Pain Management and Narcotic Sparing Approaches Jeffrey F. Barletta, PharmD, FCCM Associate...

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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

Transcript of Pain Management and Narcotic Sparing Approaches Jeffrey F. Barletta, PharmD, FCCM Associate...

Pain Management and Narcotic Sparing Approaches

Jeffrey F. Barletta, PharmD, FCCMAssociate Professor & Vice Chair of Pharmacy Practice

Midwestern University, College of PharmacyGlendale, Arizona

Faculty DisclosureIt 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?

A. No obvious relationship between opioids and POI

B. Opioid usage is associated with a decreased incidence of POI

C. Opioid usage is associated with an increased incidence of POI

C. 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

• 40 Patients Undergoing ColectomyCorrelation 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)

Cali RL, et al. Dis Colon Rectum. 2000;43:163-168.

Hours to First Bowel Movement

R = 0.48

P = 0.002

Total morphine (mg)

40 60 80 100 120 140 160

350

300

250

200

150

100

50

0For more information on this study, click herehttp://www.ncbi.nlm.nih.gov/pubmed/10696888

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?

A. No, any use of opioids is associated with increased risk for POI

B. A cumulative opioid dose of ≥ 10 mg over 3 to 5 days

C. If ≥ 2 mg of hydromorphone is given on any postoperative day, the incidence of POI is increased

C. 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?

Inclusion:• Elective colorectal surgery • Use of an enhanced recovery

protocol

Exclusion: • Epidural analgesia • Major intraabdominal complication • Major medical complication

Objective: To evaluate the relationship between opioid dose, POI and LOS To determine the opioid measure that is most strongly associated with POI

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 LAPprocedures respectively

Barletta JF, et al. Ann Pharmacother. 2011;45:916-923. CART: classification and regression tree

Opioid Dose and Postoperative Ileus

Surgical Technique

LAP (n = 160)

Max Daily Hydromorphone Dose ≥ 2 mg Max Daily Hydromorphone Dose ≥ 2 mg

Yes(n = 81)

No(n = 38)

POI = 22.2%1

POI = 2.6%1,3

Yes(n = 90)

No(n = 70)

POI = 5.6%2,3

POI = 0%2

Open(n = 119)

1P = 0.006; 2P = 0.068; 3P = 0.669

The threshold where POI increased was if ≥ 2 mg of hydromorphone was given on any postoperative day

Barletta JF, et al. Ann Pharmacother. 2011;45:916-923.

• Max daily hydromorphone dose ≥ 2 mgOR (95% CI) = 9.9 (1.2 to 82.2); P = 0.034

• Open surgeryOR (95% CI) = 3.1 (1 to 9.6); P = 0.045

• Days of IV opioid therapyOR (95% CI) = 1.5 (1.2 to 2); P = 0.003

Independent Risk Factors for POI:Multivariate Analysis

Barletta JF, et al. Ann Pharmacother. 2011;45:916-923.

For more information about this study, click here: http://www.ncbi.nlm.nih.gov/pubmed/21730280

Opioid Dose and Length of Stay

Surgical Technique

Open(n = 119)

LAP(n = 160)

Max Daily Hydromorphone Dose ≥ 2 mg Max Daily Hydromorphone Dose ≥ 2 mg

Yes(n = 81)

No(n = 38)

LOS = 7 ± 3.41 LOS = 5.2 ± 2.21

Yes(n = 90)

No(n = 70)

LOS = 4.4 ± 1.52 LOS = 3.7± 1.22

1P = 0.0012P = 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?

A. Epidural analgesia

B. Non-steroidal anti-inflammatory agents

C. Intravenous lidocaine

D. Gabapentin

E. All of the above

E. 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 combinationHolte 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)Marret E, et al. Br J Surg. 2007;94:665-673.

For more information on this meta-analysis, click here: http://www.ncbi.nlm.nih.gov/pubmed/17514701

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– Bupivacaine and fentanyl epidural vs. morphine PCA– 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)Chen JY, et al. Clin J Pain. 2009;25:485-489.

M: morphine; K: ketorolac

To read more about this study, click here: http://www.ncbi.nlm.nih.gov/pubmed/19542795

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 LidocaineRCTs in Patients Following Colorectal Surgery

Study

Herroeder

Kaba

Kuo

Harvey

N

60

40

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

Ho KY, et al. Pain. 2006;126:91-101.

Gabapentin can reduce opioid requirements in a mixed group of surgical patients

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?

A. Increase morphine dose

B. Add an NSAID

C. Place an epidural

D. IV Lidocaine

B. 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