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A Comprehensive Review of Treating Acute Pain

A Comprehensive Review of Treating Acute Pain. Kelly W. Jones, Pharm.D., BCPS Florence, South Carolina kjones@mcleodhealth.org. Disclaimer . I have no conflict of interest relating to the material covered in our discussion today. I do not serve on any speaker bureau.

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A Comprehensive Review of Treating Acute Pain

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

  2. 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.

  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

  4. The STEPS Approach • Safety • Tolerability • Efficacy • Price • Simplicity

  5. The STEPS approach • S Safety • respiratory depression • T Tolerability • itching, constipation, addiction, etc • E Efficacy • efficacy? • P Price • depends on delivery system • S Simplicity • depends on patient and condition

  6. Efficacy - Acute Pain • Outcome: # with at least 50% pain relief

  7. Efficacy - Acute Pain

  8. Pain Ladder Nonpharmacologic Approaches

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

  10. Pain Ladder Acetaminophen or nonacetylated salicylates Nonpharmacologic Approaches

  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

  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

  13. OTC Analgesics – AcetaminophenFinal ruling – label changes to reflect new safety information FDA 4/29/09 • 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.

  14. AcetaminophenFDA 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

  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

  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

  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

  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

  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

  20. Pain Ladder NSAIDs Acetaminophen or nonacetylated salicylates Nonpharmacologic Approaches

  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..?)

  22. NSAID-Induced UlcersRisk Reduction through Choice of Agent • 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

  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)

  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

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

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

  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®)

  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

  29. Pharmacokinetics • Time to reach Cmax • PO, SL, PR 60 to 90 min • IM 30 min • SQ, IV 10 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

  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).

  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

  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

  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®)

  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)

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

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

  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

  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

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

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

  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

  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)

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

  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

  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

  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

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

  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

  49. New CII for Pain • 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

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