Use of the Personal Therapy Manager With Prialt ® (Ziconotide Intrathecal Infusion) for Patient-controlled Analgesia: C

1. Use of the Personal Therapy Manager WithPrialt® (Ziconotide Intrathecal Infusion) for Patient-controlled Analgesia:Case Series Gladstone C. McDowell, II, MDIntegrated Pain Solutions, Columbus, Ohio

2. Personal Therapy Manager (PTM) and Prialt® (ziconotide intrathecal infusion) • PTM • Patient-activated delivery of physician-programmed supplemental dose of intrathecal (IT) medication as needed • Ziconotide • IT analgesic for chronic severe pain1 • Inhibits N-type calcium channels, believed to reduce signaling along the spinal pain pathways2 • We have used the PTM in patients receiving continuous infusion of IT ziconotide (monotherapy or combination) 1. PRIALT® (ziconotide intrathecal infusion) [package insert]. 2008. 2. McGivern JG. Neuropsychiatr Dis Treat. 2007;3(1):69-85.

3. PTM is Contraindicated for Use With Ziconotide • However, • Bolus trials are routinely used to test effectiveness of ziconotide for individuals2-4 • Ziconotide overdose does not lead to respiratory depression or death5 • Formal study is needed to define usage criteria to ensure efficacy and safety and minimize side effects “Contraindications … Do not prescribe or use the Personal Therapy Manager for administration of an intrathecal infusion of ziconotide, because ziconotide has a defined titration scheme.”1 1. Personal Therapy Manager for Synchromed II [Product Insert]. 2007. 2. Baumgartl WH. (poster) 10th Annual Meeting of NANS; 2006. 3. Rosenblum SM. (Abstract A1566) ASA Annual Meeting; 2008. 4. Grigsby E, et al. (Abstract 14) ASRA 2010 Annual Pain Meeting and Workshops; 2010. 5. Charapata S and Ellis D. Pain Medicine. 2002;3(2):189-190.

4. Dosing considerations • PTM with ziconotide monotherapy • Simpler, safer than combination therapy • PTM with ziconotide in combination with opioid • Calculate programmed dose based on ziconotide infusion dose (minding opioid overdose) • Bolus doses equivalent to ~10% of daily continuous dose • Ziconotide bolus dose range, 0.15 to 0.25 mcg • Intervals of 1−2 hours (cancer patients) to 4−6 hours (nonmalignant disease patients)

5. Tolerability and Pain Relief • This treatment strategy was well tolerated • No severe adverse effects • A few patients experienced nausea or dizziness with PTM doses that exceeded 60% of their simple continuous ziconotide dose • The addition of PTM increased patient satisfaction and decreased office visits • Patient compliance was related directly to proper and adequate education regarding the utility and beneficial effects of the PTM device

6. PTM Cases • Ziconotide monotherapy, 3 patients: • 1 patient with arachnoiditis • 1 patient with rheumatoid arthritis and osteoarthritis • 1 patient with chronic pancreatitis • Ziconotide + hydromorphone, 11 patients: • 4 patients with metastatic breast cancer • 1 patient with large anal cancer • 1 patient with metastatic pancreatic cancer • 3 patients with lumbar postlaminectomy syndrome • 1 patient with diabetic peripheral neuropathy • 1 patient with interstitial cystitis and lumbar postlaminectomy syndrome

7. Ziconotide (IT) Monotherapy Cases (1) • Arachnoiditis Simple continuous dose Ziconotide 14.983 mcg/d PTM dose Ziconotide 0.25 mcg q4h Status Pain 4/10, maintains active lifestyle Minimal contact, generally seen only for pump refills • Rheumatoid arthritis and osteoarthritis Simple continuous dose Ziconotide 4.8 mcg/d PTM dose Ziconotide 0.20 mcg q3h Status (Oral) oxymorphone ER 5 mg q12h Pain 4–5/10, more functional Seen only for pump refills

8. Ziconotide (IT) Monotherapy Cases (2) • Chronic pancreatitis (failed SCS) Simple continuous dose Ziconotide 1.5 mcg/d PTM dose Ziconotide 0.15 mcg q2h Status Pain 5/10, functional Phone calls reduced, seen only for pump refills and titration

9. Combination Therapy Cases (1) • Metastatic breast cancer – lumbar spine metastases Simple continuous dose Ziconotide 6.701 mcg/d + hydromorphone 6.7 mg/d PTM dose Ziconotide 0.25 mcg + hydromorphone 0.25 mg q8h Status Pain 6/10, now fully ambulatory and more active Minimal unscheduled contact, generally seen only for pump refills • Metastatic breast cancer – thoracic/lumbar spine, bilateral femur, and extensive pelvis metastases with fractures Simple continuous dose Ziconotide 14.408 mcg/d + hydromorphone 3.0 mg/d PTM dose Ziconotide 0.10 mcg + hydromorphone 0.02 mg q3h Status Pain remains high, but she is functional despite continued tumor spread No hospital admissions or ER visits, seen monthly for pump refills and occasional dose increases

10. Combination Therapy Cases (2) • Metastatic pancreatic cancer – L5 metastasis Simple continuous dose Ziconotide 1.0 mcg/d + hydromorphone 1.5 mg/d PTM dose Ziconotide 0.10 mcg + hydromorphone 0.15 mg q8h Status Pain 1/10 within 1 month, rare PTM use, doses reduced by 5% Minimal phone contact, receiving home pump refills • Lumbar post-laminectomy syndrome (failed SCS) Simple continuous dose Ziconotide 3.994 mcg/d + hydromorphone 1.33 mg/d PTM dose Ziconotide 0.20 mcg + hydromorphone 0.067 mg q3h Status Pain 4–5/10, young patient remains active Generally seen only for pump refills

11. Combination Therapy Cases (3) • Diabetic peripheral neuropathy Simple continuous dose Ziconotide 6.0 mcg/d Hydromorphone 1.2 mg/d PTM dose Ziconotide 0.25 mcg q3h Hydromorphone 0.05 mg q3h Status More active, less neuropathy pain, less frequent anxiety flares Minimal unscheduled contact, generally seen only for pump refills

12. Conclusions • The PTM can be used with ziconotide monotherapy or with ziconotide in combination with an opioid with acceptable tolerability and improved pain relief outcomes • Individualization of therapy and communication with patient are essential for successful PTM use • Formal study is needed to provide evidence for • Efficacy, safety, tolerability • Dosing parameters • Guidelines for physicians