A Comprehensive Review of Treating Acute Pain

Kelly W. Jones, Pharm.D., BCPS Florence, South Carolina [email protected]

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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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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 3

The STEPS Approach

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Safety

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Tolerability

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Efficacy

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Price

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Simplicity

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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 5

Efficacy - Acute Pain

 Outcome: # with at least 50% pain relief Analgesic NNT Acetaminophen 4 Aspirin Ibuprofen Diclofenac 2.0

2.4

2.3

CI 2.3-9.5

1.8-2.2

2.0-4.2

2.0-2.7

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Efficacy - Acute Pain

Analgesic Tylenol #3 Percocet Codeine Morphine IM Tramadol NNT 2.2

2.2

16.7

2.9

4.8

CI 1.7-2.9

1.7-3.2

11-48 2.6-3.6

3.8-6.1

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Pain Ladder

Nonpharmacologic Approaches 8

Nonpharmacologic Approach

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

Pain Ladder

Acetaminophen or nonacetylated salicylates Nonpharmacologic Approaches 10

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 11

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 12

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

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Acetaminophen

FDA advisory committee: options to reduce risk of liver damage

  Limit dose formulations for over-the-counter liquid preparations  Restrict to a single mid-strength concentration  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) Eliminate OTC (and possibly prescription) combination acetaminophen products  Vote was 20 to 17 in favor to pull acetaminophen out in combination with narcotics 14

FDA Advisory Committee public hearing 6/30/09

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%) 15 Am J Gastroent 2007;102:2459-63

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

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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 warning.” • the new studies justify removal of the alcohol 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?

17 Hepatology 1995;22:767-73; Al Pharm & Ther 2007;26:283-90 Federal Register 2009;74(81):19385-19409

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 18

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 19

Pain Ladder

NSAIDs Acetaminophen or nonacetylated salicylates Nonpharmacologic Approaches 20

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..?) 21

NSAID-Induced Ulcers

Risk 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

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non-acetylated salicylates 22

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) 23

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 24

Pain Ladder

NSAIDs NSAID + Acetaminophen Acetaminophen or nonacetylated salicylates Nonpharmacologic Approaches 25

Pain Ladder

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

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®) 27

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 28

Pharmacokinetics

 Time to reach Cmax  PO, SL, PR  IM  SQ, IV 60 to 90 min 30 min 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 29

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).

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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 31

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 32

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®) 33

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) 34

Pain Ladder

What’s in the basement?

Tylenol #3 or Tramadol NSAIDs NSAID + Acetaminophen Acetaminophen or nonacetylated salicylates Nonpharmacologic Approaches 35

Pain Ladder

NSAIDs What’s in the basement?

Tylenol #3 or Tramadol NSAID + Acetaminophen Darvocet® Acetaminophen or nonacetylated salicylates Nonpharmacologic Approaches 36

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 37

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 38

Pain Ladder

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

Pain Ladder

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

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 41

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) 42

Pain Ladder

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

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 44

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 45

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 46

Pain Ladder

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

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 48

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 49

Pain Ladder

Ladder Extension Hydromorphone 50

Hydromorphone products

 Dilaudid tablets  1 mg, 2 mg, 3 mg, 4 mg, 8 mg  Extended release formulation  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 Exalgo® 51

Pain Ladder

Ladder Extension Fentanyl Hydromorphone 52

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 53

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.

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New Fentanyl Product

 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 55

[email protected]

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