KEY CONCEPTS IN ACUTE

PAIN MANAGEMENT

John Penning MD FRCPC Director Acute Pain Service

Objectives

Why is acute pain management important?

Clinical concepts not readily found in texts– COX-inhibitors, the foundation of all acute

pain protocols– Opioid dose:response variability– Limitations of T#3– Role of NMDA antagonists

Consequences of poorly managed acute post-operative/trauma 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/trauma pain

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

The Healthcare professional– Morale– Complaints to College– 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– JCAHCO standards, Pain is the “Fifth Vital sign”

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 pain management

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

What is the “Best Way” to manage acute post-operative/trauma 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

Opioids

Local Anesthetics

NMDA antagonists– Ketamine, dextromethorphan

Cell Membrane Phospholipids

Arachidonic Acid

Endoperoxides

Thromboxane

Prostaglandins Prostacyclin

Toxic Oxygen Radicals

Cyclo-oxygenaseC O X

Phospholipase

Tissue Trauma

Case Problem: Inadequate Analgesia with IV PCA after Open Cholecystectomy

45 yr. female c/o severe pain at rest and difficulty breathing due to incisional pain- 4 hrs. post-op– IV PCA morphine: 1mg bolus, 5 min. lock-out– 150 demands : 28 good– has stopped using PCA because, “it is making me sick(N/V)

and it’s not working”– received 25 mg gravol X 2 one hour ago which helped just a

little with the N/V, but did make her quite groggy

Solution?– “Between a rock and a hard place!” as far as the

use of opioids goes.

Case Problem: Inadequate Analgesia with IV PCA after Open Cholecystectomy

Problem: Patient unable to attain required morphine blood level due to intolerable side-effects (N/V, sedation)

Solution:– Administer COX-inhibitor

• Toradol IV/IM or Naproxen 500 mg PR Q12H, this may be changed to 250 mg PO TID with meals once eating

– Control N/V• Stemetil, Ondansetron, Decadron• May need to consider changing opioid i.e. Demerol

– Local Anesthetics: intercostals, paravertebral, epidural

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.”

AnalgesiaSide-effects

The rationale for COX-Inhibitors in acute pain management

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 in opioid naïve patients!

• 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.

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 COX-inhibitor– morphine’s respiratory depressant effect opposed

by the stimulatory effects of pain, busy PACU environment

– COX-inh. decreases pain, morphine’s effect unappossed

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

Add COX-inhibitor adjunct early

Monitor closely for sedation and respiratory depression after pain is alleviated by any means

Analgesia with Opioids alone

The harder we “push” with single mode analgesia, the greater the degree of side-effects

Analgesia

Side-effectsResp Depression

Pain

Opioid

Opioid

The rationale for COX-Inhibitors in acute pain management

CONCEPT # 1The foundation of all acute pain Rx

protocols.“First on : last off”

sole agent in mild /moderate pain

Analgesic efficacy is limited inherently– “ceiling” effect for analgesia exists, but toxicity

may continue to increase with increasing dosage

The rationale for COX-Inhibitors in acute pain management

Opioid dose sparing of 30 – 50%– Less c/o opioid S/E

Dose:response is quite uniform from patient to patient– S/E and contra-indications well described

The rationale for COX-Inhibitors in acute pain management• Improved pain scores, especially with

activity• Greater patient satisfaction

• Safer for the patient

The rationale for pre-operative administration of COX-inh.

The benefits of “Pre-emptive Analgesia”– Goal: prevent the establishment of peripheral and

central sensitization (“wind-up”), conditions that lead to an augmented response to pain stimuli

• i.e. prevention of “hyper-algesic” state– Requirements: the analgesic must be

pharmacologically active at the time of surgical incision and it’s activity must be maintained peri- operatively. ( > 1 hr. pre-op for PO/PR COX-inh)

Why a Selective COX-2 inhibitor?

Equivalent analgesic efficacy with non- selective COX-inhibitors

No effects on platelets! 0, ZIPPO

Much reduced incidence of upper GI S/E compared to non-selective

Duration of action about 24 hr.

Cyclo-oxygenase inhibitorsConcept # 2

All patient having surgical procedures associated with post-operative pain should receive a pre-emptive COX inhibitor, provided there are no patient contra- indications.

COX-2 for everyone probably the safest and easiest to organize.

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

Opioids

What are the factors that determine the dose of opioid we choose?

Opioids

The dose of opioid administered is dependant upon multiple factors

• Pharmacological tolerance to opioids?• Route of administration

– PO, IM/SC, IV bolus, intrathecal

• Age• Weight• Severity of pain

Opioids

A dose of opioid that is inadequate for patient A can lead to significant S/E or even death in patient B.

OpioidsPharmacokinetic + Pharmacodynamicpatient to patient variability results in1000 % variability in opioid dose requirements

Concept # 1– opioid dosage must be individualized

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

Patient Controlled Analgesia with Intravenous Opioids

IV PCA:– morphine

• golden standard, pruritus a common problem– meperidine

• a little faster onset than morphine• normeperidine a toxic metabolite is a problem for

patients with decreased renal function or using large dosages for more than a few days

– hydromorphone• less confusion in elderly patients?

PCA order parameters

Bolus dose

Lock-out Interval

Continuous infusion

One hour max. limit

OpioidsIssueWith parenteral opioids the patient may experience intolerable side

effects before adequate analgesia is attained

Opioids

CONCEPT # 2Targeted regionaladministration of opioidresults in enhancement ofthe therapeutic index (ratioof analgesia/side effects)

The proper use of oral opioids

The limitations of combination drugs

Codeine is a “pro-drug”

Potent oral opioids are under-utilized

Offer “around the clock” not “prn”

In stable situations long acting, slow release formulations may be indicated

The Limitations of Tylenol # 3

Codeine is a “pro-drug”“codeine is methylated morphine and needs to

be de-methylated to active morphine” (up to 10% of patients may not be able to convert codeine to morphine), on the other hand, some patients may “over”convert and be sensitive

Net result is unpredictability

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

The Limitations of Tylenol # 3

The problem with combination drugs– The codeine dose is limited by the maximum

allowed dose for acetaminophen• 4 grams/day = 12 tabs/day • 12 X 30 mg = 360 mg codeine = 60 mg morphine• 60 mg PO = 15 – 30 parenteral morphine• Equals about 1 mg/hr IV/s.c.• Adequate for moderate pain in average patient?

– Net result is limited efficacy

The Limitations of Tylenol # 3

The problem with combination drugs– Acetaminophen therapy may be limited by

intolerance to codeine• Patient sensitive to codeine may only want to

take 1 T#3 or even 1/2. If all they can tolerate is 15 mg of codeine Q4H, the patient is not receiving the benefit of optimum dose of acetaminophen

The Limitations of Tylenol # 3

The constipation problem– Codeine may be more constipating than other

opioids

The codeine “allergy” problem– True immunological allergy is extremely rare– > 99% of “allergy” are sensitivities

• N/V, excessive sedation, confusion• Need to perform adequate drug history,

otherwise problems may arise when an even more potent opioid, such as Percocet is substituted for T#3.

The Limitations of Tylenol # 31/ Codeine is a “pro-drug”

2/ The problem with combination drugsa. The codeine dose is limited by the maximum allowed dose for acetaminophenb. Acetaminophen therapy may be limited by intolerance to codeine

3/ The constipation problem

4/ The codeine “allergy” problem

Solution to the T #3 limitations Provided codeine works in your Patient

The oral analgesic ladder

TT

T#3 T

T#3 T#3

T#3 T#3 Oxy5 mg

Solution to the T #3 limitations

Every 12 hours

COX-2inhibitor

Long ActingOpioid

For breakthough painRegular opioid PO Q4h prn

Acetaminophen 650 mg PO Q4h prn

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

CONCEPT # 3Under utilization of high efficacy PO opioids

PO opioid equivalence of 10 mg morphine IM/SC *

morphine 20 mg codeine 120 mghydromorphone 4 mg meperidine 200 mgoxycodone 10 mg

Opioids

Dilaudid 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

Opioids: Rational multi-route orders?

Foundation of Acetaminophen/COX-inh.

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

NMDA Receptor Antagonists - To prevent or reverse “pathological” acute pain

Ketamine, Dextromethorphan– Ketamine is widely known as a dissociative

“general anesthetic” - 3 mg/Kg IV bolus– Ketamine 0.15 - 0.3 mg/kg IV with induction of

general anesthesia has pre-emptive analgesic effects - less pain and less opioid use post-op

– Ketamine 2.5 - 5.0 mg IV bolus for analgesia in post-surgery/ trauma patient -

– Ketamine as co-analgesic - combined 1:1 with morphine IV PCA. Better analgesia, less S/E

– Dextromethorphan 45 mg PO Q12H

Concluding Remarks

The foundation of all acute pain Rx protocols is a COX-Inhibitor “First on : last off”

Opioid dosage must be individualizedA dose of opioid that is inadequate for patient

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

Limitations of Tylenol # 3

Texts

Managing Pain. The Canadian Healthcare Professional’s Reference

Edited by Roman Jovey MDEndorsed by the CPSAvailable free from Purdue Pharma

Medical Pharmacology by Katzung (Lange Series)