KEY CONCEPTS IN ACUTE PAIN MANAGEMENT - 1SURGERY RESIDENTS Dec. 18, 2007

John Penning MD FRCPC

Director Acute Pain Service

Objectives

General Key Concepts– The “real cost” of acute pain– Multi-modal analgesia

Discuss key concepts of each modality– COX-inhibitor as foundational analgesic– Coxibs – “platelet sparing” cox-inhibitors– Tylenol # 3 has it’s limitations – Opioids – think outside the “box”– Tramacet – a “me too” drug? Or something

to new to add?

Consequences of poorly managed acute post-operative pain The Patient suffers

– CVS: MI, dysrhythmias– Resp: atelectasis, pneumonia– GI: ileus, anastamosis failure– Endocrine: “stress hormones”– Hypercoagulable state: DVT, PE– Impaired immunological state

• Infection, cancer, wound healing

– Psychological:• Anxiety, Depression, Fatigue

– Chronic Post-surgery/trauma Pain

Consequences of poorly managed acute post-operative pain The Hospital

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

The Healthcare professional– Morale– Complaints to College– Litigation

Benefits of Optimal Acute Post-Operative Pain Management

The Hospital– Increased patient satisfaction– Increased staff morale– Compliance with national guidelines, accreditation

criteria

– Cost Savings• Earlier ambulation and enteral feeding• Decreased complications/ICU expenditures• Decreased Length of Stay

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

The New Challenges in Managing Acute Pain after Surgery and Trauma

The Opioid Tolerant Patient– The greatest change in practice/attitudes in

the last 10 years is the now wide spread acceptance of the use of opioids for CHRONIC NON-MALIGNANT PAIN

– Renders the “usual” standard “box” orders totally inadequate in these patients

Get an accurate Drug History– The Brief Pain Inventory – “BPI”

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

KEY POINTS “Emphasis is placed on the utilization of a

multimodal analgesic approach to maximize analgesia while minimizing side-effects.” – Transduction– Transmission– Modulation– Perception

There is as of yet no single silver bullet!!

Pain Pathways

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

Cell Membrane Phospholipids

Arachidonic Acid

Endoperoxides

Thromboxane

Prostaglandins Prostacyclin

Toxic Oxygen Radicals

Cyclo-oxygenaseCOX

Phospholipase

Tissue Trauma

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

Case Problem: Severe Respiratory Depression after Toradol?

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 Toradol 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 Toradol? 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

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

With opioids analgesic efficacy is limited by side-effects

“Optimal” analgesia is often difficult to titrate– 10 – fold variability in opioid dose:response for

analgesia– A dose of opioid that is inadequate for patient A

can lead to significant S/E or even death in patient B.

• Many patient factors add to the difficulty– Opioid tolerance, anxiety, obstructive sleep

apnea, sleep deprivation, concomitantly administered sedative drugs

The rationale for COX-Inhibitors in acute pain management

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

– 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.

NSAID and Acetaminophen

CONCEPT # 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 %

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

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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”

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

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).

Contra-indications to Celecoxib/NSAIDs

Patients with the “ASA triad”– Risk of severe asthma, angioedema precipitated

with COX-inhibitor 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

Contra-indications to Celecoxib/NSAIDs

Congestive heart failure

Active peptic ulcer disease

Risk of non-union in bone surgery or non-fusion in spine surgery– COX-1 proven a problem in high doses– COX-2? Proven OK for 5 days

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

The Opioids

We have to stop trying to put every patient in the “analgesic dose box”

Meperidine 75 mg

IM Q4Hprn

Tylenol #31 – 2 PO

Q4H prn

OpioidsCONCEPT # 2

Pharmacokinetic + Pharmacodynamic

patient to patient variability results in 1000 %

variability in opioid dose requirements (standardized procedure, opioid naïve patient)

– opioid dosage must be individualized

– therefore, if parenteral therapy indicated, IV PCA much better suited to individual patient needs than IM/SC

Opioids *Cancer Pain Monograph (H&W, 1984)

CONCEPT # 3

Under utilization of high efficacy PO opioids

PO opioid equivalence of 10 mg morphine IM/SC *

Morphine 20 mg meperidine 200 mg

Hydromorphone 4 mg codeine 200 mg

oxycodone 10 mg

True or False? One opioid is just like any other, in terms

of analgesic efficacy and side-effects.

Opioids – Are they all the same?

Morphine Hydromorphone (dilaudid) Fentanyl

Oxycodone (parenteral n/a)

Meperidine (demerol)

Opioids – Do they all act the same?

Opioids work as analgesics by activating endogenous inhibitory pain modulating systems

Opioid receptors– Mu, Delta and Kappa– Large genetic variability in expression

Good choice in one patient may be poor choice in another– Analgesic efficacy – Side-effect profile

MorphineMeperidine

Fentanyl

Atropine

Bupivacaine

True or False? One opioid is just like any other, in terms

of analgesic efficacy and side-effects.

Answer. There is considerable variability between patients in response to different opioids.

True or False?

Meperidine should be eliminated from the hospital formulary?

Meperidine Pharmacology

Opioid agonist – Mu and some kappa NMDA antagonist (weak) Local anesthetic action – equipotent to

lidocaine SSRI (weak) Muscaric blockade – “atropine-like”

– Central anti-cholinergic effects often causes confusion in the elderly

Meperidine’s major problem Normeperidine

– The “ugly” metabolite• Neuroexcitatory: twitches, dilated pupils,

hallucinations, hyperactive DTR, seizures• Non-opioid receptor mediated, no tolerance• Half-life is 15 – 20 hours

N-demethylation

Meperidine and MAO Inhibitors

Meperidine blocks the neuronal re-uptake of serotonin, may result in serotonergic crisis in patients being treated with MAO inhibitors– Excitatory reaction with delirium, hyper or hypo

tension, hyperthermia, rigidity, seizures, coma, death

– Supportive management, ? Benzos, dopaminergics?

When to use Meperidine?

As a third line opioid when other choices have failed– Especially if patient has Hx of such

Less than 600 mg per day Short duration of 2 days or less Avoid in elderly or renal failure patients

May be useful in small IV doses to supplement other opioids– 25 mg IV Q1H prn

Who still uses Tylenol # 3 ?

WHY ??

Opioid Myths that still prevail!

Codeine is a “weak” opioid?

Codeine is inherently safer than the more potent opioids?

CODEINE – A drug whose time has come and gone?

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

Problems with Codeine

62 yr. male with CLL, presents with bilateral pneumonia.

Broncho-lavage revealed yeast– Anti-biotics: Ceftriaxone, clarithromycin,

voriconazole– Codeine 25 mg PO TID for cough

Problems with Codeine Day 4 became markedly sedated, pin-

point pupils and ABG reveals PaCO2 of 80 mmHg. Marked improvement with Naloxone.

What’s the expected morphine blood level?

Answer: 1 to 4 mcg/L This patient’s morphine blood level?

– 80 mcg/L

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

Hydromorphine 1 – 4 mg PO/IM/IV Q4H prn

NOT!This represents up to 30 fold range in peak

effect in any given patient

1 mg PO ---- 4 mg IV bolus

homeopathic dose ---- potentially lethal

STOP

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!

Is Tramadol New? Just recently available in Canada, as

Tramacet Synthesized in 1962, available in Germany

since 1977, UK 94, US 95 where IV formulation is also available

Minimal risk of respiratory depression and abuse potential, never been a “scheduled” drug

Now #1 prescribed centrally acting analgesic worldwide > 50 million patients

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

Does Tramacet work?

Combination tramadol plus acetaminophen for postsurgical pain.

Adam B. Smith et al.The American Journal of Surgery2004; V187: 521 – 527.

1 tab of Tramacet = 1 tab T #3 – IN YOUR AVERAGE PATIENT !!

Tramacet Precautions Liver Toxicity

– Risk of acetaminophen dose exceeding recommended 4 gm/day in 70 kg patient, if patient inadvertently takes other acetaminophen products, especially OTC.

Risk of seizures, very rare– U.K. Safety Committee reports 1:7000– Most cases involving interaction with pro-

convulsant agents or large IV doses of tramadol– Risk taking tramadol similar to that with other

opioids– Product monograph lists as warning/precaution

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, SSRIs, meperidine

– 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– Ibuprofen 200 – 400 mg Q6H – Hydromorphone 1 or 2 mg tabs, 1 – 2 tabs Q3HOR– Ibuprofen or celecoxib/Tramacet/Hydromorphone

The Tramacet Titration Tree

A

A A

A

A

A A

A

A

TT

T T TT

T

T TD

D

Acetaminophen 325 mg

Tramacet

Dilaudid 2 mg

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.

Opioid Conversions – Parenteral to Oral

and Equivalents (approx.)

Morphine 10 mg Morphine 20 mg

Hydromorphone 2 mg Hydro…. 4 mg

Meperidine 75 mg Meperidine 200 mg

Codeine 120 mg Codeine 200 mg

Oxycodone (n/a) Oxycodone 10 mg

Opioid Conversions – Oral to Parenteral

and Equivalents (approx.)

Morphine 40 mg Morphine 10 mg

Hydromorphone 8 mg Hydro…. 2 mg

Meperidine 300 mg Meperid.. 75 mg

Codeine 300 mg Codeine 120 mg

Oxycodone 15 mg Oxycodone (n/a)