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Morphine Codeine Hydrocodone Oxycodone Propoxyphene “Caine Drugs” Aspirin Ibuprofen Naproxen COX-2s.

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Presentation on theme: "Morphine Codeine Hydrocodone Oxycodone Propoxyphene “Caine Drugs” Aspirin Ibuprofen Naproxen COX-2s."— Presentation transcript:

1 Morphine Codeine Hydrocodone Oxycodone Propoxyphene “Caine Drugs” Aspirin Ibuprofen Naproxen COX-2s

2 Construction in Mouth

3 Erythoxylum Coca Shrub

4 NE 11 11 Cocaine End Result: Accumulation of Norepinephrine, Sensitization of receptors, CNS Stimulation, Vasoconstriction, Tachycardia, Increased Contraction Force, Avoid Epinephrine NE COMT Inactive MAO

5 DA 11 Cocaine End Result: Dopamine Accumulation, Receptor sensitization, Euphoria, Physical and Psychological Dependence, Cardiac Stimulation DA COMT Inactive MAO Inactive

6 Cocaine + Vasoconstrictors =

7 Esters N H2NH2N H2NH2NCOCH 2 CH 3 COCH 2 CH 2 O Benzocaine O N C2H5C2H5 C2H5C2H5 Procaine COCH 2 CH 2 N CH 3 O H H9C4H9C4 Tetracaine Aromatic Group Intermediate Chain Amino Terminus Other Ester: Cocaine H2NH2NCOOH Para-amino-benzoic acid (PABA)

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13 TreatmentsResponders, n (%) Vehicle (n=115)81 (70.4) 10% Benzocaine (n=233)188 (80.7) 20% Benzocaine (n=228)199 (87.3) Pair Wise Comparisons Observed Treatment Differences (%) 20% Benzocaine vs. Vehicle16.8<0.001* 10% Benzocaine vs. Vehicle * 20% Benzocaine vs. 10% benzocaine Hersh EV et al Efficacy, Tolerability and Label Compliance of Topical 10% and 20% Benzocaine Gels in Patients with Acute Toothache. JADA;2013; 144:

14 *** * ** * * * * * + Hersh EV et al Efficacy, Tolerability and Label Compliance of Topical 10% and 20% Benzocaine Gels in Patients with Acute Toothache. JADA;2013; 144:

15 Vehicle n= % Benzocaine* n= % Benzocaine* n=228 Poor or Fair Global Efficacy Evaluation Poor (0) Fair (1) Good (2) Very Good (3) Excellent (4) Good, Very Good or Excellent

16 400 mg of 20% benzocaine = 80 mg benzocaine 400 mg of 10% benzocaine = 40 mg benzocaine

17 Methemoglobinemia Fe ++  Fe +++ Reduced Oxidized or Meth Threshold dose for benzocaine = 15 mg/kg 150 pound adult = 1000 mg benzocaine 15 pound teething infant = 100 mg benzocaine Vast majority of published cases (>95%) associated with endoscopy, fiberoptic intubations, bronchoscopies and transesophageal echocardiography. Antidote = Intravenous Methylene Blue Townes PL, Geertsma MA, White MR. Benzocaine-induced methemoglobinemia. Am J Dis Child 1977; 131: month old receiving 3300 mg of a 7.5% benzocaine product (250 mg benzocaine).

18 Other Drugs Associated with Methemoglobinemia GENERIC NAMECOMMON TRADE NAMES Aniline Benzocaine Ciprofloxacin Dapsone Flutamide Metoclopramide Nitric Oxide Nitrates and nitrites Phenazopyridine Phenelzine Phenobarbital Prilocaine Quinine Resorcinol Trimethoprim/sulfamethoxazole Various dyes and inks Americaine, Hurricaine Cipro Dapsone UPS Eulexin Reglan Nitrostat, Nitro-Dur, Isordil Urobiotic, Pyridium Nardil Various generics Citanest Various generics Bensulfoid Cream Bactrim

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20 Topical benzocaine was absolutely awesome for my battery acid burns

21 Why Use This? St. Renatus, LLC

22 3% Tetracaine plus 0.05% Oxymetazoline

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24 Target area for nasal mist anesthesia St. Renatus, LLC

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26 *

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28 Subject With Most Pronounced Pressor Response

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30 Safety and Efficacy of a Novel Nasal Spray for Maxillary Dental Anesthesia S.G. Ciancio1, M.C. Hutcheson, F. Ayoub, E.A. Pantera, Jr.1, C.T. Pantera1, D.A. Garlapo, B.D. Sobieraj, and S.A. Almubarak. J Dent Res(Suppl) of 30 subjects (83.3%) who received 3% tetracaine plus 0.05% oxymetazoline nasal spray did not require a rescue local anesthetic injection compared to 14 of 15 subjects (93%) who received a 2% lidocaine plus 1:100,000 epinephrine injection.

31 Placebo Spray Tetracaine Alone Tetracaine/Oxymetazoline (n = 22) (n = 44) (n= 44)

32 Amides I NHCCH 2 O Lidocaine Aromatic GroupIntermediate Chain Amino Terminus CH 3 N C2H5C2H5 C2H5C2H5 NHCCH O C2H5C2H5 N C2H5C2H5 C3H7C3H7 Etidocaine NHCCH N CH 3 Mepivacaine O NHCCH O N C4H9C4H9 Bupivacaine

33 Amides 2 NHCCH O N H C3H7C3H7 Prilocaine Aromatic Group Intermediate Chain Amino Terminus CH 3 S NHCCH CH 3 O N H C3H7C3H7 H 3 COC O Articaine Paresthesias?

34 Introduction of Articaine Haas DA, Lennon D. J Can Dent Assoc 1995;61:

35 AnestheticFrequencyFrequency % Articaine 50/ % Prilocaine 43/ % Lidocaine 5/ % Mepivacaine 4/ % Bupivacaine 0/ % Unknown 47/ % Frequency of Paresthesias by Anesthetic Agent: Remember: Articaine was not available till 1983.

36 Anesthetic Agent Total # of Cartridges Observed Frequency % Chances of paresthesia Articaine4,398, %2.3/1,000,000 Lidocaine3,062, % 0 Prilocaine2,352, %1.7/1,000,000 Mepivacaine1,569, % 0 Bupivacaine 241, % 0 Review of 1993 Paresthesia Data Adapted from Haas DA, Lennon D. J Can Dent Assoc 1995;61:

37 Pka = pH + log (cation)/(free base) 7.4 = log (cation)/(free base) 0 = log (cation)/(free base) 1/1 = (cation)/free base Pka = pH + log (cation)/(free base) 7.4 = log (cation)/(free base) 2 = log (cation)/(free base) 100/1 = (cation)/(free base)

38 pka, Ionization and Onset at pH 7.4 DrugpKa% Cationic% Free BaseOnset Time Mepivacaine % 33% 2-4 min Lidocaine % 29% 2-4 min Prilocaine % 29% 2-4 min Articaine % 29% 2-4 min Bupivacaine % 17% 5-8 min Procaine % 3%14-18 min pKa = pH + log (cationic)/(free base) 7.4 = log (cationic)/(free base) 0 = log (cationic)/(free base) 10 0 =1/1=(cationic)/(free base) pKa = pH + log (cationic)/(free base) 8.4 = log (cationic)/(free base) 1 = log (cationic)/(free base) 10 1 =10/1=(cationic)/(free base)

39 Data from Jastak JT, Yagiela JA, Donaldson D: Local Anesthesia of the Oral Cavity, WB Saunders, 1995.

40 The Effects of Lidocaine on the Compound Action Potential

41 Blockade of all sodium channels in 3 consecutive nodes of ranvier

42 Na -NHCRN O R R Sodium Channel Blockade -NHCRN O R R O R R Membrane Expansion Na Local Anesthetic Mechanisms

43 CH-CH 2 -NHHO OH Epinephrine CH-CH-NH 2 OH CH 3 Levonordefrin HO CH-CH 2 -NH 2 HO OH Norepinephrine CH-CH-NH CH 3 OHCH 3 Ephedrine HOCH 2 -CH 2 -NH 2 Tyramine

44 2% LIDO/1:100,000 EPI 2% LIDOCAINE PLAIN 3% MEPIVACAINE PLAIN Local Anesthetic Blood Levels – 1 cartridge Adapted from Goebel et al, 1978, 1980.

45 Anesthetic Success and Duration Maxillary Arch % SuccessPulpal DurationLip Duration 2% LIDO PLAIN 2% LIDO/EPI 1:200,000 2% LIDO/EPI 1:100,000 38% 97% 6 minutes 35 minutes 63 minutes 60 minutes 155 minutes 193 minutes 2% MEP PLAIN 3% MEP PLAIN 2% MEP/EPI 1:200,000 2% MEP/EPI 1:100,000 82% 91% 94% 93% 13 minutes 17 minutes 35 minutes 36 minutes 82 minutes 103 minutes 155 minutes 145 minutes Berling C. Odontol Rev 1958;9:

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47 * * * p ≤ 0.01 vs Art plain Chi square test Moore PA, Boynes, SG, Hersh EV, DeRossi SS, Sollecito TP et al. JADA 2006;137: N=63, 3-way crossover

48 n=47 n=58n=60 * * Moore PA, Boynes, SG, Hersh EV, DeRossi SS, Sollecito TP et al. JADA 2006;137: * p ≤ 0.01 vs Art plain

49 4% articaine plus 1:100,000 epi 2% lidocaine plus 1:100,000 epi Maxillary lateral incisor infiltration EPT crossover Evans G, Nusstein J, Drum M, Reader A, Beck M. J Endo 2008;34:

50 Maxillary first molar infiltration EPT crossover 2% lidocaine plus 1:100,000 epi 4% articaine plus 1:100,000 epi

51 Mandibular first molar infiltration EPT crossover. Robertson D, Nusstein J, Reader A, Beck M, McCartney M. J Am Dent Assoc Aug;138(8): st molar 2 nd molar 1 st premolar

52 ANESTHETICBLOOD LOSS (ML) 2% LIDO/EPI 1:100, % MEPIVACAINE 32 BLOOD LOSS 3 rd MOLAR INFILTRATION BLOOD LOSS MAXILLARY PERIO SURGERY ANESTHETICBLOOD LOSS (ML) 4% ART/EPI 1:100, % ART/EPI 1:200, Moore PA, Doll B, Delie RA, Hersh EV, Korostoff J, et al. J Periodontol 2007;78: Sveen K, Int J Oral Surg 1979;8:

53 PLASMA EPINEPHRINE CONCENTRATIONS FOLLOWING INJECTION OF VARIOUS LOCAL ANESTHETIC SOLUTIONS Local Anesthetic Baseline1 - 3 Minutes5 – 8 minutes 2% Lidocaine (2 ml) 3% Mepivacaine (OMS) (10.8 ml) 2% Lido/Epi 1:100,000 (2 ml) 2% Lido/Epi (OMS) 1:100,000 (14.4ml) 4% Art/Epi (OMS) 1:200,000 (4 ml) 4% Art/Epi (OMS) 1:100,000 (4 ml) 0.21 nmol/L 10 pg/ml 0.21 nmol/L 17 pg/ml 0.67 nmol/L 0.46 nmol/L 0.25 nmol/L 15 pg/ml 0.42 nmol/L 460 pg/ml 1.14 nmol/L 1.67 nmol/L 0.20 nmol/L 15 pg/ml 0.42 nmol/L 275 pg/ml 1.45 nmol/L 1.84 nmol/L Knoll-Kohler et al, J Dent Res 1989;68: , Knoll-Kohler et al, J Oral Maxillofac Surg 1991; 49: , Troullos ES et al, Anesth Prog 1987, 34:10-13.

54 Vasoconstrictor Concerns Resting BP > 200/115 Myocardial infarction < 6 months Stroke < 6 months Coronary artery bypass < 6 months Unstable or daily episodes of angina Uncontrolled CHF or cardiac arrhythmias Uncontrolled hyperthyroidism Sulfite sensitive asthma or true allergy Certain Drugs: Cocaine, B-Blockers, TCAs

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56 Beta Blockers and Epinephrine Non – Selective (B1, B2) Major Concern Propranolol (Inderal®) Nadolol (Corgard®) Timolol (Blocadren) Sotalol (Betapace®) Cardioselective (B1) Minor Concern Atenolol (Tenormin®) Metoprolol (Lopressor®) Acebutolol (Sectral®) Betaxolol (Kerlone®) Limit epinephrine dose to 0.04 mg (2 carps 1:100,000)

57 Epinephrine Receptor Actions RECEPTORRESPONSE Alpha – 1 Adrenergic Beta – 1 Adrenergic Beta –2 Adrenergic Vasoconstriction skin and mucous membranes Increased heart rate Increased contraction force Bronchodilation Vasodilation skeletal muscle and internal organs

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59 * * p < 0.05 vs A200 7 carpules of Articaine with Epi in Healthy Young Adults Hersh EV, Giannakopoulos H, Levin LM, Secreto S, Moore PA, Peterson C, Hutcheson M, Bouhajib M, Mosenkis A, Townsend RR. JADA 2006; 137:

60 ** p < 0.05 vs A200 7 carpules of Articaine with Epi in Healthy Young Adults Hersh EV, Giannakopoulos H, Levin LM, Secreto S, Moore PA, Peterson C, Hutcheson M, Bouhajib M, Mosenkis A, Townsend RR. JADA 2006; 137:

61 Epinephrine/Propranolol (B 1 B 2 ) Hypertensive Interaction RECEPTORRESPONSE Alpha – 1 Adrenergic Beta – 1 Adrenergic Beta –2 Adrenergic Vasoconstriction skin and mucous membranes Increased heart rate Increased contraction force Bronchodilation Vasodilation skeletal muscle and internal organs

62 Epinephrine/Metoprolol (B 1 ) Lack of Interaction RECEPTORRESPONSE Alpha – 1 Adrenergic Beta – 1 Adrenergic Beta –2 Adrenergic Vasoconstriction skin and mucous membranes Increased heart rate Increased contraction force Bronchodilation Vasodilation skeletal muscle and internal organs

63 Houben H, Thien T, vant Laar A. Effect of low-dose epinephrine infusion on hemodynamics after selective and nonselective beta-blockade in hypertension. Clin Pharmacol Ther 1982: 31: 685–690. M P Baseline M PM P 16 ug 32 ug M P M = metoprolol P = propranolol * Systolic Blood Pressure Changes

64 Houben H, Thien T, vant Laar A. Effect of low-dose epinephrine infusion on hemodynamics after selective and nonselective beta-blockade in hypertension. Clin Pharmacol Ther 1982: 31: 685–690. M P Baseline M PM P 16 ug 32 ug M P M = metoprolol P = propranolol * Diastolic Blood Pressure Changes *

65 Six Cases of Severe Hypertension With Reflex Bradycardia in Plastics Literature 1)55 year old woman, propranolol 40 mg BID for migraines, sedated with secobarbital, hydroxizine, meperidine and diazepam for facial and eyelid plasty. BP after sedation = 110/70 Pulse Rate = 72. Infiltrate with 12 cc of 1%lidocaine/1:100,000 epi. BP increases to 190/110, Pulse Rate drops = 38. After 15 minutes BP fell = 130/90, Pulse Rate = 70, eyelidplasty completed 2)61 year old woman, propranolol 40 mg BID for hypertension. Sedated with perphenazine, meperidine, lorazepam, propranolol 20 mg and diazepam for eyelid plasty. BP after sedation = 120/80, Pulse Rate = 70. Infiltrate with 10 cc 1% lidocaine/100,000 epi. BP rose to 200/100, Pulse Rate fell to 32. Over period of one hr BP fell to 140/90, pulse rose to 60, procedure completed. Foster CA, Aston SJ. Propranolol-Epinephrine Interaction: A Potential Disaster Plastic and Reconstructive Surgery 1983;72:74-78

66 Six Cases of Severe Hypertension With Reflex Bradycardia in Plastics Literature 3)52 year old woman, propranolol 40 mg BID for hypertension, sedated with hydroxyzine, meperidine and propranolol, diazepam for facial and eyelid plasty. No pre-op BP listed. Infiltrate with 13 cc of 0.5% lidocaine/1:200,000 epi. BP increases to 200/110 followed by cardiac arrest (ventricular fibrillation) Converted to normal sinus rhythm by defibrillator. Patient completely recovers. 4)58 year old man, propranolol 20 mg TID/dyazide 50 mg QD for hypertension. Sedated with hydroxyzine, lorazepam, diazepam, meperidine for eyelid plasty. BP after sedation = 120/80, Pulse = 60 Methohexital given immediately before infiltration of 8 cc 1/2% lidocaine/1:200,000 epi. BP rose to 260/150, Pulse Rate fell to 52. Hydralazine administered. Over period of 10 minutes BP fell to 130/80, pulse rose to 58, procedure completed. Foster CA, Aston SJ. Propranolol-Epinephrine Interaction: A Potential Disaster Plastic and Reconstructive Surgery 1983;72:74-78

67 TCAs (Tricyclic Antidepressants) Potential for ADR MAOIs (Monoamine Oxidase Inhibitors) No Concern for ADR SSRIs (Selective Serotonin Reuptake Inhibitors) No Concern for ADR Amtriptyline (Elavil®) Desipramine (Norpramin®) Doxepin (Sinequan®) Imipramine (Tofranil®) Isocarboxazid (Marplan®) Phenelzine (Nardil®) Tranylcypromine (Parnate®) Fluoxitene (Prozac®) Paroxitene (Paxil®) Sertraline (Zoloft®) Citalopram (Celexa®) Antidepressants and Vasoconstrictors

68 NE 11 11 TCA End Result: Accumulation of Epinephrine, Cardiac Arrhythmias, Hypertension Use epinephrine cautiously-no more 2 cartridges 1:100,000, Avoid levonordefrin NE EPI Vasoconstrictor Interaction With Tricyclic Antidepressants COMT Inactive COMT MAO Inactive

69 Ser 11 11 SSRI End Result: No interaction, Serotonin reuptake blockade has no affect on the disposition of epinephrine. Epinephrine utilizes NE reuptake pump. Ser EPI Lack of Vasoconstrictor Interaction With Selective Serotonin Reuptake Inhibitors COMT Inactive

70 Epinephrine Pseudoephedrine A B C D Naïve nerve terminal (A) Nerve terminal plus MAOI (B,C,D) No ADR Hypertenion, Arrhythmias MAO Inactive Lack of interaction with catecholamine vasoconstrictors COMT Inactive

71 Other Potential Drug Interactions Involving Vasoconstrictors Adrenergic Neuronal Blocking Agents –Guanethidine (Ismeline®) –Reserpine (Serpasil®) Digitalis Glycosides –Digoxin (Lanoxin®) –Digitoxin (Crystodigin®) COMT Inhibitors –Entacapone (Comtam®) –Tolcapone (Tasmar®) Receptor Upregulation L-Dopa COMT Inactive Epinephrine COMT Inactive

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73 INJECTION TYPE% POSITIVE Inferior Alveolar Mental Incisive Posterior Superior Alveolar Anterior Superior Alveolar Long Buccal 11.7% 5.7% 3.1% 0.7% 0.5% PERCENT POSITIVE ASPIRATIONS

74 Local Anesthetic Dosage Considerations 2% = 20 mg/ml x 1.8 ml/carp = 36 mg/carp MRD Lido/Epi = 3.2 mg/lb; Max = 500 mg 150 lb adult = 14 carps 50 lb child = 4 ½ carps 3% = 30 mg/ml x 1.8 ml/carp = 54 mg/carp MRD Mepivacaine = 2.6 mg/lb; Max = 400 mg 150 lb adult = 7 carps 50 lb child = 2 ½ carps 4% = 40 mg/ml x 1.8 ml/carp = 72 mg/carp MRD Prilocaine = 4 mg/lb; Max = 600 mg 150 lb adult = 8 carps 50 lb child = 2 ¾ carps 4% = 40 mg/ml x 1.7 ml/carp = 68 mg/carp MRD Articaine = 3.2 mg/lb; Max = 500 mg 150 lb adult = 7 carps 50 lb child = 2 ½ carps

75 ConcentrationCNS EffectCVS Effect < 5 ug/ml AnticonvulsantAntiarrhythmic 5 –10 ug/ml Light –headedness, slurred speech, drowsiness, nausea, diplopia, muscle twitching, dysphoria 10 – 15 ug/ml Disorientation, tremors, seizures, respiratory depression, unconsciousness Initially increases in BP and HR followed by decreases > 15 ug/ml Coma, respiratory arrestProfound cardiac depression and vasodilation

76 Why the heck did you take my sneaker off?

77 Local Anesthetic Overdose I 36 lb, 5 year old female, N 2 0 sedation Receives 5 cartrides 3% mepivacaine plain Total dose = 270 mg MRD = 2.6 mg/pound or 94 mg 10 minutes convulsions, transferred to nearby MD, CPR initiated Declared brain dead 3 days later Hersh EV, Helpin ML, Evans OB: J Dent Child 1991;58:

78 Local Anesthetic Overdose II 50 lb, 8 year old female, narcotic sedation Receives 6 cartridges 3% mepivacaine plain Total dose = 324 mg MRD = 2.6 mg/lb or 130 mg After 5 min, seizures and respiratory depression Naloxone (Narcan®) 0.4 mg, 1 ml epinephrine 1:1000 administered, calls 911 Resuscitation unsuccessful Moore PA: JADA 1992;123:60-64.

79 2% Lidocaine/1:100,000 Epinephrine 3% Mepivacaine Plain 4% Prilocaine Plain

80 Lip and Tongue Numbness Scales Not Numb Not Numb Completely Numb Completely Numb Place a single mark (/) on the line that shows how numb your lip feels now. Place a single mark (/) on the line that shows how numb your tongue feels now Hersh EV et al: JADA 1995;126:

81 N = 45 Hersh EV et al: JADA 1995;126: Lip Numbness Score

82 Hersh EV et al: JADA 1995;126: N = 45

83 Conclusions The time-course of soft tissue anesthesia – including onset, peak effects and overall duration was very similar between 2% lidocaine with epinephrine, 3% mepivacaine plain and 4% prilocaine plain. Combining these observations with local anesthetic dosage recommendations, it is recommended that 2% lidocaine with epinephrine be employed when performing block injections in young children.

84 Quality of Life Issues Associated with Prolonged Lip and Tongue Numbness In adults/teenagers - difficulty Smiling SpeakingDrinking/Eating And everyone’s favorite: Drooling

85 In Pediatric Dental Patients Also: Lip, Tongue and Cheek Biting/Mutilation

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87 Phentolamine mesylate History –First published study: 1950 (Hypertension) –Approved by FDA: 1953 (Regitine ®, Ciba) –Current package insert approved 1998 with generic version Mechanism of Action –Nonselective  -adrenergic blockade –Vascular dilation Current Approved Medical Indications –Prevention and treatment of dermal necrosis from extravasation of norepinephrine –Diagnosis and perioperative management of pheochromocytoma Non-Approved Usage –Hypertensive crisis Medical Dosage –Adults: 5 mg IV or IM; 5-10 mg local injection –Children: 1-3 mg IV or IM

88 Phentolamine for dentistry (OraVerse TM ) Formulation –Phentolamine mesylate mg/mL (0.4 mg/1.7 mL cartridge) Proposed Indication –Oraverse® is indicated for the reversal of soft tissue anesthesia and the associated functional deficits resulting from an intraoral injection of a local anesthetic containing a vasoconstrictor. Dosage –Adults: 1-2 cartridges ( mg) injected in same manner as local anesthetic –Children: cartridge ( mg) injected in same manner as local anesthetic

89 Purpose of Phase 3 Studies To evaluate the safety and efficacy of a new drug formulation containing the vasodilator,phentolamine mesylate, testing the hypothesesthat, in adults, OraVerse TM : is safe and well-tolerated shortens duration of STA after routine localanesthetic (lidocaine with 1:100,000 epi, articainewith 1:100,000 epi, prilocaine with 1:200,000 epi,and mepivacaine with 1:20,000 levonordefrin) 89

90 90 Phase 3 Pivotal Trials –Trial Design: multicenter, randomized, blinded, controlled Two trials: mandibular procedures, maxillary procedures Study Groups: Phentolamine (OraVerse TM ) or sham injection at end of procedure 4 leading anesthetics: one (0.4 mg) or two (0.8 mg) injections 18 U.S. sites: 11 universities and 7 private clinical research centers –Patient Population Adolescents and adults (11-92) undergoing routine dental procedures (N=484) –Primary Endpoint Time to normal lip sensation (lip tapping assessments) –Secondary Endpoints Perception of altered function, sensation and appearance as measured by STAR questionnaire Functional assessment battery (FAB), drinking, smiling, speaking, drooling time to normal tongue sensation safety and tolerability Methodology of Phase 3 Studies

91 STAR Questionnaire Not at allA little bitSome- what Quite a bit Very much 1I feel like my lip, tongue or cheek is swollen I am uncomfortable with how my lip, tongue or cheek feels I am concerned about biting my lip, tongue or cheek I have trouble drinking from a glass or cup I have trouble eating I have trouble speaking clearly I have trouble smiling I am concerned about drooling I am concerned about how long my numbness will last I am concerned about my ability to speak at work or home I am concerned about the way my mouth might look to others The numbness I feel now would cause me to avoid social activities

92 Functional Evaluations of “Suzie sewed zippers on two new dresses at Bessie’s house.” “She usually rushes to push the garage door closed.” “Ruth caught a cold because she wouldn’t wear her new, warm, wool coat.”

93 Time after study drug (min) Proportion of Patients with Normal Sensation Time to return of normal sensation in lower lip Sham (n = 122) median = 155 min P< Phentolamine (n = 122) median = 70 min

94 Time to return of normal tongue sensation Phentolamine (n = 93) median = 60 min Sham (n = 103) median = 125 min Time after study drug (min) Proportion of Patients with Normal Sensation P <0.0001

95 Time after study drug (min) Sham (n = 120) median = min Phentolamine (n = 120) median = 50 min Time to return of normal sensation in upper lip P < Proportion of Patients with Normal Sensation

96 Efficacy subgroup analysis (% reduction in median lip numbness duration) SubgroupMandibleMaxilla Age (yr)% (n = 31, 24) (n = 186, 188)5262 ≥65 (n = 27, 28)5062 Local Anesthetic Lidocaine (n = 163, 159)5463 Mepivacaine (n = 26, 27)4346 Prilocaine (n = 27, 27)370 Articaine (n = 28, 27)4869

97 Time after study drug (min) Proportion of Patients Recovered Sham (n = 120) median = min NV-101 (n = 120) median = 50 min Relationship between time-to-event functions for efficacy endpoints ( Weibull AFT model) P< Phentolamine (Oraverse TM ) - mandible

98 98 Phentolamine (OraVerse TM ) Safety Vital Signs-Systolic Blood Pressure - mandible Anesthetic* Anesthetic (standing) Prior to Randomization* 5 (standing)** (standing)** 15*30*45*60* 120*180*240*300* Discharge* Time (minutes) Systolic Blood Pressure (mmHg) Sham (N=122) OraVerse TM (N=122) * Supine or Sitting **5 (standing) is the standing value within 5 minutes of study drug administration (standing) is the standing value between 10 and 20 minutes of study drug administration

99 99 Diastolic Blood Pressure (mmHg) Sham (N=122) OraVerse TM (N=122) * Supine or Sitting **5 (standing) is the standing value within 5 minutes of study drug administration (standing) is the standing value between 10 and 20 minutes of study drug administration Phentolamine (OraVerse TM ) Safety Vital Signs-Diastolic Blood Pressure - mandible

100 Anesthetic* Anesthetic (standing) Prior to Randomization* 5 (standing)** (standing)** 15*30*45*60* 120*180*240*300* Discharge* Time (minutes) Pulse (beats per minute) Sham (N=122) OraVerse TM (N=122) * Supine or Sitting **5 (standing) is the standing value within 5 minutes of study drug administration (standing) is the standing value between 10 and 20 minutes of study drug administration Phentolamine (OraVerse TM ) Safety Vital Signs-Pulse - mandible

101 101 Pain on Administration H-P VAS Pain Rating- Mandible Clinically significant (AE ) No pain = VAS of 0 mm; mild: VAS of > 0 mm to  54 mm; moderate: VAS of > 54 mm to < 144 mm; severe: VAS of  144 mm.

102 102 Conclusions of Phase 3 Adult/Adolescent Studies Mandibular procedures –Efficacy: Phentolamine (OraVerse TM ) accelerates the time to normal lip sensation relative to sham by 85 min (54.8%; p<0.0001) –Safety: No serious adverse events No difference in non-serious adverse events No difference in vital signs or patient reported pain Maxillary procedures –Efficacy: Phentolamine (OraVerse TM ) accelerates the time to normal lip sensation relative to sham by 82.5 min (62.3%; p<0.0001) –Safety: No serious adverse events No difference in non-serious adverse events No difference in vital signs or patient reported pain

103 Time after study drug (min) Time to return of normal lip sensation – PEDs (6-11 year olds) Phentolamine (n = 72) median = 60 min Sham (n = 43) median = 135 min Proportion of Patients with Normal Sensation

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