Transcript DHEC, Bureau of Drug Control

A Comprehensive Review
of Treating Acute Pain
Kelly W. Jones, Pharm.D., BCPS
Florence, South Carolina
[email protected]
0
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.
1
2
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
 Safety
 Tolerability
 Efficacy
 Price
 Simplicity
4
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
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
6
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
7
Pain Ladder
8
Nonpharmacologic Approaches
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
10
Nonpharmacologic Approaches
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
13
Acetaminophen
FDA 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
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%)
Am J Gastroent 2007;102:2459-63
15
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
16
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
17
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
20
Nonpharmacologic Approaches
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, 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
NSAID + Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
25
Nonpharmacologic Approaches
Pain Ladder
Tylenol #3 or Tramadol for Chronic pain
NSAID + Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
26
Nonpharmacologic Approaches
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).
30
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
NSAID + Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
35
Nonpharmacologic Approaches
Pain Ladder
What’s in the basement?
Tylenol #3 or Tramadol
NSAID + Acetaminophen
Darvocet®
NSAIDs
Acetaminophen or nonacetylated salicylates
36
Nonpharmacologic Approaches
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
NSAID + Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
39
Nonpharmacologic Approaches
Pain Ladder
Hydrocodone combo
Tylenol #3 + NSAID
Tylenol #3 or Tramadol
NSAID + Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
40
Nonpharmacologic Approaches
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
NSAID + Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
43
Nonpharmacologic Approaches
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
Morphine
Pain Ladder
Oxycodone or
Oxymorphone
Hydrocodone or combo
Tylenol #3 + NSAID
Tylenol #3 or Tramadol
NSAID + Acetaminophen
NSAIDs
Acetaminophen or nonacetylated salicylates
47
Nonpharmacologic Approaches
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
Hydromorphone
Ladder Extension
50
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
51
Pain Ladder
Fentanyl
Hydromorphone
Ladder Extension
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.
54
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]
56