KEY CONCEPTS IN ACUTE PAIN MANAGEMENT - 1SURGERY RESIDENTS Dec. 15, 2009

John Penning MD FRCPC

Director Acute Pain Service

Objectives

Define consequences of acute pain Explain the rationale for cyclo-oxygenase

inhibitors as foundational analgesics Concerns with NSAIDs and Coxibs Limitations of T#3 Tramacet a “me too” or something new? Rational multi-modal orders for the routine,

uncomplicated patient

Consequences of poorly managed acute post-operative pain

The Patient suffers– Pathophysiological consequences

• See PGY-1 lecture– Psychological:

• Anxiety, Depression, Fatigue, Sleep Deprivation

– Chronic Post-surgery/trauma Pain• Are some patients at more risk?• Can we do anything to prevent it?

Consequences of poorly managed acute post-operative pain

The Hospital– Increased costs $$$– Poor staff morale– Reputation/Standing in the Community, Nationally– Accreditation

• Canadian Council on Health Services Accreditation; Acute Care Standard 7.4 2005.

• TOH Pain Management Council 2006• TOH Pain Assessment and Management Policy ADM 8

– Litigation

The New Challenges in Managing Acute Pain after Surgery and Trauma

Patients/Society more “aware” of their rights to have good pain control– We are being held accountable

Pressure from hospital to minimize length of stay– Control pain– limit S/E and complications from our

analgesic therapies

What is the “Best Way” to manage acute post-operative pain?

FIRST, DO NO HARMTherefore, the “best way” is a BALANCE

Patient Safety

Effective AnalgesicModalities

Analgesia with Opioids alone The harder we “push” with single mode analgesia, the

greater the degree of side-effects

Analgesia

Side-effects

Multi-modal Analgesia “With the multimodal analgesic approach there is

additive or even synergistic analgesia, while the side-effects profiles are different and of small degree.”

Analgesia

Side-effects

KEY POINTS There is as of yet no single silver bullet!! Acetaminophen limited efficacy NSAIDs or Coxibs still limited efficacy and

some significant adverse effects Opioids efficacy is limited by side-effects

– The Opioid Side-effect Burden Multi-modal Analgesia

– Attain analgesic goals– Avoiding S/E

Goals of Multi-Modal Analgesia

Attain analgesic goals1. VAS – 3 /10 at rest and 5/10 with activity

2. Pain is not limiting patient’s rest/activity

3. Patient satisfaction

Acute Pain Management Modalities Cyclo-oxygenase inhibitors

– Non-specific COX inhibitors(classical NSAIDs)– Selective COX-2 inhibitors, the “coxibs”– Acetaminophen is probably COX-3

Local anesthetics Opioids NMDA antagonists

– Ketamine, dextromethorphan Anti-convulsants

– Gabapentin, Pregabalin

Cyclo-oxygenase inhibitors NSAIDs/Coxibs and AcetaminophenCONCEPT # 1

The foundation of all acute pain Rx protocols. ”First on last off”

sole agent in mild /moderate pain Analgesic efficacy is limited inherently In contrast, with opioids efficacy is limited by S/E Opioids added as required opioid sparing effect 30-60 %

The problem with the “Little Pain – Little Gun”, “Big Pain – Big Gun” Approach

With opioids analgesic efficacy is limited by side-effects

– You can get some of the people comfortable some of the time BUT!,

You can’t get all of the people comfortable all of the time.

The problem with the “Little Pain – Little Gun”, “Big Pain – Big Gun” Approach

Important rationale for COX-Inhibitors in management of severe acute pain

– Patient Safety!! If the “Big Gun” is failing due to dose limiting sedation/respiratory depression, the addition at that time of the “Little Gun” may kill the patient.

Case Problem: Severe Respiratory Depression after Ketorolac?

Healthy 34 yr. patient c/o severe incisional pain in PACU after ovarian cystecomy

Received 200 g fentanyl with induction and 10 mg morphine during case

PCA morphine started in PACU, plus nurse supplements totaled 26 mg in 90 minutes

Still c/o pain, 30 mg ketorolac IM given with some relief after 15 minutes, so patient sent to ward

60 minutes later found unresponsive, cyanotic, RR 4/min.

Case Problem: Severe Respiratory Depression after ketorolac? Pharmacodynamic drug interaction between

morphine and NSAID– morphine’s respiratory depressant effect opposed

by the stimulatory effects of pain, busy PACU environment

– NSAID decreases pain, morphine’s effect unappossed

Gain control of acute pain with fast onset, short acting opioid(fentanyl)

Add NSAID adjunct early Monitor closely for sedation and respiratory

depression after pain is alleviated by any means

Mortality From NSAID-Induced GI Complications vs Other Diseases in US

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Cause of Deaths

Wolfe MM: NEJM 1999; 340: 1888-99

Penning’s Pessimistic Policy on Pain Pills Pick your “Poison” Pursuant to Patient

Profile

COX-inhibitors are potential killers “in the long run”

Opioids are potential killers “in the short run” But they can still get you in the long run

Cyclo-oxygenase inhibitors

Acetaminophen

NaproxenCelecoxib

Ketorolac

Rofecoxib

Cell Membrane Phospholipids

Arachidonic Acid

Phospholipase

Prostaglandins Prostaglandins

Gastric ProtectionPlatelet Hemostasis

Acute PainInflammationFever

COX-2 COX-1

Why a COX-2 inhibitor?

Equivalent analgesic efficacy with non-selective COX-inhibitors

No effects on platelets!

Better GI tolerability– Less dyspepsia, less N/V

Two hours before surgery associated with post-op pain

1. Celecoxib 400 mg PO If severe allergy to sulfa?

2. Naproxen 500 mg PO Contra-indications to NSAID

Acetaminophen 1000 mg PO

First on and Last Off

Celecoxib 200 mg Q12 H Ibuprofen 400 mg Q4H

– OTC 200 mg capsules Naproxen 375 mg Q8H

– OTC “Aleve” 220 mg capsules (box warning max of 3 per day)

Acetaminophen may be combined with NSAID or Coxib– 650 mg Q4H, OTC – Tylenol Arthritis LA 650 mg per tablet

• 1300 mg Q8H• Caution against other acetaminophen products

Contra-indications to Celecoxib/NSAIDs

Patients with the “ASA triad”– Chronic Nasal polyps who after ASA gets– Exacerbation of asthma– Angioedema of upper A/W

Not a true IG “E” type allergy There may be a cross reactivity with cox-

inhibitors COPD or asthma alone not a contra-

indication to NSAIDs or Coxibs

Celecoxib and “sulfa allergy” Allergy to sulfa?? History, Please!

– Most allergies are bogus: N/V, diarrhea– A rash with sulfonamide anti-biotics? Celecoxib belongs to the “other” class of

sulfonamides: furosemide, glyberide, etc.

– Do not use celecoxib is history of anaphylaxis or severe cutaneous reaction (Steven-Johnson sydrome. etc.) with a sulfonamide

Risk of renal failure with NSAIDs/Coxibs

Renal insufficiency or risk there of – especially if risk of hypovolemia periop– Vascular patients having aortic cross-clamp and/or

probable angiogram peri-operatively Poorly controlled hypertension

– Especially if pt. is on ACE inhibitor, potent loop diuretics

Terrible triad for GFR– Hypovolemia, ACE/ARB and NSAIDs

Prostaglandins Vasodilation increased flow

Angiotensin 2 Vasoconstriction Decreased flow

Contra-indications to Celecoxib/NSAIDs

Active peptic ulcer disease Congestive heart failure

– Definite risk of fluid/sodium retention– Risk of thrombosis??

DrugSummary Relative Risk for Cardiovascular Event (95% CI)

Rofecoxib, ≤ 25 mg

1.33 (1.00 - 1.79)

Rofecoxib, > 25 mg

2.19 (1.64 - 2.91)

Celecoxib 1.06 (0.91 - 1.23)

Diclofenac 1.40 (1.16 - 1.70)

Naproxen 0.97 (0.87 - 1.07)

Piroxicam 1.06 (0.70 - 1.59)

Ibuprofen 1.07 (0.97 - 1.18)

Meloxicam 1.25 (1.00 - 1.55)

Indomethacin 1.30 (1.07 - 1.60)*CI indicates confidence interval.

Source: JAMA. Published online September 12, 2006 (McGettigan and Henry).

Tissue healing issues with NSAIDs and Coxibs??

Risk of non-union in bone surgery or non-fusion in spine surgery– COX-1 proven a problem in high doses– Coxibs no definitive data

Risk of dehiscence of colon anastomosis increased from 4% to 18% with ketorolac, diclofenac, celecoxib– Very controversial– Currently TOH refraining from NSAIDS in this

population – examining data

Codeine Myths that still prevail!

Codeine is a “weak” opioid?

Codeine is inherently safer than the more potent opioids?

Who still uses Tylenol # 3 ?

WHY ??

Who still uses Tylenol # 3 ?

Prescribe over the phone Only modest risk of diversion relative to

straight potent opioids – Avoid putting hydromorphone, morphine

into community Break and enter risk with Oxys Codeine effective for diarrhea, cough

Codeine, Ultrarapid-Metabolism Genotype, and Postoperative DeathNEJM August 20, 2009 pp 827-828

Healthy 2 yr. boy 13 kg with OSA went for adenotonsillectomy

10 – 12.5 mg of codeine with 120 mg acetaminophen PO Q4 – 6 H prn found unresponsive a.m. of day 3 after surgery

Toxic morphine levels in blood

CODEINE – A drug whose time has come and gone?

N Engl J Med 351; 27 Dec. 30, 2004

Codeine Metabolism in Normal Circumstances The major pathways convert codeine to

inactive metabolites– CYP3A4 pathway yields norcodeine– Glucuronidation

The minor pathway, about 10%, yields morphine– CYP2D6, essential for analgesic effect

60 mg Codeine PO – approx. 4 mg morphine SC

Variability! 60 mg PO Codeine yields potentially 0 to 60 mg parenteral morphine

GeneticVariability And drug interactions1% Finland

10% Greek30% East Africa

Potential Codeine Drug Interactions

Major pathway – CYP3A4– Inducers decrease codeine effect– Inhibitors increase codeine effect

Minor pathway - CYP2D6– Inducers increase codeine effect– Inhibitors decrease codeine effect

Inhibitors of CYP2D6

SSRIs (potent) especially PAXIL Cimetidine, Ranitidine Desipramine Propranolol Quinidine (potent) Viagra Many anti-biotics and chemo

Why not just go with Percocet?

Too potent for some patients– 5 mg oxycodone = 60 mg codeine

It too, may be a pro-drug?– Codeine is to Morphine as – Oxycodone is to ??

Oxymorphone– The jury is still out on this one

Instead of Tylenol # 3 ? Acetaminophen 650 mg PO Q4H

with Morphine 10 – 20 mg PO Q4H prn

OR

Dilaudid 2 – 4 mg PO Q4H prn

Newly available Tramacet 1 – 2 tabs PO Q4H prn

Opioids: Rational multi-route orders?

Foundation of Acetaminophen/NSAID

Morphine 5 - 10 mg PO Q4h prn Morphine 2.5 - 5 mg s.c. Q4h prn Morphine 1-2 mg IV bolus Q1h prn

Hydromorphone 1 - 2 mg PO Q4h prn Hydromorphone 0.5 – 1 mg s.c Q4h prn Hydromorphone 0.25 – 0.5 mg IV Q1h prn

Towards a better analgesic for acute pain High level of efficacy A good drug would have an inherent

multi-modal mechanism of action Very low risk of serious side-effects Low incidence of bothersome side-

effects Very limited abuse potential Affordability

TRAMADOL

What about Tramacet?

Combination drug, 325 mg of acetaminophen + 37.5 mg of tramadol

Ordered like T#3– 1 to 2 tabs Q4H prn

Efficacy limited by max dose for acetaminophen.

Opioids can be added as required!

Tramacet - How does it work?

Inherent multimodal action – 4 distinct mechanisms

1. acetaminophen2. Weak mu agonist – very weak opioid3. Augments endogenous inhibitory nociceptive

modulation via serotonin 4. and norepinephrine pathways

Advantages of Tramacet?

Tramadol’s “strength” lies in it’s “weakness” as an opioid– Poor Mu receptor affinity

Minimal opioid effect– Less constipation, faster return to normal

bowel function– Less N/V– No sig. respiratory depression– No sig. risk for abuse (not classified as

narcotic)

Advantages of Tramacet? Tramadol’s “strength” lies in it’s

“weakness” as an opioid– Poor Mu receptor affinity

Tramadol does not antagonize the action of classic mu agonists like morphine, dilaudid or fentanyl– Unlike the partial agonist/antagonists such as

Talwin, Nubain, Stadol

Other mu agonist may be added

Why combination analgesics are not a great idea

Acetaminophen-Induced Acute Liver Failure: Results of a USA Multicenter, Prospective Study. Hepatology, Vol. 42, No. 6, 2005. Larson et al.

22 centers, 662 cases ’98 – ’03. 50% cases due to acetaminophen 50% of acetaminophen cases inadvertent

Tramacet Precautions Serotonergic Syndrome

– Patients may be at risk if Tramacet is co-administered with other serotonin increasing drugs

• MAO inhibitors, meperidine• SSRI and SNRIs (cymbalta), TCAs, Trazodone• SR Tramadol; Ultram, Tridural, Relivia

– Spectrum of severity• Mental changes: confusion, agitation• Automonic effects: fever, sweating, labile vitals• Motor effects: pyramidal rigidity, tremors• Supportive treatment

What about Codeine allergy? Is it safe to give Tramacet?

Product Monograph states: “Patients with a history of anaphylactoid reactions to codeine and other opioids may be at increased risk and therefore should not receive Tramacet.

Very cautious position, no evidence Morphine and it’s cousins much more likely to

be of concern in severe codeine allergy. DO A HISTORY! 99% of patient reported

codeine allergy are just S/E or MBE.

CODEINE MORPHINE

OXYCODONE TRAMADOL

Tramadol Fentanyl

Meperidine

Tramacet Cost? Hospital gets a deal. Price matched with T # 3.

Patient pays 62 cents per tab.

Dispensing fee $15.00 + 60 tabs = $52.00 vs. about $18.00 for T#3.

Discuss with patient?

Acute Pain Treatment for the Ambulatory Patient Pre-op: 2 hours before

– Celecoxib 400 mg or Ibuprofen 600 mg– Acetaminophen 975 mg or Tramacet 2 –3

Intra-op– Bupivacaine 0.5% epi, 0.5 ml/kg surgical wound

infiltration, pre-incision better Post-op

– Acetaminophen 650 – 975 mg Q6H– Naproxen 375 mg Q8H – Hydromorphone 1 or 2 mg tabs, 1 – 2 tabs Q4HOR– Ibuprofen or celecoxib/Tramacet/Hydromorphone

Ordering the Analgesic Ladder?

Acetaminophen 650 mg PO Q4H prn Tramacet 1 – 2 tabs PO Q4H prn Hydromorphone 2 – 4 mg PO Q4H prn

– Reduce to 1 -2 mg in elderly Hydromorphone 1 – 2 mg s.c. Q4H prn

The Analgesic Titration Tree

A

A A

A

A

A A

A

A

TT

T T TT

T

T TD

D

Acetaminophen 325 mg

Tramacet

Hydromorphone 2 mg

Foundation of NSAID or Coxib

Tramacet “titration” algorithm

Tramacet 2 tabs PO Q4H straight W/A– If pain is < 3/10 with activity and no

hydromorphone in last 4 hours, may hold 1 or 2 tabs of Tramacet and replace with 1 or 2 tabs of acetaminophen accordingly

– If pain > 5/10 with activity may supplement Tramacet with hydromorphone 1- 2 mg PO or 0.5 – 1 mg s.c. Q4H prn

Ordering the Analgesic Ladder?

Foundation of NSAID or Coxib

Acetaminophen 2 tabs

Acetaminophen 1 tab + Tramacet 1 tab

Tramacet 2 tabs

Tramacet 2 tabs + HM 2 mg

The TOH ATH Analgesic Ladder

Foundation of NSAID or Coxib

Acetaminophen 2 tabs

Acetaminophen 1 tab + Tramacet 1 tab

Tramacet 2 tabs

Tramacet 2 tabs + HM 2 mg

Acute Pain Lecture # 2

The more challenging patient with acute pain– Opioid tolerant, acute on chronic pain– How are they different?– Role of anti-pronociceptive agents

Fundamentals of IV PCA What the surgeon needs to know about

neuraxial opioids, epidurals

Useful texts

Free!! From Canadian Pain SocietyManaging Pain: The Canadian Healthcare

Professional’s Reference. Edited by Roman Jovey. 2008.

Endorsed by the CPS. Order from Purdue Pharma

Acute Pain Management: A practical guide. 3rd ed. 07

Pamela MacIntyre. Saunders/Elsevier

http://www.anzca.edu.au/publications/acutepain.pdf

The above web site has the entire document and is freely Available to download.

ACUTE PAIN MANAGEMENT:SCIENTIFIC EVIDENCE 2nd Edition June ‘05Australian and New Zealand College of AnaesthetistsAnd Faculty of Pain Medicine.

Useful websites on Pain

Prospect:Procedure Specific Post-op Pain Management

http://www.postoppain.org/frameset.htm Pain Explained

http://www.painexplained.ca/content.asp?node=4 The Canadian Pain Society

http://www.canadianpainsociety.ca/indexenglish.html

Useful websites on Pain

Pain Institute http://www.medscape.com/infosite/paininstitute/article-5?src=0_0_ad_ldr Internation Association for the Study of Pain

http://www.iasp-pain.org//AM/Template.cfm?Section

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