New Dimensions in Multi-modal Analgesia for Acute Paincshpontario.ca/_CMS/Files/PenningPresentationFeb08.pdf · management and why it may be particularly ... The rationale for COX-Inhibitors

New Dimensions in Multi-modal Analgesia for Acute Pain

February 27, 2008

John Penning MD FRCPCMedical Director, Acute Pain ServiceThe Ottawa Hospital

Objectives of PresentationDiscuss the role of peri-operative coxibs– Cyclo-oxygenase inhibitors should be referred to

as “Foundational” analgesics, not adjuncts!– Opioids are second step analgesics in acute pain

Introduce a “new dimension” in acute pain management and why it may be particularly effective in those “difficult to manage” patients– Use of anti-pronociceptive drugs

i.e. anti-hyperalgesics

Objectives of Presentation

Codeine for pain? Only if you like the idea of “gambling” with outcome. Perhaps it’s time to retire this old drug.

Tramacet – not just another “me too”opioid analgesic. What does it have to offer?

OPIOIDSEfficacy is limited by Side-EffectsThe harder we “push” with single mode analgesia, the greater the degree of side-effects

Analgesia

Side-effects

Problem with the “Little Pain – Little Gun, Big Pain – Big Gun Approach”

Opioid Side-effects – Delay convalescence / delay hospital discharge– Limit analgesic efficacy – “morphine-failure”

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 lead to serious overdose.

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

Key Concept!The foundation of all acute pain Rx protocols.

”First on last off”• 30 – 50 % opioid dose-sparing

• Less c/o opioid side-effects• Improved pain scores, especially with activity• Greater patient satisfaction• Safer for the patient

But current standard practice is to hold NSAIDs for 7 days prior to elective surgery?

Non-selective NSAIDs impair platelet function and increase the risk of bleeding complications in surgery such as total joint arthroplasty, head and neck, breast and especially tonsillectomy.

Cell Membrane Phospholipids

Arachidonic Acid

Phospholipase

Prostaglandins Prostaglandins

Gastric ProtectionPlatelet Hemostasis

Acute PainInflammationFever

COX-2COX-1

Pre-operative COX-2 inhibitor

Equivalent analgesic efficacy with non-selective COX-inhibitors

No Platelet Dysfunction!

Better GI tolerability– Less dyspepsia, less N/V– Less risk of upper GI bleeding

The last COX-2 left standing, Celecoxib.

Patients on non-selective NSAIDs. Recommend change to celecoxib 100 mg Q12H one week before surgery.

400 mg Celecoxib ASAP upon arrival to hospital day of surgery

What about risk of CV issues?

McGettigan and Henry. JAMA Oct.4 2006

*CI indicates confidence interval.

Source: JAMA. Published online September 12, 2006 (McGettigan and Henry).

1.30 (1.07 - 1.60)Indomethacin1.25 (1.00 - 1.55)Meloxicam1.07 (0.97 - 1.18)Ibuprofen1.06 (0.70 - 1.59)Piroxicam0.97 (0.87 - 1.07)Naproxen1.40 (1.16 - 1.70)Diclofenac1.06 (0.91 - 1.23)Celecoxib

2.19 (1.64 - 2.91)Rofecoxib, > 25 mg

1.33 (1.00 - 1.79)Rofecoxib, ≤25 mg

Summary Relative Risk for Cardiovascular Event (95% CI)Drug

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

Do we need another/better analgesic for acute pain?

Cyclo-oxygenase inhibitors have limited efficacy and concerns over organ toxicity– acetaminophen – naproxen ketorolac ibuprofen diclofenac indocid– Celecoxib

Opioids have side-effects that limit efficacy, have acute life-threatening risks and concerns over abuse, addiction, Opioid Induced Hyperalgesia– morphine hydromorphone meperidine– codeine oxycodone

When all you have is a hammer, everything looks like a nail.

Anti-nociceptive drugs diminish the transduction, transmission or down modulate the nociceptive signals traveling from the periphery to central pain perception regions of the CNS. Morphine the prototype powerful anti-nociceptive drugWith more pain is more morphine always the answer?

Nociceptive Stimulus Pain

Hyperalgesia

Analgesia

Pro-nociceptive modulation

Anti-nociceptive modulation

Analgesic Drugs that act by Nociceptive Modulation

Pro-antinociceptive– Promotes inhibitory modulation of

nociception i.e opioids

Anti-pronociceptive– Inhibits the facilitatory modulation of

nociception i.e. ketamine, gabapentin and pregabalin

The Analgesic Efficacy of Celecoxib, Pregabalin, and their Combination for Spinal Fusion Surgery

Scott S. Reuben et al.Anesth Analg Nov. 2006, 1271 – 1277.

Reuben et al. Anesth Analg Nov. 06, 1271 -1277

Methods – Prospective RCT– No patients on sustained release opioids– 4 groups with 20 patients per group, with capsules

given 1 hour before induction and 12 hours after– Celecoxib dosage: 400 mg : 200 mg (-1 hr and 12 h)– Pregabalin dosage: 150 mg at both times – Groups 1 hr pre 12 hr after

• Placebo + Placebo : Placebo + Placebo• Celecoxib + Placebo : Celecoxib + Placebo• Placebo + Pregabalin : Placebo + Pregabalin• Celecoxib + Pregabalin : Celecoxib + Pregabalin

Spinal fusion Scott S Reuben et al. Anesth Analg Nov 06 pg 1271- 77

Reuben. Anesth AnalgesiaNov. 2006, pg 1271-77

Reuben et al. Anesth Analg Nov. 06, 1271 -1277

Post-op Sedation Scores (0 – 4)

Time Period (h) Plac Cel Preg Both1 3.3 3.1 3.2 3.08 3.2 2.3 3.1 2.0*12 3.4 2.4 3.4 2.3*16 3.3 2.3 3.4 2.4*24 3.5 2.5 3.4 2.4*

* P < 0.05

Reuben et al. Anesth Analg Nov. 06, 1271 -1277Incidence of Side Effects

Side effect Plac Cel Preg Both PHypoxemia 6(30) 0 1(5) 0 0.001(SaO2 < 90%)Resp Depres 3(15) 0 0 0 0.025(RR < 8)Excess Sed 7(35) 1(5) 5(25) 0 0.007(SS > 4)Difficulty 5(20) 3(15) 2(10) 1(5) 0.297ConcentratingLess nursing work and increased patient safety!

Reuben et al. Anesth Analg Nov. 06, 1271 -1277Incidence of Side Effects

Side effect Plac Cel Preg Both PNausea 10(50) 5(25) 6(30) 2(10) 0.046

Vomiting 7(35) 5(25) 6(30) 1(5) 0.131

Diff urination 4(20) 2(10) 2(10) 0 0.217

Fatigue 5(20) 2(10) 2(10) 1(5) 0.249

Less nursing work and increased patient comfort!

Pregabalin for acute pain?

Acute pain is “off-label” useBe cautious of Over-sedation– Sleep deprivation– Elderly– Patient already has significant opioids

Pregabalin: The Good, The Bad and the UglyThe Good, a 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, at best not so good, sedated patient– Mild pain when simple analgesics like

acetaminophen, NSAIDs or low dose opioid or Tramacet suffice.

The Ugly, the 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 Channel75 mg PO 2 hours pre-op (50 – 150)50 mg PO Q8H for 3 to 5 days (25 – 75)

True or False?

Codeine is a “weak” opioid?

Codeine is inherently safer than the more potent opioids?

Who still uses Tylenol # 3 ?

WHY ??

Case Problem: 28 yr. Male Somali for Tonsillectomy

Co-morbidities– 6 ft. tall and 132 kg. (290 Ib.) BMI 40– Obstructive sleep apneic

• ?? Compliance with home CPAP device– Epilepsy on Dilantin– Hypertension on Diltiazem– Smokes “Pot” regularly

Is this an out-patient candidate?

Case Problem: 28 yr. Male Somali for Tonsillectomy

Get an anesthesia consult, PAU– Told to hold off on the “Pot” ? Reliability?– Importance of CPAP re-enforced, bring to hosp– Over-night surgical daycare recommended

Case finished at 10 a.m., at 2 p.m. some pain treated with morphine 10 mg s.c. Q4h and does OK with pain.

D/C next a.m., states he had poor night, difficulty sleeping in the hospital environment.

Case Problem: 28 yr. Male Somali for Tonsillectomy

What would you prescribe for pain to take home with him?Leaves with script for T # 3, 1 – 2 Q4H

Morning of Day # 3 found DEAD in bed by girlfriend.What happened?

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 CodeineDay 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/LThis 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% Finland10% Greek30% East Africa

Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother.Gideon Koren et al. Lancet 2006; 368: 704.

Healthy male infant born April ’05, lethargy day 7, poor feeding day 11 and dead on day 13.PM no anatomical abnormalities but serum morphine level 70 ng/ml. Usual in neonates breastfed by mother receiving codeine is < 2 ng/ml.Tylenol # 3 for episiotomy pain– 1 tab Q12 h, reduced after 2 days to ½ tab Q12 h.

Mother had c/o sedation, constipation– Breast milk morphine level 87 ng/ml (100 X

expected) Genotyped as ultra-rapid metabolizer

Dead 28 yr. Male Somali Tonsillectomy. What Happened??1. High risk for opioid-induced ventilatory

failure1. Obese

1. V/Q mismatching leads to hypoxemia2. Obstructive Sleep Apnea

1. Loss of upper airway patency – NO VENTILATION

3. Anxiety led to sleep deprivation even before coming to hospital and we made it worse by not providing a sleep conducive environment (most preventable significant risk factor for opioid induced death)

Dead 28 yr. Male Somali for Tonsillectomy. What Happened??

1. Genetically an ultra-rapid metabolizer(high level CytP450/2D6)

2. Drug interactions1. Major pathway, inactive metabolites,

CytP450/3A4, inhibited by diltiazem and cannabinoids

2. Usual minor pathway, CytP450/2D6, that converts codeine to morphine was induced by dilantin

3. Post-Mortem – Death from morphine

Case Problem: 32 year old patient having tonsillectomy as out-patient

Fit and healthy aside from depression/anxiety. Has been on Paxilfor 3 months.Uneventful procedure under GA.Some local infiltration into wound at end of case.Sent home with script for T # 3 In E/R at 03:00 hr with severe pain, and says T # 3 were doing nothing.

32 year old patient having tonsillectomy as out-patient. Inadequate analgesia. What Happened??

Patient was taking 3 T#3 every 4 hours and she said she might as well have been taking just extra-strength tylenol– Well she was right!Genetically low level CytP450/2D6– Usual the minor active pathway is 10%– This patient was 3% and even that was

being inhibited by Paxil, a very potent 2D6 inhibitor

Instead of just Tylenol # 3 in our cases?Celecoxib 400 mg PO 2 hours before surgery, followed by 200 mg Q12H for 5 days, then 100 mg Q12H as long as needed

Pregabalin 75 – 150 mg PO 2 hours pre-op followed by 50 mg Q8H for 5 days (new concept, in process of being defined)

Tramacet 1 – 2 tabs PO Q4H prn

Morphine 10 – 20 mg PO Q4H prnor

Dilaudid 2 – 4 mg PO Q4H prn

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

Towards a better analgesic for acute pain

High level of efficacyA good drug would have an inherent multi-modal mechanism of actionVery low risk of serious side-effectsLow incidence of bothersome side-effectsVery limited abuse potentialAffordability

TRAMADOL

Is Tramadol New?Just recently available in Canada, as TramacetSynthesized in 1962, available in Germany since 1977, UK 94, US 95 where IV formulation is also availableMinimal risk of respiratory depression and abuse potential, never been a “scheduled”drugNow #1 prescribed centrally acting analgesic worldwide > 50 million patients

Indicated in Canada and US for the short term (5 days or less) management of acute pain – 5 day limit will be lifted soon.

> 25 years experiencefor either tramadol oracetaminophen

Tramacet Global ExperienceApproved in 30 nations, including some countries

in Europe, Asia, and Latin Americafor moderate to severe pain

• > 400 million patient days

• WHO & FDA: Tramadol unscheduled

What about Tramacet?Combination drug, 325 mg of acetaminophen + 37.5 mg of tramadolOrdered like T#3– 1 to 2 tabs Q4H prn (3 tabs in pt.> 90 kg)

Analgesic efficacy similar to what we expect from normal response to T # 3 Efficacy limited by max dose for acetaminophen.Opioids can be added as required!

Tramacet - How does it work?

Inherent multimodal action – 4 distinct mechanisms

1. acetaminophen2. Weak mu agonist – very weak opioid3. Augments endogenous inhibitory nociceptive

modulation via serotonin 4. and norepinephrine pathways

How Tramadol Works

Tramadol binds to µ opioid receptors –

Receptor affinity relative to morphine is only 1: 600

weak µ agonist

Weak Serotonin/Norepin-ephrine re-uptake inhibition (SNRI) activity

How Tramadol Works

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.

Smith AB, et al. Am J Surg 2004;187:521. Copyright with permission.

Tramacet in Postsurgical Pain: Adverse Events

5 (5.1)11 (10.1)4 (4.1)Constipation

1 (1.0)4 (3.7)5 (5.1)Somnolence

8 (8.1)8 (7.3)8 (8.2)Headache

9 (9.1)16 (14.7)9 (9.2)Vomiting

3 (3.0)9 (8.3)10 (10.2)Dizziness

16 (16.2)26 (23.9)21 (21.4)Nausea

Placebon = 99 (%)

Codeine/Acetan = 109 (%)

PrTramacetn = 98 (%)

Adverse Event

Tramadol: No Respiratory Depression

Tarkkila P et al, J Clin Anesthesia 1997;9:582

Res

pira

tory

rate

(bre

aths

/min

)

Time (min)

• Tramadol♦Placebo

■ Oxycodone

Impairment of gut motility is considerably less with Tramadol than with Codeine and other opioids.

Good data to supportClinical implications?– Faster recovery– Increased patient comfort– Shortened hospital stay

Tramadol: Rate of Abuse/Dependence

Case

s per

100,0

00 In

divid

uals

Expo

sed

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q 1Q 2Q 3Q 4Q

Spontaneous ReportsAll Reports

1995 1996 1997 1998 1999 2000 2001

Cicero TJ, et al. Pharmacoepidemiol Drug Saf 2005;14:851. Copyright with permission.

Tramacet PrecautionsLiver 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 pro-

convulsant 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

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 acetaminophen50% of acetaminophen cases inadvertent

Tramacet PrecautionsSerotonergic 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 evidenceMorphine 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?

Conclusion

Think! Foundation of COX-inhibitor before opioid– Acetaminophen– NSAID– Celecoxib

COX-2 blockers do not increase bleeding risk

Conclusions

Inadequate analgesia despite cyclo-oxygenase inhibitors and opioids?– Think “Hyperalgesia”– Consider an anti-hyperalgesic like

pregabalinCodeine is a prodrug– Extreme variability in extent of conversion

to morphine

ConclusionTramacet has similar efficacy to acetaminophen/codeine, but not as subject to patient to patient response variability and has an extensive safety record worldwideMain advantages are significantly less constipation, much less risk of respiratory depression and very low abuse riskCaution with regard to risk of serotonergicsydrome in patients taking MAO inhibitors, SSRIs, meperidine.Drug cost may be a concern for some patients.

References

Stefan Grond and Armin Sablotzki. Clinical Pharmacology of Tramadol. ClinPharmacokinet 2004; 43 (13) pp. 880 – 923.E.A. Shipton. Tramadol – Present and Future. Anesth Intensive Care 2000; 28: 363 – 374.A.B. Smith et al. Combination tramadol plus acetaminophen for postsurgical pain. The American Journal of Surgery. 2004; V187: pp 521 – 527.

References

Leese PT et al. Effects of Celecoxib, a Novel cyclooxygenase-2 inhibitor, on Platelet Function in Healthy Adults: A Randomized Controlled Trial. Journal of Clinical Pharmacology. Vol 40, No. 2, Feb. 2000, pp. 124 – 132.

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.