Evidenced Based Analgesic Efficacy in Post-Surgical Dental Pain Elliot V Hersh DMD, MS, PhD Professor Oral Surgery and Pharmacology University of Pennsylvania.

Evidenced Based Analgesic Efficacy in Post-Surgical Dental PainElliot V Hersh DMD, MS, PhDProfessor Oral Surgery and PharmacologyUniversity of Pennsylvania School of Dental MedicineChair IRB#3, Office of Regulatory AffairsUniversity 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 AnalgesiaCourtesy of Sharon Gordon DMD, PhD

Pain Syndrome Total Pain Relief IndexMenstrual 17.5Arthritic 18.8Dental (general) 19.5Post-Herpetic 22.6Dental Impaction (Partial Bony) 23.2Phantom Limb 25.0Cancer 26.0Back Pain 26.3Dental 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 otherpostsurgical 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 StudiesDouble-blindRandom allocation of treatment to subjectsInclusion of placebo Inclusion of standard treatmentsIdentical appearance of study medication

ASPIRIN 650 mg(N=32)ACETAMINOPHEN 650 mg(N=56)PLACEBO(N=32)PLACEBO(N=55)Cooper, Oral SurgeryArch Intern Med 1981;141:282-285

Tylenol's maximum dose reduced to help prevent overdoses Jul 28, 2011 5:35 PMThe 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 reducethe risk of accidental acetaminophen overdoses that canlead to liver failure and death. Effective January 1, 2012.In addition, in 4 months all opioid combination drugs (i.e. acetaminophen plushydrocodone or oxycodone will not be allowed to contain more than 325 mgAPAP per tablet!! VICODIN WONT EXIST AS WE KNOW IT!!!

RONHCOCH3HONHCOCH3 NHCOCH3OAcetaminophenConjugated metaboliteN-Acetyl-benzoquinonemine (NAPQI)CYP2E1 (5%)Glucuronidation (95%)GlutathioneActiveInactiveHepatotoxicFrom Hersh EV, Moore PA.JADA 2004;135:298-311.R =

PLACEBOACETAMINOPHEN 600 mg + CODEINE 60 mgACETAMINOPHEN 600 mgCODEINE 60 mgBeaver, PostsurgicalArch Intern Med 1981; 141:293-300. N = 80(20 per group)

Acetaminophen 300 mg +Codeine 30 mg(n = 39)Acetaminophen 600 mg(n = 44)Ibuprofen 400 mg(n=40)Cooper, Oral SurgeryAmer J Med 1984; 70-77, 1984.

PLACEBOTYLENOL #3OLD VICODINHopikinson, Post-Episiotomy

Placebo(n = 38)Oxycodone 5 mg (n = 42)Acetaminophen 500 mg (n = 37) Acetaminophen 500 +Oxycodone 5 mg (n = 45) Acetaminophen 1000 +Oxycodone 5 mg (n =40)Acetaminophen 1000 +Oxycodone 10 mg (n = 45) Cooper et al, Oral SurgeryOral Surg; 1980:50:496-501.

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 10Drowsy 3 1 12 14Dizzy 0 1 4 15Lightheaded 0 0 4 6Headaches 2 1 2 2# of Side Effects 7 6 29 47# of Subjectswith Side Effects 6 3 21 29

Narcotic Equivalents5 mg oxycodone10 mg hydrocodone60 mg codeine75 mg tramadol100 mg propoxyphene

OCH3ON-CH3Codeine (In Tylenol #3)CYP2D6OHON-CH3MorphineCH3OTramadol (Ultram)CYP2D6HOO-Desmethyl TramadolOHCH2NCH3CH3OHCH2NCH3CH3Analgesic Prodrugs2D6 Inhibitors: Quinidine, chlorpheniraminine, fluoxitene, paroxiteneFrom Hersh EV, Moore PA.JADA 2004;135:298-311.

Sedation, dizziness, impairment of normal daily functionRespiratory depressionPostural hypotensionSuppression of cough reflexUrinary retention, constipationNausea and vomiting Limitations of Centrally ActingAgents: Acute

Dependence liabilityTolerancePhysical dependencePsychological dependence

Limitations of CentrallyActing Agents: Chronic

NSAIDs Approved for Acute PainSalicylatesAspirin ASA, many othersDiflunisal DOLOBIDAnthranilic acidsMeclofenamate MECLOMENMefenamic acid PONSTELPropionic acidsIbuprofen MOTRIN, ADVIL, NUPRINNaproxen ANAPROX, ALEVEPhenylacetic acidDiclofenacCATAFLAM, ZIPSOR Pyrrole acetic acidKetorolacTORADOL, SPRIX

Placebo (n=46)Codeine 60 mg(n=41)Aspirin 650 mg (n=38)Aspirin 650 mg + Codeine 60 mg (n=45)Ibuprofen 400 mg(n=38)Cooper et al, Oral SurgeryPharmacotherapy;1982:2:162-167

Placebo, N=51Meclofenamate 50mg,N=51

Ibuprofen 200mg,N=51Ibuprofen 400mg,N=49Meclofenamate 100, N=52Hersh EV, Cooper SA, Betts N, Quinn P et al. Oral Surg Oral Med Oral Pathol 1993;76:680-687.

Kleinert R, Lange C, Steup A, Black P, Goldberg J, Desjardins P. Anesth Analg. 2008 Dec;107(6):2048-55. Opioids vs Ibuprofen in Postsurgical Dental Pain

Ibuprofen Liquigel (Advil Liqui-Gels)

OTC solubilized potassium ibuprofen gel-capHigher Cmax than solid ibuprofen tablet formulationsShorter Tmax than solid ibuprofen tablet formulations

Acetaminophen CapletsIbuprofen Liquigels

Placebo ( n=27)

Acetaminophen 1000 mg (n=63)

Ibuprofen Liquigel 200 mg (n=61)

Ibuprofen Liquigel 400 mg (n=59)

Hersh EV, Levin LM, Cooper SA et al,Clin Ther 2000;22:1306-1318.

IBU 200 >PLA from 0.755 hrs, IBU 400 > PLA from 0.5-6 hrs, IBU 200 and 400 > APAP from 1-6hrs

Hersh et al; JDR 2001

Ibuprofen Liquigel 400 mg (n=94)

ASA/APAP/Caffeine (n=98)

500mg 500mg 130mg

Placebo (n=33)

Ibu Liq < Pla from 1 hr 6 hr, p

Placebo Ibuprofen Liquigel ASA/APAP/Caffeine (n=33) 400 mg (n=94) 500 mg/500 mg/130mg (n=98)

AEs# 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%)

Adverse Events by Number and Percentage

Pre-emptive IbuprofenDionne 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.

TreatmentTime to Medication PlaceboPlaceboIbuprofen 400 mgIbuprofen 400 mg 133 minutes 141 minutes 236 minutes 241 minutes

Mean Pain Intensity Flurbiprofen 100 mgAcetaminophen 650 mg + Oxycodone 10 mgFirst doseSecond doseTime (hours)****** p < 0.01Pre-emptive and Post-Surgery Flurbiprofen and Acetaminophen + OxycodoneDionne RA. Amer J Med 1986; 80(suppl 3A):41-49

Chart4

0035

11.3513.644

1217.344

21.5537.955

21.341.1566

21.4534.5566

20.833.656

19.6536.756

Flurbiprofen

APAP/Oxycodone

Sheet1

02345678

Flurbiprofen11.351221.5521.321.4520.819.65

APAP/Oxycodone13.617.337.941.1534.5533.636.7

Sheet1

Sheet2

0035

11.3513.644

1217.344

21.5537.955

21.341.1566

21.4534.5566

20.833.656

19.6536.756

Flurbiprofen

APAP/Oxycodone

Time (Hours)

Mean Pain Intensity

Sheet3

Placebo (n=62)Oxycodone 5 mg (n=63)Ibuprofen 400 mg (n=186)Ibuprofen 400 mg/Oxycodone 5 mg (n=186)Van Dyke T et al. Clin Ther. 2004;26(12):2003-14.

Litkowski LJ, Christensen SE, Adamson DN, et al. Clin Ther. 2005 Apr;27(4):418-29.

Placebo (n=45)Acetaminophen 1000 mg(n=89)Naproxen Na 440 mg(n=92)Kiersch et al, Clin Ther 16:395-404, 1994Oral Surgery

Hersh EV, Levin LM, Adamson D, et al. Dose-Ranging Analgesic Study of ProsorbDiclofenac Potassium in Postsurgical Dental Pain. Clin Ther 2004;26:1215-1227.Zipsor

Placebo(n = 68)PoorFairGoodVery GoodExcellentPercentage of Patients withPoor or Fair ResponsesPercentage of Patients withGood to Excellent ResponsesDiclofenac 100 mg (n = 66)Diclofenac 50 mg (n = 68)Diclofenac 25 mg (n = 63)79%21%6%94%84%16%32%68%

Mehlisch et al, Clin Ther 2010;32:882-895.

Figure 2Ibuprofen-APAP Combinations vs. Codeine-Nonopioid CombinationsRedrawn from: Daniels SE et al, Pain 2011; 152:632-642. Ref.#43.

ADVANTAGES OF NSAIDs FOR ACUTE PAINRelief equivalent to narcotic combosMinimum of CNS side effectsGenerally favorable therapeutic indexSeveral chemical classes

Three Categories of GI Adverse EventsAssociated With NSAID Use *Gastrointestinal (GI) symptomsHeartburn, nausea, dyspepsia, vomiting, abdominal pain (up to 50% with chronic use)Mucosal lesions seen on endoscopy or x-raygastroduodenal erosions and ulcers (up to 90% with chronic use)Serious GI complicationsBleeding, perforation, or obstruction that can lead to hospitalization or death (1-3% with chronic use)* Singh G. Am J Med. 1998;105(1B):31S38S.

ErosionUlcerMucosaMuscularisMucosaSubmucosa

Arachidonic AcidCOX-1Thromboxane A2SerotoninAspirinNSAIDsSSRIsBottom Line: SSRIs + NSAIDs = Increased Bleeding RiskPinto A., Farrar J.T., Hersh E.V.. Compend Contin Educ Dent. 30:142-151, 2009.

Relative Risk of GI Bleed Comparedto Non-Users Of Either Drug ClassDe Abajo et al. British Medical Journal 1999;319:1106 --1109

Drug ClassRelative RiskNSAIDs

SSRIs

NSAIDs + SSRIs 3.7

2.6

15.6

LIMITATIONS OF NSAID ANALGESICSPlateau of analgesic effectGastrointestinal upset/toxicityInhibition of plateletsTinnitusSpecific contraindicationsUlcersAspirin/NSAID sensitive asthmaAspirin/NSAID allergyReyes Syndrome (Aspirin)

Gordon S M, Dionne RA et al. Anesth Analg 2002;95:1351-1357Figure 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

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 DentistryPain Severity Analgesic Recommendation Mild PainIbuprofen 200-400 mg q 4-6 hours: as needed (p.r.n.) pain Mild-Moderate 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

Moderate to Severe 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 Severe 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

ConclusionsIn 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

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