KEY CONCEPTS IN ACUTE
PAIN MANAGEMENT - 1
SURGERY RESIDENTS Dec. 15, 2009
John Penning MD FRCPC
Director Acute Pain Service
Objectives
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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
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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
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The Hospital
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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
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Patients/Society more “aware” of their
rights to have good pain control
– We are being held accountable
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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?
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FIRST, DO NO HARM
Therefore, the “best way” is a BALANCE
Patient
Safety
Effective
Analgesic
Modalities
Analgesia with Opioids alone
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The harder we “push” with single mode analgesia,
the greater the degree of side-effects
Side-effects
Analgesia
Multi-modal Analgesia
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“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
KEY POINTS
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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
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Multi-modal Analgesia
– Attain analgesic goals
– Avoiding S/E
Goals of Multi-Modal Analgesia
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Attain analgesic goals
1. 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
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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
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Anti-convulsants
– Gabapentin, Pregabalin
Cyclo-oxygenase inhibitors
NSAIDs/Coxibs 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 %
The problem with the “Little Pain – Little Gun”,
“Big Pain – Big Gun” Approach
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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?
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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?
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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
# 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
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Pick your “Poison” Pursuant to Patient
Profile
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COX-inhibitors are potential killers
“in the long run”
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Opioids are potential killers
“in the short run”
But they can still get you in the long 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?
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Equivalent analgesic efficacy with nonselective COX-inhibitors
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No effects on platelets!
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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
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Celecoxib 200 mg Q12 H
Ibuprofen 400 mg Q4H
– OTC 200 mg capsules
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Naproxen 375 mg Q8H
– OTC “Aleve” 220 mg capsules (box warning max
of 3 per day)
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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
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Patients with the “ASA triad”
– Chronic Nasal polyps who after ASA gets
– Exacerbation of asthma
– Angioedema of upper A/W
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Not a true IG “E” type allergy
There may be a cross reactivity with coxinhibitors
COPD or asthma alone not a contraindication to NSAIDs or Coxibs
Celecoxib and “sulfa allergy”
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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
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Renal insufficiency or risk there of
– especially if risk of hypovolemia periop
– Vascular patients having aortic cross-clamp and/or
probable angiogram peri-operatively
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Poorly controlled hypertension
– Especially if pt. is on ACE inhibitor, potent loop
diuretics
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Terrible triad for GFR
– Hypovolemia, ACE/ARB and NSAIDs
Prostaglandins
Vasodilation
increased flow
Angiotensin 2 Vasoconstriction
Decreased flow
Contra-indications to Celecoxib/NSAIDs
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Active peptic ulcer disease
Congestive heart failure
– Definite risk of fluid/sodium retention
– Risk of thrombosis??
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).
Tissue healing issues with NSAIDs
and Coxibs??
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Risk of non-union in bone surgery or nonfusion in spine surgery
– COX-1 proven a problem in high doses
– Coxibs no definitive data
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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!
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Codeine is a “weak” opioid?
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Codeine is inherently safer than the
more potent opioids?
Who still uses Tylenol # 3 ?
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WHY ??
Who still uses Tylenol # 3 ?
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Prescribe over the phone
Only modest risk of diversion relative to
straight potent opioids
– Avoid putting hydromorphone, morphine
into community
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Break and enter risk with Oxys
Codeine effective for diarrhea, cough
Codeine, Ultrarapid-Metabolism
Genotype, and Postoperative Death
NEJM August 20, 2009 pp 827-828
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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
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The major pathways convert codeine to
inactive metabolites
– CYP3A4 pathway yields norcodeine
– Glucuronidation
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The minor pathway, about 10%, yields
morphine
– CYP2D6, essential for analgesic effect
60 mg Codeine PO – approx. 4 mg morphine SC
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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
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Major pathway – CYP3A4
– Inducers decrease codeine effect
– Inhibitors increase codeine effect
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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?
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Too potent for some patients
– 5 mg oxycodone = 60 mg codeine
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It too, may be a pro-drug?
– Codeine is to Morphine as
– Oxycodone is to ??
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Oxymorphone
– The jury is still out on this one
Instead of Tylenol # 3 ?
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Acetaminophen 650 mg PO Q4H
with
Morphine 10 – 20 mg PO Q4H prn
OR
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Dilaudid 2 – 4 mg PO Q4H prn
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Newly available
Tramacet 1 – 2 tabs PO Q4H prn
Opioids: Rational multi-route
orders?
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Foundation of Acetaminophen/NSAID
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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?
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Combination drug, 325 mg of
acetaminophen + 37.5 mg of tramadol
Ordered like T#3
– 1 to 2 tabs Q4H prn
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Efficacy limited by max dose for
acetaminophen.
Opioids can be added as required!
Tramacet - How does it work?
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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?
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Tramadol’s “strength” lies in it’s
“weakness” as an opioid
– Poor Mu receptor affinity
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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?
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Tramadol’s “strength” lies in it’s
“weakness” as an opioid
– Poor Mu receptor affinity
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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
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Other mu agonist may be added
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
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Serotonergic Syndrome
– Patients may be at risk if Tramacet is coadministered with other serotonin increasing drugs
• MAO inhibitors, meperidine
• SSRI and SNRIs (cymbalta), TCAs, Trazodone
• SR Tramadol; Ultram, Tridural, Relivia
– Spectrum of severity
•
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•
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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?
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Hospital gets a deal.
Price matched with T # 3.
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Patient pays 62 cents per tab.
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Dispensing fee $15.00 + 60 tabs = $52.00
vs. about $18.00 for T#3.
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Discuss with patient?
Acute Pain Treatment for the
Ambulatory Patient
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Pre-op: 2 hours before
– Celecoxib 400 mg or Ibuprofen 600 mg
– Acetaminophen 975 mg or Tramacet 2 –3
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Intra-op
– Bupivacaine 0.5% epi, 0.5 ml/kg surgical wound
infiltration, pre-incision better
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Post-op
– Acetaminophen 650 – 975 mg Q6H
– Naproxen 375 mg Q8H
– Hydromorphone 1 or 2 mg tabs, 1 – 2 tabs Q4H
OR
– Ibuprofen or celecoxib/Tramacet/Hydromorphone
Ordering the Analgesic Ladder?
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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
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Hydromorphone 1 – 2 mg s.c. Q4H prn
The Analgesic Titration Tree
Acetaminophen
A
325 mg
T
T
T T
A T
A A
A
D
Tramacet
D Hydromorphone
2 mg
T
T T
T
A
A A
A
Foundation of NSAID or Coxib
Tramacet “titration” algorithm
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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?
Tramacet 2 tabs + HM 2 mg
Tramacet 2 tabs
Acetaminophen 1 tab + Tramacet 1 tab
Acetaminophen 2 tabs
Foundation of NSAID or Coxib
The TOH ATH Analgesic Ladder
Tramacet 2 tabs + HM 2 mg
Tramacet 2 tabs
Acetaminophen 1 tab + Tramacet 1 tab
Acetaminophen 2 tabs
Foundation of NSAID or Coxib
Acute Pain Lecture # 2
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The more challenging patient with acute
pain
– Opioid tolerant, acute on chronic pain
– How are they different?
– Role of anti-pronociceptive agents
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Fundamentals of IV PCA
What the surgeon needs to know about
neuraxial opioids, epidurals
Useful texts
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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
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Acute Pain Management: A practical guide. 3rd ed. 07
Pamela MacIntyre. Saunders/Elsevier
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.
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.h
tml
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Useful websites on Pain
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Pain Institute
http://www.medscape.com/infosite/paininstitute/article5?src=0_0_ad_ldr
Internation Association for the Study of Pain
http://www.iasppain.org//AM/Template.cfm?Section=Home
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