Ziconotide: A New Pharmacological Class of Drug for the

Management of Pain
Vandana S. Mathur
Z

ICONOTIDE is the first in a new pharmacological class of analgesics that selectively target neuron-specific (N-type), voltage-gated calcium channels. Formerly known as SNX-111 (Elan
Pharmaceuticals, South San Francisco, CA), ziconotide is the synthetic form of a peptide,
~-conopeptide-MVIIA, derived from the venom of
fish-hunting marine snails. By selectively antagonizing N-type channels, intraspinally administered
ziconotide produces potent analgesia in animals by
mechanisms that appear to include interruption of
primary afferent transmission (Fig 1) as well as
reversal of the pathological hypersensitivity in spinal cord circuitry known as central sensitization. 1
Controlled clinical trials have demonstrated the
analgesic efficacy of ziconotide in both acute and
chronic pain, including pain refractory to opioids. z-4 Furthermore, unlike analgesics that bind to
opioid receptors, ziconotide does not produce
abuse, dependence, or tolerance, 5 nor does it cause
respiratory depression 3 or bowel dysfunction.5 Ziconotide is currently awaiting clearance by the
Food and Drug Administration for the management of pain. This article reviews the mechanism
of action of ziconotide, its pharmacological profile,
and its efficacy and safety in con~olled clinical
trials.

RATIONALE FOR TARGETING N-TYPE

CALCIUM CHANNELS FOR PAIN THERAPY
Experimental evidence suggests that the mechanisms underlying prolonged pain states involve
influx of calcium ions into neurons. For example,
in standard models of persistent pain in rats (induced by subcutaneous injection of formalin or
intraperitoneal injection of acetic acid), pain is
exacerbated by manipulations that increase calcium levels in cells and is reduced by antagonists
of voltage-gated calcium channels. 6'7
Two types of observations suggested that selective targeting of spinal N-type calcium channels
could be a successful analgesic strategy. First, Ntype channels, expressed almost exclusively by
neurons, appear to control synaptic release of neu-

rotransmitters in a variety of neurons? '9 Nociceptive sensory neurons, in particular, express N-type
calcium current, 1~ and antagonists of N-type channels block the release of the neuropeptide transmitters, substance P and calcitonin gene-related
peptide, that are typical of nociceptive sensory
neurons. 11-15 Second, as illustrated in Fig 1, although N=type calcium channels (binding sites for
ziconotide or conopeptide) are expressed in widespread regions of the brain, N-type channels are
concentrated in the superficial dorsal horn in the
spinal cord. 16'17 This zone of ziconotide binding
corresponds to the Rexed's laminae I and II where
nociceptive primary afferents synapse on spinal
pain transmission neurons. Together, these observations led to the hypothesis that the selective
antagonism of N-type calcium channels in the spinal cord would cause analgesia by blocking synaptic transmission between nociceptive sensory
neurons and neurons of the spinal cord dorsal horn.

ZICONOTIDE ANALGESIA IN ANIMALS:

IMPLICATIONS FOR NEURAL MECHANISMS
A series of studies performed in animals have
tested the hypothesis that ziconotide can cause
analgesia. In these studies, ziconotide was injected
intrathecally to selectively target N-type channels
in the spinal cord, thereby avoiding hypotension
resulting from reduction in sympathetic efferent
action in the periphery and minimizing adverse
effects on neurons in the brain. As described beFrom the University of California San Francisco, San Francisco: and current consultant for and past employee of Neurex
Pharmaceuticals , a business unit of Elan Pharmaceuticals),
South San Francisco. CA.
The Editor in Chief has determined that no conflict of interest
ts posed by the publication of this article. However, readers
should be aware of the author's presem and past affiliation with
Neurex Pharmaceuticals. which manufactures ziconotide.
Address reprint requests to Vandana S. Mathur, MD, University of California. San Francisco. Moffitt Hmpital, M-884
Box 0116. San Francisco. CA 94143.
Copyright 9 2000 by W.B. Saunders Company
027740326/00/1902-000251 O.00/0
doi: 10.1053/sa.2000.6787

Seminars in Anesthesia, Perioperative Medicine and Pain, Vol 19, No 2 (June),2000: pp 67-75

67

68

VANDANA S. MATHUR

spinothalamic

dorsal

B
Fig 1. Ziconotide binding sites are localized in pain-processing regions of the spinal cord. (A) Binding of radiolabeled
ziconotide is most dense in the superficial dorsal horn, including laminae I and II. (B) Small-diameter nociceptive primary
afferent nerve fibers terminate primarily in laminae I and II. In contrast, large-diameter primary afferent fibers transmit
non-noxious sensory information to the brain via the dorsal column pathway, largely uninterrupted by synapses in the dorsal
horn. {Reprinted with permission?)

low, in addition to reducing acute responses to

experimental noxious stimuli, 18-22 intrathecal ziconotide also can reduce responses in more persistent pain states that may be more relevant to intractable chronic pain encountered clinically.
The formalin test is useful for examining possible effects on acute nociception versus persistent
pain because it produces a biphasic behavioral
response with a well-resolved transition from acute
pain to a more persistent pain state. In this model,
a dilute formalin solution is injected subcutaneously into the rat hind paw, and nociceptive behavior is quantified as the number of flinches over
time.
Because acute pain (phase 1) occurs during the
first 10 minutes after formalin injection during the
peak of formalin-stimulated activity in nociceptive
sensory nerve fibers, it is thought to be a direct
response to stimulation of nociceptive sensory
nerve fibers. Bolus intrathecal injection of ziconotide 10 minutes before formalin injection potently reduced phase-1 flinching behavior (ED50 =
3 pmol/L18'19). This effect during phase 1 pain is
consistent with the hypothesis that ziconotide interrupts the transmission of pain-related activity
into the spinal cord by decreasing transmitter re-

lease from nociceptive primary afferent synaptic

terminals.
In addition, ziconotide even more potently reduced the flinching behavior that occurs during the
persistent phase (phase 2) of the formalin test.
Afferent activity remains relatively low during
phase 2, and pain during this phase is thought to
depend instead on activity generated by sensitized
neuronal circuitry within the spinal cord. Therefore, it has been suggested that ziconotide may
prevent the development of central sensitization by
some mechanism other than the inhibition of synaptic release of neurotransmitters from primary
afferents, is
Of particular interest from a clinical point of
view is the observation that ziconotide not only
prevented phase-2 behavior when administered before formalin injection, but it also reversed phase-2
behavior when it was administered during the second phase, is Consistent with the idea that this
results from reversal of central sensitization, another N-type calcium channel blocker, o)-conopeptide-GVIA, reverses the hyperexcitability of dorsal
horn neurons induced by subcutaneous formalin. 23
These observations raise the possibility that, with
respect to persistent clinical pain states, ziconotide

ZICONOTIDE FOR PAIN MANAGEMENT

might be useful not only for pre-emptive analgesia
(when pain can be anticipated, eg, postsurgical
pain) but also for the more common situation in
which treatment is sought long after the pain state
hag been established.

Continuous Spinal Infusion of Ziconotide: Lack

of Tolerance
Ziconotide may offer significant advantages
over morphine as an analgesic blocker of calcium
channels. Specifically, morphine modulates calcium currents via G-protein-dependent second
messenger mechanisms (Fig 2). The development
of opioid tolerance, a major complication that can
limit the effectiveness of morphine, is thought to
involve, at least in part, an impairment in the
ability of morphine to activate G-protein-dependent mechanisms via opioid receptors. 24 Because
tolerance does not appear to involve changes in the
ion channels modulated by opioids, it might be

Fig 2 . Comparison of direct

effect of ziconotide and indirect
effect of morphine on N-type
calcium channels. Morphine
also causes a decrease in Ntype calcium current in sensory
neurons indirectly via G-protein-dependent second messenger mechanisms. Tolerance
to morphine may involve an
impairment in the ability of
morphine to activate G-proteindependent mechanisms. Ziconotide, which binds directly
to the calcium channel, is not
subject to the development of
the kind of tolerance that limits
the use of morphine. (Reprinted
with permission? )

69
expected that ziconotide, which binds directly to
the calcium channel, thereby bypassing second
messenger mechanisms, may not be subject to the
development of tolerance of the sort that limits the
use of morphine. To test if the analgesic effect of
ziconotide is subject to the development of tolerance, the drug was administered by continuous
constant-rate intrathecal infusion for 7 daysY Analgesic efficacy was assessed by the formalin and
hot-plate tests. No decrease in effectiveness of
ziconotide was observed on day 7 versus day 2
(although tolerance to morphine was demonstrated). This suggests that the clinical use of ziconotide as an intrathecal analgesic should not be
complicated by the development of tolerance.

Analgesia Without Anesthesia

Finally, intrathecal administration of ziconotide
produced analgesia, but it has not been reported to
cause generalized insensitivity to nonpainful stim-

70
uli. As illustrated in Fig 2, this selective analgesic
effect may be explained by the anatomy of sensory
pathways in the spinal cord. The dorsal column
pathway is largely uninterrupted by synapses in the
spinal cord. Because electrical transmission along
axons depends primarily on sodium channels, inhibition of calcium currents in the spinal cord
should have little or no effect on activity in the
dorsal column pathway composed of axons that
transit the dorsal horn.

ANALGESIA IN HUMANS: CLINICAL TRIALS

A phase H I open-label clinical study assessed
the safety, tolerability, and analgesic efficacy of
intrathecal ziconotide.26 The study included 31
male patients with chronic painful conditions of
diverse causes including cancer, acquired immunodeficiency syndrom (AIDS), spinal cord injury,
thalamic pain, and brachial plexus avulsion. All
patients had previously failed to receive adequate
pain control with opioid therapy, including, in
many cases, intrathecal opioid therapy.
Patients received continuous infusion of ziconotide via an intrathecal catheter beginning at a
dose of 0.3 ng/kg/h, which was titrated upward to
pain relief or intolerable adverse effects, with a
maximum dose of 300 ng/kg/h. Of the 24 patients
who completed the study, 19 experienced an average reduction in their visual analogue pain scores
(VASPI) by 43%. VASPI is scored on a scale of 0
mm (no pain) to 100 mm (worst imaginable pain).
In 15 patients, concomitant use of opioids was
reduced by at least 50%. Compared with morphine.
ziconotide did not decrease respiratory function
and was not addictive. Furthermore. as predicted
by animal studies, ziconotide apparently was not
subject to the development of tolerance, even with
continuous infusion. The most commonly reported
adverse effects were nystagmus, mental confusion,
difficulty in word-finding, nausea, dizziness, headache, and disturbance of gait and balance. Such
effects are presumably due to rostral spread of the
drug from the spinal cord to the brain and were
found to reverse on decrease in dose or discontinuation of the drug.
Subsequently, two multicenter randomized, double-blind, placebo-controlled trials were conducted
to determine the safety and efficacy of intrathecal
ziconotide for the treatment of chronic intractable
pain. One trial enrolled patients with pain associated with either cancer or AIDS ("malignant

VANDANA S. MATHUR
pain"), and the other enrolled patients without
those conditions ("nonmalignant pain"). Patients
were enrolled who presented with intractable
chronic pain of any etiology, who had a mean
VASPI score of at least 50 mm while on stable oral
and systemic analgesics; and who already had intrathecal pumps or had a clinical need for such
pumps. Ziconotide or placebo was administered by
intrathecal dose titration via a programmable internal or external infusion pump. The primary end
point was the mean percent change in VASPI score
compared with baseline at the end of a 6-day
titration: Patients who responded to ziconotide
were offered entry into a long-term, open-label
extension study. Secondary end point measurements of pain included the Categorical Pain Relief
Score (CPRS), the McGill Pain Questionnaire, and
the Wisconsin Brief Pain Inventory. Results of
these pivotal nonmalignant and malignant pain trials are described below.

Ziconotide for the Management of

"Nonmalignant" Chronic Pain
Of the 257 patients treated in the nonmalignant
pain trial, 240 (n = 162 in ziconotide group; n =
78 in placebo group) were evaluable for efficacy.
Baseline characteristics--including gender, race,
and age--were similar in both treatment arms.
Nearly all patients had experienced pain for more
than 1 year. The investigators judged the patient's
pain to be primarily of "neuropathic" origin in
77.8% of the ziconotide grouRand in 77.3% of the
placeb0 group (P = .7). Patients carried any of a
multitude of pain diagnoses, including "failed back
syndrome;" peripheral neuropathy, thalamic pain,
multiple sclerosis, spinal cord injury, herpes zoster,
sympathetically mediated pain, and arthritis. Many
abnormalities were reported in the medical histories at baseline in the entire study population,
including musculoskeletal (91%), neurological
(77%), gastrointestinal (73%), psychiatric (61%),
genitourinary (61%), and allergic (54%). Physical
examination at baseline frequently detected abnormalities, including musculoskeletal (70%), dermatological (31%), abdominal (28%), ophthalmic
(25%), and neurological (sensory [61%], reflexes
[52%], gait-[52%], and motor [49%]). 4
T h e use of analgesics and analgesic adjuvants
was high and similar in both groups: More than
70% of patients were on opioids, more than 60%
were on antidepressants, more than 30% were on

ZICONOTIDE FOR PAIN M A N A G E M E N T

71

Table 1. Efficacy of Intrathecal Ziconotide in Chronic Pain

Chronic Pain Population

"Malignant"
(pain associated with malignancy or AIDS)
"Nonmalignant"
(pain not associated with malignancy or AIDS)

Mean Change
(%) in VASPI*

Trial Design

Randomized
Double-blind
Placebo-controlled
Randomized
Double-blind
Placebo-controlled

112

Ziconotide: -53
Placebo: - 18

256

Ziconotide: - 31
Placebo: - 6

Abbreviations: VASPI, Visual Analog Scale of Pain Intensity; AIDS, acquired immundeficiency syndrome.
* Mean change (%) in VASPI score at 5 to 6 days compared with baseline; negative values indicate reduction in pain.

other analgesics and antipyretic drugs, more than

24% were on anxiolytics, and approximately 20%
were on hypnotics, sedatives, and centrally acting
muscle relaxants. Mean daily morphine equivalents used at baseline in the ziconotide and placebo
groups, respectively, were 405 _~ 61 and 331 z 49
mg (P = .7). Approximately half the patients had
previously received morphine intrathecally (ziconotide group, 56.2%; placebo group, 62%, P =
.3). Of these patients who had previously received
intrathecal morphine, 48.4% in the zlconotide
group and 40.8% in the placebo group had experienced no analgesia from the morphine therapy
(P - .3).
Ziconotide produced significant analgesia in this
complex pain population as measured by mean
reduction of VASPI from baseline (v placebo).
(VASPI change was 31.0 -,- 3.5 on ziconotide v
- 6 . 0 ~- 3.3 on placebo: P < .001: Table 1),
Furthermore. in the subset of these patients with
pain refractory to intrathecal morphine ("IT
MSO4"). there also was significant analgesia (v
placebo). (VASP! change was 18.4 + 50,3 on
ziconotide v +6.4 -~ 50.3 on placebo; P = .027:
Table 2). Table 3 presents the analgesic responses
of patients categorized according to their clinical
pain diagnoses.
Forty-three percent (43%) of patients in the ziconotide group had moderate to complete pain
relief as measured by CPRS compared with 18% in
the placebo group (P - .001). The mean percent
change in global McGill pain scores was greater in
ziconotide-treated patients (P = .014). The proportion of patients who met the protocol definition of
an analgesic response (-->30% reduction in VASPI,
no increase in concomitant opioid use, no change
in type of opioid used) was 33.3% (54 of 162) in

the ziconotide group compared with 13.9% (11 of

79) in.the placebo group (P = .002).
The percentages of patients with improvement
on WBPI subsets for mood, sleep, and enjoyment
of life were significantly higher in the ziconotide
group than in the placebo group (P ~ .01). Zicontide was similarly efficacious in both genders, in
patients older than 60 years (v -<60 years), and in
whites (v other races). A statistically significantly
greater proportion of ziconotide patients reported
vestibular effects !(nystagmus, abnormal gait, and
dizziness), nausea, vomiting, amblyopia, and uri:
nary retention than did placebo patients:
The nonmalignant pain trial studied a large number of complex pain patients, who were typified by
the presence of numerous baseline abnormalities
and pain of long-standing duration, in a randomized, double-blind, placebo-controlled trial. In this
Table 2. Efficacy of Ziconotide in Patients With Chronic
Nonmalignant Pain, Refractory to Intrathecal Morphine

Nonmalignant Pain
Population
All patients

Refractory to intrathecal
morphine

N
240

66

Mean Change
(%) in VASPI*
Ziconotide:
-30.7
Placebo:
-5.9
Ziconotide:
- 18.4
Placebo:
+6.4

PI
.0002

.027

Abbreviation: VASPI, Visual Analogue Scale of Pain Intensity.

* Mean percent change in VASPI score at 5 and 6 days
compared with baseline; negative values indicate decrease in
pain.
"1 Placebo v ziconotide.

VANDANA S. MATHUR

72
Table 3. Responseto Ziconotide by Pain Diagnosis

Pain Diagnosis (n)

Abdominal pain (2)
Amputation sequelae (9)
Arachnoiditis (11)
Arnold-Chiari (1)
Atypical facial pain/trigeminal
neuralgia (3)
Back pain (2)
Brachial plexopathy (3)
Cauda equina syndrome (2)
Cervical plexopathy/subluxation (2)
Degenerative disc disease (7)
Dercum's disease (1)
Diabetic neuropathy (1)
Failed back syndrome (77)
Fibromyalagia (:3)
!nterstitial cystiti'S:(1 )
Mengioma, middle fossa (1)
Multiple sclerosis (1)
Myelomalacia (2)
Neuralgia, including pudendal
neuralgia (4)
Neuritis {1)
Neuropathic pain (19)
Osteomyelitis (2)
Osteoporosis (1)
Pancreatitis (2)
Post-traumatic (18)
Postherpetic neuralgia (4)
Radiculopathy (7)
Reflex sympathetic dystrophy (20)
Soft tissue (1)
Spinal cord injury (5)
Spinal cord injury with paralysis (17)
Spinal cord tumor (4)
Spinal stenosis (4)
Syringomyelia (2)
Thalamic pain syndrome (4)
Whiplash neck and arm pain (1)

Mean Change
(%) in VASPI
From Baseline*
-1.8
-42.3
-46.0
-22.7
-28.8
-33.7
-29.8
-6.5
+ 15.9
-51.8
- 14.9
+ 7.8
-40.4
-2!!.~4
"25.0
-34.3
-77.7
-0.3
-44.5
-38.8
-21.7
+ 12.3
+4.9
- 24.6
-24.5
-27.2
- 16.4
-25.8
-55.0
-59.9
-19.2
--19.7
-23.4
-25.7
-20.5
-6.8

Abbreviation: VASPI, Visual Analog Scale of Pain Intensity.

* Negative numbers indicate a decrease in pain.

population, in whom pain levels at baseline were

rated close to "worst imaginable" despite treatment
with multiple classes of analgesics and analgesic
adjuvants, ziconotide produced clinically and statistically significant analgesia. Subgroups of patients, such as those with "failed back syndrome"
who often do not respond well to currently available medications and procedures, responded well
to ziconotide (Table 3). Furthermore, even patients
who previously were refractory to intrathecal mot-

phine had statistically significant reductions in pain

with ziconotide (Table 3). Ziconotide significantly
improved patient quality of life as assessed by
self-reported mood, sleep, and enjoyment of life.
The fact that the study population consisted of
patients with many different painful conditions 4
suggests that the results from this trial are both
robust and generalizable.

Ziconotide for the Management of "Malignant"

Chronic Pain
Of the 112 patients treated in the malignant pain
trial, 108 (n = 68 in ziconotide group; n = 40 in
placebo group) were evaluable for efficacy. Baseline characteristi~cs--including gender, race, and
age--were similar in both treatment arms. In all,
patiefits had one or more o f 26 different types of
malignancies. The most common malignancies in
the study population were cancers of the breast,
lung, colon and rectum, prostate, and Hodgkins
and non-Hodgkins lymphoma. More than half of
the cancers were widely metastatic to bonel the
lymphatic system, and other organs. The ~etiology
of pain from many of the nonmetastatic cancers
was the direct infiltration of tumor into neural
structures, including the spine. Additionally, sometimes pain was related to complications from the
cancer or its treatment: neuropathy, postherpetic
neuralgia, pathological fractures, and radiotherapy.
Among the AIDS patients, peripheral neuropathy,
Kaposi's sarcoma, and postherpetic neuralgia were
the most frequent causes of pain. 2
The majority of patients had undergone one or
more surgical procedures for cancer excision, including hysterectomy, mastectomy, pneumonectomy, and amputation (two patients had undergone
hip disarticulatiou). Three patients liad undergone
bone marrow transplantation. Complications from
the primary disease or from opiate therapy, such as
depression, anxiety, constipation, nausea and vomiting, and anemia, were reported frequently.
All but one patient had previously shown unsatisfactory responses to systemic opioid therapy. Of
the 72 patients initially receiving ziconotide,
86.1% (62 of 72) were diagnosed with cancer and
13.9% (10 of 72) with AIDS. Of the 40 patients
initially receiving placebo, 90.0% (36 of 40) had
cancer, and 10.0% (4 of 40) had AIDS.
The ziconotide and placebo groups were comparable with regard to demographic and other

ZICONOTIDE FOR PAIN MANAGEMENT

baseline characteristics and baseline VASPI
scores. The mean percent change in VASPI scores
from baseline to the end of the initial titration
phase was significantly higher for patients in the
ziconotide group (53.1%) than for those in the
placebo group (18.1%; P < .001). Fifty-three percent (36 of 68) of patients in the ziconotide group
had moderate to complete pain relief as measured
by the CPRS compared with only 17.5% (7 of 40)
in the placebo group (P < .001). The proportion of
patients who met the protocol definition of "response" (at least 30% reduction in VASPI, no
increase in concomitant opioid Use, and no change
in type of opioid used) was 50.0% (34 of 68) in the
ziconotide group and 17.5% (7 of 40) in the placebo group (P = .001). A statistically significantly
greater proportion of ziconotide patients reported
vestibu!ar~ effects (nystagmus, abnormal gait, and
dizziness), nausea and vomiting, confusion, somnolence, and urinary retention than did placebo
patients.
Ziconotide proved to be a highly effective analgesic in this controlled clinical trial of ill patients
with chronic pain related (for the most part) to
cancer, nearly all of whom were unresponsive to
systemic opioids and many of whom were at the
end of life.

Ziconotide for the Treatment of Acute Pain

Two small randomized, double-blind, placebocontrolled trials--one using intrathecal ziconotide27
and the other using epidural ziconotide5 - demonstrated the feasibility and safety of ziconotide treatment for postoperative pain. The primary end point
for both trials was reduction in the use of PCA
(patient-controlled analgesia) morphine. Despite
the fact that neither trial was designed to demonstrate statistically significant efficacy of ziconotide
as an analgesic, statistically significant reductions
in PCA morphine Use were, in fact, achieved.
Ziconotide may have some specific clinical benefits that are particularly relevant to postoperative
pain patients. For example, because ziconotide
does not reduce bowel motility (ie, constipation
was not an observed side effect in clinical trials), 1
it may be used to minimize or eliminate the use of
postoperative opioids to facilitate postoperative
bowel recovery and thereby reduce duration of
hospitalization.

73
Ziconotide and Lack of Respiratory Depression
In addition to improving bowel function, the use
of ziconotide also may avoid the respiratory depression that can be induced by narcotic analgesics, potentially decreasing the costs and morbitity
that are associated with mechanical ventilation.
Delayed respiratory depression is reported to
occur in between 0.36% and 7 % 28-30 of patients
treated with intrathecal morphine. It is estimated
that respiratory depression requiring intervention
after administration of conventional dOses of spinal
opioids is 1%, which is the same as the incidence
during administration of intramuscular and intravenous opioids. 31 Delayed respiratory depression
is a slow and indolent process and is commonly
associated with progressive somnolence3~ and carbon dioxide retention with or without a reduction
in respiratory rate. 31 The risk of respiratory depression may be difficult to determine a priori during
dose escalation because tolerance develops at different rates to the respiratory depressant, analgesic,
emetic, pupillary constrictor, and constipatory e ffects of the opioids. 3z Further complicating this
issue is the fact that cross-tolerance betwee n opioids is incomplete32; therefore, risk of delayed
respiratory depression during a change from one
opioid to another cannot be easily predicted.
Rat models in which respiratory depression was
assessed by minute ventilation response to carbon
dioxide inhalation using a whole-body plethysmograph. In these experiments, ziconotide did not
alter minute ventilation On room air or during 10%
carbon dioxide inhalation (Fig 3), whereas morphine dose-dependently depressed the respiratory
minute ventilation response to carbon dioxide inhalation. Coadministration of ziconotide with morphine (10 mg/kg or 30 mg/kg) did not potentiate
depression of the respiratory minute ventilation
response to carbon dioxide inhalation produced by
the morphine alone. In fact, minute ventilation
during carbon dioxide inhalation was consistently
greater when ziconotide (v saline) was adminis~
tered with 10 mg/kg morphine.
The experiments described above predicted the
observations from clinical trials. In all completed
trials of intraspinal ziconotide, which included
treatment of both acute and chronic pain and delivery by both epidural and intrathecal routes (total
N = 408 patients), the incidence of hypoventilation, apnea, and hypoxia on ziconotide was no

74

V A N D A N A S. MATHUR

Ziconotide
Saline

~" 500]

E
E 400
E

_=
0

> 300
c

, B

E 200

._E
x

100
e,.

li
0

30
60
90
Time After Drug Administration (min)

higher than the incidence of those events on placebo (Table 4). 3

Therefore, unlike opioids, ziconotide does not
produce respiratory depression in humans or animals and does not aggravate morphine-induced
respiratory depression. In fact, ziconotide appears
to attenuate respiratory depression induced by
morphine.

CONCLUSION
Chronic pain experienced by humans after
acute injury (eg, surgery) is believed to be the
result of "central sensitization." That is, changes
in spinal cord pain processing that perpetuate the
pain state long after the initial nociceptive input
is gone. Ziconotide has been shown to prevent
central sensitization in animal models. 1 Controlled clinical trials in chronic pain demonstrate
robust analgesic efficacy across a wide spectrum
of painful conditions, including many that were
previously unresponsive to intrathecal opioids.
Table 4. Incidence of Respiratory Depression and
Hypoxia in Ziconotide Intraspinal Clinical Trials (N = 408)

Event

Ziconotide (%)

Placebo (%)

Apnea
Hypoventilation
Hypoxia

0.7
0.7
1

0.7
0.7
2

120

Fig 3. Effect of ziconotide on

minute ventilation during carbon dioxide breathing compared with saline control. The
rats were surgically implanted
with intrathecal catheters terminating at the lumbar enlargement, were allowed to recover
from surgery for 24 hours, and
were acclimated to test chambers. Respiration was recorded
for 10 minutes while the animals breathed normal room air
and for the next 15 minutes
while the animals breathed air
containing 10% carbon dioxide. Carbon dioxide challenges
were conducted before ond 30,
60, 90 and 120 minutes after
simultaneous administration of
saline or ziconotide (intrathecal).

Ziconotide's efficacy in controlled clinical trials

of patients with long-standing chronic pain,
where no ongoing nociceptive input is present, 2'4
further supports the hypothesis that ziconotide
affects not just afferent pain transmission but
also modulates mechanisms of chronic pain
within spinal cord circuitry.
Lack of demonstrable tolerance, dependence, or
abuse potential suggests that ziconotide will be
appropriate for use in chronic pain. Additionally,
because ziconotide will not be a scheduled substance and will not be associated with the stigma of
"narcotic abuse," it is expected to be a more acceptable analgesic than opioids both to patients and
to their health care providers.
Initial controlled clinical trials also have demonstrated that intrathecal and epidurally administered ziconotide produces analgesia in the
postoperative setting. Ziconotide has some attractive theoretical clinical advantages compared
with opioids for the treatment of acute pain. The
lack of respiratory depressant effects may allow
earlier extubation and lack of drug-induced
bowel dysfunction and may allow more rapid
recovery of postoperative ileus. Furthermore, to
the extent that use of ziconotide in the perioperative period reduces long-term morbidity and
costs of chronic pain, cost-effectiveness is expected to be high. Thus, ziconotide, the first of a

ZICONOTIDE FOR PAIN MANAGEMENT

new pharmacological class of drugs that block Ntype calcium channels, is a promising agent for the
management of both acute and chronic pain.

REFERENCES
1. Mathur V, McGuire D, Bowersox S, et al: Neuronal
N-type calcium channels: New prospect in pain therapy.
Pharma News 5:25-29, 1998
2. Ellis DJ, Wallace M, Groudine S, et al: The efficacy of
ziconotide in AIDS-related neuropathic pain: A randomized,
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