1. Case Western Reserve University School of Medicine University Hospitals Case Medical Center Cleveland, Ohio Intrathecal Hydromorphone and Bupivacaine Combination Therapy for Failed Back Surgery Syndrome Michael Hanes, M.D., I. Elias Veizi, M.D., Ph.D., Connie Wang, Salim Hayek, M.D., Ph.D. Division of Pain Medicine Department of Anesthesiology

2. Animation by: George Williams, MD Intrathecal Drug Delivery Failed back surgery syndrome (FBSS) –Most common non-cancer indication for IDDS –Localized pain –Mixed pain = neuropathic + nociceptive Hydromorphone and bupivacaine = PACC 2 nd line therapy 1.Raphael, JH. et al (2002) BMC Musculoskeletal Dis 3(17). 2.Deer, TR. et al (2010) Neuromodulation Sep 15(5)13(3): 436-466.

3. Animation by: George Williams, MD Line 1MorphineHydromorphoneZiconotideFentanyl Line 2 Morphine + bupivacaine Ziconotide + opioid Hydromorphone + bupivacaine Fentanyl + bupivacaine Line 3 Opioid (morphine, hydromorphone, or fentanyl) + clonidineSufentanil Line 4 Opioid + clonidine + bupivacaineSufentanil + bupivacaine OR clonidine Line 5 Sufentanil + bupivacaine + clonidine 2012 Polyanalgesic Algorithm for Intrathecal Therapies in Nociceptive Pain Line 1: Morphine and ziconotide are approved by the US Food and Drug Administration for IT therapy and are recommended as first-line therapy for nociceptive pain. Hydromorphone is recommended on the basis of widespread clinical use and apparent safety. Fentanyl has been upgraded to first-line use by the consensus conference. Line 2: Bupivacaine in combination with morphine, hydromorphone, or fentanyl is recommended. Alternatively, the combination of ziconotide and an opioid drug can be employed. Line 3: Recommendations include clonidine plus an opioid (ie, morphine, hydromorphone, or fentanyl) or sufentanil monotherapy. Line 4: The triple combination of an opioid, clonidine, and bupivacaine is recommended. An alternate recommendation is sufentanil in combination with either bupivacaine or clonidine. Line 5: The triple combination of sufentanil, bupivacaine, and clonidine is suggested. Deer TR 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 Sep;15(5):436-466

4. Animation by: George Williams, MD Line 1 MorphineZiconotideMorphine + Bupivacaine Line 2 Hydromorphone Hydromorphone + bupivacaine or Hydromorphone + clonidine Morphine + clonidine Line 3 ClonidineZiconotide + opioidFentanyl Fentanyl + bupivacaine or Fentanyl + clonidine Line 4 Opioid + clonidine + bupivacaineBupivacaine + clonidine Line 5 Baclofen 2012 Polyanalgesic Algorithm for Intrathecal Therapies in Neuropathic pain Line 1: Morphine and ziconotide are approved by the US Food and Drug Administration for IT therapy and are recommended as first-line therapy for neuropathic pain. The combination of morphine and bupivacaine is recommended for neuropathic pain on the basis of clinical use and apparent safety. Line 2: Hydromorphone, alone or in combination with bupivacaine or clonidine is recommended. Alternatively, the combination of morphine and clonidine may be used. Line 3: Third-line recommendations for neuropathic pain include clonidine, ziconotide plus an opioid, and fentanyl alone or in combination with bupivacaine or clonidine. Line 4: The combination of bupivacaine and clonidine (with or without an opioid drug) is recommended. Line 5: Baclofen is recommended on the basis of safety, although reports of efficacy are limited. Deer TR 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 Sep;15(5):436-466

5. Animation by: George Williams, MD Bernards CM. Curr Opin in Anaesth 2004, 17:441– 447 Bupivacaine Diffusion Veizi IE, et al. (2011) Pain Medicine 12:1481-89.

6. Animation by: George Williams, MD Study Objective Purpose: Examine the efficacy of IT coadministration of hydromorphone and bupivacaine from the outset of IT therapy and up to 24 months after implantation of IDDS.

7. Animation by: George Williams, MD Study Population Retrospective review –38 FBSS patients –2007 – 2011 –Followed for up to 2 years Age, years Mean (SEM)65 (2.1) Gender, no. (%) of patients Male Female 18 (47.3) 20 (52.6) Baseline NRS pain score Mean (SEM)8 (0.3) Oral opioid dose at time of implant (mg/day) Mean (SEM)53.6 (9.9)

8. Animation by: George Williams, MD Intrathecal Pump Implantation Stepwise multidisciplinary treatment approach. 24-48 hr in-patient trial with continuous IT infusion –Hydromorphone ~10 mcg/ml + bupivacaine 0.625 mg/ml –0.2 ml/hr  –>50% pain relief Implantation –Hydromorphone + bupivacaine –Titrated for pain relief and AE Personal therapy manager (PTM) –Set to deliver hydromorphone + bupivacaine (0.5-1.2 mg) per bolus Intrathecal Hydromorphone Daily Dose on Initiation of IDDS (mcg/day) Mean (SEM)113.8 (18.2) Intrathecal Bupivacaine Daily Dose on Initiation of IDDS (mg/day) Mean (SEM)5.7 (0.1)

9. Animation by: George Williams, MD Results Pain IntensityOral Opioid Consumption Data presented as mean (line) ± SEM (whiskers) * Denotes significant difference from time 0.

10. Animation by: George Williams, MD Intrathecal Dose Escalation Hydromorphone r 2 = 0.9939 Bupivacaine r 2 = 0.3371

11. Animation by: George Williams, MD Intrathecal Hydromorphone Dose Escalation r 2 = 0.7202 Slope = 13.93 Veizi IE, et al. (2011) Pain Medicine 12:1481-89. r 2 = 0.969 Slope (O+B) = 14.58

12. Animation by: George Williams, MD Conclusion IT hydromorphone and bupivacaine effective for FBSS. –Improved pain intensity –Reduction in oral opioid consumption –Decreased IT opioid dose escalation

13. Animation by: George Williams, MD THANK YOU!