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.
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.
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?)
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.
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.
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.
71
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.
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
VANDANA S. MATHUR
72
Table 3. Responseto Ziconotide by Pain Diagnosis
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
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)
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
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