Context Ziconotide (formerly SNX-111) selectively blocks N-type voltage-sensitive
calcium channels and may be effective in patients with pain that is refractory
to opioid therapy or those with intolerable opioid-related adverse effects.
Objective To assess the safety and efficacy of intrathecal ziconotide in patients
with pain that is refractory to conventional treatment.
Design, Setting, and Patients Double-blind, placebo-controlled, randomized trial conducted from March
12, 1996, to July 11, 1998, at 32 study centers in the United States, Australia,
and the Netherlands. Patients were 111 individuals ages 24 to 85 years with
cancer or AIDS and a mean Visual Analog Scale of Pain Intensity (VASPI) score
of 50 mm or greater. Patients were randomly assigned in a 2:1 ratio to receive
ziconotide or placebo treatment.
Interventions Intrathecal ziconotide was titrated over 5 to 6 days, followed by a
5-day maintenance phase for responders and crossover of nonresponders to the
opposite treatment group.
Main Outcome Measure Mean percentage change in VASPI score from baseline to the end of the
initial titration period.
Results Of the evaluable population, 67 (98.5%) of 68 patients receiving ziconotide
and 38 (95%) of 40 patients receiving placebo were taking opioids at baseline
(median morphine equivalent dosage of 300 mg/d for the ziconotide group and
600 mg/d for the placebo group; P = .63, based on
mean values), and 36 had used intrathecal morphine. Mean (SD) VASPI scores
were 73.6 (1.8) mm in the ziconotide group and 77.9 (2.3) mm in the placebo
group (P = .18). Mean VASPI scores improved 53.1%
(95% confidence interval [CI], 44.0%-62.2%) in the ziconotide group and 18.1%
(95% CI, 4.8%-31.4%) in the placebo group (P<.001),
with no loss of efficacy of ziconotide in the maintenance phase. Pain relief
was moderate to complete in 52.9% of patients in the ziconotide group compared
with 17.5% in the placebo group (P<.001). Five
patients receiving ziconotide achieved complete pain relief, and 50.0% of
patients receiving ziconotide responded to therapy compared with 17.5% of
those receiving placebo (P = .001).
Conclusion Intrathecal ziconotide provided clinically and statistically significant
analgesia in patients with pain from cancer or AIDS.
Ziconotide (formerly SNX-111, Neurex Pharmaceuticals, Menlo Park, Calif)
is the synthetic equivalent of ω-conopeptide MVIIA, a 25–amino-acid
polybasic peptide present in the venom of Conus magus,
a marine snail.1 Ziconotide produces potent
antinociceptive effects2 by selectively binding
to N-type voltage-sensitive calcium channels3,4 on
neuronal somata, dendrites, dendritic shafts, and axon terminals, thus blocking
neurotransmission from primary nociceptive afferents.
Ziconotide is the first selective N-type voltage-sensitive calcium channel
blocking agent to be tested in clinical trials. There is no evidence of tolerance
to ziconotide5 or of addictive behavior in
animals (Elan Pharmaceuticals Inc, unpublished data), and the drug must be
administered intrathecally to maximize antinociceptive effectiveness and minimize
sympatholysis.6
Many patients with cancer or AIDS do not receive satisfactory pain relief7,8 from systemic administration of opioids
and become potential candidates for intraspinal analgesia.9-11 However,
regardless of delivery route, concerns about addiction and abuse, and the
potential for developing tolerance, adverse effects, and pain refractoriness
limit the effectiveness of opioids.
In experimental studies of absorption, distribution, metabolism, and
elimination, intrathecal ziconotide appeared and diminished rapidly in plasma
and resulted in relatively little plasma protein binding. Intravenous ziconotide
degraded in rat brain tissue in 2 to 24 hours, produced no detectable intermediates,
and cleared quickly from both cerebrospinal fluid (CSF) and the circulatory
system. This accelerated clearance rate likely means that the distribution
of ziconotide throughout the CSF and its metabolism within the CSF are also
rapid.6
Investigators demonstrated the antinociceptive effects of ziconotide
in various animal models of acute and chronic pain (eg, formalin, hot-plate,
and ligation).12,13 Toxicology
studies revealed no organ specificity, mutogenicity, or teratogenicity, even
at higher doses than would be used in humans (Elan Pharmaceuticals Inc, unpublished
data).
In clinical pharmacokinetic studies using high intravenous doses and
low intrathecal doses, ziconotide exhibited a linear clearance from plasma
and CSF, with plasma concentrations of ziconotide below the quantitation assay
minimum of 0.039 ng/mL (Elan Pharmaceuticals Inc, unpublished data). The rate
of CSF clearance of intrathecal ziconotide approximated the CSF turnover rate
(mean elimination half-life of 4.6 hours).
An initial, open-label feasibility study evaluated 31 male patients
with chronic pain states of diverse indications, including cancer, AIDS, spinal
cord injury, thalamic pain, and brachial plexus avulsion.14 None
of the patients had received adequate pain control with opioid therapy, including,
in many cases, intrathecal opioid therapy. Patients received a continuous
infusion of ziconotide via an intrathecal catheter beginning at a dosage of
0.3 ng/kg per hour, which was titrated upward to the point of pain relief
or intolerable adverse effects, with a maximum dosage of 300 ng/kg per hour.
Of the 24 patients who completed the study, 19 experienced an average reduction
of 43% in their Visual Analog Scale of Pain Intensity (VASPI) score. Fifteen
patients were able to reduce their concomitant use of opioids by at least
50%.
Investigators have reported the following central nervous system adverse
effects associated with the use of intrathecal ziconotide: dizziness, nystagmus,
confusion, abnormal gait, somnolence, speech difficulties, amblyopia, ataxia,
amnesia, and abnormal thought processes.15 These
effects diminished or resolved when the investigators reduced the infusion
rate or ceased infusion. The patients who reported major adverse effects had
been receiving 0.2 to 5.3 µg/h of intrathecal ziconotide.
Encouraged by this preliminary evidence of human analgesia, we conducted
a randomized, double-blind, placebo-controlled trial to test the effectiveness
of intrathecal ziconotide in treating refractory pain in patients with cancer
or AIDS.
To be eligible, patients with cancer or AIDS from 32 centers in the
United States, Australia, and the Netherlands needed to have a mean VASPI
score of 50 mm or greater during the 3 days before enrollment, despite a regimen
of systemic or intrathecal analgesics. The VASPI is a scale commonly used
in assessments of pain therapy, in which patients rate their pain on a scale
of 0 mm (no pain) to 100 mm (worst pain imaginable). We discontinued intrathecal
medications in the patients with implanted pumps at least 3 days prior to
study enrollment. According to accepted clinical practice, the investigators
weaned patients from baseline intrathecal medications and maximized systemic
and oral medications to control pain during this period.
Exclusion criteria included pregnancy, sepsis or inadequately treated
infection, investigational drug use, or palliative surgical procedure(s) within
the preceding 30 days; dementia; untreated affective disorders; nonpatent
spinal canal; severe asthma, cardiac failure, or bradyarrhythmias; and neurocardiogenic
syncope. Prior to enrolling patients, each study center obtained institutional
review board/institutional ethics committee approval and obtained written
informed consent from all patients.
For this double-blind, placebo-controlled, randomized study, we used
a central call-in system to randomly assign patients in a 2:1 ratio to receive
ziconotide or placebo treatment, stratified within each center by cancer or
AIDS diagnosis and by history of intrathecal morphine use. The study began
with a screening phase and preinfusion evaluation (1-7 days). In patients
without previously implanted pumps, we implanted an intrathecal catheter and
used an external infusion system. Given the risk of infection with the use
of external systems, we limited the total time frame for drug infusion to
2 weeks for all patients.
In the initial titration phase, participants received ziconotide or
placebo for 5 days (for nonresponders, a discretionary additional day at any
given dosage or increased dosage could be given). Responders received an additional
5 days of maintenance therapy while nonresponders crossed over to the opposite
group for an additional 5 or 6 days. Ziconotide responders could enroll in
a long-term, open-label study.
The protocol defined responders as patients with a 30% or greater decrease
in mean VASPI score and no increase in concomitant opioid use or change in
opioid type. The study protocol was consistent across all study centers.
Starting from screening and preinfusion visits and in 24-hour intervals,
we calculated values for the VASPI, the 5-point Category Pain Relief Scale
(CPRS), the Wisconsin Brief Pain Inventory (WBPI), the Karnofsky Performance
Status Scale (KPSS), as well as mean percentage change in opioid use and response
to treatment.
Dosing of ziconotide (an aqueous isotonic solution of 100 µg/mL
ziconotide free-base with L-methionine and sodium chloride
as excipients) and placebo (identical vehicle) during the early stage of enrollment
in the study was 5 ng/kg per hour. To minimize variability, we changed this
dosage to 0.4 µg/h with incremental increases in titration every 12
hours to the maximum tolerated dosage of ziconotide. Based on safety evaluations
of the first 48 enrolled participants, we decreased the starting dosage for
60 subsequent participants to 0.1 µg/h or less, with upward titrations
once every 24 hours to the point of analgesic effect or to a discretionary
maximum dosage of 2.4 µg/h. We adjusted concentrations as required by
final daily doses and apparatus used. Patients could receive other systemic
medications, including opioids, as clinically indicated, but not adjuvant
intrathecal agents.
End Points and Measurements
The primary efficacy variable was mean percentage change in VASPI score
from baseline (score immediately prior to infusion) to the end of the initial
titration period (mean of the last 2 VASPI scores or of the last 3 VASPI scores
if the first 2 scores differed by more than 15 mm). Responders had a 30% or
greater decrease in VASPI scores, with no concomitant increase in opioid use
or change in opioid class.
We also calculated the percentage change in the CPRS, the WBPI, and
the KPSS; the change in opioid use; and the change in responder status from
baseline to the end of the maintenance phase and of the crossover phase, as
dictated prospectively by the protocol. We recorded adverse events, vital
signs, and the results of cognitive assessments (trail-making and digit symbol
tests), and clinical laboratory evaluations (blood chemistry, hematology,
urinalysis, and electrocardiography). For the timed cognitive tests, we asked
patients to draw a line between numbered circles or between numbered and lettered
circles, or to decode a series of 9 simple symbols.
Study sponsors, principal investigators, and patients did not know group
assignments during the trial. Only the pharmacists who prepared the study
drugs knew each patient's status.
The planned sample size was 70 evaluable patients receiving ziconotide
(with complete VASPI data at the end of the initial titration period and no
substantial violations of the protocol) and 35 evaluable patients receiving
placebo. This sample size has a 96% statistical power at the .05 significance
level to detect a greater than 30% change in VASPI scores in the 2 treatment
groups. Statistical analyses were performed using SAS version 6.12 (SAS Institute
Inc, Cary, NC). We conducted 2-way analyses of variance of the mean percentage
change in VASPI scores and KPSS scores, with treatment, previous use of intrathecal
morphine (yes/no), and treatment × previous use of intrathecal morphine
as interaction terms. We used the Cochran-Mantel-Haenszel test stratified
by history of intrathecal opioid use to analyze differences in the CPRS and
the WBPI scores between study baseline and the end of initial titration. To
compare incidence of adverse events between study groups, we used the Cochran-Mantel-Haenszel
general association test stratified by history of intrathecal opioid use.
For adverse events with fewer than 5 reports, we used the Fisher exact test.
All statistical tests were 2-sided, and we considered results statistically
significant if P≤.05.
The intent-to-treat (ITT) sample included patients who received a study
drug and had baseline and follow-up VASPI scores. The evaluable sample had
sufficient VASPI data at the end of the initial titration period and did not
substantially violate the protocol. Efficacy and demographic results cover
the evaluable sample, and safety results cover the ITT sample plus 1 open-label,
compassionate-use patient.
The study's first patient was enrolled on March 12, 1996, and the last
patient completed the study on July 11, 1998. Patients ages 24 to 85 years
were enrolled at 32 study centers. Seven centers enrolled 5 or more patients,
13 centers enrolled 2 to 4 patients, and 12 centers enrolled only 1 patient
each. We excluded 3 patients in the ziconotide group because of insufficient
VASPI data, leaving an evaluable group of 68 patients receiving ziconotide
and 40 receiving placebo, an ITT group of 71 patients receiving ziconotide
and 40 receiving placebo, and a total population of 112 patients (including
1 open-label, compassionate-use patient) (Figure 1).
More than 25 types of cancer were represented in the patient population,
and more than half of the patients had widespread metastatic disease. Many
of the nonmetastatic cancers directly infiltrated neural structures, including
the spinal cord. The most frequently mentioned cancer complications causing
pain were neuropathy, postherpetic neuralgia, pathologic fractures, and complications
of cancer radiotherapy. Among the patients with AIDS, the most frequent causes
of pain were peripheral neuropathy, Kaposi sarcoma, and postherpetic neuralgia.
The majority of patients had undergone 1 or more surgical procedures for cancer
excision, including hysterectomy, mastectomy, pneumectomy, and amputation
(2 patients had undergone hip disarticulation). Three patients had undergone
bone marrow transplantation.
At baseline (Table 1) the
mean KPSS score was near 60, and 36 patients had received intrathecal morphine.
Medication use included a median oral morphine equivalent dosage of 300 mg/d
in the ziconotide group and 600 mg/d in the placebo group. Baseline medications
included opioids (92% of patients), antidepressants (44%), anxiolytics (40%),
anticonvulsants (27%), anti-inflammatory agents (28%), and antipsychotics
(16%). The ziconotide and placebo groups had comparable demographic and clinical
characteristics, including mean VASPI scores (73.6 [SD, 1.8] mm vs 77.9 [SD,
2.3] mm, respectively; P = .18).
From baseline to the end of the initial titration phase, mean VASPI
scores for the evaluable group improved 53.1% (95% confidence interval [CI],
44.0%-62.2%) in the ziconotide group and 18.1% (95% CI, 4.8%-31.4%) in the
placebo group (P<.001) (Figure 2). Efficacy results in the ITT sample were not appreciably
different from those in the evaluable sample; the mean changes in VASPI score
for the ITT sample were 51.4% in the ziconotide group and 18.1% (95% CI, 17.3%-49.4%)
in the placebo group (P<.001).
Pain relief (based on CPRS scores) was moderate to complete in 52.9%
of the ziconotide group and in the same range but never reaching complete
in 17.5% of the placebo group (P<.001). Five patients
receiving ziconotide achieved complete pain relief; 50.0% of those receiving
ziconotide responded to therapy, compared with 17.5% of those receiving placebo
(P = .001) (Figure
3). Opioid use decreased in the ziconotide group by 9.9% but increased
in the placebo group by 5.1%.
From the protocol-defined responder group of 34 patients receiving ziconotide
and 7 receiving placebo, 2 patients (1 from each group) did not continue into
the maintenance phase. An additional 15 patients receiving ziconotide and
5 receiving placebo were identified as responders by the investigators (though
they did not meet strict protocol-defined responder criteria) and proceeded
to the maintenance phase. In patients receiving ziconotide who proceeded to
the maintenance phase of the study (n = 48), ziconotide maintained efficacy,
resulting in a 69.2% change in VASPI scores at the end of the initial titration
phase, compared with 69.4% at the end of the maintenance phase. The 26 patients
receiving placebo who crossed over to the ziconotide group during the second
phase experienced a 44.9% mean reduction in VASPI score at the end of the
crossover phase. The 12 patients receiving ziconotide who crossed over to
the placebo group experienced a 4.2% mean reduction in VASPI score at the
end of the crossover phase.
The therapeutic effect (ie, improvement in VASPI score for the ziconotide
group minus the improvement for the placebo group) was statistically significant
in both starting-dose subgroups and in each underlying disease subgroup (Figure 2). Age, sex, or prior treatment with
intrathecal morphine did not affect the improvement in VASPI scores. The treatment
groups did not register a significant difference in WBPI subsets or KPSS scores
at the end of the initial titration phase.
During the initial titration phase, 4 (10.0%) of the 40 patients receiving
placebo reported a total of 4 serious adverse events, and 22 (30.6%) of the
72 receiving ziconotide in the safety group reported a total of 31 serious
adverse events. Of these 31 events, we considered the 14 (45.2%) that involved
the nervous system (5 moderate, 9 severe) to be related to ziconotide treatment.
The remaining serious adverse events were not determined by the reporting
investigators to be related to ziconotide treatment. The most common serious
adverse events for patients who received ziconotide during the initial titration
phase were confusion, somnolence, and urinary retention (4.2% each); all others
were reported in less than 3% of the study population.
Nine types of adverse events occurred with significantly greater frequency
in the ziconotide group compared with the placebo group (Table 2), but starting at the lower dosage, using smaller dose increments,
and increasing the interval between dose titrations tended to reduce this
frequency. Table 3 shows the proportion
of patients in each starting dosage group that experienced these adverse events.
Confusion was the only of these 9 adverse events that occurred in a larger
percentage of patients with a starting ziconotide dosage of 0.1 µg/h
or less compared with patients with a starting ziconotide dosage of more than
0.1 µg/h.
Table 4 shows the mean dose
and timing of onset for the most frequently reported adverse events in patients
receiving ziconotide. Confusion occurred much more often in patients receiving
ziconotide who were older than 60 years than in those aged 60 years or younger.
Central nervous system adverse events (ie, cognitive dysfunction, vestibular
symptoms, and somnolence) had a median time to resolution of 4 days (range,
0-58 days). Adverse events led to early discontinuation in 12 patients receiving
ziconotide and in 4 receiving placebo. An additional 15 patients receiving
ziconotide and 5 receiving placebo discontinued the study for such reasons
as external catheter complications, patient request, unrelated medical conditions,
or lack of therapeutic effect. There were 5 cases of meningitis in the ziconotide
group and 2 in the placebo group—all in patients with external infusion
systems.
Thirteen patients died during the study or the 30-day follow-up period,
and we recorded 2 additional deaths after follow-up (Table 5). Death rates were not significantly different between the
ziconotide and placebo groups. Twelve patients died from cancer, 1 committed
suicide, 1 succumbed to pneumonia, and 1 died from an unknown cause. Of the
5 patients who died while receiving placebo, 2 had crossed over from the ziconotide
group. The patient who died due to unknown causes received only placebo.
Other than these deaths, no clinically significant changes in vital
signs, laboratory analyses, or cognitive function test scores occurred in
either treatment group from baseline to study termination. There were no reports
of anaphylaxis or hypersensitivity to ziconotide.
We demonstrated the clinically and statistically significant analgesic
effect of intrathecal ziconotide in a heterogeneous, complex, and treatment-refractory
patient population. Our results validate reports of the antinociceptive effects
of ziconotide,12,13 as well as
the findings of an open-label feasibility study in patients with intractable
pain.2 Animal studies suggested that our patients
would not develop tolerance to the analgesic effects of ziconotide within
the time frame of this trial, perhaps because ziconotide binds directly to
calcium channels, bypassing G-protein–dependent secondary messenger
mechanisms.13
The robust analgesic effect of ziconotide observed in our study population
underscores the finding that intrathecal ziconotide is 1000-fold more potent
than intrathecal morphine in blocking the phase-2 responses in the formalin
test that are thought to depend on central sensitization.12
Because this was a safety and efficacy study, we deliberately maximized
the incidence of ziconotide adverse events. Ziconotide produced significantly
more vestibular effects (eg, somnolence, confusion, urinary incontinence,
and fever) than did placebo, perhaps because ziconotide blocks N-channels
in the granular cell layer of the cerebellum.16 These
effects were easily recognizable and reversible, however, and their incidence
decreased when we decreased the initial dose and the frequency of titration.
The incidence of meningitis in this trial can be attributed to 2 factors.
First, the study patients were very likely immunosuppressed. Second, the limited
life expectancy of many of the patients made it prudent to administer ziconotide
via implanted catheter or external infusion systems or via preexisting implanted
pumps. Each of the 7 cases of meningitis occurred in patients with external
systems. Thus, the high rate of infection appears to be due to poor physiological
status and presence of an externalized catheter, not to an idiosyncratic effect
of the drug.
The overall frequency of deaths in our study was consistent with the
underlying disease status of the patients.
Our randomized, double-blind, placebo-controlled trial revealed the
considerable efficacy of ziconotide in patients with end-stage cancer or AIDS
and with refractory pain. Compared with placebo, ziconotide was associated
with a number of (typically dose-related) adverse events: abnormal gait, dizziness,
nystagmus, confusion, somnolence, fever, postural hypotension, urinary retention,
nausea, and vomiting. Completed and ongoing trials using lower dosages of
ziconotide and longer durations of treatment will better define the long-term
risk-benefit profile of this potent analgesic.
1.Olivera B, Gray WR, Zeikus R.
et al. Peptide neurotoxins from fish-hunting cone snails.
Science.1985;230:1338-1343.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=4071055&dopt=Abstract
Google Scholar 2.Brose W, Pheifer B, Hassenbusch S.
et al. Analgesia produced by SNX-111 in patients with morphine resistant pain. Presented at: 15th Annual Meeting of the American Pain Society; November
14-17, 1996; Washington, DC.
3.Olivera BM, Cruz LJ, de Santos V.
et al. Neuronal calcium channel antagonists: discrimination between calcium
channel subtypes using omega-conotoxin from
Conus magus venom.
Biochemistry.1987;26:2086-2090.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2441741&dopt=Abstract
Google Scholar 4.Miljanich G, Ramachandran J. Antagonists of neuronal calcium channels: structure, function, and
therapeutic implications.
Annu Rev Pharmacol Toxicol.1995;35:707-734.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7598513&dopt=Abstract
Google Scholar 5.Mathur VS, McGuire D, Bowersox SS, Miljanich GP, Luther RR. Neuronal N-type calcium channels: new prospect in pain therapy.
Pharm News.1998;5:25-29.Google Scholar 6.McGuire D, Bowersox S, Fellmann JD, Luther RR. Sympatholysis after neuron-specific, N-type, voltage-sensitive calcium
channel blockade: first demonstration of N-channel function in humans.
J Cardiovasc Pharmacol.1997;30:400-403.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9300326&dopt=Abstract
Google Scholar 7.Breitbart W, Rosenfeld BD, Passik SD, McDonald MV, Thaler H, Portenoy RK. The undertreatment of pain in ambulatory AIDS patients.
Pain.1996;65:243-249.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8826513&dopt=Abstract
Google Scholar 8.Zech DF, Gron S, Lynch J, Hertel D, Lehmann KA. Validation of World Health Organization Guidelines for cancer pain
relief: a 10-year prospective study.
Pain.1995;63:65-76.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8577492&dopt=Abstract
Google Scholar 9.Staats PS. Cancer pain: beyond the ladder.
J Back Musculoskeletal Rehabil.1998;10:69-80.Google Scholar 10.Jacox AK, Carr DB, Payne R.
et al. Clinical Practice Guideline Number 9: Management
of Cancer Pain. Rockville, Md: Agency for Health Care Policy and Research; 1994.
AHCPR publication 294-0592.
11.Ventafridda V, Spoldi E, Caraceni A, DeConno F. Intraspinal morphine for cancer pain.
Acta Anaesthesiol Scand Suppl.1987;85:47-53.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=3310498&dopt=Abstract
Google Scholar 12.Bowersox SS, Gadbois T, Singh T, Pettus M, Wang YX, Luther RR. Selective N-type neuronal voltage-sensitive calcium channel blocker,
SNX-111, produces spinal antinociception in rat models of acute, persistent
and neuropathic pain.
J Pharmacol Exp Ther.1996;279:1243-1249.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8968347&dopt=Abstract
Google Scholar 13.Malmberg AB, Yaksh TL. Effect of continuous intrathecal infusion of omega-conopeptides, N-type
calcium-channel blockers, on behavior and antinociception in the formalin
and hot-plate tests in rats.
Pain.1995;60:83-90.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7715945&dopt=Abstract
Google Scholar 14.Mathur VS. Ziconotide: a new pharmacological class of drugs for the management
of pain.
Semin Anesth.2000;19:67-75.Google Scholar 15.Penn RD, Paice JA. Adverse effects associated with the intrathecal administration of ziconotide.
Pain.2000;85:291-296.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10692631&dopt=Abstract
Google Scholar 16.Vandaele SF, Reader TA. Ca(2+)-sensitive and insensitive omega-conotoxin GVIA binding sites
in rat brain.
Neuroreport.1994;5:1121-1124.http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&Dopt=r&uid=entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8080970&dopt=Abstract
Google Scholar