KEY CONCEPTS IN ACUTE PAIN MANAGEMENT
PGY-1 Faculty of MedicineUniversity 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 PainRisk 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 HARMTherefore, 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.”
Analgesia
Side-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 # 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
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/ETissue/organ toxic neurologic dysfunc
Drug toleranceNot evident tolerance is part of
normal response Abuse potential
Nil Yes
Cyclo-oxygenase inhibitors
Acetaminophen
NaproxenCelecoxib
Ketorolac
Numerous others
Cell Membrane Phospholipids
Arachidonic Acid
Phospholipase
Prostaglandins Prostaglandins
Gastric ProtectionPlatelet Hemostasis
Acute PainInflammationFever
COX-2 COX-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?
OR
2. 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 Q4Hprn
Tylenol #31 – 2 PO
Q4H prn
OpioidsCONCEPT # 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
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
GeneticVariability And drug interactions1% Finland
10% Greek30% 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
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
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 A
A
A
TT
T T TT
T
T TD
D
Acetaminophen 325 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
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
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.