KEY CONCEPTS IN ACUTE PAIN MANAGEMENT

PGY-1 Faculty of Medicine University of Ottawa Feb.18, 2009

John Penning MD FRCPC Director Acute Pain ServiceThe Ottawa Hospital

Objectives

General Key Concepts– The “real cost” of acute pain– Multi-modal analgesia– New Dimensions in pain management– How and when to use naloxone

Objectives

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

new to add?– Anti-pronociceptive agents for difficult

acute pain

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, Sleep Deprivation

– 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

• 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

Consequences of poorly managed acute post-operative pain

The Healthcare professional– Morale– Complaints to College– Litigation

Risk Factors for severe post-op pain

While incision size and type of surgery are predictors of post-op pain, the greatest source of variability is the PATIENT.– Younger age– Female– Pre-operative pain issues– Anxiety, depression, catastrophizing

Chronic Post-Surgical Pain Risk Factors

Brandsborg B. et al. Risk factors for chronic pain after hysterectomy. Anesthesiology 2007; 106: 1003 – 12.– Pre-operative pelvic pain as the main

indication for surgery– Pain problems elsewhere– Previous C/S

Procedure done with spinal anesthesia shown to decrease incidence of CPSP.

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, yet limit the side-effect

burden and complications secondary to opioids

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 Pain/Analgesic History– The Brief Pain Inventory – “BPI”

Brief Pain Inventory:Charles Cleeland

What is the “Best Way” to manage Acute Pain?

FIRST, DO NO HARM

Therefore, 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

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, no foundational analgesic given

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

Still c/o pain, 30 mg ketorolac IV, 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

Case Problem: Severe Respiratory Depression after Ketorolac?

Safer approach?– Add NSAID foundational analgesic ASAP– Gain control of acute pain with fast onset,

short acting opioid(fentanyl)

In a patient previously “loaded” with opioids and c/o pain despite some sedation, Monitor closely for over- 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

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.”

AnalgesiaSide-effects

Pain Pathways

There is as of yet no single silver bullet!!

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

NSAID, Coxibs and Acetaminophen

CONCEPT # 1The 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 %

COX-INHIBITORS vs. OPIOIDS

EfficacyLimited Inherently Limited by S/E

Inter-patient dose variabilitySmall Large, making dose

titration difficult

Life threatening complicationsUpper GI bleeding Resp. depressionWith chronic use Risk is early

COX-INHIBITORS vs. OPIOIDS

Toxicity, S/E

Tissue/organ toxic neurologic dysfunc

Drug tolerance

Not evident tolerance is part ofnormal response

Abuse potential

Nil Yes

Cyclo-oxygenase inhibitors

AcetaminophenNaproxen

Celecoxib

Ketorolac

Numerous others

Cell Membrane Phospholipids

Arachidonic Acid

Phospholipase

Prostaglandins Prostaglandins

Gastric ProtectionPlatelet Hemostasis

Acute PainInflammationFever

COX-2COX-1

Why a COX-2 inhibitor?

No effects on platelets!

Better GI tolerability– Less dyspepsia, less N/V

Equivalent analgesic efficacy with non- selective COX-inhibitors

Celecoxib and “sulfa allergy”

Allergy to sulfa?? History, Please!– Most reported 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

Two hours before surgery associated with post-op pain

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

OR2. Naproxen 500 mg PO

Contra-indications to NSAID?Plus

Acetaminophen 1000 mg PO

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– Patient on ACE inhibitors or ARBs– 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– Fluid/sodium retention

Active peptic ulcer disease

The Opioids

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

Meperidine75 mg

IM Q4Hprn

Tylenol #31 – 2 PO

Q4H prn

OpioidsCONCEPT # 2

Pharmacokinetic + Pharmacodynamicpatient 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

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

Presenter

Presentation Notes

We recognize the morphine structure, top right. What are the other structures? Can we guess what class of drugs they are. The Sesame street kids! Which structure doesn’t belong? Actually 3 are opioids and 2 are not!

MorphineMeperidine

Fentanyl

Atropine

Bupivacaine

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

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.

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

Presenter

Presentation Notes

In contrast to morphine, codeine is about 60% as effective orally as parenterally. The greater oral efficacy is due to less 1st pass metabolism in the liver. However, Codeine has exceptionally low affinity for opioid receptors and the analgesic effect of codeine is due to it’s conversion to morphine (O-demethylation, about 10% of codeine is O-demethylated to morphine). The conversion of codeine to morphine is effected by the cytochrome P450 enzyme CYP2D6. Well characterized genetic polymorphisms in this enzyme lead to the inability of convert codeine to morphine, thus making codeine in-effective as an analgesic for about 10% of the Caucasian population(Eichelbaum and Evert, 1996). Other polymorhisms can lead to enhanced metabolism and enhanced effect. Ref(Goodman and Gilman 10th ed. 2001 pg 589

GeneticVariability And drug

interactions1% Finland10% Greek30% East Africa

Presenter

Presentation Notes

From Yvan Gasche et.al. Codeine intoxication associated with ultrarapid CYP2D6 Metabolism. NEJM Dec 30 2004. What happened with our patient? Strike #1 CYP2D6 genotyping showed three or more functioning alleles, a finding consistent with ultrarapid metabolism. The capacity to convert codeine to morphine was greatly increased. Strike #2, The CYP3A4 pathway was inhibited by the anti-microbials, thereby shunting a much greater percent of codeine to the CYP2D6 pathway with increased morphine. Strike #3, see next slide

Presenter

Presentation Notes

Strike #3 Morphine is metabolized to M-3 and M-6 glucuronides with a polar and cleared by the kidney. This patient had moderated renal insufficiency leading to accummulation of morphine and M6G.

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

Presenter

Presentation Notes

The carbon 3 position appears to be important for opioid receptor binding and the nitrogen part of the molecule important for intrinsic activity. Some authors are stating that hydrocodone is a prodrug for hydromorphone and oxycodone for oxymorphone. Remember the lunar module analogy. The base is important for docking and the Canada arm important for the work of the molecule.

Instead of Tylenol # 3 ?

Acetaminophen 650 mg PO Q4Hwith

Morphine 10 – 20 mg PO Q4H prnOR

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 bolushomeopathic 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

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 anti-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.

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

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

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 AA

A

TT

T T TT

T

T TDD

Acetaminophen325 mg

Tramacet

Dilaudid 2 mg

The Tramacet Titration Tree

Tramacet 2 tabs Q4H W/A– If patient reports pain 2/10 or less may

replace one or two tabs with plain acetaminophen 325 mg per tab

– If patient reports pain greater than 5/10 with activity, may add hydromorphone 1-2 mg PO Q4H prn

Presenter

Presentation Notes

We are expanding our scope of thinking of how analgesics really work. Entering the clinical reality of a 3rd dimension in analgesic therapy.

Nociceptive Stimulus Pain

Hyperalgesia

Analgesia

Pro-nociceptive modulation

Anti-nociceptive modulation

Analgesic Drugs that act by Nociceptive Modulation

Pro-antinociceptive– Augments inhibitory modulation of

nociception i.e opioids

Anti-pronociceptive– Inhibits the facilitatory modulation of

nociception i.e. ketamine, gabapentin and pregabalin

Presenter

Presentation Notes

Pregabalin binds wit high affinity to the alpha2-delta subunit protein of volatage-gated calcium channels in the CNS tissues and acts as a presynaptic modulator of the excessive release, in hyperexceited neurons, of various excitatory neurotransmitters.

Pregabalin for acute pain?

Acute pain is “off-label” use

Be cautious of Over-sedation– Sleep deprivation– Elderly– Patient already has significant opioids

Pregabalin: The Good, The Bad and the Ugly

The Good – happy patient– Chronic pain in region of surgery, when

pronociceptive mechanisms play a role such as joint arthroplasty, bowel surgery in IBD patients, chronic limb ischemic pain, opioid tolerant patients

The Bad – sedated patient– Mild pain when simple analgesics like

acetaminophen, NSAIDs or low dose opioid or Tramacet suffice.

The Ugly – ICU bound patient– Too large a dose in sleep deprived patient already

in state of “morphine-failure”

Pregabalin dosage

This is NOT a one size fits all.– Drugs binding to receptors have

considerable patient to patient variability in dose:response

Alpha-2 delta sub-unit of Voltage-Gated Calcium Channel

75 mg PO 2 hours pre-op (50 – 150)

50 mg PO Q8H for 3 to 5 days (25 – 75)

How do we stop all these drugs?

48 yr patient had a laparotomy for SBO and sent home on celecoxib, tramacet and hydromorphone

How do we stop all these drugs?

Last on first off and first on last off.– Discontinue hydromorphone first– Next reduce and stop Tramacet– NSAID– Acetaminophen

Out-patient support– Family doctor?– APS nurse?

Naloxone, a two-edged sword!

Is there a down side to the administration of naloxone, 0.4 mg IV in the post-op patient where opioid induced respiratory depression is suspected?

Severe acute pain, sympathetic response, pulmonary edema, MI, dysrhythmias

Case Presentation: Somnolence and hypoxemia while on IV PCA Morphine

65 yr. Female with large ventral hernia repair on IV PCA morphine

PMHx: Angioplasty 9 yr. ago, MI, CHF in past– Moderate COPD, NIDDM

Doing well day 1, but day 2 found to be somewhat confused, somnolent and SaO2 remains in high 80s despite Oxygen by N/P

Is Narcan Indicated? Urgently?

Case Presentation: Somnolence and hypoxemia while on IV PCA Morphine

Further patient evaluation– Patient arousable, RR 8-16, pupils slightly

constricted, BP 130/70, pulse 90 and reg.– Chest: A/E fair bil. And some mild basilar creps– ABG: pH 7.46 pCO2 50 pO2 55 BiCarb 36 FiO2 > .50– Chest X-ray: Extensive bilateral, diffuse,

interstitial infiltrate consistent with ARDS

Naloxone would probably have had a serious adverse effect on this patient. Hypoxemia despite supplemental O2 in a breathing patient. Look beyond the Opioids!

Case Presentation: Somnolence and hypoxemia while on IV PCA Morphine

Management of suspected opioid induced respiratory depression– Support A/W– Stimulate breathing– Supply supplemental oxygen– Assess SaO2, BP, Pulse– Naloxone titration, IF INDICATED

• 0.04 mg Q5 min. X 3 as needed

Hypoxemia is a medical emergency

Hypercarbia is NOT

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 texts

Free!! From Canadian Pain Society

Managing 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. 07Pamela MacIntyre. Saunders/Elsevier

Useful websites on Pain

Prospect:Procedure Specific Post-op Pain Management

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

Pain Explainedhttp://www.painexplained.ca/content.asp?node=4

The Canadian Pain Societyhttp://www.canadianpainsociety.ca/indexenglish.h

tml

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 Painhttp://www.iasp-

pain.org//AM/Template.cfm?Section=Home