ASRA Pain Medicine Update

Ziconotide (Prialt®) is an intrathecally delivered, nonopioid analgesic used for the treatment of severe and intractable pain. The drug is indicated in patients with intolerances or demonstrated ineffective treatment following the administration of systemic analgesics, adjunctive therapies, or intrathecal morphine. Ziconotide is a selective and reversible neural-type calcium channel blocker and is believed to exert its action through prevention of calcium entry into presynaptic nerve terminals. Ultimately, it decreases the release of neurotransmitters and neuropeptides that mediate nociception.

Intrathecal ziconotide often allows for a reduction in oral doses of neuropathic and opioid medications with accompanying decreases in the incidence and severity of their side effects.

The abundance of preclinical and clinical evidence supports the 2016 Polyanalgesic Consensus Guidelines (PACC) that recommended ziconotide as first-line therapy for cancer and noncancer pain in intrathecal drug delivery systems.¹ According to the marketing division of Medtronic Inc, the manufacturer of the Synchromed II pump system, of the approximately 80,000 currently active pumps, 2%–3% have ziconotide as a single agent (Personal communication, 6/18/18).

In private practice, many reasons exist ziconotide’s low use, including reimbursement issues, trialing, and patient selection and management. Reimbursement issues represent a major obstacle to the more widespread use of ziconotide in private practice. Current Centers for Medicare and Medicaid Services (CMS) guidelines dictate a buy-and-bill practice where a physician buys the drug according to wholesale acquisition cost (WAC) pricing and then is paid directly for services and cost of the drug. Each Medicare intermediary local coverage decision has different rules regarding billing units and types of drug coverage. Medicare through part B will pay 80% of WAC and expects patients or secondary insurance to pay the other 20%, which may be approximately $700. For other patients, Medicare supplemental insurance will cover the remaining amount. Patients insured by Medicare primary and Medicaid secondary have coverage for the cost of the drug but not for the full price WAC. Twenty percent of WAC is lost in those patients.

Commercial carriers have better reimbursement rates and may offer a profit in the buy-and-bill practices. Sometimes, various pharmacies and home care services will take on the risk of buy-and-bill for practices where the physician focuses only on professional and facility fees. Experienced practices have investigated and maximized billing of facility, drug, and professional fees.

In practice, proper submission and coding is needed to attempt to negotiate with insurance providers following denial determinations. A letter of medical necessity may be needed for patients to receive insurance coverage. Jazz Pharmaceuticals, the manufacturer of ziconotide, has a financial hardship program and resources for practices to perform proper coding and billing to maximize reimbursement of ziconotide administration.

Trials for intrathecal drug delivery systems are performed either by bolus injections or continuous infusions. The recent Patient Registry for Intrathecal Ziconotide Management (PRIZM) study suggests that more than 90% of ziconotide trials are performed by the bolus technique.² Its convenience in the office or surgical center makes a bolus trial very popular. In bolus trials, a rapid response will help determine whether ziconotide is efficacious, but it carries the risk of rapid onset of side effects such as nausea, sedation, and orthostatic hypotension.

If an infusion trial is performed, efficacy and side effects may be insidious. The advantage of an infusion trial is that it provides more accurate information about the ultimate starting dose for the pump implantation. For example, if a patient gets relief at 4.4 mcg/day, then the starting point of the constant infusion can be at 4.4 mcg because the trial mimics the constant infusion of an implantable pump. Given the desire to get a rapid response, I have employed a bolus of 1.2 or 2.4 mcg as a loading dose and then initiated an infusion at 0.1 mcg/hr with the potential for repeat boluses and increases in the basal infusion. In most cases, pain reduction is noted within 24 hrs.

Once a trial is completed, implantation is performed and ziconotide is slowly but steadily escalated to determine a dose that maximizes pain control while simultaneously minimizing the incidence of major side effects. With bolus trialing alone, the starting dose for titration of constant infusions via the implantable pump is unknown and a slow and steady escalation is recommended. PACC and Jazz Pharmaceutical guidelines recommended to start at 1.2 or 2.4 mcg/day with weekly increase of 0.2 mcg. Achieving a dose of 6 mcg/day would take 20–26 weeks. In select patients, rate increases can be performed at three-day intervals, taking 10–16 weeks to achieve 6 mcg/day. In my experience, the median dose of benefit is around 4.5–6 mcg/day. Patients must understand that the slow and steady titration process takes time.  

Discussions with patients regarding expected degree of pain relief, what would constitute a satisfactory trial, and what improvements in quality of life might be experienced are useful to ensure that expected outcomes are appropriate. Studies and clinical practice suggest that ziconotide can reduce pain by 30%–40% in most patients, similar to the analgesic response rates from oral antidepressants and gabapentinoids for painful peripheral neuropathic conditions.³ However, intrathecal ziconotide often allows for a reduction in oral doses of neuropathic and opioid medications with accompanying decreases in the incidence and severity of their side effects. For example, a reduction in opioid consumption may improve bowel function and reduce sedation, thereby improving patients’ quality of life. Furthermore, reductions in opioid requirements may allow for better compliance with the Centers for Disease Control and Prevention and CMS guidelines on opioids for chronic pain.

In my experience, ziconotide, like pregabalin and gabapentin, works best for burning and dysesthesia type neuropathic pain. Gabapentinoids (gabapentin, pregabalin) act primarily to reduce hyperalgesic states under conditions of inflammation and nerve injury. Like gabapentinoids, ziconotide binds and modulates voltage-gated calcium channel expression in the presynaptic terminals of primary afferent nociceptors,⁴ which is why the side-effect profile of gabapentinoids is similar to ziconotide. In our practice, we specifically ask if the component of burning dyesthesia is improved during intrathecal ziconotide titration. Once this is achieved or side effects such as memory loss or confusion occur, the dose should not be increased. Further titration may be attempted in a few weeks when tolerance may have developed to previously bothersome side effects.

Another option is to add intrathecal agents such as morphine, hydromorphone, or clonidine to the ziconontide. The PRIZM study suggests that approximately 50% of pumps use combinations of intrathecal medications by 18 months.⁵ Adding a low dose of morphine (0.2–1 mg daily dose), hydromorphone (0.2–1 mg daily dose), or clonidine (50–150 mcg daily dose) may have synergistic or additive effects with ziconotide. Drug compatibility studies have been done, but more clinical studies need to be conducted to determine drug-drug interaction and benefits.

Ziconotide is still a preferred and first-line agent for intrathecal drug delivery for chronic pain. Reimbursement, patient selection, and trialing requirements are the main reasons why this drug is not used more frequently. Ziconotide can be used in your clinic practice safely and effectively. In addition, it is a rewarding experience to offer this therapy because patients are often grateful and feel you saved them from a life of chronic pain. 

References 

1. Deer TR, Pope JE, Hayek SM, et al. The Polyanalgesic Consensus Conference (PACC): recommendations on intrathecal drug infusion systems best practices and guidelines. Neuromodulation. 2017;20(2):96–132. https://doi.org/10.1111/ner.12538
2. Deer T, Rauck RL, Kim P, et al. Effectiveness and safety of intrathecal ziconotide: interim analysis of the patient registry of intrathecal ziconotide management. Pain Pract. 2018;18(2):230–238. https://doi.org/10.1111/papr.12599
3. Haanpää ML, Backonja MM, Bennett MI, et al. Assessment of neuropathic pain in primary care. Am J Med. 2009;122(10 Suppl.):S13–S21. https://doi.org/10.1016/j.amjmed.2009.04.006
4. Lyseng-Williamson KA, Perry C. Ziconotide. CNS Drugs. 2006;20(4):331–341.