1. 0 A Comprehensive Review of Treating Acute Pain Kelly W. Jones, Pharm.D., BCPS Florence, South Carolina kjones@mcleodhealth.org

2. 1 Disclaimer I have no conflict of interest relating to the material covered in our discussion today. I do not serve on any speaker bureau. I do not have any grants concerning the area of discussion.

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4. 3 2 types of pain Acute and chronic Nociceptive and neuropathic  Nociceptive is sharp, throbbing, aching It is easy to describe, localize Hard to describe if visceral  Neuropathic is described as burning, tingling, shooting, stabbing, electrical Both may need opioids and adjuvants

5. 4 The STEPS Approach  Safety  Tolerability  Efficacy  Price  Simplicity

6. 5 The STEPS approach SSafety respiratory depression TTolerability itching, constipation, addiction, etc EEfficacy efficacy? PPrice depends on delivery system SSimplicity depends on patient and condition

7. 6 Efficacy - Acute Pain Outcome: # with at least 50% pain relief AnalgesicNNTCI Acetaminophen42.3-9.5 Aspirin2.01.8-2.2 Ibuprofen2.42.0-4.2 Diclofenac2.32.0-2.7

8. 7 Efficacy - Acute Pain AnalgesicNNTCI Tylenol #32.21.7-2.9 Percocet2.21.7-3.2 Codeine16.711-48 Morphine IM2.92.6-3.6 Tramadol4.83.8-6.1

9. 8 Pain Ladder Nonpharmacologic Approaches

10. 9 Nonpharmacologic Approach Comprehensive therapy with many approaches  Spiritual advise  Rest  Exercise  Biofeedback or Psychotherapy  Heat/cool packs  Hot baths  Complementary medicine

11. 10 Pain Ladder Nonpharmacologic Approaches Acetaminophen or nonacetylated salicylates

12. 11 Acetaminophen Analgesic No more than 4 grams per day Extra strength = 500 mg 5 grains = 325 mg Caution in alcoholics and those with liver disease - 2 grams/day limit Caution with warfarin Drug of choice for OA

13. 12 Acetaminophen toxicity Poison of choice in teenagers  They don’t consider it dangerous Use nomogram to determine toxicity Measure serum level of acetaminophen after 4 hours of ingestion Antedote: acetylcysteine 140 mg/kg x 1, then 70 mg/kg for 17 more doses Acetadote® (acetylcysteine)  Injectable form for acetaminophen overdose

14. 13 OTC Analgesics – Acetaminophen Final ruling – label changes to reflect new safety information Ingredient “acetaminophen” prominently identified on product’s container and carton Labels contain new warnings that highlight the potential for liver toxicity and warn against  Using more than the recommended dose of acetaminophen;  Using more than one product (over-the-counter or prescription) containing with acetaminophen  Taking acetaminophen with moderate amounts of alcohol. FDA 4/29/09

15. 14 Acetaminophen FDA advisory committee: options to reduce risk of liver damage Reduce the current dose recommendations for maximum adult daily dose and single adult dose  Limit single adult dose to maximum of 650 mg  Lower max daily dose from 4000mg to 3250 mg  Clarify dosing for alcohol users (> 3 drinks/day) Limit dose formulations for over-the-counter liquid preparations  Restrict to a single mid-strength concentration Eliminate OTC (and possibly prescription) combination acetaminophen products Vote was 20 to 17 in favor to pull acetaminophen out in combination with narcotics FDA Advisory Committee public hearing 6/30/09

16. 15 The Best the FDA has… Only one study does the argument any justice.  Study in Atlanta from 2000 to 2004 94 patients admitted to hospital in 5 yrs with acute liver failure 29 adults with liver failure from acetaminophen 15 were unintentional, 14 intentional overdoses Study defines incidence 5 cases/million/year in Atlanta Extrapolation - 350 unintentional cases/300,000,000/year in USA (0.000001 or 0.0001%) Am J Gastroent 2007;102:2459-63

17. 16 Do we live in a no risk world? 2005 data  Odds of dying from any injury - 1 in 2,517  Odds of dying from a fall - 1 in 15,085  Odds of dying from an auto injury - 1 in 20,331  Odds of dying from complications from medical and surgical care - 1 in 111,763  Odds of dying from a firearm - 1 in 375,801  Odds of having unintentional liver injury from acetaminophen - 1 in 850,000 (NOT “odds of dying”)  Odds of dying from fireworks - 1 in 57,588,244 National Safety Council. The odds of dying in 2005 http://www.nsc.org/research/odds.aspx

18. 17 More beliefs! Acetaminophen in alcoholics  6 trials  All trials done with 4 gm There are no 2 gram studies!  There were NO changes in liver function as compared to placebo on days 4 and 11 as compared to day 0.  No changes in LFT’s in 3 or 5 day study  “We do not believe the new studies justify removal of the alcohol warning.” Claim small numbers, people use longer than 10 days  Because these new studies do not adequately demonstrate that alcohol use is NOT a risk factor….we believe an alcohol warning continues to be necessary.” Was the study designed to answer this question? Hepatology 1995;22:767-73; Al Pharm & Ther 2007;26:283-90 Federal Register 2009;74(81):19385-19409

19. 18 Non-acetylated Salicylates Does not interfere with platelet aggregation Rarely associated with GI bleeding Does not affect renal function Safe in aspirin allergic patients “Weak” antiinflammatory agents:  No RCTs demonstrating efficacy in chronic pain  Onset of action slower than NSAIDs

20. 19 Non-acetylated Salicylates Products Diflunisal (Dolobid®)  500 mg - dose is 2 tabs loading dose, then 1 tab twice daily  Generic price - $1.00 per tablet Choline magnesium trisalicylate (Trilisate®)  500 mg, 750 mg, 1000 mg tabs  Typical dose is 1500 mg BID Salsalate (Disalcid®)  500 mg, 750 mg tabs Magnesium Salicylate  Doan’s Pills - OTC

21. 20 Pain Ladder Nonpharmacologic Approaches Acetaminophen or nonacetylated salicylates NSAIDs

22. 21 NSAIDs Allergy to aspirin = allergy to NSAIDs If one NSAID does not work, does not mean others will not work. Analgesic effects are single dose Anti-inflammatory effects occur between days 7 and 14 Long-acting vs short-acting NSAIDs What happened to the COX-2 inhibitors? Consider monitoring LFT’s in patients taking diclofenac (hepatitis - 1 to 5/100,000, hum..?)

23. 22 High: aspirin, indomethacin, ketorolac, meclofenamate, piroxicam, tolmetin Medium:diclofenac, fenoprofen, flurbiprofen, ketoprofen, ibuprofen, naproxen, oxaprozin, sulindac, mefanamic acid Low: etodolac, nabumetone Lowest: celecoxib, non-acetylated salicylates NSAID-Induced Ulcers Risk Reduction through Choice of Agent

24. 23 New NSAIDs Diclofenac epolamine 1.3% (Flector® Patch)  NSAID patch for acute pain from strains, sprains, contusions  Dose is one patch twice a day  Do not apply to damaged skin  Do NOT wear while bathing or showering  Wash hands after application  Come in a box of 2 envelopes, each envelope has 5 patches  $156/#30 patches Ibuprofen injection (Caldolor®)  Acute pain - 400 mg to 800 mg IV infusion over 30 min every 6h prn  Fever - 400 mg every 4 to 6 hrs prn (can use lower doses)

25. 24 New NSAIDs Diclofenac Potassium for Oral Solution (Cambia®)  Oral solution for acute migraine, get level within 5 min,max in 15 min  50 mg dose, mix powder in 1-2 oz of water  Buy in a co-joined dose pack of three or a box of nine Diclofenac (Zipsor®)  Liquid-filled capsule formulation for mild to moderate pain

26. 25 Pain Ladder Nonpharmacologic Approaches Acetaminophen or nonacetylated salicylates NSAIDs NSAID + Acetaminophen

27. 26 Pain Ladder Nonpharmacologic Approaches Acetaminophen or nonacetylated salicylates NSAIDs NSAID + Acetaminophen Tylenol #3 or Tramadol for Chronic pain

28. 27 The Opiates Narcotic agonist  Natural (opiates) - morphine, codeine  Semisynthetic (opioids) - hydromorphone, oxycodone  Synthetic (opioids) - fentanyl, methadone Narcotic agonist/antagonist  Nalbuphine, butorphanol Narcotic antagonist  Naloxone (Narcan®)

29. 28 Opioid Allergy? True allergic and anaphylactic reactions are rare  Single case reports with meperidine, morphine and fentanyl  Most cases reported use of other medications likely to cause allergy  None documented cross-sensitivity with other opioids Urtiacaria, pruritis, sneezing, and exacerbations of asthma are common  Opioids cause a histamine release… this is NOT an allergic reaction, only allergy-like symptoms!  Does this mean the patient is “cross-sensitive” to other opioids? Naturally occurring and semi-synthetic are more potent histamine releasers than synthetic Risk of cross-sensitivity is extremely low if at all

30. 29 Pharmacokinetics Time to reach Cmax  PO, SL, PR60 to 90 min  IM30 min  SQ, IV10 to 15 min Duration of effect is somewhere around 3 to 5 hours for PO/PR PO is generally weaker than IV/IM due to first-pass effect, ~3 to 5 times weaker

31. 30 Immediate release dosing Dose every 4 hours  PRN is OK for acute pain Can adjust dose daily for chronic use The exception is methadone, which is immediate release with a long half-life (more later).

32. 31 Sustained-release dosing Especially important for chronic pain management Dosed every 8h, 12h, 24h, depending on the product and formulation. Don’t crush or chew these Adjust dose every 2 to 4 days

33. 32 Tylenol #3 Codeine 30 mg + acetaminophen Chronic codeine causes lots of side effects:  Constipation  Urinary retention Tylenol #2 contains 15 mg of codeine Tylenol #4 contains 60 mg of codeine Empirin with Codeine® (codeine and aspirin)  325mg/30mg; 325mg/60mg

34. 33 Tramadol Binary analgesic Drug interactions with SSRI’s and TCA’s  Seizure risk? Cross-sensitive allergy with codeine is possible Regular release and extended release products (100 mg, 200 mg, 300 mg) Combination with acetaminophen (Ultracet®)

35. 34 New Binary Analgesic Tapentadol (Nucynta®)  Strong narcotic (C-II) + NE reuptake inhibitor Watch with look-alike Nuvigil® (armodafinil)  Analgesic for acute moderate to severe pain  Approved for those > 18 years of age  50 mg, 75 mg, 100 mg tabs every 4-6 hrs prn Dose the second dose as soon an hour after first dose if not relief  Tapentadol is metabolized, but there are no known interactions  No effect on QT elongation or other EKG parameters, even in combination with moxifloxacin (pkg insert)

36. 35 Pain Ladder Nonpharmacologic Approaches Acetaminophen or nonacetylated salicylates NSAIDs NSAID + Acetaminophen Tylenol #3 or Tramadol What’s in the basement?

37. 36 Pain Ladder Nonpharmacologic Approaches Acetaminophen or nonacetylated salicylates NSAIDs NSAID + Acetaminophen Tylenol #3 or Tramadol What’s in the basement? Darvocet®

38. 37 Darvocet Research Observations Listed on the “Beer’s” list  Why? Increase side effects from the metabolite norpropoxyphene  long half-life (36 hrs) and the risk of accumulation Studies show no enhanced analgesic effects from the addition of propoxyphene to acetaminophen

39. 38 Propoxyphene Products Darvocet-N 50® (generic available)  50 mg propoxyphene + 325 mg acetaminophen Darvocet-N 100® (generic available)  100 mg propoxyphene + 325 mg acetaminophen Wygesic® Tablets (generic available)  65 mg propoxyphene + 650 mg acetaminophen New Product  Darvocet A500®  100 mg propoxyphene + 500 mg acetaminophen

40. 39 Pain Ladder Nonpharmacologic Approaches Acetaminophen or nonacetylated salicylates NSAIDs NSAID + Acetaminophen Tylenol #3 or Tramadol Tylenol #3 + NSAID

41. 40 Pain Ladder Nonpharmacologic Approaches Acetaminophen or nonacetylated salicylates NSAIDs NSAID + Acetaminophen Tylenol #3 or Tramadol Tylenol #3 + NSAID Hydrocodone combo

42. 41 Hydrocodone Derivative of codeine Many different products: Lorcet 10mg/650 mg (acetaminophen) Lorcet HD & Vicodin 5 mg/500 mg Lorcet Plus 7.5 mg/650 mg Lortab 2.5 mg/500mg, 5 mg/500 mg, 7.5 mg/500 mg, 10 mg/500 mg Lortab Elixir 2.5 mg/167 mg per 5 ml

43. 42 Hydrocodone Vicodin 5 mg/500 mg Vicodin ES 7.5 mg/750 mg Vicodin HP 10 mg/660 mg Vicoprofen 7.5 mg/200 mg Zydone 5 mg/400 mg, 7.5 mg/400 mg Norco 10 mg/325 mg Anexsia 5 mg/325, 5/500, 7.5/325, 7.5/650 Maxidone 10 mg/750 mg (max of 5 tabs a day)

44. 43 Pain Ladder Nonpharmacologic Approaches Acetaminophen or nonacetylated salicylates NSAIDs NSAID + Acetaminophen Tylenol #3 or Tramadol Tylenol #3 + NSAID Hydrocodone or combo Oxycodone or Oxymorphone

45. 44 Oxycodone Percodan® contains aspirin Percocet® contain acetaminophen Combunox®  (oxycodone 5 mg + ibuprofen 400 mg) Lots of new Percocet® products:  2.5 mg/325 mg  7.5 mg/325 mg, 7.5 mg/500 mg  10 mg/325 mg, 10 mg/650 mg Tylox® 5mg/500 mg Oxycontin®: 10 mg, 20 mg, 40 mg, 80 mg, 160 mg

46. 45 Immediate-release oxycodone Oxycodone or Roxicodone Tablets - 5 mg, 15 mg, 30 mg Capsules - 5 mg Oral solution - 5 mg/5 ml Concentrate - 20 mg/ml

47. 46 New CII for Pain Oxymorphone Semi-synthetic metabolite of oxycodone Long-acting formulations not for opioid-niave patients; standard dose determined from previous opioid dose  Opana® - oxymorphone - 5 mg ($2.40 per tab), 10 mg ($4.30 per tab) Dose 10 to 20 mg every 4-6 hours prn  Opana ER® - oxymorphone - 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg ($11 per tab), given every 12 hours  10 mg oxymorphone = 20 mg hydrocodone, 20 mg oxycodone, 20 mg methadone, 30 mg oral morphine

48. 47 Pain Ladder Nonpharmacologic Approaches Acetaminophen or nonacetylated salicylates NSAIDs NSAID + Acetaminophen Tylenol #3 or Tramadol Tylenol #3 + NSAID Hydrocodone or combo Oxycodone or Oxymorphone Morphine

49. 48 Morphine products Sustain-release  MS-Contin® 15 mg, 30 mg, 60 mg, 100 mg, 200 mg  Avinza® once daily 30 mg, 60 mg, 90 mg, 120 mg  Kadian® once daily 10 mg, 20 mg, 30 mg, 50 mg, 60 mg, 80 mg, 100 mg, 200 mg capsule  DepoDur® (morphine extended release, epidural) Immediate-release  Tablets  Oral solution 10 mg/5 ml, 20 mg/5ml, 20mg/ml  Supp: 5 mg, 10 mg, 20 mg, 30 mg

50. 49 Morphine/naltrexone (Embeda®)  24 hour analgesic for moderate to severe pain Can give daily or twice daily  Extended-release capsule, not “prn” medication  20mg/0.8mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, 80 mg/3.2 mg, 100 mg/4 mg New CII for Pain

51. 50 Pain Ladder Hydromorphone Ladder Extension

52. 51 Hydromorphone products Dilaudid tablets  1 mg, 2 mg, 3 mg, 4 mg, 8 mg Extended release formulation - Exalgo®  For chronic pain Liquid  5 mg/5 ml Injection  1 mg, 2 mg, 4 mg, 10 mg per ml Suppositories  3 mg Dilaudid cough syrup  1 mg/5 ml; + 100 mg guaifenesin

53. 52 Pain Ladder Hydromorphone Ladder Extension Fentanyl

54. 53 Fentanyl Products Injection  0.05 mg/ml Transmucosal (Fentanyl Oralet®, Actiq®)  Oralet®-100 mcg, 200 mcg, 300 mcg, 400 mcg  Actiq® - 200 mcg, 400 mcg, 600 mcg, 800 mcg, 1200 mcg, 1600 mcg Transdermal  Duragesic® -12 mcg, 25 mcg, 50 mcg, 75 mcg, 100 mcg

55. 54 Transdermal Fentanyl C max = 24 hours Patch last 48 to 72 hours Watch if used on skinny folks  need fat to absorb it predictably Do not use in opiate naive patients.  25 mcg patch is ~50 mg IR morphine per day Watch in patients with fever, use of heating pad, blankets, hot tubs, etc.

56. 55 Fentanyl (Onsolis®)  Buccal soluble film formulation for rescue cancer pain  200, 400, 600, 800, 1200 mcg  No more than 4 doses per day  Separate by at least 2 hours  Patient has to enroll into the FOCUS program  Get medication from a special pharmacy New Fentanyl Product

57. 56 kjones@mcleodhealth.org