1. 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

2. 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.

3. 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

4. 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

5. 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)

6. 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

7. 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 times daily

8. 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?

9. 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?

10. 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

11. 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.

12. Opioid Usage and Postoperative Ileus
Hours to First Bowel Movement
R = 0.48
P = 0.002
Total morphine (mg)
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
Cali RL, et al. Dis Colon Rectum. 2000;43:

13. 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:

14. 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

15. 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

16. 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:
CART: classification and regression tree

17. 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:
1P = 0.006; 2P = 0.068; 3P = 0.669

18. 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:
Barletta JF, et al. Ann Pharmacother. 2011;45:

19. 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:

20. 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?

21. 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

22. 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

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

24. 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:
Steinbrook R. Anesth Analg. 1998;86:
Jorgensen H, et al. Cochrane Database Syst Rev. 2001;CD

25. 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:
Marret E, et al. Br J Surg. 2007;94:

26. 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:
Zutshi M, et al. Am J Surg 2005;189:
Turunen P, et al. Surg Endosc. 2009;23:31-37.

27. 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

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

29. 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:
Chen JY, et al. Clin J Pain. 2009;25:

30. 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:

31. 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:
Kaba A, et al. Anesthesiology. 2007;106:11-18.
Kuo CP, et al. Br J Anaesthesia. 2006; 97:
Harvey KP, et al. Am J Surg. 2009;198:

32. 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 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:
Kaba A, et al. Anesthesiology. 2007;106:11-18.
Kuo CP, et al. Br J Anaesthesia. 2006; 97:
Harvey KP, et al. Am J Surg. 2009;198:
To read about the use of IV lidocaine in patients following colorectal surgery, click here.

33. 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:

34. 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

35. 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

36. 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

37. 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

38. 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