Redefining Local Anesthetic Infiltration Therapy Dr. Eugene Viscusi Department of Anesthesiology Jefferson Medical College

Post-operative Pain Management: Traditional Methods Previous guidelines for post-operative analgesics were “one size fits all” -- general recommendations for all surgical procedures based on pooled data1 Anesthesiologist’s primary role in traditional setting2 Pre-operative preparation Provide optimal surgical conditions Minimize pain immediately after surgery 1 Kehlet, Anesthesiology Clin N Am 2005 23:203-210 2 White, Kehlet, et al, Anesthesia & Analgesia 2007 104:1380-1396

Early Changes in Post-operative Pain Management Early changes in therapy included: 1985 – Injection of bupivacaine following wound closure: patient free of pain for 11.5 hours1 1985 – First acute pain services established in the US and Germany2 1990 – “Balanced” analgesia used to prevent post-operative pain in colorectal surgery3 1997 – Kehlet introduces multimodal concept for post-operative care4 Early clinical guidelines for post-operative pain 2001 – US Veteran’s Health Administration5 1 Porter, Davis, An Royal Coll Surgeons Eng 1985; 67: 293-294. 2 Werner, Soholm, et al Anesth Analg 2002; 95:1361-72. 3 Dahl, Rosenberg, et al, Br J Anes 1990; 64:581-520. 4 Kehlet, Bri J Anes 1997;78:606-617. 5 www.oqp.med.va.gov/cpg/PAIN/PAIN_about.doc Accessed 10-116-08

Suboptimal Management of Post-operative Pain Patient’s worst pain “Pain can be relieved effectively in 90% of patients, but is not relieved effectively in 80% of patients.” Warfield CA, Kahn CH. Anesthesiology. 1995;83:1090-1904. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Anesth Analg. 2003;97:534-540.

Multimodal Management of Post-operative Pain Definition: Multimodal (balanced) anesthesia involves use of two or more analgesic agents with different mechanisms of action to achieve optimal analgesic effect by additive or synergistic effects.1,2 “Pain neurobiology is a complex of dynamic interrelated systems. Unimodal analgesia cannot be sufficient to provide optimal pain management. Additive and synergistic effects of multiple modes should improve outcomes.” Hamed Umedaly, MD3 1 White, Kehlet, et al, Anesthesia & Analgesia 2007 104:1380-1396 2 European Society of Regional Anaesthesia and Pain Therapy, post-operative Pain Management—Good Clinical Practice. 3 Umedaly, Multimodal Perioperative Pain Management and Multimodal Strategies to Enhance Post Operative Outcomes. http://www.phsa.ca/NR/rdonlyres/C879B328-3259-4753-BD39- 3E2C22408FCA/15620/9MultimodalPerioperativePainDrHamedUmedaly1.pdf. Accessed 10-16-2008

Multimodal and Multi-Disciplinary Approach Controlling post-operative physiology Pre-operative information Attenuation Pain Exercise Enteral Growth and teaching of stress relief nutrition factors Reduced morbidity and accelerated convalescence Adapted from graph: Kehlet, Bri J of Anes 1997; 78:614

Multimodal Management of Post-operative Pain Pre-operative issues Risk stratification Anesthetic and analgesic plan Intra-operative issues Local anesthesia Infiltration Regional anesthesia IV regional, peripheral nerve blocks, neuraxial blocks General anesthesia Post-operative issues Pain management Nausea and Vomiting Ileus and constipation PT

Benefits of Multimodal Pain Management Reduced morbidity Enhanced post-operative recovery of organ functions Accelerated convalescence1 Reduction of opioid use Reduced doses of each analgesic Improved antinociception due to synergistic/additive effects Reduction in severity of side effects2 1 Kehlet, Bri J Anes 1997;78:606-617. 2 Umedaly, Multimodal Perioperative Pain Management and Multimodal Strategies to Enhance Post Operative Outcomes. http://www.phsa.ca/NR/rdonlyres/C879B328-3259-4753-BD39- 3E2C22408FCA/15620/9MultimodalPerioperativePainDrHamedUmedaly1.pdf. Accessed 10-16-2008.

Post-operative Pain Management Current Practice Multidisciplinary pain management team: Surgeon Anesthesiologist Pain nurse Pharmacist Physical therapist/occupational therapist Floor nurse White, Kehlet, et al, Anesthesia & Analgesia 2007 104:1380-1396

New Clinical Guidelines for post-operative Pain Need for new guidelines US Veteran’s Health Administration- no updates since 20011 Growing evidence that the efficacy of analgesic agents differs between surgical procedures2 Current post-operative pain management is not optimal prospect – Procedure-Specific post-operative Pain Working Group is a collaboration of international anesthesiologists and surgeons New prospect guidelines include: Procedure-specific evidence from review of literature Transferable evidence from other surgical procedures Guidelines specific to each surgical procedure Recommendations to support clinical decisions Web-based data, quick and easy to access 1 www.oqp.med.va.gov/cpg/PAIN/PAIN_about.doc Accessed 10-16-08 2 Gray, Kehlet, er al. Br J Anaesth 2005; 94 (6): 710–14. 3 prospect web site: www.postoppain.org. Accessed 10-16-2008.

Looking Ahead in Post-operative Pain Management Expansion of anesthesiologist’s role Identify pre-operative risk factors Develop multimodal non-opioid analgesic regimens Outreach services to physical therapy/occupational therapy Practice changes Pre-operative conditioning for patients – aerobic and resistance exercises 3-4 weeks prior to surgery Intensified nurse-based preoperative patient education Multi-disciplinary approaches before and after surgery White, Kehlet, et al, Anesthesia & Analgesia 2007 104:1380-1396

Nicholson, Brown, et al American Hernia Society, 2008 Abstract Post-operative Pain Control with Extended-Release Bupivacaine Formulation After Hernia Repair Current results from a Phase IIb, multicenter, double-blind, parallel-group, placebo controlled dose-finding trial SABER™ delivery system consists of a sucrose acetate isobutyrate (SAIB) solvent with which the drug is mixed - POSIDUR™(SABER™-Bupivacaine) 5.0 mL significantly improved mean pain intensity AUC on movement compared with placebo post-surgery for 48 and 72 hours - Patients treated with SABER-Bupivacaine 5.0 mL required significantly less opioid rescue medications post-operatively compared with placebo - Over the study period, SABER-Bupivacaine 5.0 mL prolonged the time to first opioid use compared with placebo. Nicholson, Brown, et al American Hernia Society, 2008 Abstract

Extended-Release Liposomal Formulation of Bupivacaine for Post-Operative Pain Management after Hernia Repair Surgery Materials and Methods This is a Phase 2, double-blind study, in which 41 patients were randomized within sequential cohorts to receive either DepoBupivacaine (175 mg in Cohort 1, 225 mg in Cohort 2) or bupivacaine 100 mg The study drug was administered via surgical wound infiltration, in a 40-mL total injection volume Supplemental use of analgesics – administered as needed after surgery – and pain scores – measured on a 0-100 mm visual analog scale (VAS) – were recorded for 96 hours post-dose Wound healing scores (0-100 mm VAS) and adverse events (AE) were used to monitor drug safety The study has a dose-escalation design and is currently ongoing Preliminary data from the first two cohorts are reported Presented: ASRA 31st Annual Regional Anesthesia Meeting & Workshops, Rancho Mirage, California April 7, 2006.

Results - Safety There were no deaths in the study and no patients were discontinued because of adverse events The incidence of local and systemic AEs was comparable across treatment groups and did not appear treatment- or dose-related There was only one serious adverse event (SAE) in the study reported in the DepoBupivacaine 225-mg group, which was noted as "Post-Operative Hematoma" and required overnight hospitalization for observation This SAE was considered ‘not related’ to the study drug and resolved in two days without other intervention. Mean wound healing scores were 86.5 (SD=15.8), 89.4 (SD=11.9), and 79.8 (SD=14.27) in the DepoBupivacaine 175-mg, DepoBupivacaine 225-mg, and bupivacaine 100-mg groups, respectively (where 0=worst healing and 100=best healing) Presented: ASRA 31st Annual Regional Anesthesia Meeting & Workshops, Rancho Mirage, California April 7, 2006.

Results - Efficacy The proportion of patients requiring supplemental opioid medication for POP management was higher in the bupivacaine group (59%) compared with any of the DepoBupivacaine groups (25%) Pain intensity scores at rest (VAS-R) and particularly with activity (VAS-A) were lower for the DepoBupivacaine groups To assess pain intensity with activity, patients were asked to take a deep breath and cough forcefully Differences in VAS-A scores were statistically significant (95% confidence intervals) at 4, 8, 12, and 24 hours for DepoBupivacaine 175-mg dose and at 8, 12, and 24 hours for DepoBupivacaine 225-mg dose, compared to the bupivacaine group There were no clear differences between study groups regarding the time from the end of surgery to the first administration of supplemental pain medication Presented: ASRA 31st Annual Regional Anesthesia Meeting & Workshops, Rancho Mirage, California April 7, 2006.

Pain Intensity with Activity (VAS-A) 100 bupivacaine 100 mg DepoBupivacaine 175 mg DepoBupivacaine 225 mg 80 60 VAS-A (0 - 100 mm) 40 20 4 8 12 24 48 72 96 Time (hr) Presented: ASRA 31st Annual Regional Anesthesia Meeting & Workshops, Rancho Mirage, California April 7, 2006.