Case Report 8: Ziconotide Delivered in a Novel Intrathecal Drug Delivery System

Intrathecal therapy continues to evolve concurrently with our understanding of the intrathecal space. Evidence suggests that it is a necessary and viable component of pain care.^1,2 The historical methodology of the chronic delivery of intraspinal medicine was weighted toward low-volume, slow, continuous delivery. Advancement was seemingly tied to finding a new intrathecal medication, with goals of mitigating dose escalation and improving safety.^3,4

Tied to the historical placement of a pump as a salvage therapy, and with the added complexity of FDA mandates with existing technologies, a limited number of advanced pain physicians seem to be interested in adoption of the therapy.⁵ Unfortunately, there has been little innovation in the development pipeline of intrathecal medicine, exclusive of ziconotide (Prialt, Jazz, Figure 1).⁶ However, there is some innovation in the space. New infusion strategies are becoming more prominently adopted. New catheters and software advancements are being realized. A new pump recently entered into the market, which may offer new technology to address concerns regarding intrathecal therapy and potentially make it an alternative to spinal cord stimulation in appropriate patients.

Figure 1. Ziconotide (Prialt).

Case Report

A 65-year-old woman presented with a history of severe back and leg pain despite having surgery 2 years previously. The axial component of her pain was markedly greater than her leg pain. She had undergone numerous epidural injections, with transient relief lasting 6 to 8 weeks, and failed to respond to opioid therapy at a dose of 300 mg of morphine equivalents per day. She reported a previously unsuccessful trial of conventional tonic spinal cord stimulation, which did not significantly reduce her pain despite adequate paresthesia. The trial leads were discontinued, and the patient was asked to return for further assessment 2 weeks later. Intrathecal therapy was introduced at that time as an option and a trial of intrathecal ziconotide was performed. The patient underwent 2 controlled trials with ziconotide at a dose of 2 mcg. The patient reported significant improvement with both trials of greater than 70% relief and was then implanted with a novel implantable pump (Prometra II, Flowonix Medical). The pump was initiated with a bolus-only dosing strategy using a planned bolus with 1 dose every 24 hours at 2 mcg, delivered in 23 minutes with a basal infusion of 0 mcg. Weekly titration of 0.1 mcg was performed, and the patient is now on a dose of 2.3 mcg per day with sustained pain relief at 6 months after implantation.

Discussion

We present a case utilizing a novel dosing strategy with a new intrathecal pain pump. Currently, there are 2 FDA-approved medications to treat pain intrathecally: morphine and ziconotide. Of those, ziconotide is only indicated for use with the Medtronic SynchroMed II and the Smiths Medical CADD Micro infusion pumps.⁷ Recent insights have highlighted that sustained use is achievable with low-dose, slow titration, employing mindful dosing and infusion therapies.^1,6,8-11 It is important to highlight these differences.

The SynchroMed II device requires a volume of 0.048 cc per day to be delivered for the availability of additional programming features, including flexed dosing or patient-controlled bloused dosing. As described in a recent article, this dosing strategy was investigated in a pilot study.¹²

The Prometra II programmable pump by Flowonix is an implantable, programmable pump that uses a valve-gated bellow delivery mechanism. It has a flow gate valve that is activated by the presence of a magnetic field, requiring removal of the intrathecal medication from the reservoir and reprogramming after MRI is performed, similar to the needed interrogation following MRIs with other pumps available.

In addition, data suggest that the pump is extremely accurate (≥97.1%; 90% CI, 96.2%-98.0%).^13-15 Of note, the Prometra II system allows for zero flow in between doses, allowing for accommodation of our recent insights with the pharmacokinetics of intrathecal therapy.

Conclusion

Ziconotide is the only nonopioid intrathecal agent that is FDA approved for pain management. Its mechanism of action centers on presynaptic calcium channel blockade on the dorsal horn of the spinal cord.¹⁶ It is an n-type calcium channel blocker, as demonstrated in animal models.

It is used for nociceptive and neuropathic pain,¹⁷ and with recent interest in bolus-only strategies,¹⁸ delivery via a Prometra II system, which has been shown to be very accurate in dose delivery,¹⁴ allows for zero flow, and may improve sustainability of ziconotide monotherapy—specifically when dosing is in micrograms and titration is in tenths of micrograms. Further prospective studies are needed to confirm this theory, but from an engineering standpoint the dosing characteristics are very favorable.

References

1. Pope JE, Deer TR, McRoberts W. Intrathecal therapy: the burden of being positioned as a salvage therapy. Pain Med. 2015;16(10):2036-2038.
2. Hayek SM, Deer TR, Pope JE, et al. Intrathecal therapy for cancer and non-cancer pain. Pain Physician. 2011;14(3):219-248.
3. Veixi IE, Hayek SM, Narouze S, et al. Combination of intrathecal opioids with bupivacaine attenuates opioid dose escalation in chronic noncancer pain patients. Pain Med. 2011;12(10):1481-1489.
4. Coffey RJ, Owens ML, Broste SK, et al. Mortality associated with implantation and management of intrathecal opioid drug infusion systems to treat noncancer pain. Anesthesiology. 2009;111(4):881-891.
5. Pope JE, Deer TR. Intrathecal drug delivery for pain: a clinical guide and future directions. Pain Manag. 2015;5(3):175-183.
6. Deer TR, Pope JE. Factors to consider in the choice of intrathecal drug in the treatment of neuropathic pain. Expert Rev Clin Pharmacol. 2015;8(5):507-510.
7. Pope JE, Deer TR. Ziconotide: a clinical update and pharmacologic review. Expert Opin Pharmacother. 2013;14(7):957-966.
8. Mohammed SI, Eldabe S, Simpson KH, et al. Bolus intrathecal injection of ziconotide to evaluate the option of continuous administration via an implanted intrathecal drug delivery system: a pilot study. Neuromodulation. 2013;16(6):576-581.
9. Backryd E, Sorensen J, Gerdle B. Ziconotide trialing by intrathecal bolus injections: an open-label non-randomized clinical trial in postoperative/posttraumatic neuropathic pain patients refractory to conventional treatment. Neuromodulation. 2015;18(5):404-412.
10. Hayek S, Hanes MC, Wang C, et al. Ziconotide combination intrathecal therapy for noncancer pain is limited secondary to delayed adverse effects: a case series with a 24-month follow-up. Neuromodulation. 2015;18(5):397-403.
11. Toilapi L, Bondi F, De Carolis G, et al. Ziconotide use in the Prometra Programmable Infusion Pump: initial results. Presented at: North American Neuromodulation Society World Congress; December 6-9, 2012; Las Vegas, Nevada.
12. Pope JE, McRoberts P, Deer TR. Randomized, prospective study to assess the safety of a novel intrathecal bolus-only delivery strategy as compared to traditional simple slow continuous delivery. Presented at: North American Neuromodulation Society World Congress; December 11-14, 2014; Las Vegas, Nevada.
13. Rauck R, Deer T, Rosen S, et al. Accuracy and efficacy of intrathecal administration of morphine sulfate for treatment of intractable pain using the Prometra Programmable Pump. Neuromodulation. 2010;13(2):102-108.
14. Rauck R, Deer T, Rosen S. Long-term follow-up of a novel implantable programmable infusion pump. Neuromodulation. 2013;16(2):163-167.
15. Rosen SM, Bromberg TA, Padda G, et al. Intrathecal administration of Infumorph^® vs compounded morphine for treatment of intractable pain using the Prometra^® programmable pump. Pain Med. 2013;14(6):865-873.
16. Prialt [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc.; 2013.
17. Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference 2012: recommendations for the management of pain by intrathecal (intraspinal) drug delivery: report of an interdisciplinary expert panel. Neuromodulation. 2012;15(5):436-464; discussion 464-466.
18. Pope JE, Deer TR. Intrathecal pharmacology update: novel dosing strategy for intrathecal monotherapy ziconotide on efficacy and sustainability. Neuromodulation. 2015;18(5):414-420.

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Managing Chronic Pain: Nine Informative Patient Presentations

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