KEY CONCEPTS IN ACUTE
PAIN MANAGEMENT - 1
SURGERY 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 PostOperative 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 HARM
Therefore, the “best way” is a BALANCE
Patient
Safety
Effective
Analgesic
Modalities
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


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Local anesthetics
Opioids
NMDA antagonists
– Ketamine, dextromethorphan

Anti-convulsants
– Gabapentin, Pregabalin
Tissue Trauma
Cell Membrane Phospholipids
Phospholipase
Arachidonic Acid
C
O
X
Cyclo-oxygenase
Endoperoxides
Thromboxane
Prostaglandins
Toxic Oxygen Radicals
Prostacyclin
Analgesia with Opioids alone

The harder we “push” with single mode analgesia,
the greater the degree of side-effects
Side-effects
Analgesia
Multi-modal Analgesia

“With the multimodal analgesic approach there is
additive or even synergistic analgesia, while the sideeffects profiles are different and of small degree.”
Side-effects
Analgesia
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?



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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
Big Pain – Big Gun Approach”
Gun,
– 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”



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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 %
# of Deaths in thousands
Mortality From NSAID-Induced GI
Complications vs Other Diseases in US
25
20
15
10
5
0
Leukemia
HIV
NSAIDs- Multiple Asthma
Myeloma
GI
Cause of Deaths
Wolfe MM: NEJM 1999; 340: 1888-99
Cervial
Cancer
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
Naproxen
Celecoxib
Ketorolac
Rofecoxib
Cell Membrane Phospholipids
Phospholipase
Arachidonic Acid
COX-1
COX-2
Prostaglandins
Prostaglandins
Gastric Protection
Platelet Hemostasis
Acute Pain
Inflammation
Fever
Why a COX-2 inhibitor?

Equivalent analgesic efficacy with nonselective 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
Drug
Summary Relative Risk for
Cardiovascular Event (95% CI)
Rofecoxib, ≤
25 mg
1.33 (1.00 - 1.79)
Rofecoxib, >
25 mg
Celecoxib
Diclofenac
2.19 (1.64 - 2.91)
Naproxen
Piroxicam
Ibuprofen
0.97 (0.87 - 1.07)
1.06 (0.70 - 1.59)
1.07 (0.97 - 1.18)
Meloxicam
1.25 (1.00 - 1.55)
Indomethacin
1.30 (1.07 - 1.60)
1.06 (0.91 - 1.23)
1.40 (1.16 - 1.70)
*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 Q4H
prn
Tylenol #3
1 – 2 PO
Q4H
prn
Opioids
CONCEPT # 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
Hydromorphone 4 mg
oxycodone 10 mg
meperidine 200 mg
codeine 200 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)

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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
Meperidine
Morphine
Atropine
Fentanyl
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”

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– 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
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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
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Day 4 became markedly sedated, pinpoint 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
Genetic
Variability
And drug
interactions
1% Finland
10% Greek
30% 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
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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
STOP
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
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
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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
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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 sideeffects
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?



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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. acetaminophen
2. Weak mu agonist – very weak opioid
3. 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 Surgery
2004; 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 proconvulsant 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

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

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 coadministered 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?



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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
OXYCODONE
MORPHINE
TRAMADOL
Tramadol
Meperidine
Fentanyl
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 Q3H
OR
– Ibuprofen or celecoxib/Tramacet/Hydromorphone
The Tramacet Titration Tree
Acetaminophen
A
325 mg
T
T T
A T
A A
A
D
T
Tramacet
D
Dilaudid 2 mg
T
T T
T
A
A A
A
ACUTE PAIN MANAGEMENT:
SCIENTIFIC EVIDENCE 2nd Edition June ‘05
Australian and New Zealand College of Anaesthetists
And Faculty of Pain Medicine.
http://www.anzca.edu.au/publications/acutepain.pdf
The above web site has the entire document and is freely
Available to download.
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
Hydromorphone 8 mg
Meperidine 300 mg
Codeine 300 mg
Oxycodone 15 mg
Morphine 10 mg
Hydro…. 2 mg
Meperid.. 75 mg
Codeine 120 mg
Oxycodone (n/a)