. The following safety measurements were performed at screening, baseline, and termination: laboratory evaluations (chemistry and hematology), vital signs, 12-lead electrocardiogram (ECG), Mini Mental State Examination (MMSE),
For women of childbearing potential, pregnancy tests were done at screening and termination. At every clinic visit, patients were assessed for AEs and SAEs, and changes in concomitant medication use. In addition, if patients were experiencing a study drug-related AE at the end of the study, they required follow-up visits at 2 week intervals until the event resolved or to a new chronic baseline. Data collected at the end of the stabilization period (baseline) served as the pretreatment values for safety and efficacy measures.
Statistical Analysis
For the primary efficacy measure, the planned sample size of 110 randomized patients in each group provided 80% power to detect a between-treatment-group difference of at least 15 percentage points in the mean percentage change as measured on the VASPI from baseline to Week 3. The sample size was estimated based on the use of a two-sample t-test with a standard deviation (SD) of 39.5% for both treatment groups (estimated from the two previous efficacy controlled trials) at the 5% level of significance. Statistical analyses were performed using SAS version 8.2 (SASI Inc., Cary, NC). The intended to treat (ITT) population included all randomized patients (n=220) and was used for all safety analyses, the primary efficacy analysis and the secondary efficacy analyses of VASPI. Analyses for all remaining efficacy parameters used observed data only. Baseline and demographic characteristics were compared between the two treatment groups using two-sample t-tests for continuous variables, Chi-squared tests for categorical variables with all expected cell counts ≥5, and Fisher's exact test for categorical variables with at least one expected cell count <5.
The mean percentage change from baseline to each weekly visit on the VASPI was compared between treatment groups using the two-sample t-test, incorporating the last observation carried forward (LOCF) imputation method. The LOCF imputation method substitutes the last observed value for subsequent missing data points. This method allows patients to be included in the analysis, and standard statistical techniques for complete data can be used; without imputing missing data, patients with missing data would be excluded from the analysis. A number of sensitivity analyses were also performed to investigate possible bias introduced by using the LOCF method, including observed case analysis (i.e., no imputation), imputing the median percentage change from all patients in the same treatment group at each weekly visit, and imputing the smallest (i.e., “worst”) percentage change from all patients in the same treatment group at each weekly visit. Descriptive statistics were also calculated for several subgroups (patient demographics and pain etiology) on the primary efficacy measure. The proportion of VASPI responders in the two treatment groups was compared using the two-sample binomial test.
The distribution of CGI responses in the two treatment groups was compared using the Mantel-Haenszel Chi-squared test (one degree of freedom) assuming equally spaced scores for the CGI categories. Two-sample t-tests were used to compare the change from baseline in the Global McGill Pain Relief total score and the change from baseline in the TOPS total pain experience score at the termination visit between the two treatment groups. The Mantel-Haenszel Chi-squared test (one degree of freedom) was used to compare the two treatment groups on the CPRS and sleep questionnaire responses at termination, and the change from baseline to termination on the BPI subscales. The percentage change in weekly opioid consumption from the pretreatment stabilization period to Week 3 was compared between the two treatment groups using a two-sample t-test.
A modified Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) dictionary was used to code AEs into body systems and preferred terms; for AEs reported by 10% or more patients in either treatment group, the number of AEs reported were compared between treatment groups using Fisher's exact test. The total number of SAEs reported and the number of discontinuations due to AEs were compared between the treatment groups using the Chi-squared test. The two treatment groups were compared with respect to their mean change from baseline to termination in total MMSE and HAM-D scores using the two-sample t-test. Within each treatment group, McNemar's test was used to test laboratory changes from normal to abnormal (low or high) and vice-versa from baseline.
All statistical tests were two-sided, and results were considered statistically significant if P≤0.05.
Results
Fig. 1 summarizes the disposition of patients in the study. Of the 248 patients enrolled at screening, 220 were randomized to study drug (112 ziconotide, 108 placebo). The majority of screened patients (79.8%; n=198) were receiving IT morphine and/or other IT drugs and required weaning. The weaning process was successful in 92.9% of these patients and only 14 patients dropped out during weaning due to inability to tolerate withdrawal of IT drugs, AEs, noncompliance, or at the patient's request. There were 44 patients who enrolled with only saline in their pumps and they proceeded directly into the stabilization period. Stabilization on systemic analgesics and other non-IT medications was successful for 96.5% of patients who entered this period. The dropout rate after randomization during the double-blind treatment period was essentially equal between the ziconotide (8.0%) and placebo (7.4%) groups; the reason for discontinuation was due primarily to AEs or lack of efficacy.
Fig. 1Patient disposition and termination by treatment group. a44 patients did not require weaning of IT medications and entered the stabilization period directly. (Of the 44 patients who did not enter weaning, 23 had their pump implanted less than a month before the study; one, 3 months before consent; and the other 20 had their pumps for greater than 200 days. Of these 44 patients, three were on low-dose opioid monotherapy and the other 41 had no IT drugs at screening). b184 patients completed the weaning period and entered the stabilization period.
There were no significant differences between the two groups at randomization on demographic and pain history variables (Table 1). This patient population had severe chronic pain as evidenced by an extremely high mean VASPI score of 80.7 mm and a mean duration of pain of 14–15 years. The majority of the pain was classified as neuropathic, and failed back surgery syndrome (FBSS) was the single most common etiology of pain (58%). Descriptive statistics for several subgroups (patient demographics and pain etiology) on the primary efficacy measure are provided in Table 2.
Table 1Patient Baseline and Demographic Characteristics
From two-sample t-tests (t) for continuous variables, (χ) Chi-squared tests, (C) for categorical variables with all expected cell counts ≥5, and Fisher's exact test (E) for categorical variables with at least one expected cell count <5.
Oral morphine equivalent (mg/day) was calculated using oral morphine equivalent during stabilization period divided by number of days.
Mean (SD)
300.2 (336.16)
268.0 (306.51)
0.46 (t)
Baseline VASPI score, mm
Mean (SD)
80.7 (15.0)
80.7 (14.9)
0.98 (t)
a From two-sample t-tests (t) for continuous variables, (χ) Chi-squared tests, (C) for categorical variables with all expected cell counts ≥5, and Fisher's exact test (E) for categorical variables with at least one expected cell count <5.
b A patient may have more than one pain classification.
c Oral morphine equivalent (mg/day) was calculated using oral morphine equivalent during stabilization period divided by number of days.
The majority of patients (97%) were considered refractory to treatment by their physicians and 90% had already been treated with IT morphine. More than one IT drug had already been used by 58% of the patients prior to enrollment. Other prior therapies included oral opioids (99%), spinal cord stimulation (40%), spinal surgery (67%), neuroablation (10.5%), physical therapy (94%), and a wide variety of behavioral and psychological interventions. The median amount of IT opioid prior to dosing, expressed as oral morphine equivalents, was 1200 mg/day (range 13–51,000). The median amount of systemic opioids taken during the stabilization period was 183 mg/day (range 0–2126 mg/day) expressed as oral morphine equivalents.
With the exception of IT medications, all other medications were allowed during the treatment period. Patients took an average of 12 nonopioid medications during the treatment period. Opioids were the most commonly used medication during blinded treatment, used by 98% of patients. In descending order, the most commonly used opioids were oxycodone±acetaminophen (41%), morphine (34%), hydrocodone±acetaminophen (28%), methadone (24%), fentanyl (18%), and hydromorphone (13%). Other adjuvant medications included antidepressants (64%), anticonvulsants (48%), muscle relaxants (42%), anxiolytics (40%), nonsteroidal anti-inflammatory drugs (34%), and sedative hypnotics (27%).
Efficacy
The initial dose of blinded study drug was 0.1 μg/hour (2.4 μg/day). At Week 3, the mean dose was 0.29 μg/hour (6.96 μg/day) for the ziconotide group and 0.44 μg/hour (10.56 μg/day) for the placebo group. The maximum dose used by any ziconotide-treated patient was 0.8 μg/hour (19.2 μg/day) and the maximum dose used by any placebo patient was 0.9 μg/hour (21.6 μg/day).
In the primary efficacy analysis, VASPI scores improved from baseline to Week 3 by a mean of 14.7% in the ziconotide-treated group and 7.2% in the placebo group (P=0.036; Fig. 2). The onset of efficacy was observed among ziconotide-treated patients at Week 1, with a mean percent improvement on the VASPI of 16.6%, compared to a mean percent improvement of 5.0% among the placebo patients (P=0.0026). At Week 2, the mean percent improvement in VASPI scores for the ziconotide-treated group (13.8%) was greater than that for the placebo group (8.2%), but this difference was not statistically significant (P=0.12). Results from the sensitivity analyses were not appreciably different from those results seen when the LOCF method was used. The proportion of treatment responders (i.e., those with at least 30% VASPI score improvement) did not differ significantly between groups (16.1% for ziconotide, 12.0% for placebo, P=0.39) at Week 3.
Fig. 2Mean percentage change in VASPI score from baseline to Weeks 1, 2, and 3 using the LOCF imputation method. The primary efficacy outcome was the mean percentage change in VASPI score from baseline to Week 3. Baseline VASPI score was 80.7 (SD 15).
At study termination, 28.4% of patients in the ziconotide group reported “a lot” or “complete” satisfaction with therapy on the CGI Satisfaction scale, compared with 12.1% of patients in the placebo group (Fig. 3a). On the CGI Overall Pain Control measure, 11.9% of ziconotide-treated patients reported “very good” or “excellent” pain control at study termination, compared with 0.9% of placebo-treated patients (Fig. 3b). Results of other secondary efficacy and quality-of-life parameters are presented in Table 3.
Fig. 3(a) and (b). CGI at termination. For satisfaction with therapy (a) and Overall Pain Control (b), the difference between the two treatment groups was statistically significant (P=0.0027 and P=0.0004, respectively; Mantel-Haenszel Chi-squared test with one degree of freedom, assuming equally spaced scores).
The change in the Global McGill Pain Relief total score was significantly reduced in the ziconotide group compared to the placebo group (P=0.026). The CPRS showed a trend in favor of ziconotide but the difference did not reach significance (P=0.0596). The impact of pain on quality of life, assessed using the TOPS questionnaire did not show a significant difference in mean change between the two treatment groups after only 3 weeks of treatment (ziconotide mean 3.9 [SD=11.13]; placebo mean 1.8 [SD=11.44]; P=0.1837). The TOPS total pain experience score was 67.6 for ziconotide and 67.5 for placebo patients at study termination. The normative score for a healthy population was 14.2 and for a pain clinic population was 63.4.
Thus, the study population was severely impaired by pain and had a poor quality of life as measured by the TOPS. Finally, using a sponsor-defined sleep questionnaire, sleep pattern (uninterrupted hours of sleep and sleep quality) were both significantly improved by ziconotide treatment compared to placebo (Table 3). Most of the BPI subscales were not improved by treatment; specifically, no statistically significant difference between treatment groups was found for the following subscales: sleep, relations, work, mood, and walking. However, the enjoyment of life subscale of the BPI showed a statistically significant improvement for ziconotide; 42.2% of ziconotide-treated patients improved by at least one unit from baseline to termination compared with 27.4% for placebo-treated patients (P=0.019) (Table 4).
In the ziconotide group, there was a 23.7% mean decrease in weekly opioid use (in morphine equivalents) from pretreatment stabilization to Week 3, compared to a 17.3% decrease in the placebo group (P=0.44). Mean weekly opioid consumption for the ziconotide group was 2101 mg (SD 2353 mg) during pretreatment stabilization and 1524 mg (SD 1627 mg) at Week 3. For the placebo group, mean weekly opioid consumption was 1876 mg (SD 2146 mg) during pretreatment stabilization and 1453 mg (SD 1579 mg) at Week 3.
Safety
During the treatment period, 92.9% of patients in the ziconotide group and 82.4% of patients in the placebo group reported AEs (P=0.023). The severity of AEs reported was primarily mild or moderate (ziconotide, 83.6%; placebo, 83.8%). The AEs most frequently occurring during the three-week treatment period in either group are listed in Table 5. The AEs related to the central nervous system (CNS), such as dizziness, confusion, ataxia, abnormal gait, and memory impairment, were significantly reported more frequently in the ziconotide-treated patients than in placebo-treated patients (Table 5). The median time to onset for the most commonly reported ziconotide-related AEs (i.e., dizziness, nausea, confusion, ataxia, and asthenia) ranged from 3.0 to 9.5 days (Table 6). The median ziconotide dose at the time of AE onset ranged narrowly from 0.11 to 0.30 μg/hour (2.6 to 7.2 μg/day) and thus AEs occurred at the therapeutic doses. For patients reporting AEs at the end of the treatment period, the median time to resolution for most of these AEs was within 1–2 weeks of drug discontinuation (dizziness, median 3.0 [range 1–15]; nausea, median 3.0 [range 1–45]; confusion, median 3.5 [range 2–7]; abnormal gait [including ataxia], median 4.0 [range 1–32]; and asthenia [including myasthenia], median 15 [range 15]).
Table 5Adverse Events Most Frequently Reported During the Treatment Period (Incidence ≥10% in Either Treatment Group)
During the treatment period, 11.6% of ziconotide patients (13/112) reported a total of 19 SAEs and 9.3% of placebo patients (10/108) reported a total of 25 SAEs (P=0.57). Serious AEs were considered study drug related by the investigator in 1.8% of ziconotide patients (2/112) and in 1.9% of placebo patients (2/108). Ziconotide-related SAEs included chest pain, hypertension, ataxia, dizziness, and neuralgia. No cases of anaphylaxis or hypersensitivity to ziconotide were reported.
The discontinuation rate due to AEs during the treatment period was comparable in the ziconotide (n=6, 5.4%) and placebo groups (n=5, 4.6%; P=0.80). An additional three patients in each group discontinued treatment for other reasons: two ziconotide and two placebo patients due to lack of efficacy; one ziconotide patient voluntarily withdrew consent; and one placebo patient with a history of severe obstructive pulmonary disease and heart failure died from ventricular fibrillation.
At baseline, the mean MMSE total scores were similar between treatment groups (ziconotide, 29.0; placebo, 29.2). No significant difference between treatment groups was seen for the change in total MMSE score from baseline to termination (ziconotide, −0.4; placebo, −0.1; P=0.21). Similar results were seen with the HAM-D total score. At baseline, the mean total score was 13.3 for ziconotide and 11.5 for placebo. The mean change from baseline to termination was −0.3 for ziconotide and 0.4 for placebo (P=0.25).
No clinically significant changes in vital signs or ECGs were noted in either treatment group from baseline to termination.
In ziconotide-treated patients, statistically significant shifts from normal at baseline to above normal at termination were reported for uric acid, lactate dehydrogenase, and creatine kinase (CK). Two of the ziconotide-treated patients had CK levels greater than three times the upper limit of normal (ULN) at baseline (198 IU/L). These two patients plus an additional three patients had elevations in CK levels greater than three times the ULN at study endpoint. Of these five patients, only one experienced an SAE (hypokalemia), which the investigator reported as not related to ziconotide. Four of these patients did report muscular symptoms such as myalgia and muscle cramps during ziconotide treatment. No placebo patients had CK elevations greater than three times the ULN at baseline or termination. All other changes in blood chemistry values from baseline were relatively small in both groups and had no apparent trends.
Discussion
This is the third double-blind, placebo-controlled study with ziconotide that formed the basis of the recent approval by the U.S. Food and Drug Administration. Ziconotide appears to be the most studied IT analgesic, with a total of 583 patients in randomized, double-blind, placebo-controlled clinical trials. In the current study, almost all of the 220 patients (96.8%) were determined by their physicians to be refractory to existing analgesic treatments. In three-quarters of these patients, neuropathic pain was a significant component or the sole type of their pain. Even with the use of concomitant oral opioid medication in >98% of patients, ziconotide effectively reduced pain after 3 weeks of treatment with the onset of significant efficacy observed at Week 1 (Fig. 2).
Although there was a statistically significant difference between the ziconotide and placebo groups in the primary efficacy analysis, mean percentage change in VASPI at Week 3 using LOCF, the magnitude of the improvement was small in both treatment groups. Nevertheless, this outcome was confirmed by the sensitivity analyses that did not use LOCF. Moreover, the clinical significance of this improvement in VASPI is supported by statistically significant differences between the two treatment groups in a number of secondary outcome measures, such as CGI Satisfaction, CGI Overall Pain Control, and the Global McGill Pain Relief total score. The magnitude of the improvement in VASPI score was also smaller in this study than in the two previous controlled trials. This difference is most likely due to the lower doses used in this study (mean dose 0.29 μg/hour, maximum dose 0.8 μg/hour) compared with those used in the two previous studies (mean doses of 0.91–1.02 μg/hour [range 21.8–24.5 μg/day], maximum dose 2.4 μg/hour [57.6 μg/day]). It may also be the result of the greater number of refractory patients enrolled or the longer treatment duration of 3 weeks in an outpatient setting in this study compared to the 5–6 days in the hospital in the previous two studies.
In the current study, low dropout rates were observed, not only during the weaning (7.1%) and stabilization (3.5%) periods, but also during the three-week placebo-controlled treatment phase (8.0% ziconotide, 7.4% placebo). This finding is in contrast to the two previous controlled, fast-titration trials, in which discontinuation rates of 32.4% and 28.4% were observed during the double-blind treatment phase. The improved retention rate in this study is likely a result of the low-dose, slow titration schedule, which allowed for individualization of dose by the physician for each patient. Moreover, the majority of patients receiving ziconotide in the current trial (87%) expressed a desire to continue receiving the medication in an open-label follow-up study.
Compared with the two previous controlled trials of ziconotide, not only was the discontinuation rate low, but the overall safety profile was improved. Although the overall frequency of AEs was similar, fewer SAEs and AEs leading to discontinuations were reported. In the two previous studies using a fixed, high-dose, fast titration schedule, many patients initiating treatment at >0.1 μg/hour (2.4 μg/day) reported rapid onset of AEs, particularly nervous-system related SAEs. In the previous malignant pain study, 22 ziconotide-treated patients (30.6%) reported 31 SAEs during the initial titration period, 14 (45.2%) of which involved the nervous system and were considered ziconotide-related by the investigator (5 moderate and 9 severe).
In the previous nonmalignant pain study, 28 ziconotide-treated patients (16.5%) reported 45 SAEs during the initial titration period, 20 (44.4%) of which involved the nervous system and were considered ziconotide-related by the investigator (2 mild, 7 moderate, and 11 severe).
In the current trial, two (1.8%) patients reported SAEs that were considered ziconotide-related by the investigator (chest pain, hypertension, ataxia, dizziness, and neuralgia); the majority of reported AEs were mild or moderate and did not lead to discontinuation from the study. This finding suggests that increasing ziconotide doses slowly and in small increments on an individualized patient basis is the best way to achieve analgesia with an improved safety profile.
The U.S. prescribing information for ziconotide contains a box warning for severe psychiatric symptoms and neurologic impairment.
Compared with the two previous studies, the current study had a higher incidence of AEs related to higher cortical functions, such as confusion and memory impairment. Such differences could be attributable to the longer duration of the current study and the higher cumulative dose over three weeks compared to only 5–6 days in the two previous controlled trials. However, results from the MMSE in the current study indicated no substantial changes in mental status and no significant differences between the ziconotide and placebo groups.
Elevations in CK levels greater than three times the ULN were noted in five ziconotide-treated patients at termination. Such CK elevations appear to be related to ziconotide, but their etiology remains unclear. For some patients, CK levels rose during the weaning and stabilization periods, suggesting that CK level elevations were not attributable to ziconotide therapy alone. Although there did not appear to be any clinical sequelae of CK elevations in these patients, further investigation of the possible consequences of elevated CK levels in ziconotide-treated patients would be warranted.
The time course of ziconotide's observable pharmacologic action appears to develop more slowly than the kinetics of the distribution of ziconotide into the cerebrospinal fluid (CSF). The median time to onset of the most commonly reported AEs ranged from 3 to 9.5 days. In contrast, the half-life of ziconotide in human CSF is 4.6 hours,
suggesting that an approximation to steady-state CSF concentration is achieved within 24 hours (approximately five half-lives). In the current study, dose changes could be made two to three times per week and no more frequently than every 24 hours. The relatively slow onset of AEs suggests that increments in the dosing of ziconotide be made no more frequently than weekly.
The apparent lag between CSF pharmacokinetics and the pharmacodynamics of ziconotide may reflect the drug's slow penetration into the CNS parenchyma. Consistent with ziconotide's molecular weight of approximately 2500 daltons and its polycationic nature, microdialysis studies in rat brain with radioiodinated ziconotide have shown that no detectable ziconotide diffused more than 1 mm from the dialysis probe in 2 hours of perfusion.
The slow diffusion of ziconotide in neural tissue may also explain the slower-than-expected time course of resolution of AEs with discontinuation of ziconotide therapy. As stated above, based on the 4.6 hour CSF half-life of the drug, pharmacologically active concentrations of ziconotide would be expected to be cleared within 24 hours. However, for patients experiencing AEs at the end of their treatment period, the time to resolution for most of these AEs was up to 2 weeks after ziconotide discontinuation. Other factors, such as a slow-off rate for ziconotide binding to its receptor (based upon animal studies), the N-type calcium channel, may also contribute to the slow reversal of AEs. The above result suggests that the full impact of reductions in ziconotide dosing may not be seen for several days. If an AE occurs, ziconotide can be immediately discontinued without the occurrence of withdrawal effects as seen.
Finally, the median ziconotide dose at the time of AE onset ranged narrowly from 0.11 to 0.30 μg/hour (2.6 to 7.2 μg/day), consistent with the observation that time of onset for most AEs was within the first week of ziconotide therapy at the starting dose of 0.1 μg/hour (2.4 μg/day). As mentioned above, efficacy was demonstrated in the first week of treatment. These results suggest that when titrating ziconotide, the starting dose should be no greater than 0.1 μg/hour (2.4 μg/day). It should not be surprising that efficacy and AEs begin to manifest at similar doses. Because of the very high specificity of ziconotide for its target, efficacy and AEs are both likely due to inhibition of N-type calcium channels. Thus, as the results of the current study show, ziconotide has a narrow therapeutic index and must be administered carefully to provide maximum benefit for the patient.
Ziconotide, a new nonopioid analgesic, reduced pain as measured by the VASPI in patients with severe chronic pain who were intolerant of and/or refractory to treatment with other analgesics including IT morphine. Using the slow dose titration regimen starting at 0.1 μg/hour (2.4 μg/day) and titrating to a mean dose of 0.29 μg/hour (6.96 μg/day) over three weeks, the degree of pain relief was less than that noted in the two previous controlled trials of ziconotide, but better patient retention and an improved safety profile were observed.
Taken together, the three controlled trials demonstrate that, to achieve the best overall treatment outcome, slow titration of ziconotide at low doses is necessary to identify each patient's individualized therapeutic window. As the most comprehensively studied IT analgesic in controlled trials, ziconotide appears to have a place in the management of severe chronic pain.
Acknowledgments
The authors gratefully acknowledge the following investigators for their contributions to this study: Donald D. Bacon, MD (San Antonio, TX); Zahid Bajwa, MD (Boston, MA); Yogendra Bharat, MD (Cudahy, WI); Casey Blitt, MD (Tuscon, AZ); Daniel Brookhoff, MD (Memphis, TN); Allen W. Burton, MD (Houston, TX); Ronald Collins, MD (Huntsville, AL); M. Carl Covey, MD (Little Rock, AR); John W. Culclasure, MD (Nashville, TN); Miles R. Day, MD (Lubbock, TX); Timothy R. Deer, MD (Charleston, WV); Maria Theresa Ferrer-Brechner, MD (Bakersfield, CA); Robert Fisher, MD (Fort Smith, AR); Kerri A. Kolehma, MS, MD (Charleston, SC); Peter S. Kosek (Eugene, OR); James Kowalcyzk, MD (Syracuse, NY); Elliot S. Krames, MD (San Francisco, CA); John D. Loeser, MD (Seattle, WA); Timothy Lubenow (Chicago, IL); Eugene A. Mangieri, MD (Northport, AL); Steven A. Mortazavi, MD (Bethlehem, PA); John C. Oakley, MD (Billings, MT); Gnyandev S. Patel, MD (Anaheim, CA); Robert J. Plunkett, MD (Buffalo, NY); Larry P. Putnam, MD (Tucson, AZ); Gabor B. Racz (Lubbock, TX); Stuart Rosenblum, MD, PhD (Portland, OR); Joel R. Saper, MD (Ann Arbor, MI); David M. Schultz, MD (Minneapolis, MN); Raymond Sorensen, DO (Tulsa, OK); Marvin D. Tark, MD (Marietta, GA); Nolan Tzou, MD (Huntington, NY); and David Zylberger, MD (New York, NY).
The authors would like to acknowledge the contributions that Robert Presley, MD, made to this study and to the development of ziconotide prior to his death.
The authors would also like to acknowledge Tonya Marmon, DrPH, and Elizabeth Ludington, PhD, for their statistical support in the analyses of the data from this study; George Miljanich, PhD, for his critical review and comments of the manuscript; Graham McLennan for his critical review of the manuscript and the operational oversight of the study; and Elizabeth S. O. Barton, MS, for her technical writing contributions to the manuscript.
References
Thimineur M.A.
Kravitz E.
Vodapally M.S.
Intrathecal opioid treatment for chronic nonmalignant pain: a 3-year prospective study.
Use of intrathecal SNX-11, a novel, N-type, voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain.
Guy W. Clinical global impression. ECDEU assessment manual for psychopharmacology. US Department of Health, Education and Welfare,
Rockville, MD1976 (Publication No. ADM 76–336)
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