This document addresses the use of Prialt® (ziconotide intrathecal infusion), a non-opioid analgesic, for treatment of severe chronic pain.

Medically Necessary:

Prialt (ziconotide intrathecal infusion) is considered medically necessary for the management of severe chronic pain in those individuals  for whom intrathecal (IT) therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies or IT morphine.

Investigational and Not Medically Necessary:

All other uses of Prialt, including but not limited to treatment of post-operative pain, acute brain injury, and spasticity associated with spinal cord trauma are considered investigational and not medically necessary.

On December 28, 2004, the U.S. Food and Drug Administration (FDA) approved Prialt (ziconotide intrathecal infusion) for the management of severe chronic pain in those for whom IT therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies or IT morphine. FDA approval of Prialt was based on the treatment of more than 1,200 participants and three Phase III clinical trials, which evaluated the efficacy and safety of IT Prialt in those with severe chronic pain that was not adequately managed despite a regimen of systemic and/or IT analgesic and other drugs.

Rauck and colleagues (2006) conducted the most recent Phase III trial in response to the FDA's request for additional data using lower doses and a slower titration. This randomized double-blind, placebo-controlled study was conducted at 39 sites in the U.S. and included 220 adults with opioid-resistant, severe chronic pain. Most of the subjects had neuropathic pain. All subjects had programmable IT infusion systems and were randomized to receive IT Prialt (n=112) or placebo (n=108). At baseline, the mean Visual Analog Scale of Pain Intensity (VASPI) score, the most commonly used pain assessment scale for clinical trials, for both placebo and Prialt groups was 80.7 mm (VASPI score of 0 mm = no pain; 100 mm = worst possible pain). Treatment was initiated at 2.4 mcg/day (0.1 mcg/hour) and was increased by less than or equal to 2.4 mcg/day (less than or equal to 0.1 mcg/hour), no more than two to three times a week for three weeks. The primary efficacy measure was mean percent change in the VASPI score at week three, which showed statistically significant improvement in those receiving Prialt vs. placebo (p=0.036). Improvement in VASPI score was seen as early as week one. The

 mean dose at week three was 6.9 mcg/day (0.29 mcg/hour). The majority of secondary efficacy endpoints also showed statistically significant improvement in those receiving Prialt. The majority of adverse events were mild or moderate. The four most frequently reported adverse events in this clinical trial were dizziness, ataxia (unsteady walking), confusion, and abnormal gait (difficulty walking). Study discontinuation amongst the Prialt group due to adverse events was comparable with that for placebo (5.4 percent and 4.6 percent, respectively).

In another study, Staats and associates (2004), conducted a multicenter, double-blind, placebo-controlled randomized, IT-administered Prialt trial using a high dose, fast titration method. This trial involved 111 participants with refractory pain due to AIDS or cancer and a mean Visual Analog Scale of Pain Intensity (VASPI) score of 50 mm or greater. Subjects were randomized 2:1 to receive ziconotide or placebo, respectively. A mean change in VASPI score from baseline to the end of the titration period was the main outcome measure of the study. IT medications were discontinued in those who were already receiving IT therapy and those who were not yet receiving IT therapy received implantation of an intrathecal catheter with an external infusion pump system. All participants continued to receive systemic and oral analgesics during the study period. Subjects underwent a 5-day titration period and "responders" (defined as those with a 30% or greater decrease in VASPI with no concomitant increase in opioid use or change in opioid class) were continued on a 5-day maintenance phase; all drug responders could opt to enroll in a long-term open-label study of the drug. Nonresponders were allowed to cross over to the opposite group for 5 or 6 days. The main efficacy results reported by the study are:  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 those in the ziconotide group compared with 17.5% in the placebo group (P<.001). Five participants receiving ziconotide achieved complete pain relief, and 50.0% of those receiving ziconotide responded to therapy compared with 17.5% of those receiving placebo (P =.001). Twelve subjects in the ziconotide group had to discontinue therapy because of adverse events, compared with 4 in the placebo group. During the titration phase, 4 placebo participants (10%) and 22 Prialt participants (30.6%) reported 31 serious adverse events and, of these, 14 involving the nervous system (5 moderate, 9 severe) were considered to be related to Prialt therapy. The most common serious adverse events experienced by Prialt subjects during the initial titration phase were confusion, somnolence and urinary retention.

Wallace and colleagues (2008) reported long term results of a safety and efficacy study of ziconotide. Six-hundred and forty-four participants with severe chronic pain participated in this open-label, multicenter study. Ziconotide titration was followed by long-term infusion. Efficacy assessments included the Visual Analog Scale of Pain Intensity. Safety was assessed via adverse events (AEs), vital signs, and routine laboratory values. Of this group, 119 participants received ziconotide for greater than or equal to 360 days. Median duration of ziconotide therapy was 67.5 days (range, 1.2-1215.5 days). The mean dose at last infusion was 8.4 microg/d (range, 0.048-240.0 microg/d). Median Visual Analog Scale of Pain Intensity scores at baseline, one month and the last available observation up to two months were 76 mm (range, 4-100 mm), 68 mm (range, 0-100 mm), and 73 mm (range, 0-100 mm), respectively. Most participants (99.7%) experienced one or more adverse events. Most adverse events were of mild (43.5%) or moderate (42.3%) severity and 58.6% of adverse events were considered unrelated to ziconotide. The most common adverse events reported included nausea, dizziness, headache, confusion, pain, somnolence and memory impairment. Clinically significant abnormalities in creatine kinase levels were reported in 0.9% of the subjects at baseline, 5.7% at one month and 3.4% at ziconotide discontinuation. No drug-related deaths, IT granulomas, or permanent adverse sequelae occurred with ziconotide therapy.

In a 2010 literature review, Schmidtko and colleagues noted that ziconotide is the first member of a new class of analgesics that selectively target N-type voltage-sensitive calcium channels. Currently, intrathecal injection of drugs such as morphine, hydromorphone, fentanyl, clonidine, or local anesthetics, given alone or in combination, are being used to manage chronic pain, but some individuals may be intolerant or may not achieve adequate pain relief with these drugs. Although ziconotide has been effective in those with opioid refractive pain, the authors caution that ziconotide has a narrow therapeutic window and must be administered and titrated with utmost accuracy to appropriate individuals.

Chronic pain is a leading cause of adult disability in the United States. Severe chronic pain is defined as pain lasting longer than six months and has multiple causes such as failed back surgery, accident, cancer, AIDS and other nervous system disorders. Some of the most severe chronic pain is neuropathic in origin, which means that it involves damage to the nervous system. It can result from diseases that affect the nerves (such as diabetes) or from trauma, or it can be a consequence of certain types of treatment, such as from chemotherapy for cancer.  It can also occur without direct injury to the nerves (e.g., complex regional pain syndrome, also know as reflex sympathetic dystrophy-causalgia).

Pain management has increasingly turned to interdisciplinary combinations of techniques customized for the individual patient. Pain treatment typically starts with nonsteroidal anti-inflammatory drugs and progresses to mild opioids, such as codeine, and then to stronger opioids such as morphine, hydromorphone, oxycodone, methadone and fentanyl. If these measures do not work, alternative therapies such as corrective surgery, nerve blocks or epidural injections can be utilized. IT drug administration is generally reserved for severe chronic pain in those who fail conventional therapies, and involves administering an analgesic drug into the fluid surrounding the spinal cord through a pump.

Prialt contains ziconotide a synthetic equivalent of a naturally occurring conopeptide found in the piscivorous marine snail, Conus magus, and is in a class of non-opioid analgesics known as N-type calcium channel blockers. Research suggests that ziconotide's mechanism of action works by targeting and blocking N-type calcium channels on nerves that ordinarily transmit pain signals.

Prialt should be administered intrathecally (IT) by or under the direction of a physician experienced in the technique of IT administration and who is familiar with the drug and device labeling. Prialt is intended for IT delivery using a programmable implanted variable-rate microinfusion device or an external microinfusion device and catheter. Prialt is not intended for intraveneous administration. Ziconotide produces analgesia by blocking neurotransmitter release from primary nociceptive afferents terminating in the superficial layers of the spinal cord dorsal horn.

Taken together, the findings from the Prialt clinical trials are conclusive evidence that this therapy represents a significant treatment option in those individuals who do not have adequate pain relief from other therapies. The body of research demonstrates that this therapy provides relief for individuals suffering from severe chronic pain that warrants intrathecal therapy. Furthermore, Prialt is not associated with the risk of addiction and therapy can be interrupted or discontinued abruptly without evidence of withdrawal effects in the event of serious neurological or psychiatric signs or symptoms.

FDA label black box warning: 

"WARNING: Severe psychiatric symptoms and neurological impairment may occur during treatment with Prialt. Patients with a pre-existing history of psychosis should not be treated with Prialt. All patients should be monitored frequently for evidence of cognitive impairment, hallucinations, or changes in mood or consciousness. Prialt therapy can be interrupted or discontinued abruptly without evidence of withdrawal effects in the event of serious neurological or psychiatric signs or symptoms."

The four most frequently reported adverse events associated with Prialt were dizziness, nausea, confusion and headache. There was a higher incidence of meningitis when Prialt was used with an external pump. Meningitis can occur due to inadvertent contamination of the microinfusion device and other means such as direct spread from an infected pump pocket or catheter tract. While meningitis is rare with an internal microinfusion device and surgically implanted catheter, the incidence increases substantially with external devices.

Afferent: Carrying inward to a central organ or section, as nerves that conduct impulses from the periphery of the body to the brain or spinal cord.

Intrathecal space: The space between the spinal cord and the surrounding membrane, which is filled with cerebrospinal fluid.

Neuropathic pain: Pain resulting from actual damage to the nervous system.

Nociceptive pain: Pain resulting from irritation, rather than damage, to the nerves.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

When services are Investigational and Not Medically Necessary:
For all diagnosis codes when criteria are not met; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

Peer Reviewed Publications:

1. Atanassoff PG, Hartmannsgruber MW, Thrasher J, et al: Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain. Reg Anesth Pain Med. 2000; 25(3):274-278.
2. Lo EH, Singhal AB, Torchilin VP, Abbott NJ. Drug delivery to damaged brain. Brain Res Rev. 2001; 38(1-2):140-148.
3. Mathur VS. Ziconotide: a new pharmacological class of drugs for the management of pain. Semin Anesth Periop Med Pain, 2000; 19:67-75.
4. McGivern JG, McDonough SI. Voltage-gated calcium channels as targets for the treatment of chronic pain. Curr Drug Targets CNS Neurol Disord. 2004; 3(6):457-478.
5. Miljanich GP. Ziconotide: Neuronal calcium channel blocker for treating severe chronic pain. Curr Med Chem. 2004; 11(23):3029-3040.
6. Rauck RL, Wallace MS, Leong MS, et al. A randomized, double-blind, placebo-controlled study of intrathecal ziconotide in adults with severe chronic pain. J Pain Symptom Manage. 2006; 31(5):393-406.
7. Ridgeway B, Wallace M, Gerayli A: Ziconotide for the treatment of severe spasticity after spinal cord injury. Pain. 2000; 85(1-2):287-289.
8. Schmidtko A, Lötsch J, Freynhagen R, Geisslinger G. Ziconotide for treatment of severe chronic pain. Lancet. 2010; 375(9725):1569-1577.
9. Staats PS, Yearwood T, Charapata SG, et al: Intrathecal ziconotide in the treatment of refractory pain in patients with cancer or AIDS: a randomized controlled trial. JAMA. 2004; 291(1):63-70.
10. Wallace MS. Ziconotide: a new nonopioid intrathecal analgesic for the treatment of chronic pain. Expert Rev Neurother. 2006; 6(10):1423-1428.
11. Wallace MS, Rauck R, Fisher R, et al. Intrathecal ziconotide for severe chronic pain: safety and tolerability results of an open-label, long-term trial. Anesth Analg. 2008; 106(2):628-637.
12. Webster LR, Fisher R, Charapata S, Wallace MS. Long-term intrathecal ziconotide for chronic pain: an open-label study. J Pain Symptom Manage. 2009; 37(3):363-372.
13. Wermeling DP, Berger JR. Ziconotide infusion for severe chronic pain: case series of patients with neuropathic pain. Pharmacotherapy. 2006; 26(3):395-402.
14. Wermeling DP. Ziconotide, an intrathecally administered N-type calcium channel antagonist for the treatment of chronic pain. Pharmacotherapy. 2005; 25(8):1084-1094. 

Government Agency, Medical Society, and Other Authoritative Publications:

1. American Hospital Formulary Service (AHFS). AHFS Drug Information 2006. Bethesda, MD: American Society of Health-System Pharmacists; 2006. Available at:  http://www.ahfsdruginformation.com/. Accessed on November 29, 2010.
2. Ziconotide. In: DrugPoints System [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Available at: http://www.thomsonhc.com. Accessed on: November 29, 2010.

Prialt^®
Ziconotide

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