Pain Management and Narcotic Sparing Approaches Jeffrey F. Barletta, PharmD, FCCM Associate Professor & Vice Chair of Pharmacy Practice Midwestern University, College of Pharmacy Glendale, Arizona

Faculty Disclosure It is the policy of The France Foundation to ensure balance, independence, objectivity, and scientific rigor in all its sponsored educational activities. All faculty, activity planners, content reviewers, and staff participating in this activity will disclose to the participants any significant financial interest or other relationship with manufacturer(s) of any commercial product(s)/device(s) and/or provider(s) of commercial services included in this educational activity. The intent of this disclosure is not to prevent a person with a relevant financial or other relationship from participating in the activity, but rather to provide participants with information on which they can base their own judgments. The France Foundation has identified and resolved any and all conflicts of interest prior to the release of this activity. Jeffrey F. Barletta, PharmD, has indicated that he is a consultant for Pacira Pharmaceuticals.

Educational Learning Objective Evaluate the evidence for therapeutic options that may improve gastrointestinal recovery postsurgery and integrate these efforts toward supporting overall surgical quality measures

Patient Case Goals Describe the relationship between systemic opioid use and postoperative ileus Describe the relationship between opioid dosage and return of GI function Describe strategies to decrease systemic opioid usage

Patient Case AB is a 64-year-old male who is diagnosed with adenocarcinoma of the colon and is scheduled for an immediate open hemicolectomy Past medical history is significant for coronary artery disease (aspirin 81 mg daily, simvastatin 10 mg daily) and hypertension (metoprolol 50 mg BID) Past surgical history is significant for a laparoscopic cholecystectomy (9 years ago)

Intraoperative Management Midazolam and fentanyl administered as premedications Intra-op anesthesia provided using propofol, fentanyl, and sevoflurane A low anterior resection is performed with excision of a 4 cm tumor and a colorectal anastomosis During the surgery, blood loss was minimal and hemodynamics were stable Surgery duration was 3 hours Patient was extubated and transferred to the PACU

Postoperative Management NG-tube was removed in PACU Pain management provided using morphine via patient-controlled analgesia (PCA) Dose = 2 mg Lockout = 8 minutes Continuous infusion = none Nutrition: full liquids, advance as tolerated Activity: out of bed evening of surgery, ambulate 5 times daily

Pain Management: Postoperative Day 1 Patient continues on morphine via PCA for pain control Pain scores on visual analog scale (VAS) over the last 24 hours have ranged from 5 to 10 with the most recent 3 scores being 9, 6, and 7 Total morphine usage over the last 4 hours has been 48 mg Is this patient at risk for developing postoperative ileus?

Opioids and Postoperative Ileus: Questions to Address What is the relationship between opioid usage and the development of POI? Is there a threshold for opioid dose where POI becomes more prominent? Is “opioid-sparing potential” a relevant clinical endpoint? What strategies exist to reduce systemic opioid utilization? Do these strategies shorten length of stay?

Question Which of the following best characterizes the relationship between opioid usage and the development of POI? No obvious relationship between opioids and POI Opioid usage is associated with a decreased incidence of POI Opioid usage is associated with an increased incidence of POI

Opioid usage is associated with an increased incidence of POI Narcotic exposure is a central factor in the development of POI. This relationship is illustrated in a study by Cali et al, presented on the next slide.

Opioid Usage and Postoperative Ileus Hours to First Bowel Movement R = 0.48 P = 0.002 Total morphine (mg) 40 60 80 100 120 140 160 40 Patients Undergoing Colectomy Correlation between morphine PCA dose and: First bowel movement (r = 0.48; P = 0.002) First bowel sounds (r = 0.74; P = 0.001) Flatulence (r = 0.47; P = 0.003) 350 300 250 200 150 100 50 For more information on this study, click here http://www.ncbi.nlm.nih.gov/pubmed/10696888 Cali RL, et al. Dis Colon Rectum. 2000;43:163-168.

Opioids and Duration of Postoperative Ileus Retrospective review of 88 patients who underwent open abdominal surgery POI defined as the number of days between surgery and the patient’s ability to tolerate a solid diet in the absence of nausea, vomiting, or distention Duration of ileus = 5.4 ± 3 days Multivariate regression analysis identified total opioid dose (P = 0.031) and estimated blood loss (P = 0.021) as being independently associated with the duration of POI Artinyan A, et al. World J Surg. 2008;32:1495-1500.

Question Is there a threshold for opioid dose where POI becomes more prominent? No, any use of opioids is associated with increased risk for POI A cumulative opioid dose of ≥ 10 mg over 3 to 5 days If ≥ 2 mg of hydromorphone is given on any postoperative day, the incidence of POI is increased

If ≥ 2 mg of hydromorphone is given on any postoperative day, the incidence of POI is increased As illustrated in the results of a recent study (see next few slides), a maximum daily intravenous dose of ≥ 2 mg was the opioid measure most associated with POI

How Much Opioid Is Too Much? Objective: To evaluate the relationship between opioid dose, POI and LOS To determine the opioid measure that is most strongly associated with POI Inclusion: Elective colorectal surgery Use of an enhanced recovery protocol Exclusion: Epidural analgesia Major intraabdominal complication Major medical complication Procedure: IV opioid doses were quantified & converted to hydromorphone equivalents POI defined as: 3 episodes of N/V over 24 hrs Cessation of oral diet Insertion of NGT within 5 days of surgery CART analysis was used to identify the threshold for opioid use and POI Results stratified for open and LAP procedures respectively Barletta JF, et al. Ann Pharmacother. 2011;45:916-923. CART: classification and regression tree

Opioid Dose and Postoperative Ileus The threshold where POI increased was if ≥ 2 mg of hydromorphone was given on any postoperative day Surgical Technique LAP (n = 160) Max Daily Hydromorphone Dose ≥ 2 mg Yes (n = 81) No (n = 38) POI = 22.2%1 POI = 2.6%1,3 (n = 90) (n = 70) POI = 5.6%2,3 POI = 0%2 Open (n = 119) Barletta JF, et al. Ann Pharmacother. 2011;45:916-923. 1P = 0.006; 2P = 0.068; 3P = 0.669

Independent Risk Factors for POI: Multivariate Analysis Max daily hydromorphone dose ≥ 2 mg OR (95% CI) = 9.9 (1.2 to 82.2); P = 0.034 Open surgery OR (95% CI) = 3.1 (1 to 9.6); P = 0.045 Days of IV opioid therapy OR (95% CI) = 1.5 (1.2 to 2); P = 0.003 For more information about this study, click here: http://www.ncbi.nlm.nih.gov/pubmed/21730280 Barletta JF, et al. Ann Pharmacother. 2011;45:916-923.

Opioid Dose and Length of Stay Surgical Technique Open (n = 119) LAP (n = 160) Max Daily Hydromorphone Dose ≥ 2 mg Yes (n = 81) No (n = 38) LOS = 7 ± 3.41 LOS = 5.2 ± 2.21 (n = 90) (n = 70) LOS = 4.4 ± 1.52 LOS = 3.7± 1.22 1P = 0.001 2P = 0.005 Barletta JF, et al. Ann Pharmacother. 2011;45:916-923.

Opioids and Postoperative Ileus: Questions to Address What is the relationship between opioid usage and the development of POI? Opioid usage is associated with an increased incidence of POI Is there a threshold for opioid dose where POI becomes more prominent? If ≥ 2 mg of hydromorphone is given on any postoperative day, the incidence of POI is increased Is “opioid-sparing potential” a relevant clinical endpoint? Yes. Lower opioid utilization is associated with a decrease in LOS What strategies exist to reduce systemic opioid utilization? Do these strategies shorten length of stay?

Question Which of the following is an evidence-based strategy for decreasing systemic opioid utilization for colorectal surgeries? Epidural analgesia Non-steroidal anti-inflammatory agents Intravenous lidocaine Gabapentin All of the above

All of the above Each of these strategies are potential options to decrease systemic opioid utilization. Evidence relevant to each of these approaches is included in the following slides

Strategies to Decrease Systemic Opioid Utilization Epidural analgesia Nonsteroidal anti-inflammatory agents Intravenous lidocaine Gabapentin

Epidural Analgesia Epidurals have several theoretical advantages to decrease the incidence of POI: Blockade of afferent and efferent inhibitory reflexes Efferent sympathetic blockade with a resulting increase in splanchnic blood flow Anti-inflammatory effects via systemic absorption of local anesthetics Reduction of afferent neural impulses decreasing the stress response to local inflammation Epidural must be placed in the mid-thoracic region Epidurals with local anesthetics are associated with a reduced time to GI recovery versus epidurals with opioids but pain relief may be better with an epidural with a local anesthetic/opioid combination Holte K, et al. Br J Surg. 2000;87:1480-1493. Steinbrook R. Anesth Analg. 1998;86:837-844. Jorgensen H, et al. Cochrane Database Syst Rev. 2001;CD001893.

Meta-analysis: Epidural Analgesia vs. Parenteral Opioid Analgesia 16 trials published between 1987 and 2005 14 trials, open surgery 2 trials, laparoscopic surgery 8 trials employed additional measures to improve GI recovery (eg, removal of NG-tube, active oral feeding) Pain on day 1 (VAS score): WMD – 15 (-19 to -11, P < 0.001) Duration of GI dysfunction: WMD – 1.55 (-2.27 to -0.84, P < 0.001) Length of stay: WMD 0.07 (-0.4 to 0.54, P = 0.76) For more information on this meta-analysis, click here: http://www.ncbi.nlm.nih.gov/pubmed/17514701 Marret E, et al. Br J Surg. 2007;94:665-673.

There Are Few Data Evaluating Epidurals With Laparoscopic Surgery in the Setting of ERP Senagore et al Bupivacaine and fentanyl epidural vs. morphine PCA Improvement in pain relief at 6 hrs and 18 hrs vs. PCA No difference in LOS (2.4 vs. 2.3 days) Zutshi et al No improvement in pain relief No difference in NG reinsertion (9.7% vs. 25%, P = 0.12) No difference in LOS (5 vs. 5 days, P = 0.94) Turunen et al Ropivacaine vs. control Decreased systemic opioid consumption with epidural No difference in return of bowel function (2 vs. 2 days, P = 0.56) No difference in LOS (3 vs. 3 days, P = 0.81) Senagore AJ, et al. Br J Surg. 2003;90:1195-1199. Zutshi M, et al. Am J Surg 2005;189:268-272. Turunen P, et al. Surg Endosc. 2009;23:31-37.

Epidural Analgesia Epidural analgesia can be an effective strategy in providing pain relief and reducing systemic opioid consumption but… They have not been shown to decrease length of stay Other factors to consider are whether or not the risks of epidural analgesia can justify the benefits especially in the setting of laparoscopic surgery where LOS is low (ie, < 3 days) The provision of safe and effective analgesia requires a dedicated team of experts who are readily available and able to address complications when they arise

Nonsteroidal Anti-inflammatory Agents NSAIDs such as ketorolac: Decrease inflammation by decreasing prostaglandin production Reduce systemic opioid requirements

Ketorolac Prospective, randomized, double-blind study 102 patients receiving open, elective colorectal resection Ketorolac (1.2 mg/ml ) + morphine (1 mg/ml) PCA vs. Morphine PCA (1 mg/ml) PCA settings: 2 ml with 10-minute lockout Total morphine consumption: Ketorolac/Morphine = 66 mg Morphine = 81 mg (P < 0.05) Time to first bowel movement: Ketorolac/Morphine = 1.8 days Morphine = 2.4 days (P < 0.05) M: morphine; K: ketorolac To read more about this study, click here: http://www.ncbi.nlm.nih.gov/pubmed/19542795 Chen JY, et al. Clin J Pain. 2009;25:485-489.

Ketorolac in Laparoscopic Surgery Prospective, randomized, double-blind study 44 patients receiving elective laparoscopic segmental colon resection Ketorolac 30 mg IV every 6 hours x 48 hours vs. placebo All patients received morphine PCA Total morphine consumption: Ketorolac = 33 mg Placebo = 63 mg (P = 0.011) Time to full diet: Ketorolac = 2.5 days Morphine = 3 days (P = 0.033) Length of stay: Ketorolac = 3.6 days Morphine = 4.5 days (P = 0.142) Schlachta CM, et al. Surg Endosc. 2007;21:2212-2219.

Intravenous Lidocaine RCTs in Patients Following Colorectal Surgery Study Herroeder Kaba Kuo Harvey N 60 40 22 IV Lidocaine regimen 1.5 mg/kg before induction, then 2 mg/min until 4 hrs post skin closure 1.5 mg/kg at induction, then 2 mg/kg/hr intra-op and 1.33 mg/kg/hr for 24 hrs post-op 2 mg/kg, the 3 mg/kg/hr started 30 minutes before surgery throughout surgery 1 mg/min for 24 hours Herroeder S, et al. Ann Surg. 2007;246:192-200. Kaba A, et al. Anesthesiology. 2007;106:11-18. Kuo CP, et al. Br J Anaesthesia. 2006; 97:640-646. Harvey KP, et al. Am J Surg. 2009;198:231-236.

Intravenous Lidocaine Results Herroeder et al Time to tolerate oral diet: 74 vs. 99 hrs (P < 0.001) Length of stay: 7 vs. 8 days (P = 0.004) Kaba et al Time to first bowel movement: 28 vs. 51 hrs (P = 0.001) Length of stay: 2 vs. 3 days (P = 0.001) Kuo et al Time to first flatus: 60 vs. 72 hrs (P < 0.01) Length of stay: 6.9 vs. 7.1 days (P = NS) Harvey et al Time to first bowel movement: 88 vs. 116 hrs (P = 0.029) Length of stay: 3.76 vs. 4.93 days (P = 0.028) In each example, first value is for lidocaine, second value is for control Herroeder S, et al. Ann Surg. 2007;246:192-200. Kaba A, et al. Anesthesiology. 2007;106:11-18. Kuo CP, et al. Br J Anaesthesia. 2006; 97:640-646. Harvey KP, et al. Am J Surg. 2009;198:231-236. To read about the use of IV lidocaine in patients following colorectal surgery, click here. http://www.ncbi.nlm.nih.gov/pubmed/17197840

Gabapentin: Cumulative Morphine Consumption Single dose, 1200 mg pre-op Single dose, < 1200 mg pre-op Gabapentin can reduce opioid requirements in a mixed group of surgical patients Ho KY, et al. Pain. 2006;126:91-101.

Opioids and Postoperative Ileus: Questions to Address What is the relationship between opioid usage and the development of POI? Opioid usage is associated with an increased incidence of POI Is there a threshold for opioid dose where POI becomes more prominent? If ≥ 2 mg of hydromorphone is given on any postoperative day, the incidence of POI is increased Is “opioid sparing potential” a relevant clinical endpoint? Yes. Lower opioid utilization is associated with a decrease in LOS What strategies exist to reduce systemic opioid utilization? Thoracic epidurals, NSAIDs, IV lidocaine and gabapentin are potential options to decrease systemic opioid utilization. Careful planning pre-operatively is necessary to maximize the usefulness of these interventions Do these strategies shorten length of stay? Most studies are underpowered for this endpoint and lack control for confounding variables. The only strategy that has demonstrated a reduction in LOS is IV lidocaine

Back to the Case: Pain Management: Postoperative Day 1 Patient continues on morphine via PCA for pain control Pain scores on visual analog scale (VAS) over the last 24 hours have ranged from 5 to 10 with the most recent 3 scores being 9, 6 and 7 Total morphine usage over the last 4 hours has been 48 mg

Back to the Case: Question What would be the best option for pain management that balances pain relief and risk for POI? Increase morphine dose Add an NSAID Place an epidural IV Lidocaine

Add an NSAID In this example, morphine can be increased but AB is already using a substantial amount of morphine that puts him at high risk for POI An epidural would decrease systemic opioid exposure but since we are already at POD1, there are other interventions that could be tried first IV lidocaine is typically initiated intra-op and continued for 4–24 hours post-op At this point, addition of an NSAID would be the best option

Moving Forward… Multimodal pain management with an emphasis on opioid reduction should be implemented as part of an enhanced recovery protocol Pre-operative education is a crucial component of that protocol. Patients should be informed of the risks of opioid therapy and the importance of balancing pain relief with excessive opioid usage and POI Institutions should work to develop a standardized approach to pain (eg, PCA vs. epidurals) NSAIDs should be included as part of that pathway