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Health Sciences Assistant Clinical Professor of Pharmacy, Department of Clinical Pharmacy, University of California, San Francisco, CA
Health Sciences Assistant Clinical Professor of Pharmacy, Department of Clinical Pharmacy, University of California, San Francisco
at time of writing, Clinical Pharmacist— Drug Information, Blue Shield of California Pharmacy Services; now, Product Evaluation Pharmacist—Drug Information Services, Kaiser Permanente, Oakland, CA
Reprints: Dr. Lynch, Department of Clinical Pharmacy, University of California, San Francisco, Box 0622, C-152, 521 Parnassus Ave., San Francisco, CA 94143-0622, fax 415/476-6632, lynchs{at}pharmacy.ucsf.edu
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DATA SOURCES: A PubMed/MEDLINE search (1966-June 2006) was conducted using the terms ziconotide, Prialt, and SNX-111. Manufacturer-provided data, the Food and Drug Administration medical review of ziconotide, and abstracts presented at American Pain Society meetings (2001-2006) were also reviewed.
STUDY SELECTION AND DATA EXTRACTION: Human studies evaluating the efficacy and safety of ziconotide for the treatment of chronic pain were considered. Animal data were excluded.
DATA SYNTHESIS: Ziconotide is the first and only neuronal-type (N-type) calcium-channel blocker. Ziconotide must be administered intrathecally via continuous infusion. A programmable implanted variable-rate microinfusion device, or an external microinfusion device and catheter must be utilized. In double-blind, placebo-controlled studies, ziconotide significantly improved patient perception of pain from baseline to the end of the study periods, which ranged from 11 to 21 days. Patients enrolled in clinical trials were intolerant of or refractory to other treatment modalities. There have been no studies that directly compared ziconotide with other intrathecal or systemic analgesics. Key ziconotide-related adverse events are neuropsychiatric, including depression, cognitive impairment, and hallucinations; depressed levels of consciousness; and elevation of creatine kinase levels. Ziconotide is also associated with a risk of meningitis due to possible contamination of the microinfusion device.
CONCLUSIONS: Ziconotide is a therapeutic option for treatment of severe chronic pain in patients who have exhausted all other agents, including intrathecal morphine, and for whom the potential benefit outweighs the risks of serious neuropsychiatric adverse effects and of having an implanted device. Further studies are needed to determine the comparative efficacy of ziconotide and other pain therapies.
Key Words: chronic pain, intrathecal, N-type calcium-channel blocker, refractory pain, ziconotide
Published Online, July 11, 2006. www.theannals.com, DOI 10.1345/aph.1G584
THIS ARTICLE IS APPROVED FOR CONTINUING EDUCATION CREDIT
ACPE UNIVERSAL PROGRAM NUMBER: 407-000-06-014-H01
Pharmacologic treatments for chronic pain include opioid, nonopioid (eg,
nonsteroidal antiinflammatory drugs, salicylates, acetaminophen) and adjuvant
(eg, antidepressants, anticonvulsants, 
-adrenergic blockers, muscle
relaxants) analgesics. Localized anesthesia, surgery (eg, spinal
decompression), and spinal analgesia may also be
performed.5
Spinal analgesia is typically reserved for severe pain after other drug
therapies by less invasive routes have failed. Spinal analgesia may be
considered for patients with an observable pathology for whom surgical
interventions are likely to have little or no
benefit.5-7
Before implanting an intrathecal drug delivery device, patients should
generally undergo a screening test to determine whether they will respond to
medications given by this
route.7
There are limited data describing the safety and efficacy of various drugs for pain management via the intrathecal route. Morphine is the only analgesic with a Food and Drug Administration (FDA) indication for intrathecal use. Other agents, such as bupivacaine, ketamine, midazolam, clonidine, and lidocaine, have been administered intrathecally off-label for treatment of severe chronic pain. Data supporting use of these agents are generally limited to small (<100 pts.) trials, retrospective studies, surveys, and case reports.6
Ziconotide (Prialt, Elan Pharmaceuticals, San Diego, CA) received FDA approval in December 2004 for management of severe chronic pain not relieved by systemic analgesics, adjunctive therapies, or intrathecal morphine in patients who are appropriate candidates for intrathecal therapy. It is the first nonopioid, intrathecally administered neuronal-type (N-type) calcium-channel blocker approved in the US. Ziconotide was approved in Europe in February 2005 for treatment of severe chronic pain in patients requiring intrathecal analgesia.
This review addresses the pharmacology, efficacy, and safety of ziconotide for treatment of severe, refractory chronic pain in patients who are candidates for intrathecal therapy.
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-conotoxin MVIIA, is a component of the venom used to immobilize the
snail's prey. Ziconotide is a specific and selective N-type voltage-sensitive
calcium-channel (N-type VSCC) blocker. Blockade of N-type VSCCs in the
superficial lamina of the dorsal horn in the spine prevents presynaptic
release of pain-mediating neurotransmitters such as substance P, calcitonin
gene-related peptide, and
glutamate.8
Ziconotide does not bind to opioid, cholinergic, monoaminergic, or peptidergic
receptors.9 Systemic exposure following intrathecal administration of ziconotide is expected to be minimal. Following passage from the cerebrospinal fluid (CSF) into the general circulation, it is expected that ziconotide would be broken down by various peptidases and proteases found in most organs (eg, kidney, liver, lung) to peptide fragments and free amino acids.10
In a pharmacokinetic study of patients with chronic pain, 3 of 22 patients had measurable plasma ziconotide concentrations at time points up to 8 hours following intrathecal administration of 7.5 or 10 µg of the drug.11 Concentrations ranged from 0.0431 to 0.115 ng/mL (lower limit of assay detectability 0.0391 ng/mL). No direct relationship was observed between CSF pharmacokinetics and blood pressure, heart rate, respiratory rate, or body temperature. Plasma concentrations of ziconotide were measured following 5-6 days of continuous intrathecal infusions ranging from 0.1 to 7.0 µg/h in 2 clinical trials.12,13 Measurable concentrations were detected in 44% of patients in one trial and 30% of patients in the other. No relationship between the average hourly intrathecal infusion rate and plasma concentrations was noted.12
The CSF pharmacokinetics of ziconotide following intrathecal administration in chronic pain patients are described in Table 1.11
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18 y) with chronic
malignant and nonmalignant
pain.12-14
FDA approval of ziconotide was based on safety and efficacy in one of the
trials that evaluated efficacy in chronic
pain.14 The primary efficacy measure evaluated in all of the studies was the change in Visual Analog Scale of Pain Intensity (VASPI) score. The VASPI is a subjective measure of a patient's perception of pain. Scores may range from 0 (no pain) to 100 (worst imaginable pain) mm. Subjects were required to have a baseline VASPI score of 50 mm or greater despite use of other pain medications. Responders were defined as patients who experienced a 30% or greater reduction from baseline in mean VASPI score without any increases in opioid use.12-14 Secondary endpoints included measurements of the Category Pain Relief Scale (CPRS), Clinical Global Impression, Wisconsin Brief Pain Inventory, and use of opiates.12-14
Ziconotide was evaluated in 112 adults with chronic pain secondary to cancer or AIDS that was refractory to other systemic or intrathecal medications.13 Previous therapies included opioids (92% of subjects), antidepressants (44%), anxiolytics (40%), anticonvulsants (27%), antiinflammatory drugs (28%), antipsychotics (16%), and intrathecal morphine (32.4% of ziconotide group, 35% of placebo group). Intrathecal medications were discontinued at least 3 days prior to enrollment, although drugs given by other routes could be continued throughout the study period. Concomitant oral opioids were equivalent to a mean oral morphine dose of 6200 mg/day in the ziconotide group and 4200 mg/day in the placebo group (p = 0.63). Other than opiates, use of concomitant drug therapies was not described in detail. Patients were randomized to receive ziconotide or placebo for a 5 day titration phase followed by a 5 day maintenance phase. The initial infusion rate was 0.005 µg/kg/h and could be titrated upward as frequently as every 12 hours to the maximum tolerated dose. The starting infusion rate was changed twice during the trial, based on tolerability, and was ultimately decreased to 0.1 µg/h, with a titration interval of no more often than every 24 hours. The dose was titrated to achieve analgesia rather than to the maximum tolerated dose at this point in the trial. The planned sample size had a 96% power to detect a greater than 30% change in VASPI scores at a 5% significance level.
Efficacy results were described for all starting infusion rates and titration schedules combined. At the end of titration, ziconotide-treated patients had a significantly greater decrease in mean VASPI score from baseline than did placebo-treated patients (51.4% vs 18.1%; p < 0.001). Opioid use decreased by 9.9% for ziconotide recipients compared with a 5.1% increase in opioid use with placebo. Significantly more ziconotide-treated patients were categorized as responders compared with subjects receiving placebo (50% vs 17.5 %; p = 0.001).13
During the 5 day maintenance phase, nonresponders to initial therapy were crossed over to the alternative treatment (either ziconotide or placebo). Patients who initially received placebo and crossed over to ziconotide treatment (n = 26) experienced a 44.9% mean reduction in VASPI score. Meanwhile, ziconotide nonresponders (n = 12) who crossed over to placebo experienced a 4.2% reduction in VASPI score. Of note, 15 patients in the ziconotide group and 5 patients in the placebo group were labeled as responders, although they did not meet the strict protocol-defined criteria. The authors concluded that ziconotide provided clinically significant pain relief in patients with pain associated with cancer or AIDS.13
Adverse effects were presented for all infusion rates pooled and were also stratified by infusion rates starting at greater than 0.1 µg/h and less than or equal to 0.1 µg/hour. The most common adverse events occurring at any infusion rate were dizziness, nystagmus, fever, somnolence, and confusion. With the exception of confusion, infusions that began at rates greater than 0.1 µg/h were noted to have a greater incidence (from 6.3% to 22.4%) of adverse effects than infusions that were initiated at rates of 0.1 µg/h or less.13
In a similarly designed study, 260 patients with chronic nonmalignant pain were randomized to receive ziconotide or placebo.12 Pain was described as neuropathic in origin for the majority of patients (77.8% ziconotide, 77.3% placebo). As in the chronic malignant pain trial, the initial infusion rate was 0.005 µg/kg/h, with a titration interval of 12 hours to achieve the maximum tolerated dose. Due to poor patient tolerability, the starting infusion rate was subsequently decreased to no more than 0.1 µg/h, and the titration interval was increased from every 12 hours to at least every 24 hours to achieve pain relief. This trial used a 6 day titration and a 5 day maintenance phase and allowed nonresponders to cross over to the alternative treatment during the maintenance phase. The sample size had 90% power to detect a treatment difference at a 5% significance level.
At the end of titration, the mean VASPI score decreased by 30.7% (95% CI 23.9 to 37.5) in the ziconotide group and 6.2% (95% CI 0.1 to 12.6) in the placebo group (p = 0.0002). The improvement in VASPI score was statistically significant (p value not reported) for patients with neuropathic pain, but not for patients with non-neuropathic pain.12 The lack of statistical significance for patients with non-neuropathic pain may have been due to the small sample size (n = 28 pts. with non-neuropathic pain, n = 185 pts. with neuropathic pain). There was a greater proportion of responders in the ziconotide group (31.4% vs 15.1%; p = 0.131). More patients in the ziconotide group than in the placebo group experienced nystagmus, abnormal gait, dizziness, nausea, vomiting, amblyopia, and urinary retention.
In a subanalysis of this study, the efficacy of fast (0.4-7 µg/h, n = 52) and slow (2.4 µg/h, n = 186) infusion rates was compared with matched placebo.15 The efficacy of a fast infusion rate was not directly compared with that of a slow infusion rate. Subjects who received the fast infusion rate experienced a greater improvement in VASPI score from baseline to the end of the study period compared with those receiving placebo, but the size of the treatment group was too small for statistical analysis (25.4% vs 4.3%; n = 52). The slow infusion rate group (n = 186) experienced a significantly greater improvement in VASPI score from baseline compared with those receiving placebo (31.8% vs 6.6%; p = 0.002). The slower infusion rate was determined to be safe and effective, producing adequate analgesia in these patients. The authors stated that adverse events were dose- and time-related, but these data were not described in detail.
In both of the previously described trials, the starting dose and the titration protocol were adjusted midtrial due to poor tolerability of the initially selected regimen. Efficacy results of all dosing regimens were pooled. These studies ranged in duration from 11 to 14 days, a short period for assessment of efficacy in patients with chronic pain. Safety issues associated with long-term use of the external or internal microinfusion device were not addressed. Use of opiates decreased by 9.9% in the ziconotide group in the chronic malignant pain trial,13 but the relatively high baseline opiate use (mean oral morphine equivalent of 6200 mg/day in the ziconotide group) makes the clinical significance of this change modest.
FDA approval of ziconotide was based on results of the third trial, also known as study 301.14 This study evaluated efficacy of ziconotide at a starting infusion rate of 0.1 µg/h, considered the best tolerated starting rate by the previous trials and proposed for the manufacturer's product labeling. The infusion rate could be increased by increments of up to 0.1 µg/h, no more frequently than every 24 hours. In this study, 220 patients with chronic pain refractory to systemic and/or intrathecal analgesics (intrathecal morphine, bupivacaine, and/or clonidine) were randomized to receive ziconotide or placebo for 21 days. Pain was neuropathic in origin for 76% of the patients in the ziconotide group and 71% of those in the placebo group. The most common cause of pain was failed back surgery (58% of subjects). Intrathecal pain medications were discontinued prior to trial initiation.
Concomitant drugs included antidepressants (64% of pts.), anxiolytics (40% of pts.), and opiates (98% of pts.). Concomitant oral opiate use was equivalent to a mean oral morphine dose of 300 mg/day in the ziconotide group and 268 mg/day in the placebo group, following weaning of prior intrathecal medications. Ziconotide was titrated to a level that produced analgesia. This trial had 80% power to detect a treatment difference at a 5% significance level.14
After 21 days, the change in mean VASPI scores in the ziconotide group was
significantly greater than in the placebo group (14.7% vs 7.2%; p = 0.036). No
difference was observed in the number of treatment responders (16.1% in the
ziconotide group vs 12% in the placebo group, p = 0.39). The mean VASPI scores
at 21 days were 67.9 ± 22.89 in the ziconotide group versus 74.1
± 21.28 in the placebo
group.12
Relative to placebo, a greater proportion of ziconotide recipients also
reported complete satisfaction (Clinical Global Impression, score 3, where
0 = no satisfaction and 4 = complete satisfaction) with therapy (28% vs 12%; p
= 0.003), very good or excellent pain control (12% vs 0.9%; p = 0.004), and
improved enjoyment of daily life (42% vs 27%; p = 0.02). Opioid use decreased
by 24% in the ziconotide group and by 17% in the placebo group (p =
0.44).14
Adverse effects that occurred significantly more often (p 
0.05) in the
ziconotide group included dizziness, confusion, ataxia, abnormal gait, and
memory impairment (Table
2).
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An expert consensus statement, developed after the drug was marketed, recommends a starting dose of not more than 0.5 µg/24 hours intrathecally and a less frequent titration interval of not more than 0.5 µg/24 hours intrathecally once weekly.16 A slower starting rate and less frequent titration schedule may decrease the likelihood of serious adverse effects. Faster titration schedules should be considered only if there is an urgent need for analgesia and potential benefits outweigh risks to patient safety, in instances such as palliative care. However, clinicians should be aware that, when starting at faster infusion rates, adverse effects may require temporarily withholding the medication, thus delaying pain relief for the patient.16
Ziconotide is indicated only for intrathecal use. Administration of ziconotide requires the implantation of the Medtronic SynchroMed EL, SynchroMed II infusion pump, or use of the external Simms Deltec Cadd Micro microinfusion device and catheter. The device manuals and the ziconotide prescribing information should be consulted for specific instructions on rinsing the pump reservoir, initial filling, refilling the reservoir, and infusion rate programming. Ziconotide may be adsorbed on internal device surfaces or lost by dilution in the residual space of the device; thus, proper rinsing and priming of the pump reservoir is critical to ensure accurate concentration of the final pump solution.10,16
The Medtronic devices should be primed by rinsing the internal surfaces 3 times with undiluted ziconotide 25 µg/mL prior to the first use. The reservoir should be emptied and refilled at 14 days after the initial fill to ensure proper dosing. Then, the reservoir should be emptied and refilled at least once every 40 days if diluted ziconotide is being given and at least once every 60 days if undiluted ziconotide is being given.10 The CADD -micro ambulatory infusion pump should be filled with ziconotide at a 5 µg/mL concentration.
Each ziconotide vial is intended for single use only, either undiluted (100 µg/mL formulation) or diluted with preservative-free NaCl 0.9% to achieve the desired concentration. Aseptic technique must be used during pump and drug preparation. If diluted, the mixed solution may be refrigerated for up to 24 hours. The infusion should begin within 24 hours of mixing.10
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Other contraindications include medical conditions incompatible with intrathecal therapy, infection at the infusion site, uncontrolled bleeding diathesis, spinal cord obstruction that impairs cerebrospinal fluid circulation, and hypersensitivity to any components of the solution.10
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Serum creatine kinase levels should be monitored at least biweekly for the first month of therapy and monthly thereafter as clinically indicated.10 Checking the serum creatine kinase level is recommended if the patient experiences new myalgia, myasthenia, muscle cramps, or unusual fatigue.
Since ziconotide is administered via the intrathecal route, contamination of the microinfusion device or seeding from an infected pump pocket or catheter tract may lead to meningitis. The risk of meningitis is higher with external microinfusion devices than with internal microinfusion devices with a surgically implanted catheter. Meningitis occurred at a rate of 3% (40 cases per 662 patient-years) among clinical trial patients who received ziconotide versus 1% (1 case per 5 patient-years) among those who received placebo.10 Patients, caregivers, and healthcare providers should be alert for signs and symptoms of meningitis including fever, headache, stiff neck, changes in mental status, nausea, vomiting, or seizures.
Cognitive impairment was reported in up to 33% of patients in clinical trials. The most common cognitive adverse events included confusion, memory impairment, speech problems, and aphasia. Cognitive adverse effects were generally reversible within 2 weeks of drug discontinuation. Unresponsiveness or stupor occurred at a rate of 2%. If reduced levels of consciousness occur, ziconotide should be discontinued until symptoms resolve.10
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65 y of age) are more likely to experience confusion.
The frequency of adverse effects was greater at infusion rates faster than 0.1
µg/h or when doses were titrated upward more frequently than every 24
hours. Serious adverse events and treatment discontinuations for adverse
events were less likely to occur if the drug was titrated slowly over 21 days.
Adverse effects that occurred at a frequency of 10% or greater in study
patients who started therapy at the manufacturer's recommended infusion rate
(0.1 µg/h) are listed in Table
2.10 Although the manufacturer's labeling states that tolerance to the analgesic effect does not occur, patients may better tolerate adverse effects with continued therapy. In a retrospective analysis of 231 patients who received ziconotide for 6 or more months, the incidence of adverse effects was less frequent in the sixth month of therapy compared with the first month.17 Higher intrathecal catheter tip placement has also been associated with a higher incidence of adverse events, although a definite correlation has not been established.18
Drug-drug interaction studies have not been completed. More than 90% of patients in clinical trials used concurrent systemic opiates. Other drugs frequently given with intrathecal ziconotide in clinical trials included antidepressants, anxiolytics, anticonvulsants, neuroleptics, and sedatives. An increased likelihood of CNS adverse effects such as dizziness and confusion may be expected when ziconotide is given with drugs with CNS depressant activity.
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Patients should be instructed to contact their physicians immediately if the following signs or symptoms occur: changes in mental status, including lethargy, confusion, disorientation, or decreased alertness; changes in mood or perception, such as hallucinations or unusual tactile sensations in the oral cavity; depression or thoughts of suicide; signs or symptoms of meningitis, including nausea, vomiting, seizures, fever, headache, and/or stiff neck; and signs or symptoms of rhabdomyolysis such as new or worsening muscle pain, soreness, or weakness, with or without dark urine. Patients should be trained on proper handling of external microinfusion devices and care of the catheter skin site to reduce the risk of bacterial contamination.
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Ziconotide is the first and only FDA-approved N-type calcium-channel blocker and the second agent granted FDA approval for intrathecal pain management. However, its efficacy in placebo-controlled trials is limited to treatment periods of less than one month. In the trial on which FDA approval was based, the final mean VASPI scores were only modestly different between the groups (67.9 in the ziconotide group vs 74.1 in the placebo group, on a scale of 0-100 mm). Ziconotide has potentially serious CNS and psychiatric adverse effects and requires careful dosage titration. Clinical experience has begun to accumulate since marketing of the drug; an expert consensus statement has already recommended changes in the manufacturer's recommended dosing schedule to decrease the risk of these serious adverse effects. Before deciding to start ziconotide therapy, these risks, as well as those of intrathecal administration (eg, possible meningitis) should be considered and weighed against possible morbidity, functional disability, unemployment, and quality of life of the patient.
Because of the potential for serious adverse effects, it is currently recommended that ziconotide be used only for chronic pain refractory to other therapies including systemic analgesics, adjuvant analgesics, or intrathecal morphine. Additional clinical experience and comparative studies are needed to determine whether ziconotide will be preferred therapy versus agents that are currently used off-label for chronic pain management.
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