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

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Presentation on theme: "Evidenced Based Analgesic Efficacy in Post-Surgical Dental Pain Elliot V Hersh DMD, MS, PhD Professor Oral Surgery and Pharmacology University of Pennsylvania."— Presentation transcript:

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2 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

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4 A New Breed of Analgesic !

5 From PAIN to PASTA!!!

6 Blood, bone and guts !

7 Remove the bone and split the tooth!

8 Sew them up !

9 University of Pennsylvania Surgical Tray

10 Pioneers in oral surgery!

11 (Cyclooxygenase)

12 Peripheral Targets for Analgesia Courtesy of Sharon Gordon DMD, PhD

13 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:

14 Barden J, Edwards JE, McQuay HJ, Moore RA. Pain 2004;107: 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.

15 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

16 ASPIRIN 650 mg (N=32) ACETAMINOPHEN 650 mg (N=56) PLACEBO (N=32) PLACEBO (N=55) Cooper, Oral Surgery Arch Intern Med 1981;141:

17 Tylenol's maximum dose reduced to help prevent overdoses Jul 28, :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, 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!!!

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19 RO NHCOCH 3 HO NHCOCH 3 O Acetaminophen Conjugated metabolite N-Acetyl-benzoquinonemine (NAPQI) CYP2E1 (5%) Glucuronidation (95%) Glutathione Active Inactive Hepatotoxic From Hersh EV, Moore PA. JADA 2004;135: R =

20 PLACEBO ACETAMINOPHEN 600 mg + CODEINE 60 mg ACETAMINOPHEN 600 mg CODEINE 60 mg Beaver, Postsurgical Arch Intern Med 1981; 141: N = 80 (20 per group)

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

22 PLACEBO TYLENOL #3 OLD VICODIN Hopikinson, Post-Episiotomy

23 Placebo (n = 38) Oxycodone 5 mg (n = 42) Acetaminophen 500 mg (n = 37) Acetaminophen Oxycodone 5 mg (n = 45) Acetaminophen Oxycodone 5 mg (n =40) Acetaminophen Oxycodone 10 mg (n = 45) Cooper et al, Oral Surgery Oral Surg; 1980:50:

24 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 Drowsy Dizzy Lightheaded Headaches # of Side Effects # of Subjects with Side Effects

25 Narcotic Equivalents 5 mg oxycodone 10 mg hydrocodone 60 mg codeine 75 mg tramadol 100 mg propoxyphene

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27 O CH 3 O N-CH 3 Codeine (In Tylenol® #3) CYP2D6 O HO N-CH 3 Morphine CH 3 O Tramadol (Ultram®) CYP2D6 HO O-Desmethyl Tramadol OH CH 2 N CH 3 OH CH 2 N CH 3 Analgesic Prodrugs 2D6 Inhibitors: Quinidine, chlorpheniraminine, fluoxitene, paroxitene From Hersh EV, Moore PA. JADA 2004;135:

28 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: Acute

29 Dependence liability Tolerance Physical dependence Psychological dependence Limitations of Centrally Acting Agents: Chronic

30 NSAIDs Approved for Acute Pain Salicylates Aspirin ASA, many others Diflunisal DOLOBID® Anthranilic acids Meclofenamate MECLOMEN® Mefenamic acid PONSTEL® Propionic acids Ibuprofen MOTRIN®, ADVIL®, NUPRIN® Naproxen ANAPROX®, ALEVE® Phenylacetic acid Diclofenac CATAFLAM®, ZIPSOR® Pyrrole acetic acid Ketorolac TORADOL®, SPRIX®

31 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 Surgery Pharmacotherapy;1982:2:

32 Placebo, N=51 Meclofenamate 50mg, N=51 Ibuprofen 200mg, N=51 Ibuprofen 400mg, N=49 Meclofenamate 100, N=52 Hersh EV, Cooper SA, Betts N, Quinn P et al. Oral Surg Oral Med Oral Pathol 1993;76:

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

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35 Acetaminophen CapletsIbuprofen Liquigels

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37 Hersh et al; JDR 2001

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39 Pre-emptive Ibuprofen TreatmentTime to Medication Placebo Ibuprofen 400 mg 133 minutes 141 minutes 236 minutes 241 minutes Dionne RA, Campbell RA, Cooper SA, Hall DL, Buckinham B. J Clin Pharmacol 1983;:23: Dionne RA, Cooper SA. Oral Surg, Oral Med, Oral Pathol 1978;45:

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

41 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):

42 Litkowski LJ, Christensen SE, Adamson DN, et al. Clin Ther Apr;27(4):

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

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

45 Placebo (n = 68) Poor Fair Good Very Good Excellent Percentage of Patients with Poor or Fair Responses Percentage of Patients with Good to Excellent Responses Diclofenac 100 mg (n = 66) Diclofenac 50 mg (n = 68) Diclofenac 25 mg (n = 63) 79%21% 6%94% 84% 16% 32% 68%

46 Mehlisch et al, Clin Ther 2010;32:

47 Hours Following Dosing Sum of Pain Intensity Difference and Pain Relief Score Ibuprofen 400 mg/APAP 1000 mg Ibuprofen 200 mg/APAP 500 mg Ibuprofen 400 mg/codeine 25 mg APAP 1000 mg/codeine 30 mg Placebo Figure 2 Ibuprofen-APAP Combinations vs. Codeine-Nonopioid Combinations Redrawn from: Daniels SE et al, Pain 2011; 152: Ref.#43.

48 ADVANTAGES OF NSAIDs FOR ACUTE PAIN Relief equivalent to narcotic combos Minimum of CNS side effects Generally favorable therapeutic index Several chemical classes

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50 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.

51 Erosion Ulcer Mucosa MuscularisMucosa Submucosa

52 Arachidonic Acid COX-1 Thromboxane A2 Serotonin Aspirin NSAIDs SSRIs Bottom Line: SSRIs + NSAIDs = Increased Bleeding Risk Pinto A., Farrar J.T., Hersh E.V.. Compend Contin Educ Dent. 30: , 2009.

53 Drug ClassRelative Risk NSAIDs SSRIs NSAIDs + SSRIs Relative Risk of GI Bleed Compared to Non-Users Of Either Drug Class De Abajo et al. British Medical Journal 1999;319:

54 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)

55 Gordon S M, Dionne RA et al. Anesth Analg 2002;95: 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

56 Adapted from:

57 Adapted from Gaskell H, Derry S, Moore RA, McQuay HJ. Cochrane Database Syst Rev Jul 8;(3):CD Review.

58 Stepwise Guidelines for Acute Postoperative Pain Management in Dentistry Pain Severity Analgesic Recommendation Mild PainIbuprofen mg q 4-6 hours: as needed (p.r.n.) pain Mild-Moderate Pain Ibuprofen 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 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 mg plus APAP 600/ hydrocodone 10 mg q 6 hours: fixed interval for hours Then ibuprofen mg plus APAP 500 mg q 6 hours p.r.n. pain

59 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.

60 Before Hersh Knew Anything About Pharmacology

61 After Hersh Studied Pharmacology


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