KEY CONCEPTS IN ACUTE PAIN MANAGEMENT - 1 SURGERY RESIDENTS Dec. 15, 2009

1. KEY CONCEPTS IN ACUTE PAIN MANAGEMENT - 1SURGERY RESIDENTS Dec. 15, 2009 John Penning MD FRCPC Director Acute Pain Service

2. Objectives • 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

3. Consequences of poorly managed acute post-operative pain • 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?

4. 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

5. 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 from our analgesic therapies

6. 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

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

8. 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

9. KEY POINTS • 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 • Multi-modal Analgesia • Attain analgesic goals • Avoiding S/E

10. Goals of Multi-Modal Analgesia • Attain analgesic goals • VAS – 3 /10 at rest and 5/10 with activity • Pain is not limiting patient’s rest/activity • Patient satisfaction

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

13. Cyclo-oxygenase inhibitorsNSAIDs/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 %

14. The problem with the “Little Pain – LittleGun”, “Big Pain – Big Gun” Approach • 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.

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

16. 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 • 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.

17. 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 • 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

18. Foundational

19. Mortality From NSAID-Induced GI Complications vs Other Diseases in US Chronic opioid use related deaths Wolfe MM: NEJM 1999; 340: 1888-99

20. 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” But they can still get you in the long run

21. Cyclo-oxygenase inhibitors Acetaminophen Naproxen Celecoxib Ketorolac Rofecoxib

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

23. 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

24. 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

25. First on and Last Off • Celecoxib 200 mg Q12 H • Ibuprofen 400 mg Q4H • OTC 200 mg capsules • Naproxen 375 mg Q8H • OTC “Aleve” 220 mg capsules (box warning max of 3 per day) • 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

26. Contra-indications to Celecoxib/NSAIDs • Patients with the “ASA triad” • Chronic Nasal polyps who after ASA gets • Exacerbation of asthma • Angioedema of upper A/W • Not a true IG “E” type allergy • There may be a cross reactivity with cox-inhibitors • COPD or asthma alone not a contra-indication to NSAIDs or Coxibs

27. 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

28. Risk of renal failure with NSAIDs/Coxibs • 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 • Terrible triad for GFR • Hypovolemia, ACE/ARB and NSAIDs

29. Prostaglandins Vasodilation increased flow Angiotensin 2 Vasoconstriction Decreased flow

30. Contra-indications to Celecoxib/NSAIDs • Active peptic ulcer disease • Congestive heart failure • Definite risk of fluid/sodium retention • Risk of thrombosis??

32. Tissue healing issues with NSAIDs and Coxibs?? • Risk of non-union in bone surgery or non-fusion in spine surgery • COX-1 proven a problem in high doses • Coxibs no definitive data • 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

33. Foundational

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

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

36. Who still uses Tylenol # 3 ? Prescribe over the phone Only modest risk of diversion relative to straight potent opioids Avoid putting hydromorphone, morphine into community Break and enter risk with Oxys Codeine effective for diarrhea, cough

38. Codeine, Ultrarapid-Metabolism Genotype, and Postoperative DeathNEJM August 20, 2009 pp 827-828 • 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

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

41. 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

42. Genetic Variability And drug interactions 1% Finland 10% Greek 30% East Africa

44. 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

45. Inhibitors of CYP2D6 • SSRIs (potent) especially PAXIL • Cimetidine, Ranitidine • Desipramine • Propranolol • Quinidine (potent) • Viagra • Many anti-biotics and chemo

46. 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

48. 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

49. 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

50. Towards a better analgesic for acute pain • 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 side-effects • Very limited abuse potential • Affordability