Clinical Update: Multmodal Perioperative Analgesia by Kate O’Hanlan, MD

• Review tissue damage cyclooxygenase cascade releasing pain transmitters.

•Discuss COX 1 inhibition and reduction of platelet aggregation, gastric mucosal integrity, and reduction of renal blood flow.

•Discuss COX 2 inhibition and reduction of pain, with coronary vasoconstriction.

• Understand the differences in risk profile between the two parenteral NSAID’s.

• Explain the CNS efficacy of parenteral acetaminophen.• Integrate the published evidence to write a multimodal analgesic regimen for your surgical patients.

COX-1(Constitutive) COX-2(Inducible)

Arachidonic Acid

↑ Inflammation↑ Pain↑ Fever

↑ GI Cytoprotection↑ Platelet Function↑ Renal Function

Prostaglandins Prostaglandins

Tissue Injury Tissue Injury

NSAID’s NSAID’s

↓ GI Cytoprotection↓ Platelet Function↓ Renal Function

↓ Inflammation↓ Pain↓ Fever↑ Prothrombotic Effects

Cyclooxengase 1 and 2 inhibitors: antipyretic and analgesic

ØCOX-1- prostaglandin synthesis in response to stimulation by circulating hormones, as well as maintenance of normal renal function, gastric mucosal integrity, and platelet aggregation.

ØCox -1 Selective inhibition bad for GI, good for heart.

ØCOX-2: Released by IL-1, TNF, lipopolysaccharide, mitogens, and reactive oxygen intermediates in vasculature,

ØCOX-2 Selective inhibition is good for GI. Potent anti-inflammatory, no prostacyclin and a lot of thromboxane, so no good for CABG.

Inhibition of COX-2 Relative to COX-1

KetorolacNaproxen

IbuprofenDiclofenac

Celecoxib

Meloxicam

COX-1 COX-2

-350 -300 -250 -200 -150 -100 -50 0 50 100 150

Warner, TD et al, Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis. Proc Natl Acad Sci U S A. 1999 June 22; 96(13): 7563–7568. Pharmacology

NSAID’s and platelet aggregation

• Aspirin strong inhibitory effect on platelet function, significantly reducing RBC aggregation. 1

• Platelet effects of ketorolac were moderate, whereas ibuprofen had a minor impact on platelet function.1

• Ketorolac has increased COX-1 inhibition compared with naproxen and ibuprofen.2

1. Bozzo et al. Prohemorrhagic potential of dipyrone, ibuprofen, ketorolac, and aspirin: mechanisms associated with blood flow and erythrocyte deformability. J Cardiovasc Pharmacol 2001 Aug;38(2):183-90.2. Uzan A. The unexpected side effects of new nonsteroidal anti-inflammatory drugs. Expert Opin Emerg Drugs 2005 Nov;10(4):687-8.

NSAID’s and UGI bleeds• Systematic review of observational studies on NSAIDs and upper

GI bleeding/perforation published between 2000 and 2008.1 – Ibuprofen RRs was 2.69 [95% CI 2.17-3.33]).1 – ketorolac RR was 14.54 [95% CI 5.87-36.04]).1

• More COX-1 inhibition associatied with more UGI bleeds.1

• Ibuprofen OR for UGI bleed was 1.5. 2 • IV ketorolac OR for UGI bleed was 5.76.2 • Parenteral NSAIDs posed a higher risk, but celecoxib and

ibuprofen posed a lower risk than other NSAIDs. 2

1. Masso et al. Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding. Arthritis Rheum 2010 Jun;62(6):1592-601.2. Chang et al. Risk of hospitalization for upper gastrointestinal adverse events associated with nonsteroidal anti-inflammatory drugs: a nationwide case-crossover study in Taiwan. Pharmacoepidemiol Drug Saf 2011 Jul;20(7):763-71.

Determinants of UGI Bleeding RR 95% CI

Age 75-89 4.1 (3.5-4.7)NSAID use 4.4 (3.7-5.3)Multiple NSAIDs 7.8 (5.6-11.0)Heavy Smoking 1.6 (1.3-1.9)Antiulcer med 3.7 (3.2-4.2)Ulcer (no complic) 5.3 (4.2-6.7)Corticosteroids 1.6 (1.2-2.2)

Risser et al. NSAID prescribing precautions. American family physician. Dec 15 2009.Masso Gonzalez et al. Variability among nonsteroidal antiinflammatory drugs in risk of upper gastrointestinal bleeding.

Arthritis Rheum. Jun 2010.Singh G. Gastrointestinal complications of prescription and over-the-counter nonsteroidal anti-inflammatory drugs: a view

from the ARAMIS database. Arthritis, Rheumatism, and Aging Medical Information System. Am J Ther. Mar 2000.

Ø81% of pts in ARAMIS study with serious GI complications had no prior GI symptoms.

IV IBU 5-7 Minute Infusion

Pavliv, L., B. Voss, et al. (2011). "Pharmacokinetics, safety, and tolerability of a rapid infusion of i.v. ibuprofen in healthy adults." American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists 68(1): 47-51.

0.0

20.0

40.0

60.0

80.0

100.0

120.0

140.0

0 2 4 6 8 10 12Time Post-dose (hours)

IBU

(gm

/mL)

800 mg IV Ibuprofen800 mg PO Ibuprofen

Narcotic use after800 mg IV IBU

First 24 hours at rest 21%

First 24 hours with movement 14%

Reduction in median narcotic use 19%

Reduction in mean narcotic use 16% (P < 0.001)

• 319 women had elective abdominal hysterectomy received placebo or 800 IV IBU initiated intra-op and q 6h x 8 doses then q 6 h prn for 5 days.

• Also had morphine PCA pump or patient request.

Pre-op IV Ibuprofen

Kroll et al. A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (i.v.-ibuprofen) in the management of postoperative pain following abdominal hysterectomy. Pain Pract. Jan-Feb 2011;11(1):23-32.

IV IBU pre- and post-operatively

Pain reduction Narcotic reductionHysterectomy1 19% 16%Joint rplcmt2 32% 31%No significant difference bleeding adverse events, blood transfusions or other serious adverse events. More patients receiving IV ibuprofen experienced vomiting and more patients receiving placebo experienced dyspepsia.

1. Kroll PB, Meadows L, Rock A, Pavliv L. A multicenter, randomized, double-blind, placebo-controlled trial of intravenous ibuprofen (i.v.-ibuprofen) in the management of postoperative pain following abdominal hysterectomy. Pain Pract. Jan-Feb 2011;11(1):23-32.

2. Singla N, Rock A, Pavliv L. A multi-center, randomized, double-blind placebo-controlled trial of intravenous-ibuprofen (IV-ibuprofen) for treatment of pain in post-operative orthopedic adult patients. Pain Med. Aug 2010;11(8):1284-1293.

VAS = visual analog scale * Statistical significance at each assessment point.

At Rest With Movement

Surg

ery

Surg

ery

0 4 8 12 16 20 24 28

90

80

70

60

50

40

90

80

70

60

50

40

Hours 6-28 (P < 0.001)

Placebo800 mg IV IBU

Hours 6-28 (P<.001)

-32% -26%

Reduction in Pain Intensity Scores After Orthopedic Surgery

• 185 patients: knee or hip replacement, reconstruction, or arthroplasty• Randomized: 800 IBU or placebo at induction, q6h x 5, prn q6h x 5d.• Rescue with: morphine PCA or patient request.

Placebo800 mg IV IBU

0 4 8 12 16 20 24 28

Singla, et al A multi-center, randomized, double-blind placebo-controlled trial of intravenous-ibuprofen (IV-ibuprofen) for treatment of pain in post-operative orthopedic adult patients. Pain Med. Aug 2010;11(8):1284-1293.

IV ibuprofen contraindications

‒NSAIDs increase risk of serious GI adverse events, including bleeding,

ulceration, and perforation of the stomach or intestines, which can be fatal.• Events can occur at any time without warning symptoms.• Elderly patients are at greater risk.

• Respiratory: • Patients experiencing asthma, urticaria, or allergic-type

reactions after taking aspirin or other NSAIDs

• Gastrointestinal risk

8

‒NSAIDs may increase risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. Risk may increase with duration of use.‒ IV IBU is contraindicated for the treatment of perioperative pain in the

setting of CABG surgery.

• Cardiovascular risk

Cox-3ØCOX-3 and two smaller COX-1 proteins identified

(PCOX-1)

ØSelectively inhibited by acetaminophen.

ØMay explain why acetaminophen is antipyretic and analgesic without affecting COX-1 or COX-2.

ØPotently inhibited by diclofenac, aspirin, and ibuprofen.

ØNew drug development that selectively inhibits COX-3.

Senior K. Homing in on Cox-3 – the elusive target of paracetamol. Lancet 2002 vol 1 399.Schwab JM, Schluesener HJ, Laufer S. Lancet 2003; 361: 981-982.

ASA, Ibuprofen and acetaminophenØ1/3-1/2 less GI adverse effect than aspirin ØLowest risk of NSAIDs for UGI bleed or perforationØBlinded RCT comparing adverse events for 8233.

l ASA tabs (up to 3 g/day)l Acetaminophen (up to 3 g/d) and l Ibuprofen (up to 1.2 g/day)

ØAdverse events: l Ibuprofen 13.7%, acetaminophen 14.5% aspirin 18.7%. l No stat difference between ibuprofen and acetaminophen l GI events:

• ibuprofen (4%) acetaminophen (5.3%) aspirin (7.1%) l 6 GI bleeds: 4 with acetaminophen and 2 with aspirin.

Moore N, van Ganse E, Le Parc J-M et al (1999) . The PAIN study: paracetamol, aspirin and ibuprofen new tolerability study. A large-scale, randomized clinical trial comparing the tolerability of aspirin, ibuprofen and paracetamol for short-term analgesia. Clin Drug Invest 18:89-98

Peri-operative acetaminophen (ACET)• “Theory is that of ACET's positive effects on the serotonergic descending inhibitory

pathways. However, interactions with opioidergic systems, eicosanoid systems, and/or nitric oxide containing pathways may be involved as well. Furthermore, endocannabinoid signaling may play a role in ACET's activation of the serotonergic descending inhibitory pathways.”1

• Theorized that ACET has no affinity for the active site of cyclo-oxygenase but instead blocks central activity by reducing the active oxidized form of cyclo-oxygenase to an inactive form.2

• Combination ACET/IBU better analgesia than Tylenol No. 3 (p = 0.018). More side effects and higher discontinuation with Tylenol No. 3 (p = 0.045).3

• Need CNS levels for effect: – Analgesia better when ACET given early at induction compared to end of case.4

– Even IV ACET 30 min preoperatively not better than oral post op IBU.5

1. Smith HS. Potential analgesic mechanisms of acetaminophen. Pain Physician 2009 Jan-Feb;12(1):269-80.

2. Lucas R, Warner TD, Vojnovic I, Mitchell JA. Cellular mechanisms of acetaminophen: role of cyclo-oxygenase. Faseb J 2005 Apr;19(6):635-7.

3. Mitchell A, van Zanten SV, Inglis K, Porter G. A randomized controlled trial comparing acetaminophen plus ibuprofen versus acetaminophen plus codeine plus caffeine after outpatient general surgery. Journal of the American College of Surgeons 2008 Mar;206(3):472-9.

4. Arici S, Gurbet A, Turker G, Yavascaoglu B, Sahin S. Preemptive analgesic effects of intravenous paracetamol in total abdominal hysterectomy. Agri 2009 Apr;21(2):54-61

5. Alhashemi JA, Alotaibi QA, Mashaat MS, Kaid TM, Mujallid RH, Kaki AM. Intravenous acetaminophen vs oral ibuprofen in combination with morphine PCIA after Cesarean delivery. Can J Anaesth 2006 Dec;53(12):1200-6.

Plasma CSF  levels

Gastric absorption of oral ACET is unreliable perioperatively in the starved and stressed patient. Parenteral ACET gave therapeutic concentrations in 96% given parenteral, and 67% given oral ACET. Parenteral ACET gave higher plasma concentrations throughout the study period. Parenteral ACET gave more reliable therapeutic plasma concentrations than oral.van der Westhuizen, et al. (2011). "Randomised controlled trial comparing oral and intravenous paracetamol (acetaminophen) plasma levels when given as preoperative analgesia." Anaesthesia and intensive care 39(2): 242-246.

Randomized controlled trial IV acetaminophen 2g

Pain reduction Narcotic reductionHysterectomy1 -- 30%

• Highly selective COX-2,3 inhibitor blocks uptake of endogenous cannabinoid/vanilloid anandamide by pain neurons. CNS analgesia.• Lower incidence of postop N&V with IV acetaminophen. • IV provides better serum levels than PO.2

1. Moon YE, et al The effects of preoperative intravenous acetaminophen in patients undergoing abdominal hysterectomy. Archives of gynecology and obstetrics. 2011.2.! van der Westhuizen J, et al Randomised controlled trial comparing oral and intravenous

paracetamol (acetaminophen) plasma levels when given as preoperative analgesia. Anaesth Intensive Care. 2011.

1. Adapted from Gottschalk A & Smith D. Am Fam Physician. 2001;63:1979-84. 2. Iyengar S et al. J Pharmacol Exp Ther. 2004;311:576-84.

A Multimodal Approach Addresses the Complex Nature of Pain Transmission

Peripheral nociceptors

Descending modulation Ascending input via

Spinothalamic tract

Peripheral nerve

Dorsal horn

Local anesthetics

(epidural), Opioids,

Alpha-2 agonists1

Opioids, Alpha-2 agonists1 Acetaminophen, some NSAIDs

NE-reuptake inhibitors2

Local anesthetics

(peripheral nerve block)1

NE = norepinephrine NSAIDs = nonsteroidal anti-inflammatory drugs

Local anesthetics (field block),

NSAIDs, Coxibs1

Pain

12

Multimodal perioperative analgesia

ØMust be parenteral for effective pre-incision serum and CSF levels.

ØIV Ibuprofen safe and effective, more expensive.

ØIV Ketorolac highest risk of GI bleed, cheapest. Must halve dose for age>65.

ØIV Acetaminophen: no GI risk. Not for hepatic impairment. Complements either IBU or KET.

Kate’s picks• Pre-op:

–IV IBU 800mg + IV acetaminophhen 1,000mg for all.–IV Protonix 40 for those with GERD, PUD.

• Redose in PACU if transfused >3 uPRBC.• Post-op:

–Age>65: IV IBU 800 q6h until PO Naproxen 500 q6h –Age<65: IV KET 30 q6h until PO Naproxen 500 q6h–IV acetaminophhen 1,000mg for all, until PO

Acetaminophen 650 q6h.• Discharge: continue NSAID/acetaminophen 650

q6h x3days