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A Comprehensive Review of Treating Acute Pain

Kelly W. Jones, Pharm.D., BCPS

Florence, South Carolina

kjones@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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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

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

Nonpharmacologic Approaches

Acetaminophen or nonacetylated salicylates

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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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Pain Ladder

Nonpharmacologic Approaches

Acetaminophen or nonacetylated salicylates

NSAIDs

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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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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

Hydromorphone

Ladder Extension

Fentanyl

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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

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kjones@mcleodhealth.org