Evidenced Based Analgesic Efficacy
in Post-Surgical Dental Pain
Elliot V Hersh DMD, MS, PhD
Professor Oral Surgery and Pharmacology
University of Pennsylvania School of Dental Medicine
Chair –IRB#3, Office of Regulatory Affairs
University of Pennsylvania
A New Breed of Analgesic!
From PAIN to PASTA!!!
Blood, bone and guts!
Remove the bone and split the tooth!
Sew them up!
University of Pennsylvania Surgical Tray
Pioneers in oral surgery!
(Cyclooxygenase)
Peripheral Targets for Analgesia
Courtesy of Sharon Gordon DMD, PhD
Pain Syndrome
Total Pain Relief Index
Menstrual
17.5
Arthritic
18.8
Dental (general)
19.5
Post-Herpetic
22.6
Dental Impaction (Partial Bony) 23.2
Phantom Limb
25.0
Cancer
26.0
Back Pain
26.3
Dental Impaction (Full Bony)
32.4
Adapted From Melzack,: Pain 1976, 1:277-299
Barden J, Edwards JE, McQuay HJ, Moore RA. Pain 2004;107:86-90.
In response to placebo more than 60% of dental pain trials had less than 15%
of their patients achieving 50% maximum pain relief compare to only 40% of other
postsurgical pain models. In fact only 11% of dental pain trials had more than 30%
of their patients achieving more than 50% pain relief from placebo compared
to more than 30% of other postsurgical pain models.
Basic Principles Of Clinical Studies
Double-blind
Random allocation of treatment to subjects
Inclusion of placebo
Inclusion of standard treatments
Identical appearance of study medication
ACETAMINOPHEN 650 mg
(N=56)
PAIN RELIEF SCORES
2.5
2
ASPIRIN 650 mg
(N=32)
1.5
1
0.5
PLACEBO
(N=55)
PLACEBO
(N=32)
0
0
0.5
1
1.5
Cooper, Oral Surgery
Arch Intern Med 1981;141:282-285
2
HOURS
2.5
3
3.5
4
Tylenol's maximum dose reduced to help prevent overdoses
Jul 28, 2011 5:35 PM
The maximum daily dose for Tylenol will be lowered on all
acetaminophen-containing adult products from 4,000 mg
(8 Extra Strength Tylenol pills) to 3,000 mg (6 pills),
the manufacturer said today. The move is intended to reduce
the risk of accidental acetaminophen overdoses that can
lead to liver failure and death. Effective January 1, 2012.
In addition, in 4 months all opioid combination drugs (i.e. acetaminophen plus
hydrocodone or oxycodone will not be allowed to contain more than 325 mg
APAP per tablet!! VICODIN WON”T EXIST AS WE KNOW IT!!!
From Hersh EV, Moore PA.
JADA 2004;135:298-311.
Active
R=
NHCOCH3
HO
Glucuronidation
(95%)
RO
Acetaminophen
NHCOCH3
O
CYP2E1 (5%)
NHCOCH3
Glutathione
Conjugated metabolite
Inactive
N-Acetyl-benzoquinonemine
(NAPQI)
Hepatotoxic
PAIN RELIEF SCORES
3
ACETAMINOPHEN 600 mg + CODEINE 60 mg
2.5
ACETAMINOPHEN 600 mg
2
CODEINE 60 mg
1.5
1
PLACEBO
0.5
0
0
1
Beaver, Postsurgical
Arch Intern Med 1981; 141:293-300.
2
3
HOURS
4
N = 80
(20 per group)
5
Ibuprofen 400 mg
(n=40)
2
1.75
Acetaminophen 600 mg
(n = 44)
Pain Releif
1.5
1.25
Acetaminophen 300 mg +
Codeine 30 mg
(n = 39)
1
0.75
0.5
0.25
0
0
1
Cooper, Oral Surgery
Amer J Med 1984; 70-77, 1984.
2
Hours
3
4
2.5
PAIN RELIEF SCORE
OLD VICODIN
2
1.5
TYLENOL #3
1
PLACEBO
0.5
0
0
1
Hopikinson, Post-Episiotomy
2
3
HOURS
4
5
6
Pain Intensity Difference
1.4
Acetaminophen 1000 +
Oxycodone 10 mg (n = 45)
1.2
1
Acetaminophen 1000 +
Oxycodone 5 mg (n =40)
0.8
Acetaminophen 500 +
Oxycodone 5 mg
(n = 45)
Acetaminophen 500 mg
(n = 37)
0.6
0.4
Oxycodone 5 mg
(n = 42)
0.2
Placebo
(n = 38)
0
0
Cooper et al, Oral Surgery
Oral Surg; 1980:50:496-501.
1
2
Hours
3
4
SIDE EFFECT PROFILE
PLACEBO
(N=38)
ACET
500 mg
(N=37)
ACET
500 mg +
OXYCOD
5 mg
(N=45)
ACET
1000 mg +
OXCOD
10 mg
(N=45)
Nausea
2
3
7
10
Drowsy
3
1
12
14
Dizzy
0
1
4
15
Lightheaded
0
0
4
6
Headaches
2
1
2
2
# of Side
Effects
7
6
29
47
# of Subjects
with Side Effects
6
3
21
29
Narcotic Equivalents
•
•
•
•
•
5 mg oxycodone
10 mg hydrocodone
60 mg codeine
75 mg tramadol
100 mg propoxyphene
From Hersh EV, Moore PA.
JADA 2004;135:298-311.
N-CH3
Analgesic Prodrugs
N-CH3
CYP2D6
CH3O
HO
O
O
Morphine
Codeine (In Tylenol® #3)
CH3 CH3
N
CH3
CH3
N
CH2
CH2
OH
OH
CYP2D6
CH3O
HO
Tramadol (Ultram®)
O-Desmethyl Tramadol
2D6 Inhibitors: Quinidine, chlorpheniraminine, fluoxitene, paroxitene
Limitations of Centrally Acting
Agents: Acute
• Sedation, dizziness, impairment of normal
daily function
• Respiratory depression
• Postural hypotension
• Suppression of cough reflex
• Urinary retention, constipation
• Nausea and vomiting
Limitations of Centrally
Acting Agents: Chronic
Dependence liability
• Tolerance
• Physical dependence
• Psychological dependence
NSAIDs Approved for Acute Pain
Salicylates
Propionic acids
Aspirin
ASA, many others
Diflunisal
DOLOBID®
Ibuprofen
MOTRIN®, ADVIL®, NUPRIN®
Naproxen
ANAPROX®, ALEVE®
Anthranilic acids
Meclofenamate
MECLOMEN®
Mefenamic acid
PONSTEL®
Phenylacetic acid
Diclofenac
CATAFLAM®, ZIPSOR®
Pyrrole acetic acid
Ketorolac
TORADOL®, SPRIX®
Ibuprofen 400 mg
(n=38)
2.5
Pain Relief
2
Aspirin 650 mg + Codeine 60 mg
(n=45)
1.5
Aspirin 650 mg (n=38)
1
Codeine 60 mg
(n=41)
0.5
Placebo (n=46)
0
0
1
Cooper et al, Oral Surgery
Pharmacotherapy;1982:2:162-167
2
Hours
3
4
2.5
Meclofenamate 100, N=52
Ibuprofen 400mg,
N=49
2
Ibuprofen 200mg,
N=51
1.5
Pain
Relief
Meclofenamate 50mg,
N=51
1
0.5
Placebo, N=51
0
0
1
2
3
4
5
6
Time (hours)
Hersh EV, Cooper SA, Betts N, Quinn P et al. Oral Surg Oral Med Oral Pathol 1993;76:680-687.
7
8
Opioids vs Ibuprofen in Postsurgical Dental Pain
Kleinert R, Lange C, Steup A, Black P, Goldberg J, Desjardins P. Anesth Analg. 2008 Dec;107(6):2048-55.
Ibuprofen Liquigel (Advil® Liqui-Gels)
• OTC solubilized potassium ibuprofen
gel-cap
• Higher Cmax than solid ibuprofen tablet
formulations
• Shorter Tmax than solid ibuprofen tablet
formulations
Acetaminophen Caplets
Ibuprofen Liquigels
4
Ibuprofen Liquigel 200 mg (n=61)
Ibuprofen Liquigel 400 mg (n=59)
3.5
Pain Relief
3
2.5
2
1.5
Acetaminophen 1000 mg (n=63)
1
Placebo ( n=27)
0.5
0
0
1
Hersh EV, Levin LM, Cooper SA et al,
Clin Ther 2000;22:1306-1318.
2
3
Time (hours)
4
5
6
IBU 200 >PLA from 0.75–5 hrs,
IBU 400 > PLA from 0.5-6 hrs,
IBU 200 and 400 > APAP from 1½-6hrs
Hersh et al; JDR 2001
100
Cum % Remedicating
90
Placebo (n=33)
80
70
60
50
ASA/APAP/Caffeine (n=98)
500mg 500mg
40
130mg
30
20
Ibuprofen Liquigel 400 mg
(n=94)
10
0
0
1
2
Ibu Liq < Pla from 1½ hr – 6 hr, p<0.001
Ibu Liq < AAC from 3 hr – 6 hr, p<0.01
3
4
5
6
Time (hours)
AAC < Pla from 1½ hr – 6 hr, p<0.001
Adverse Events by Number and Percentage
AE’s
Placebo Ibuprofen Liquigel ASA/APAP/Caffeine
(n=33)
400 mg (n=94) 500 mg/500 mg/130mg (n=98)
# Subjects
6 (18.2%)
9 (9.6%)
12 (12.2%)
Headache
3 (9.1%)
7 (7.4%)
4 (4.1%)
Nausea
2 (6.1%)
2 (2.1%)
2 (2.0%)
Dizziness
2 (6.1%)
2 (2.1%)
2 (2.0%)
Numbness 1 (3.0%)
1 (1.1%)
3 (3.1%)
Pre-emptive Ibuprofen
Treatment
Placebo
Placebo
Ibuprofen 400 mg
Ibuprofen 400 mg
Time to Medication
133 minutes
141 minutes
236 minutes
241 minutes
Dionne RA, Campbell RA, Cooper SA, Hall DL, Buckinham B. J Clin Pharmacol 1983;:23:47-53.
Dionne RA, Cooper SA. Oral Surg, Oral Med, Oral Pathol 1978;45:851-856.
Pre-emptive and Post-Surgery Flurbiprofen and
Acetaminophen + Oxycodone
60
Mean Pain Intensity
Acetaminophen 650 mg + Oxycodone 10 mg
50
40
30
*
20
*
*
*
*
10
Flurbiprofen 100 mg
0
0
First dose
2
4
6
Second dose
Time (hours)
Dionne RA. Amer J Med 1986; 80(suppl 3A):41-49
* p < 0.01
8
Mean Pain Relief
3
Ibuprofen 400 mg/Oxycodone 5 mg (n=186)
2.5
Ibuprofen 400 mg (n=186)
2
1.5
Oxycodone 5 mg (n=63)
1
Placebo (n=62)
0.5
0
0
1
2
3
Time (hrs)
Van Dyke T et al. Clin Ther. 2004;26(12):2003-14.
4
5
6
Litkowski LJ, Christensen SE, Adamson DN, et al. Clin Ther. 2005 Apr;27(4):418-29.
Mean Pain Relief
2.5
Naproxen Na 440 mg
(n=92)
2
1.5
Acetaminophen 1000 mg
(n=89)
1
0.5
Placebo (n=45)
0
0
1
2
3
Kiersch et al, Clin Ther 16:395-404, 1994
Oral Surgery
4
5
6
7
8
Hours After Dose
9
10 11 12
Diclofenac 25 mg (n=63)
Diclofenac 50 mg (n=68)
Diclofenac 100 mg (n=66)
Placebo (n=68)
4
Mean Pain Relief Score
3.5
3
2.5
2
Zipsor®
1.5
1
0.5
0
0
1
2
3
4
5
Hours Postdose
Hersh EV, Levin LM, Adamson D, et al. Dose-Ranging Analgesic Study of Prosorb®
Diclofenac Potassium in Postsurgical Dental Pain. Clin Ther 2004;26:1215-1227.
6
Poor
Fair
Good
Very Good
Excellent
Diclofenac 25 mg (n = 63)
32%
Diclofenac 50 mg (n = 68)
Diclofenac 100 mg (n = 66)
Placebo
(n = 68)
79%
Percentage of Patients with
Poor or Fair Responses
68%
84%
16%
6%
94%
21%
Percentage of Patients with
Good to Excellent Responses
Mehlisch et al, Clin Ther 2010;32:882-895.
Figure 2
Sum of Pain Intensity Difference and Pain Relief Score
Ibuprofen-APAP Combinations vs. Codeine-Nonopioid Combinations
5
4
3
Ibuprofen 400 mg/APAP 1000 mg
2
Ibuprofen 200 mg/APAP 500 mg
Ibuprofen 400 mg/codeine 25 mg
1
APAP 1000 mg/codeine 30 mg
Placebo
0
0
60
120
180
240
300
360
420
480
Hours Following Dosing
Redrawn from: Daniels SE et al, Pain 2011; 152:632-642. Ref.#43.
ADVANTAGES OF NSAIDs FOR ACUTE PAIN
•
•
•
•
Relief equivalent to narcotic combos
Minimum of CNS side effects
Generally favorable therapeutic index
Several chemical classes
Three Categories of GI Adverse Events
Associated With NSAID Use *
• Gastrointestinal (GI) symptoms
•
•
– Heartburn, nausea, dyspepsia, vomiting, abdominal
pain (up to 50% with chronic use)
Mucosal lesions seen on endoscopy or x-ray
– gastroduodenal erosions and ulcers (up to 90% with
chronic use)
Serious GI complications
– Bleeding, perforation, or obstruction that can lead to
hospitalization or death (1-3% with chronic use)
* Singh G. Am J Med. 1998;105(1B):31S–38S.
Erosion
Ulcer
Mucosa
Muscularis
Mucosa
Submucosa
Pinto A., Farrar J.T., Hersh E.V.. Compend Contin Educ Dent. 30:142-151, 2009.
Arachidonic Acid
COX-1
Aspirin
NSAIDs
Thromboxane A2
Serotonin
SSRIs
Bottom Line: SSRIs + NSAIDs = Increased Bleeding Risk
Relative Risk of GI Bleed Compared
to Non-Users Of Either Drug Class
Drug Class
Relative Risk
NSAIDs
3.7
SSRIs
2.6
NSAIDs + SSRIs
15.6
De Abajo et al. British Medical Journal 1999;319:1106 --1109
LIMITATIONS OF NSAID ANALGESICS
• Plateau of analgesic effect
• Gastrointestinal upset/toxicity
• Inhibition of platelets
• Tinnitus
• Specific contraindications
–
–
–
–
Ulcers
Aspirin/NSAID sensitive asthma
Aspirin/NSAID allergy
Reyes Syndrome (Aspirin)
Figure 3. Pain intensity in the immediate postoperative period over the first 4 h after
surgery, depicted as the sum of pain intensity (upper panel), and at 48 h after surgery
(lower panel), as measured by a 200-mm verbal descriptor scale
Gordon S M, Dionne RA et al. Anesth Analg 2002;95:1351-1357
Adapted from:
Adapted from Gaskell H, Derry S, Moore RA, McQuay HJ. Cochrane
Database Syst Rev. 2009 Jul 8;(3):CD002763. Review.
Stepwise Guidelines for Acute Postoperative
Pain Management in Dentistry
Pain Severity
Mild Pain
Mild-Moderate Pain
Moderate to Severe Pain
Severe Pain
Analgesic Recommendation
Ibuprofen 200-400 mg
q 4-6 hours: as needed (p.r.n.) pain
Ibuprofen 400-600 mg
q 6 hours: fixed interval for 24 hours
Then ibuprofen 400 mg q 4-6 hours:
as needed (p.r.n.) pain
Ibuprofen 400-600 mg plus APAP 500 mg
q 6 hours: fixed interval for 24 hours
Then ibuprofen 400 mg plus APAP 500 mg
q 6 hours p.r.n. pain
Ibuprofen 400-600 mg plus APAP 600/
hydrocodone 10 mg q 6 hours:
fixed interval for 24-48 hours
Then ibuprofen 400-600 mg plus
APAP 500 mg q 6 hours p.r.n. pain
Conclusions
• In postsurgical dental pain studies NSAIDs at optimal doses
are superior in efficacy to single entity opioids and are at
least as efficacious as optimal doses of peripheral-narcotic
combination drugs.
• In postsurgical dental pain studies NSAIDs have a much
more favorable side effect profile than agents that contain an
opioid.
• The use of pre-emptive NSAIDs and long-acting local
anesthetics appear to greatly delay the onset of post-surgical
dental pain and may have benefit beyond the immediate
postoperative period.
• NSAIDs should be considered the first line drugs in most
cases of postsurgical dental pain.
Before Hersh Knew Anything About Pharmacology
After Hersh Studied Pharmacology