KEY CONCEPTS IN ACUTE PAIN MANAGEMENT - 1 SURGERY RESIDENTS Dec. 18, 2007

1. KEY CONCEPTS IN ACUTE PAIN MANAGEMENT - 1SURGERY RESIDENTS Dec. 18, 2007 John Penning MD FRCPC Director Acute Pain Service

2. 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?

3. 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

4. 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

5. Benefits of Optimal Acute Post-Operative 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

6. 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

7. 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”

8. What is the “Best Way” to manage acute post-operative pain? • FIRST, DO NO HARM Therefore, the “best way” is a BALANCE Effective Analgesic Modalities Patient Safety

9. 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!!

10. Pain Pathways

11. 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

12. Tissue Trauma Cell Membrane Phospholipids Phospholipase Arachidonic Acid COX Cyclo-oxygenase Endoperoxides Toxic Oxygen Radicals Thromboxane Prostacyclin Prostaglandins

13. Analgesia with Opioids alone • The harder we “push” with single mode analgesia, the greater the degree of side-effects Side-effects Analgesia

14. 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.” Side-effects Analgesia

15. 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.

16. Case Problem: Severe Respiratory Depression after Toradol? • 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 isalleviated by any means

17. The problem with the “Little Pain – LittleGun”, “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

18. The rationale for COX-Inhibitors in acute pain management • The problem with the “Little Pain – Little Gun, Big Pain – Big Gun Approach” • 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.

19. NSAID 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 %

20. Mortality From NSAID-Induced GI Complications vs Other Diseases in US Wolfe MM: NEJM 1999; 340: 1888-99

21. 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”

22. Cyclo-oxygenase inhibitors Acetaminophen Naproxen Celecoxib Ketorolac Rofecoxib

23. Cell Membrane Phospholipids Phospholipase Arachidonic Acid COX-2 COX-1 Prostaglandins Prostaglandins Acute Pain Gastric Protection Inflammation Platelet Hemostasis Fever

24. Why a COX-2 inhibitor? • Equivalent analgesic efficacy with non-selective COX-inhibitors • No effects on platelets! • Better GI tolerability • Less dyspepsia, less N/V

25. Two hours before surgery associated with post-op pain • Celecoxib 400 mg PO If severe allergy to sulfa? • Naproxen 500 mg PO Contra-indications to NSAID Acetaminophen 1000 mg PO

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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 mgmeperidine 200 mg Hydromorphone 4 mgcodeine 200 mg oxycodone 10 mg

33. True or False? • One opioid is just like any other, in terms of analgesic efficacy and side-effects.

34. Opioids – Are they all the same? • Morphine • Hydromorphone (dilaudid) • Fentanyl • Oxycodone (parenteral n/a) • Meperidine (demerol)

35. 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

37. Meperidine Morphine Atropine Fentanyl Bupivacaine

38. 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.

39. True or False? • Meperidine should be eliminated from the hospital formulary?

40. Meperidine Pharmacology • Opioid agonist – Mu and some kappa • NMDA antagonist (weak) • Local anesthetic action – equipotent to lidocaine • SSRI (weak) • Muscaric blockade – “atropine-like” • Central anti-cholinergic effects often causes confusion in the elderly

41. 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

42. 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?

43. When to use Meperidine? • As a third line opioid when other choices have failed • Especially if patient has Hx of such • 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

44. Who still uses Tylenol # 3 ? • WHY ??

45. Opioid Myths that still prevail! • Codeine is a “weak” opioid? • Codeine is inherently safer than the more potent opioids?

47. CODEINE – A drug whose time has come and gone? N Engl J Med 351; 27 Dec. 30, 2004

48. 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

49. 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

50. 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