Medical Policy



Subject: Ziconotide Intrathecal Infusion (Prialt®) for Severe Chronic Pain
Document #: DRUG.00027 Current Effective Date:    03/29/2017
Status: Reviewed Last Review Date:    02/02/2017

Description/Scope

This document addresses ziconotide (Prialt, Jazz Pharmaceuticals® Inc., Palo Alto, CA), a non-opioid analgesic drug that reduces pain and is used to treat individuals with severe chronic pain.  Ziconotide is infused into the intrathecal space, a fluid filled space between the thin layers of tissue that cover the brain and spinal cord.

Position Statement

Medically Necessary:

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 ziconotide intrathecal infusion, 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.

Rationale

On December 28, 2004, the U.S. Food and Drug Administration (FDA) approved ziconotide intrathecal infusion (Prialt) 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 1200 participants and three phase III clinical trials, which evaluated the efficacy and safety of IT ziconotide infusion in those with severe chronic pain that was not adequately managed despite a regimen of systemic and/or IT analgesic and other drugs.

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.  Ziconotide does not bind to opioid receptors and opioid antagonists do not block the pharmacological effects of ziconotide (Product Information Label, 2013).

Rauck and colleagues (2006) conducted the 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 ziconotide (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 ziconotide 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 2 to 3 times a week for 3 weeks.  The primary efficacy measure was mean percent change in the VASPI score at week 3, which showed statistically significant improvement in those receiving ziconotide IT infusion versus placebo (p=0.036).  Improvement in VASPI score was seen as early as week 1.  The mean dose at week 3 was 6.9 mcg/day (0.29 mcg/hour).  The majority of secondary efficacy endpoints also showed statistically significant improvement in those receiving ziconotide IT infusion.  Adverse events were mild or moderate for a majority of the participants.  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 ziconotide group due to adverse events was comparable with that for placebo (5.4% and 4.6%, respectively).

In another study, Staats and associates (2004), conducted a multicenter, double-blind, placebo-controlled randomized trial using a high-dose IT ziconotide, fast titration method.  This trial involved 111 participants with refractory pain due to acquired immune deficiency syndrome (AIDS) or cancer and a mean 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 were: 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<0.001), 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<0.001).  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=0.001).  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 ziconotide 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 ziconotide therapy.  The most common serious adverse events experienced by ziconotide 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.  A total of 644 participants with severe chronic pain participated in this open-label, multicenter study.  Ziconotide titration was followed by long-term infusion.  Efficacy assessments included the VASPI score.  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 with a median duration of therapy of 67.5 days (range, 1.2-1215.5 days).  The mean dose at last infusion was 8.4 mcg/d (range, 0.048-240.0 mcg/d).  Median VASPI scores at baseline, 1 month, and the last available observation up to 2 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 1 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 IT 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.

An observational study involving 20 participants with intractable chronic pain related to disseminated cancer and metastases to the vertebrae were treated with combination IT ziconotide and morphine.  The primary endpoint was to assess the safety and efficacy of the combination IT therapy at days 2, 7 and 28 compared to the baseline VASPI score.  The mean VASPI score at rest on enrollment was 90 ± 7.  The VASPI scores decreased significantly from baseline at days 2, 7 and 28 with scores of 39 ± 13% (95% CI, 13.61-64.49; p<0.001), 51 ± 12% (95% CI, 27.56-74.56; p<0.001), and 62 ± 13% (95% CI, 36.03-87.89; p<0.001), respectively.  The investigators concluded that low IT doses of ziconotide and morphine allowed "safe and rapid control of oral opioid-refractory malignant pain" (Alicino, 2012).

A multi-center, observational study investigated the impact of low starting dosages of ziconotide with slow titration and the incidence of adverse events in individuals treated for intractable cancer pain.  A total of 77 participants requiring high-dose opioid therapy and/or experiencing severe opioid-related adverse events were enrolled into the trial.  The mean ziconotide starting dosage was 0.93 ± 0.43 μg/d (range 0.25-2.4 μg/d) and the mean incremental dose increase was 0.07 ± 0.02 μg/d at a mean interval of 10 days between increments.  The mean maximum dosage was 4.2 ± 3.4 μg/d (range 0.5-19 μg/d) and the overall mean ziconotide dosage in the study population was 3.5 ± 2.8 μg/d.  Adverse events occurred in 44 (57%) participants, and the most common was nausea, which affected 30% of the participants.  Serious adverse events resulting in termination of IT treatment occurred in 9% (7 participants), and for 2 of these participants the adverse events were not clearly related to ziconotide.  A statistically significant improvement in pain control was reported with a decrease in maximum pain intensity from baseline 8.07 ± 1.27 to 4.14 ± 1.37 after 30 days (p<0.01).  A decrease in the mean pain intensity was reported by 48% after 1 month of therapy.  The authors concluded the rate of adverse events compared to previous studies may be improved due to lower starting dosage and a slow increment schedule.  Additional studies regarding stability and efficacy when combining ziconotide with other analgesics were recommended (Dupoiron, 2012).

The American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine's updated guideline (2010) recommended that "Ziconotide infusion may be used in the treatment of a select subset of patients with refractory chronic pain."

The NCCN clinical practice guideline for adult cancer pain (V2.2016) indicates that ziconotide is a commonly used IT interventional procedure.  However, no specific criterion for the use of ziconotide is included.

There is sufficient published, scientific evidence of improved relief from severe chronic pain to support the use of continuous IT ziconotide infusion for select individuals who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies or IT morphine.  The use of bolus IT ziconotide has been investigated in an international clinical trial (NCT01373983 Intrathecal Bolus Doses of Ziconotide).  However, data have not been published from this study.

Background/Overview

Chronic pain is a leading cause of adult disability in the United States.  Severe chronic pain is defined as pain lasting longer than 6 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.  Severe chronic pain can also occur without direct injury to the nerves (for example, complex regional pain syndrome, also known as reflex sympathetic dystrophy-causalgia).

Pain management has increasingly turned to interdisciplinary combinations of techniques customized for the individual.  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.

Ziconotide should be administered intrathecally using a programmable implanted variable-rate microinfusion device or an external microinfusion device and catheter, 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.  Ziconotide is not intended for intravenous administration.  Ziconotide produces analgesia by blocking neurotransmitter release from primary nociceptive afferents terminating in the superficial layers of the spinal cord dorsal horn.  The combination of ziconotide with IT opiates is not recommended (Product Information Label, 2013).

Taken together, the findings from the ziconotide IT infusion 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 IT therapy.  Furthermore, ziconotide IT infusion 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.

Adverse Events and Warnings

Black box warnings and recommendations from the FDA Product Information Label (2013) include the following: 

WARNING: Neuropsychiatric Adverse Reactions.  Severe psychiatric symptoms and neurological impairment may occur during treatment with Prialt.  Prialt is contraindicated in patients with a preexisting history of psychosis.  Monitor all patients 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. 

Additional information and recommendations from the product information (2013) include the following:

The four most frequently reported (greater than 25%) adverse events associated with ziconotide were dizziness, nausea, confusional state and nystagmus.  Reduced levels of consciousness with a 2% incidence of unresponsiveness or stupor were reported in clinical trials.  There is no known pharmacologic antagonist for this effect.  Individuals using concomitant antiepileptics, neuroleptics, sedatives, or diuretics may be at higher risk of depressed levels of consciousness.  There was a higher incidence of meningitis when ziconotide 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.

Definitions

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.

Nystagmus: Fast, uncontrollable movements of the eye.

Coding

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: 

HCPCS  
J2278 Injection, ziconotide, 1 microgram
   
ICD-10 Diagnosis  
  All diagnoses

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.

References

Peer Reviewed Publications:

  1. Alicino I, Giglio M, Manca F, et al. Intrathecal combination of ziconotide and morphine for refractory cancer pain: a rapidly acting and effective choice. Pain. 2012; 153(1):245-249.
  2. 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.
  3. Deer TR, Kim C, Bowman R, et al. Intrathecal ziconotide and opioid combination therapy for noncancer pain: an observational study. Pain Physician. 2009; 12(4):E291-E296.
  4. Dupoiron D, Bore F, Lefebvre-Kuntz D, et al. Ziconotide adverse events in patients with cancer pain: a multicenter observational study of a slow titration, multidrug protocol. Pain Physician. 2012; 15(5):395-403.
  5. Lo EH, Singhal AB, Torchilin VP, Abbott NJ. Drug delivery to damaged brain. Brain Res Brain Res Rev. 2001; 38(1-2):140-148.
  6. Mathur VS. Ziconotide: a new pharmacological class of drugs for the management of pain. Semin Anesth Periop Med Pain. 2000; 19:67-75.
  7. 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.
  8. Miljanich GP. Ziconotide: neuronal calcium channel blocker for treating severe chronic pain. Curr Med Chem. 2004; 11(23):3029-3040.
  9. Mohammed SI, Eldabe S, Simpson KH, et al. Bolus intrathecal injection of ziconotide (Prialt® ) to evaluate the option of continuous administration via an implanted intrathecal drug delivery (ITDD) system: a pilot study. Neuromodulation. 2013; 16(6):576-581.
  10. 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.
  11. Ridgeway B, Wallace M, Gerayli A. Ziconotide for the treatment of severe spasticity after spinal cord injury. Pain. 2000; 85(1-2):287-289.
  12. Schmidtko A, Lötsch J, Freynhagen R, Geisslinger G. Ziconotide for treatment of severe chronic pain. Lancet. 2010; 375(9725):1569-1577.
  13. 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.
  14. Wallace MS. Ziconotide: a new nonopioid intrathecal analgesic for the treatment of chronic pain. Expert Rev Neurother. 2006; 6(10):1423-1428.
  15. Wallace MS, Kosek P, Staats P, et al. Phase II, open-label, multicenter study of combined intrathecal morphine and ziconotide: addition of ziconotide in patients receiving intrathecal morphine for severe chronic pain. Pain Med. 2008; 9(3):271-281.
  16. Wallace MS, Rauck RL, Deer T. Ziconotide combination intrathecal therapy: rationale and evidence. Clin J Pain. 2010; 26(7):635-644.
  17. 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.
  18. 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.
  19. Wermeling DP. Ziconotide, an intrathecally administered N-type calcium channel antagonist for the treatment of chronic pain. Pharmacotherapy. 2005; 25(8):1084-1094. 
  20. Wermeling DP, Berger JR. Ziconotide infusion for severe chronic pain: case series of patients with neuropathic pain. Pharmacotherapy. 2006; 26(3):395-402.

Government Agency, Medical Society, and Other Authoritative Publications: 

  1. American Society of Anesthesiologists Task Force on Chronic Pain Management; American Society of Regional Anesthesia and Pain Medicine. Practice guidelines for chronic pain management: an updated report by the American Society of Anesthesiologists Task Force on Chronic Pain Management and the American Society of Regional Anesthesia and Pain Medicine. Anesthesiology. 2010; 112(4):810-833.
  2. NCCN Clinical Practice Guidelines in Oncology® . © 2017 National Comprehensive Cancer Network, Inc. Adult Cancer Pain (V2.2016). Revised March 17, 2016. For additional information visit the NCCN website: http://www.nccn.org/index.asp. Accessed on January 5, 2017.
  3. Prialt [Product Information]. Palo Alto, CA. Jazz Pharmaceuticals Inc.; Updated on February 2013. Available at: http://www.prialt.com/wp-content/uploads/2014/02/prialt-prescribing-information.pdf. Accessed on January 5, 2017.
  4. Ziconotide. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated October 26, 2016. Available at: http://www.micromedexsolutions.com. Accessed on January 5, 2017.
  5. Ziconotide Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS® ) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised August 1, 2006. Accessed on January 5, 2017.
Websites for Additional Information
  1. U.S. National Institutes of Health. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/. Accessed on January 5, 2017.
Index

Prialt
Ziconotide

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History

Status

Date

Action

Reviewed 02/02/2017 Medical Policy & Technology Assessment Committee (MPTAC) review. Description, Rationale and References sections updated.
Reviewed 02/04/2016 MPTAC review. Rationale, Background and Reference sections updated. Removed ICD-9 codes from Coding section.
Reviewed 02/05/2015 MPTAC review. Updated Description/Scope, Rationale, Background and References sections.
Reviewed 02/13/2014 MPTAC review. Updated Description/Scope, Rationale, Background and References sections. Added Websites section.
Reviewed 02/14/2013 MPTAC review. Updated Description/Scope, Rationale, Background and References sections.
Revised 02/16/2012 MPTAC review. Clarified drug name in Position Statements. Rationale, Definitions and References updated.
Reviewed 02/17/2011 MPTAC review. Rationale, Definitions and References updated.
Revised 02/25/2010 MPTAC review. Removed infusion device language from criteria. References updated.
Reviewed 02/26/2009 MPTAC review. References updated.
Reviewed 02/21/2008 MPTAC review. References updated. The phrase "investigational/not medically necessary" was clarified to read "investigational and not medically necessary." This change was approved at the November 29, 2007 MPTAC meeting.
Reviewed 03/08/2007 MPTAC review. Coding updated; removed HCPCS S0118 deleted 12/31/2005.
Reviewed 03/23/2006 MPTAC review. References updated. 
  01/01/2006 Updated Coding section with 01/01/2006 CPT/HCPCS changes.
New 04/28/2005 MPTAC initial document development.