|
Analgesic Efficacy of Ziconotide in Chronic, Intractable Neuropathic Pain |
1Peter Staats, M.D., 2Steven Charapata, M.D., 3Robert Presley, M.D., 4Thomas L. Yearwood, M.D., 5Theresa Ferrer-Brechner, M.D., 6Michelle Gaudette, 6Martha Mayo, Pharm.D., 6Dawn McGuire, M.D., 6Alan Jacobs, M.D., Ph.D., 6Robert R. Luther, M.D.
Abstract-- Purpose: Ziconotide (SNX-111) is the synthetic form of
omega-conopeptide MVIIA from the marine snail Conus magus. Intrathecal ziconotide
selectively inhibits neuron-specific, N-type, voltage-sensitive calcium
channels (VSCCs), located in the superficial laminae of the dorsal horn, the
site of primary nociceptive afferent synapses.
In animal models of acute, persistent and chronic pain, ziconotide was
100 times more potent than morphine, without causing respiratory depression or
tolerance. Interim results are presented
in a study of intrathecal ziconotide in patients with chronic intractable pain. Methods:
This double-blind, randomized,
placebo-controlled trial included patients with chronic, intractable,
neuropathic pain whose pain scores were > 50 on the 100 mm Visual
Analog Scale of Pain Intensity (VASPI) despite “best regimen” of systemic
analgesics. Pain assessments and study-drug
titration were performed at scheduled intervals. Primary efficacy variable was a parallel
comparison of change from baseline in VASPI at 144 hours. Responders (> 30% decrease in VASPI
from baseline, without increasing opioid requirement) continued on blinded drug
assignment for 5 more days; placebo nonresponders switched to open-label
ziconotide. Ziconotide responders
continued treatment in a long-term, open-label extension study. Results: 102 of 104 patients were evaluable. Average VASPI decrease in the ziconotide group
was 36.97%, compared with 2.85% for placebo (p £
0.0002). Adverse events, regardless of
causality, included dizziness, nausea, nystagmus, abnormal gait, constipation,
confusion, and urinary retention. Drug-related
adverse events resolved upon dosage reduction or discontinuation. Conclusions: Ziconotide markedly
improves analgesia in a group of refractory chronic pain patients and appears
promising as a new therapeutic modality.
Introduction
Ziconotide (SNX-111) is the synthetic form of the omega-conopeptide MVIIA, a polypeptide isolated from the marine snail Conus magus. Ziconotide is the first neuronal selective voltage-sensitive calcium channel (VSCC) blocker to enter clinical studies. VSCCs are found in myocytes (skeletal, smooth and cardiac muscle), neurons and neuroendocrine cells.1,2 By regulating the flux of calcium across cellular membranes, these channels modulate intracellular calcium concentration, and thereby control numerous cellular processes including membrane excitability, signal transduction and neurotransmitter release. At least six unique types of neuronal VSCCs have been identified (designated as L, N, P, Q, R, T), each with distinctive functional and structural features and cellular distribution. The L-type VSCCs expressed in cardiac and vascular smooth muscle are the target of the classical dihydropyridine, phenylalkylamine and benzothiazepine calcium channel blockers developed to treat cardiovascular diseases.3 Concomitant administration of L-type VSCC blockers with opioids potentiates and prolongs the analgesic effect of morphine in both rodent models of neuropathic pain and in cancer patients.3 However, parenteral L-type VSCCs inconsistently block evoked nociceptive responses4,5,6 and intrathecal administration suppressed only the persistent pain phase of subcutaneous formalin injection, without altering the acute nociceptive phase7,8 or the mechanical allodynia of experimental nerve injury.9
Selective antagonists of N-type VSCCs, in contrast, are antinociceptive in animal models of acute and chronic nociceptive and neuropathic pain. Ziconotide binds with high affinity to N-type VSCCs located on neuronal somata, dendritic spines and axon terminals. In the spinal cord, binding sites for ziconotide are located in the superficial lamina of the dorsal horn (Rexed laminae I and II), the site where primary nociceptive afferent Ad and C fibers synapse.10 When administered intrathecally, ziconotide is antinociceptive in different animal models of experimentally induced acute, chronic and neuropathic pain states. In the hot plate and paw pressure tests of thermal and mechanical nociceptive pain, bolus intrathecal injection produced significant robust antinociceptive effects.7 Subcutaneous injection of formalin models both acute and persistent pain states by inducing a characteristic biphasic nociceptive response, wherein an acute nociceptive phase during the first 10 minutes post injection is followed by a tonic phase occurring from 10 - 90 minutes post injection. Continuous, constant-rate intrathecal infusion of ziconotide suppresses both the acute and tonic phases of the formalin test at doses of 14 ng/hr and 0.8 ng/hr, respectively.11 Ziconotide is similarly effective at reducing pain in nerve ligation models of neuropathic pain, such as the spinal nerve ligation model of Kim and Chung12 which produces spontaneous pain, heat hyperalgesia and both thermal and tactile allodynia in the portion of the hindlimb innervated by the ligated nerves. A single intrathecal dose of ziconotide reduces tactile allodynia by 67%, unlike L- or P-type calcium channel blockers, which have no antinociceptive effect9,11 and intrathecal morphine which is not consistently antinociceptive in this model.13,14 The antiallodynic effect of ziconotide persists for at least 2 hours. There was no sign of tolerance to the antinociceptive effects of ziconotide when it was administered intrathecally for up to 7 days of treatment in the nerve ligation model or the rat paw formalin test.15 Furthermore, ziconotide does not cause respiratory depression and is not addicting. In contrast, administration of morphine is dose-limited by respiratory depression and there is marked tolerance to intrathecal opioids. While intrathecal morphine significantly attenuates nociceptive responses in the formalin test after 2 days of continuous infusion, it is ineffective at blocking nociception when a infusion is begun 7 days prior to formalin injection.15
In a pilot trial of patients with severe, intractable chronic pain treated with intrathecally administered ziconotide, 21 of 25 evaluable patients reported partial to complete pain relief.16 Etiologies of pain syndromes were malignancy, AIDS neuropathy, phantom limb pain, spinal cord injury or thalamic pain syndrome. One patient, a 43 year old man with intractable deafferentation phantom limb pain due to brachial plexus avulsion 23 years prior, experienced complete elimination of hyperesthesia and allodynia with continuous cervical intrathecal infusion of ziconotide.17
I.
Methods
This current study is a phase II/III double-blind, randomized, placebo-controlled trial of continuous intrathecal ziconotide in patients with chronic, intractable, neuropathic pain. Study drug dose was titrated upwards every 24 hours until satisfactory pain control was attained or the development of intolerable adverse effects were deemed dose limiting. The study was designed for enrollment of up to 200 patients with intractable pain whose pain scores were > 50 on the 100 mm Visual Analog Scale of Pain Intensity (VASPI) despite “best regimen” of systemic analgesics. All patients had failed systemic opioids and adjuvant therapies, many of whom were therapeutic failures of intrathecal opioids. Routine pain assessments by VASPI and study drug uptitration were performed at scheduled 24 hour intervals. Systemic opioids and adjuvant analgesics or sedatives were acceptable for rescue analgesia, but intrathecal analgesics, anesthetics and other adjuvants were prohibited.
The primary efficacy variable was a parallel comparison of change from baseline in VASPI at 144 hours (6 days). Responders were defined as > 30% decrease in VASPI from baseline, without increasing use of concommitant opioid or change in opioid class. The efficacy VASPI score was the average of the last two VASPI scores taken within a 2 hour period and, if these two were different by > 15 mm, a third VASPI score was obtained and the mean calculated. At the end of the 6-day inpatient initial dose titration period, responders were continued on the same treatment for an additional 5 days as outpatients, at which point the study was terminated and the blind broken. Patients receiving ziconotide where then given the option of enrolling into a long-term, open-label extension trial. For patients that were non-responders at the end of the 6-day titration period, the blind was broken and those receiving placebo were crossed-over into an open-label arm consisting of a second in-patient titration trial, this time with ziconotide. At the end of the open-label titration period, enrollment in the study was terminated, and responders were given the option of continuing into a long-term, open-label extension trial. The primary efficacy endpoint was measured at the end of the randomized, blinded, placebo controlled, initial titration period, prior to either the maintenance period or open-label cross-over.
II.
Results
The interim analysis plan was designed with a scheduled blinded comparison of the two treatment groups for the primary efficacy variable to confirm the adequacy of the planned sample size and power calculations. The primary efficacy variable for comparison was the mean change in VASPI from baseline to the final VASPI at the end of the initial 6-day blinded titration period. Final VASPI scores were the mean of the last 2 (or 3) VASPI scores recorded. A single final VASPI score was carried forward and used if a patient prematurely discontinued from the trial due to an intolerable adverse event. The study was constructed with 90% power to detect a > 30% mean reduction in VASPI from baseline in the ziconotide-treated group compared to the placebo-treated group at the end of the initial 6-day titration period. All investigators and the sponsor remained blinded to the clinical trial results until the last patient completed the study and the database was locked.
Figure 1: Efficacy in Nonmalignant Pain
Of the 104 patients enrolled at the time of this interim analysis, 102 were evaluable. The average VASPI score decrease in the ziconotide group was 37.0% compared with 2.9% for the placebo group (p < 0.0002, Figure 1). Adverse events, regardless of causality, included dizziness, nausea, nystagmus, abnormal gait, constipation, confusion and urinary retention. Drug-related adverse events resolved upon dosage reduction or discontinuation.
III.
Conclusions
Chronic pain remains one of
societies greatest health care problems, affecting more people than cancer and
heart disease combined. Although
conventional therapies are effective in most patients, intrathecal delivery of
opioids and other analgesics relieves pain when these simpler therapies have
failed.18 Intrathecal
delivery has the advantage of higher concentrations to the spinal cord without
a large systemic effect.
Unfortunately, intrathecal opioids
are not effective in all patients and novel
analgesics are needed19.
Ziconotide is remarkably efficacious in the treatment of intractable,
non-malignant chronic, neuropathic pain in those patients who have been
refractory to conventional pain management strategies, including intrathecal
opioids. A significant number of these
patients had already failed intrathecal opiates. Thus success in this group is especially
promising. At the time of the blinded
interim analysis, > 200 patients in 47 investigative sites in the
IV.
References
1. Olivera, BM, Miljanich, GP, Ramachandran, J, Adams ME. Calcium channel diversity and neurotransmitter release: the w-conotoxins and w-agatoxins. Annu Rev Biochem, 1994; 63:823-867.
2.
Hoffman, F,
3.
4. Miranda, HF, Bustamante, D, Kramer V, Pelisser, T, Saavedra, H, Paeile, C, Fernandez E, Pinardi, G. Antinociceptive effects of Ca2+ channel blockers. Eur J Pharmacol, 1992; 217:137-141.
5. Mecke, E, Kauppila, T, Carlson, S, Pertovaara, A. Differential effects of verapamil, a clacium channel antagonist, on morphine and cocaine-induced analgesia and locomotor behavior in rats. Neurosci Res Commun, 1991; 9:137-142.
6. Contreas, E, Tamayo, L, Amigo, M. Calcium channel antagonists increase morphine-induced analgesia and antagonize morphine tolerance. Eur J Pharmacol, 1988; 148:463-466.
7.
8. Coderre, TJ, Melzack, R. The role of NMDA receptor-operated calcium channels in persistent nociception after formalin-induced tissue injury. J Neurosci, 1992; 12:3671-3675.
9. Chaplan, SR, Pogrel, JQ, Yaksh TL. Role of voltage-dependent calcium channel subtypes in experimental tactile allodynia. J Pharmacol Exp Ther, 1994b; 269:1117-1123.
10.
Gohil, K,
11. Bowersox, SS, Gadbois, T, Singh, T, Pettus, M, Wang, Y-X, 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.
12. Kim, SH, Chung, JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain, 1992; 50:355-363.
13. Nichols, ML, Ossipov, MH, Lai, J, Porreca, F. Regulation of morphine antiallodynic efficacy by cholecystokinin in a model of neuropathic pain in rats. J Pharmacol Exp Ther, 1995; 275:1339-1345.
14. Yaksh, TL, Pogrel JW, Lee, YW, Chapl;an, SR. Reversal of nerve ligation-induced allodynia by spinal a2 adrenoceptor agonists. J Pharmacol Exp Ther, 1995; 273:207-214.
15. Malmberg, AB, Yaksh, TL. Effect of continuous intrathecal infusion of w-conopeptides, N-type calcium channel blockers, on behavior and antinociception in the formalin and hot-plate tests in rats. Pain, 1995; 60:83-90.
16. Brose, W, Pfeifer, B, Hassenbusch, K, et al., SNX-111 produces analgesia in patients with intractable pain: Phase I/II results. 11th World Congress of Anaesthesiologists, Australia; April 1996.
17. Brose, WG, Gutlove, DP, Luter, RR. Use of intrathecal SNX-111, a novel, N-type voltage-sensitive, calcium channel blocker, in the management of intractable brachial plexus avulsion pain. J Clin Pain, 1997; 13:256-259.
18. Oakley J and Staats PS. “Intrathecal pumps” Practical management of Pain, 3rd Edition, Mosbey, in press.
19. Staats PS and Mitchell VD. Future directions for intrathecal therapies. Progress in Anesthesiology, Oct 1997, 367-384.