A Comprehensive Review of Treating Acute Pain

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A Comprehensive Review of Treating Acute Pain

• Kelly W. Jones, Pharm.D., BCPS
• Florence, South Carolina
• kjones_at_mcleodhealth.org

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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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(No Transcript)
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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

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The STEPS Approach

• Safety
• Tolerability
• Efficacy
• Price
• 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

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Efficacy - Acute Pain

• Outcome with at least 50 pain relief

Analgesic NNT CI
Acetaminophen 4 2.3-9.5
Aspirin 2.0 1.8-2.2
Ibuprofen 2.4 2.0-4.2
Diclofenac 2.3 2.0-2.7
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Efficacy - Acute Pain
Analgesic NNT CI
Tylenol 3 2.2 1.7-2.9
Percocet 2.2 1.7-3.2
Codeine 16.7 11-48
Morphine IM 2.9 2.6-3.6
Tramadol 4.8 3.8-6.1
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Pain Ladder
Nonpharmacologic Approaches
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Nonpharmacologic Approach

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

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Pain Ladder
Acetaminophen or nonacetylated salicylates
Nonpharmacologic Approaches
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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

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Acetaminophen toxicity

• Poison of choice in teenagers
• They dont 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

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OTC Analgesics AcetaminophenFinal ruling
label changes to reflect new safety information

• Ingredient acetaminophen prominently identified
  on products 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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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 (gt 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
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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 20071022459-63
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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 LFTs 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 199522767-73 Al Pharm Ther
200726283-90 Federal Register
200974(81)19385-19409
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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

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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
• Doans Pills - OTC

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Pain Ladder
NSAIDs
Acetaminophen or nonacetylated salicylates
Nonpharmacologic Approaches
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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 LFTs in patients taking
  diclofenac (hepatitis - 1 to 5/100,000, hum..?)

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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, non-acetylated salicylates

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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)

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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

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Pain Ladder
NSAID Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
Nonpharmacologic Approaches
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Pain Ladder
Tylenol 3 or Tramadol for Chronic pain
NSAID Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
Nonpharmacologic Approaches
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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)

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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

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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

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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.
• Dont crush or chew these
• Adjust dose every 2 to 4 days

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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

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Tramadol

• Binary analgesic
• Drug interactions with SSRIs and TCAs
• 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)

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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 gt 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)

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Pain Ladder
Whats in the basement?
Tylenol 3 or Tramadol
NSAID Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
Nonpharmacologic Approaches
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Pain Ladder
Whats in the basement?
Tylenol 3 or Tramadol
Darvocet
NSAID Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
Nonpharmacologic Approaches
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Darvocet Research Observations

• Listed on the Beers 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

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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

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Pain Ladder
Tylenol 3 NSAID
Tylenol 3 or Tramadol
NSAID Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
Nonpharmacologic Approaches
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Pain Ladder
Hydrocodone combo
Tylenol 3 NSAID
Tylenol 3 or Tramadol
NSAID Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
Nonpharmacologic Approaches
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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

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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)

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

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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

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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

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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
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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

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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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Pain Ladder
Hydromorphone
Ladder Extension
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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

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Pain Ladder
Fentanyl
Hydromorphone
Ladder Extension
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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

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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

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kjones_at_mcleodhealth.org