0 a comprehensive review of treating acute pain kelly w. jones, pharm.d., bcps florence, south...
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A Comprehensive Review of Treating Acute Pain
Kelly W. Jones, Pharm.D., BCPS
Florence, South Carolina
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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 chronicNociceptive 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
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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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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Acetaminophen
AnalgesicNo more than 4 grams per dayExtra strength = 500 mg5 grains = 325 mgCaution in alcoholics and those with
liver disease - 2 grams/day limitCaution with warfarinDrug of choice for OA
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Acetaminophen toxicity
Poison of choice in teenagers They don’t consider it dangerous
Use nomogram to determine toxicityMeasure serum level of acetaminophen
after 4 hours of ingestionAntedote: 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 – AcetaminophenOTC Analgesics – AcetaminophenFinal ruling – label changes to reflect new safety Final ruling – label changes to reflect new safety information 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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AcetaminophenAcetaminophenFDA advisory committee: options to reduce risk of FDA advisory committee: options to reduce risk of liver damage 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
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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 2007;102:2459-63
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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 2005http://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 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;26:283-90Federal Register 2009;74(81):19385-19409
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Non-acetylated Salicylates
Does not interfere with platelet aggregationRarely associated with GI bleedingDoes not affect renal functionSafe 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 Doan’s Pills - OTC
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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 LFT’s in patients taking
diclofenac (hepatitis - 1 to 5/100,000, hum..?)
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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
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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 nineDiclofenac (Zipsor®)
Liquid-filled capsule formulation for mild to moderate pain
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Pain Ladder
Nonpharmacologic Approaches
Acetaminophen or nonacetylated salicylates
NSAIDs
NSAID + Acetaminophen
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Pain Ladder
Nonpharmacologic Approaches
Acetaminophen or nonacetylated salicylates
NSAIDs
NSAID + Acetaminophen
Tylenol #3 or Tramadol for Chronic pain
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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 useThe 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 theseAdjust 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 analgesicDrug interactions with SSRI’s and TCA’s
Seizure risk?Cross-sensitive allergy with codeine is
possibleRegular 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 > 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
Nonpharmacologic Approaches
Acetaminophen or nonacetylated salicylates
NSAIDs
NSAID + Acetaminophen
Tylenol #3 or Tramadol
What’s in the basement?
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Pain Ladder
Nonpharmacologic Approaches
Acetaminophen or nonacetylated salicylates
NSAIDs
NSAID + Acetaminophen
Tylenol #3 or Tramadol
What’s in the basement?
Darvocet®
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Darvocet Research ObservationsListed 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
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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
Nonpharmacologic Approaches
Acetaminophen or nonacetylated salicylates
NSAIDs
NSAID + Acetaminophen
Tylenol #3 or Tramadol
Tylenol #3 + NSAID
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Pain Ladder
Nonpharmacologic Approaches
Acetaminophen or nonacetylated salicylates
NSAIDs
NSAID + Acetaminophen
Tylenol #3 or Tramadol
Tylenol #3 + NSAID
Hydrocodone combo
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Hydrocodone
Derivative of codeineMany different products:Lorcet 10mg/650 mg (acetaminophen)Lorcet HD & Vicodin 5 mg/500 mgLorcet Plus 7.5 mg/650 mgLortab 2.5 mg/500mg, 5 mg/500 mg, 7.5 mg/500 mg, 10 mg/500 mgLortab 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
Nonpharmacologic Approaches
Acetaminophen or nonacetylated salicylates
NSAIDs
NSAID + Acetaminophen
Tylenol #3 or Tramadol
Tylenol #3 + NSAID
Hydrocodone or combo
Oxycodone or Oxymorphone
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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 RoxicodoneTablets - 5 mg, 15 mg, 30 mgCapsules - 5 mgOral solution - 5 mg/5 mlConcentrate - 20 mg/ml
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New CII for Pain Oxymorphone
Semi-synthetic metabolite of oxycodoneLong-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
Nonpharmacologic Approaches
Acetaminophen or nonacetylated salicylates
NSAIDs
NSAID + Acetaminophen
Tylenol #3 or Tramadol
Tylenol #3 + NSAID
Hydrocodone or combo
Oxycodone or Oxymorphone
Morphine
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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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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
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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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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 hoursPatch last 48 to 72 hoursWatch 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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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