KEY CONCEPTS IN ACUTE PAIN
MANAGEMENT
PGY-1 Faculty of Medicine
University of Ottawa Feb.18, 2009
John Penning MD FRCPC
Director Acute Pain Service
The 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
Analgesic
Modalities
Analgesia with Opioids alone

The harder we “push” with single mode analgesia,
the greater the degree of side-effects
Side-effects
Analgesia
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 oversedation 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 sideeffects profiles are different and of small degree.”
Side-effects
Analgesia
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 # 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 %
COX-INHIBITORS vs. OPIOIDS

Efficacy
Limited Inherently

Inter-patient dose variability
Small

Limited by S/E
Large, making dose
titration difficult
Life threatening complications
Upper GI bleeding
With chronic use
Resp. depression
Risk is early
COX-INHIBITORS vs. OPIOIDS

Toxicity, S/E
Tissue/organ toxic

Drug tolerance
Not evident

neurologic dysfunc
tolerance is part of
normal response
Abuse potential
Nil
Yes
Cyclo-oxygenase inhibitors
Acetaminophen
Naproxen
Celecoxib
Ketorolac
Numerous
others
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?

No effects on platelets!

Better GI tolerability
– Less dyspepsia, less N/V

Equivalent analgesic efficacy with nonselective 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?
2.
OR
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”
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
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
Meperidine
Morphine
Atropine
Fentanyl
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, 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







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





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. acetaminophen
2. Weak mu agonist – very weak opioid
3. 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 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.
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 proconvulsant 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 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?




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
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
Hyperalgesia
Pro-nociceptive modulation
Nociceptive
Stimulus
Anti-nociceptive modulation
Pain
Analgesia
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
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
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.