MorphineCodeineHydrocodoneOxycodonePropoxyphene

“Caine Drugs”

AspirinIbuprofenNaproxenCOX-2s

Construction in Mouth

Erythoxylum Coca Shrub

NE

NE

NE1

1NE

Cocaine

End Result: Accumulation of Norepinephrine, Sensitization of receptors,

CNS Stimulation, Vasoconstriction, Tachycardia, Increased Contraction Force, Avoid Epinephrine

NE

NENENENENE

COMT

Inactive

InactiveMAO

DA

DA

DA

1DA

Cocaine

End Result: Dopamine Accumulation, Receptor sensitization,

Euphoria, Physical and Psychological Dependence, Cardiac Stimulation

DADADA

CO

MT

Inactive

MAOInactive

Cocaine + Vasoconstrictors =

Esters

N

H2N

H2N COCH2CH3

COCH2CH2

O

BenzocaineO

NC2H5

C2H5Procaine

COCH2CH2N

CH3

CH3

O

H

H9C4

Tetracaine

Aromatic Group Intermediate Chain

AminoTerminus

Other Ester: CocaineH2N COOH

Para-amino-benzoic acid(PABA)

A STUDY OF BENZOCAINE GEL IN TOOTHACHE

Elliot V Hersh DMD, MS, PhD, Eric T Stoopler DMD, Stacey A Secreto, Scott S DeRossi DMD

J Clin Dent 2005;16:103-108.

Benzocaine Background

• OTC since 1926 for temporary relief of toothache• Category I status for temporary relief of oral

mucosal pain– Apthous ulcers– Denture irritation– Orthodontic appliances– Teething

• Category III status for temporary relief of toothache

Treatments Responders, 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 (%) P-value@

20% Benzocaine vs. Vehicle 16.8 <0.001*

10% Benzocaine vs. Vehicle 10.3 0.038*

20% Benzocaine vs. 10% benzocaine

6.6 0.043

Hersh EV et al Efficacy, Tolerability and Label Compliance of Topical 10% and 20% Benzocaine Gels in Patients with Acute Toothache. JADA;2013; 144:517-526.

**** **

* * *

**+

Hersh EV et al Efficacy, Tolerability and Label Compliance of Topical 10% and 20%

Benzocaine Gels in Patients with Acute Toothache. JADA;2013; 144:517-526.

Vehicle n=115

26 13 12 24 25

10 9 23 33 24

10% Benzocaine*n=233

8 13 25 27 27

20% 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

281

227

51

124 1

0

100

200

300

# of

par

tici

pant

s

Product applied (mg)

18-200 201-400 401-600 601-800 801-1000 >1000

400 mg of 20% benzocaine = 80 mg benzocaine

400 mg of 10% benzocaine = 40 mg benzocaine

Methemoglobinemia

Fe++ Fe+++

Reduced Oxidized or Meth

Threshold dose for benzocaine = 15 mg/kg150 pound adult = 1000 mg benzocaine15 pound teething infant = 100 mg benzocaine

Vast majority of published cases (>95%) associated withendoscopy, fiberoptic intubations, bronchoscopies and transesophageal echocardiography. Antidote = Intravenous Methylene Blue

Townes PL, Geertsma MA, White MR. Benzocaine-induced methemoglobinemia. Am J Dis Child 1977; 131:697-698. 14 month old receiving 3300 mg of a 7.5% benzocaine product (250 mg benzocaine).

Other Drugs Associated with Methemoglobinemia

GENERIC NAME COMMON TRADE NAMES

AnilineBenzocaineCiprofloxacinDapsoneFlutamideMetoclopramideNitric OxideNitrates and nitritesPhenazopyridinePhenelzine PhenobarbitalPrilocaineQuinineResorcinolTrimethoprim/sulfamethoxazole

Various dyes and inksAmericaine, HurricaineCiproDapsone UPSEulexinReglan-----------Nitrostat, Nitro-Dur, IsordilUrobiotic, PyridiumNardilVarious genericsCitanestVarious genericsBensulfoid CreamBactrim

Gingiva

Tooth

Tongue

Topical benzocainewas absolutelyawesome for mybattery acid burns

Why Use This?

St. Renatus, LLC

3% Tetracaine plus 0.05% Oxymetazoline

Target area for nasal mist anesthesia

St. Renatus, LLC

*

**

Subject With Most Pronounced Pressor Response

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) 2013.

25 of 30 subjects (83.3%) who received 3% tetracaineplus 0.05% oxymetazoline nasal spray did not require a rescue local anesthetic injection compared to 14 of 15subjects (93%) who received a 2% lidocaine plus1:100,000 epinephrine injection.

0102030405060708090

Percentage Sucess

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

Amides I

NHCCH2

O

Lidocaine

Aromatic Group Intermediate Chain

AminoTerminusCH3

N

CH3

C2H5

C2H5

CH3

CH3CH3

CH3

CH3

CH3

NHCCH

O

C2H5

N

C2H5

C3H7

Etidocaine

NHCCH NCH3

Mepivacaine

O

NHCCH

O

NC4H9

Bupivacaine

Amides 2

NHCCH

ON

H

C3H7

Prilocaine

Aromatic Group Intermediate Chain

AminoTerminus

CH3

CH3

S

CH3

NHCCHCH3

O

NH

C3H7

H3COC

OArticaine

Paresthesias?

Frequency of Paresthesias in Ontario

02468

10121416182022

1973 1975 1977 1979 1981 1983 1985 1987 1989 1991 1993

Year

Rep

orte

d C

ases

Introduction of Articaine

Haas DA, Lennon D. J Can Dent Assoc 1995;61:319-330

Anesthetic Frequency Frequency %

Articaine 50/149 33.6%

Prilocaine 43/149 28.9%

Lidocaine 5/149 3.4%

Mepivacaine 4/149 2.7%

Bupivacaine 0/149 0.0%

Unknown 47/149 31.5%

Frequency of Paresthesias by Anesthetic Agent:1973-1993

Remember: Articaine was not available till 1983.

Anesthetic

Agent

Total # of

Cartridges

Observed

Frequency

Frequency

%

Chances of

paresthesia

Articaine 4,398,970 10 71.4% 2.3/1,000,000

Lidocaine 3,062,613 0 0.0% 0

Prilocaine 2,352,615 4 28.6% 1.7/1,000,000

Mepivacaine 1,569,037 0 0.0% 0

Bupivacaine 241,679 0 0.0% 0

Review of 1993 Paresthesia Data

Adapted from Haas DA, Lennon D. J Can Dent Assoc 1995;61:319-330

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

Pka = pH + log (cation)/(free base)7.4 = 5.4 + log (cation)/(free base)2 = log (cation)/(free base)100/1 = (cation)/(free base)

pka, Ionization and Onset at pH 7.4

Drug pKa % Cationic % Free Base Onset Time

Mepivacaine 7.7 67% 33% 2-4 minLidocaine 7.8 71% 29% 2-4 minPrilocaine 7.8 71% 29% 2-4 minArticaine 7.8 71% 29% 2-4 minBupivacaine 8.1 83% 17% 5-8 minProcaine 8.9 97% 3% 14-18 min

pKa = pH + log (cationic)/(free base)7.4 = 7.4 + log (cationic)/(free base)0 = log (cationic)/(free base)100 =1/1=(cationic)/(free base)

pKa = pH + log (cationic)/(free base)8.4 = 7.4 + log (cationic)/(free base)1 = log (cationic)/(free base)101 =10/1=(cationic)/(free base)

Drug Lipid Solubility

Marketed Concentration

Articaine 40 4%

Mepivacaine 42 2-3%

Prilocaine 55 4%

Lidocaine 110 2%

Bupivacaine 560 0.5%

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

The Effects of Lidocaine on the Compound Action Potential

Blockade of all sodium channels in 3 consecutive nodes of ranvier

Na

Na

-NHCRN

O

R

RSodium Channel Blockade

-NHCRN

OR

R-NHCRN

O R

R

Membrane ExpansionNa

Local Anesthetic Mechanisms

CH-CH2-NHHO

HO

OH

Epinephrine

CH-CH-NH2

OHCH3 CH3

Levonordefrin

HO

HO

HO

CH-CH2-NH2HO

OH

Norepinephrine

CH-CH-NH

CH3OH CH3

Ephedrine

HO CH2-CH2-NH2

Tyramine

0

0.1

0.2

0.3

0.4

0.5

0.6

0 15 30 45 60 75 90 105 120

Minutes After Injection

Con

cent

rati

on (

ug/m

l)

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.

Anesthetic Success and Duration Maxillary Arch% Success Pulpal Duration Lip Duration

2% LIDO PLAIN

2% LIDO/EPI

1:200,000

2% LIDO/EPI

1:100,000

38%

97%

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;9:254-267.

75.8 93.5 95.2

0

10

20

30

40

50

60

70

80

90

100

Perc

enta

ge s

ucce

ss

Articaine plain Articaine plus1:200,000 epi

Articaine plus1:100,000 epi

* *

* p ≤ 0.01 vs Art plain Chi square test

Moore PA, Boynes, SG, Hersh EV, DeRossi SS, Sollecito TP et al. JADA 2006;137:1572-1581

N=63, 3-way crossover

0

10

20

30

40

50D

ura

tio

n t

ime (

min

ute

s)

Articaine plain Articaine plus1:200,000 epi

Articaine plus1:100,000 epi

n=47

n=58 n=60

**

Moore PA, Boynes, SG, Hersh EV, DeRossi SS, Sollecito TP et al. JADA 2006;137:1572-1581

* p ≤ 0.01 vs Art plain

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;34:389-393.

Evans G, Nusstein J, Drum M, Reader A, Beck M. J Endo 2008;34:389-393.

Maxillary first molar infiltration EPT crossover

2% lidocaine plus 1:100,000 epi

4% articaine plus 1:100,000 epi

Mandibular first molar infiltration EPT crossover. Robertson D, Nusstein J, Reader A, Beck M, McCartney M. J Am Dent Assoc. 2007 Aug;138(8):1104-12.

1st molar

2nd molar1st premolar

ANESTHETIC BLOOD LOSS (ML)

2% LIDO/EPI 1:100,000 14

3 % MEPIVACAINE 32

BLOOD LOSS 3rd MOLAR INFILTRATION

BLOOD LOSS MAXILLARY PERIO SURGERY

ANESTHETIC BLOOD LOSS (ML)

4% ART/EPI 1:100,000 55

4% ART/EPI 1:200,000 70

Moore PA, Doll B, Delie RA, Hersh EV, Korostoff J, et al. J Periodontol 2007;78:247-253

Sveen K, Int J Oral Surg 1979;8:301-306

PLASMA EPINEPHRINE CONCENTRATIONS FOLLOWINGINJECTION OF VARIOUS LOCAL ANESTHETIC SOLUTIONS

Local Anesthetic Baseline 1 - 3 Minutes 5 – 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;68:1098-1101, Knoll-Kohler et al, J Oral Maxillofac Surg 1991; 49:957-962, Troullos ES et al, Anesth Prog 1987, 34:10-13.

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

CH-CH2-NHHO

HO

OH

Epinephrine

CH3

• 1:50,000 = 1 gram/50,000 ml = 1000 mg/50,000 ml =

0.02 mg/ml x 1.8 ml/carpule = 0.036 mg/carpule

• 1:100,000 = 1 gram/100,000 ml = 1000 mg/100,000 ml = 0.01 mg/ml x 1.8 ml/carpule = 0.018 mg/carp

• 1:200,000 = 1 gram/200,000 ml = 1000 mg/200,000 ml = 0.005 mg/ml x 1.8 ml/carpule =0.009 mg/carp

MRD in 150 lb adult = 0.20 mg (11 cartridges of 1:100,000)

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 to0.04 mg (2 carps 1:100,000)

Epinephrine Receptor Actions

RECEPTOR RESPONSE

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

60.0

62.0

64.0

66.0

68.0

70.0

72.0

74.0

76.0

78.0

80.0

0 10 20 30 40 50 60 70 80 90 100 110 120

Time (minutes)

Hea

rt R

ate

(bea

ts/m

in) A100

A200

* * 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; 137:1562-1571.

115.0

117.0

119.0

121.0

123.0

125.0

127.0

129.0

131.0

133.0

0 10 20 30 40 50 60 70 80 90 100 110 120

Time (minutes)

Sys

tolic

BP

A100

A200

68.0

69.0

70.0

71.0

72.0

73.0

74.0

0 10 20 30 40 50 60 70 80 90 100 110 120

Time (minutes)

Dia

sto

lic

BP

A100

A200

* * 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; 137:1562-1571.

Epinephrine/Propranolol (B1B2) Hypertensive Interaction

RECEPTOR RESPONSE

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

Epinephrine/Metoprolol (B1) Lack of Interaction

RECEPTOR RESPONSE

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

Houben H, Thien T, vant Laar A. Effect of low-dose epinephrineinfusion on hemodynamics after selective and nonselective beta-blockade in hypertension. Clin Pharmacol Ther 1982: 31: 685–690.

120

130

140

150

160

170

180

190

M PBaseline

M P16 ug 32 ug

M P

M = metoprolol

P = propranolol

*Systolic Blood Pressure Changes

Houben H, Thien T, vant Laar A. Effect of low-dose epinephrineinfusion on hemodynamics after selective and nonselective beta-blockade in hypertension. Clin Pharmacol Ther 1982: 31: 685–690.

90

95

100

105

110

115

120

125

130

M PBaseline

M P16 ug 32 ug

M P

M = metoprolol

P = propranolol*

Diastolic Blood Pressure Changes

*

Six Cases of Severe Hypertension WithReflex 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 DisasterPlastic and Reconstructive Surgery 1983;72:74-78

Six Cases of Severe Hypertension WithReflex 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 DisasterPlastic and Reconstructive Surgery 1983;72:74-78

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

NE

NE

NE

1

1TCAEnd Result: Accumulation of Epinephrine,Cardiac Arrhythmias, HypertensionUse epinephrine cautiously-no more2 cartridges 1:100,000, Avoid levonordefrin

NE

NENE

NENE

NE

EPIEPIEPIEPI

Vasoconstrictor Interaction With Tricyclic Antidepressants

COMT In

activ

e

InactiveCOMT

MAOInactive

Ser

Ser

Ser

1

1SSRIEnd Result: No interaction, Serotonin reuptake blockade has noaffect on the disposition of epinephrine.Epinephrine utilizes NE reuptake pump.

Ser

Ser

Ser

Ser

Ser

EPI

Lack of Vasoconstrictor Interaction With Selective Serotonin ReuptakeInhibitors

COM

T

Inactive

Epinephrine

Pseudoephedrine

A

B

C

D

Naïve nerve terminal (A)

Nerve terminal plus MAOI (B,C,D)

No ADR

Hypertenion,Arrhythmias

MAOInactive

Lack of interaction withcatecholamine vasoconstrictors

COMTInactive

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-DopaCOMT

Inactive

Epinephrine COMT Inactive

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

Local Anesthetic Dosage Considerations2% = 20 mg/ml x 1.8 ml/carp = 36 mg/carp

MRD Lido/Epi = 3.2 mg/lb; Max = 500 mg150 lb adult = 14 carps 50 lb child = 4 ½ carps

3% = 30 mg/ml x 1.8 ml/carp = 54 mg/carpMRD Mepivacaine = 2.6 mg/lb; Max = 400 mg150 lb adult = 7 carps 50 lb child = 2 ½ carps

4% = 40 mg/ml x 1.8 ml/carp = 72 mg/carpMRD Prilocaine = 4 mg/lb; Max = 600 mg150 lb adult = 8 carps 50 lb child = 2 ¾ carps

4% = 40 mg/ml x 1.7 ml/carp = 68 mg/carpMRD Articaine = 3.2 mg/lb; Max = 500 mg150 lb adult = 7 carps 50 lb child = 2 ½ carps

Concentration CNS Effect CVS Effect

< 5 ug/ml Anticonvulsant Antiarrhythmic

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 arrest Profound cardiac depression and vasodilation

Why the heck did you take my sneaker off?

Local Anesthetic Overdose I

• 36 lb, 5 year old female, N20 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;58:489-491.

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.

2% Lidocaine/1:100,000 Epinephrine

3% Mepivacaine Plain

4% Prilocaine Plain

Lip and Tongue Numbness Scales

NotNumb

NotNumb

CompletelyNumb

CompletelyNumb

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.

0 100

0 100

Hersh EV et al: JADA 1995;126:1531-1536

0

10

20

30

40

50

60

70

80

90

1000 15 30 45 60 75 90 105

120

135

150

165

180

195

210

225

240

255

270

285

300

Minutes After Injection

2% Lido/Epi 3% Mepivacaine 4% Prilocaine

N = 45

Hersh EV et al: JADA 1995;126:1531-1536

Lip

Num

bnes

s S

core

0

10

20

30

40

5060

70

80

90

1000 15 30 45 60 75 90 105

120

135

150

165

180

195

210

225

240

255

270

285

300

Minutes After Injection

Ton

gue

Num

bnes

s Sc

ore

2% Lido/Epi 3% Mepivacaine 4% Prilocaine

Hersh EV et al: JADA 1995;126:1531-1536

N = 45

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.

Quality of Life Issues Associated with Prolonged Lip and Tongue Numbness

• In adults/teenagers - difficulty

Smiling Speaking Drinking/Eating

And everyone’s favorite:

Drooling

In Pediatric Dental Patients Also:

Lip, Tongue and Cheek Biting/Mutilation

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

Phentolamine for dentistry(OraVerseTM)

• Formulation– Phentolamine mesylate 0.235 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 (0.4-0.8 mg) injected in same manner as

local anesthetic– Children: 0.5-1 cartridge (0.2-0.4 mg) injected in same manner as

local anesthetic

Purpose of Phase 3 Studies

To evaluate the safety and efficacy of a new drug formulation containing the vasodilator, phentolamine mesylate, testing the hypotheses that, in adults, OraVerseTM :

• is safe and well-tolerated• shortens duration of STA after routine local

anesthetic (lidocaine with 1:100,000 epi, articaine with 1:100,000 epi, prilocaine with 1:200,000 epi, and mepivacaine with 1:20,000 levonordefrin)

89

90

• Phase 3 Pivotal Trials– Trial Design: multicenter, randomized, blinded, controlled

• Two trials: mandibular procedures, maxillary procedures• Study Groups: Phentolamine (OraVerseTM) 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

STAR QuestionnaireNot at all A little bit Some-

whatQuite a bit

Very much

1 I feel like my lip, tongue or cheek is swollen 0 1 2 3 4

2 I am uncomfortable with how my lip, tongue or cheek feels 0 1 2 3 4

3 I am concerned about biting my lip, tongue or cheek 0 1 2 3 4

4 I have trouble drinking from a glass or cup 0 1 2 3 4

5 I have trouble eating 0 1 2 3 4

6 I have trouble speaking clearly 0 1 2 3 4

7 I have trouble smiling 0 1 2 3 4

8 I am concerned about drooling 0 1 2 3 4

9 I am concerned about how long my numbness will last 0 1 2 3 4

10 I am concerned about my ability to speak at work or home 0 1 2 3 4

11 I am concerned about the way my mouth might look to others0 1 2 3 4

12 The numbness I feel now would cause me to avoid social activities0 1 2 3 4

91

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.”

60 120 180 240 3000

100

50

0

Time after study drug (min)

Pro

po

rtio

n o

f P

atie

nts

wit

h N

orm

al S

ensa

tio

nTime to return of normal sensation in lower lip

Sham (n = 122)median = 155 min

P<0.0001

Phentolamine (n = 122)median = 70 min

Time to return of normal tongue sensation

Phentolamine (n = 93) median = 60 min

Sham (n = 103)median = 125 min

0

50

100

0 60 120 180 240 300Time after study drug (min)

Pro

po

rtio

n o

f P

atie

nts

wit

h N

orm

al S

ensa

tio

n

P <0.0001

60 120 180 240 3000

100

50

0

Time after study drug (min)

Sham (n = 120)median = 132.5 min

Phentolamine (n = 120)median = 50 min

Time to return of normal sensation in upper lip

P <0.0001

Pro

po

rtio

n o

f P

atie

nts

wit

h N

orm

al S

ensa

tio

n

Efficacy subgroup analysis(% reduction in median lip numbness duration)

Subgroup Mandible Maxilla

Age (yr) % %

12-17 (n = 31, 24) 63 23

18-64 (n = 186, 188) 52 62

≥65 (n = 27, 28) 50 62

Local Anesthetic

Lidocaine (n = 163, 159) 54 63

Mepivacaine (n = 26, 27) 43 46

Prilocaine (n = 27, 27) 37 0

Articaine (n = 28, 27) 48 69

60 120 180 240 3000

100

50

0.0

Time after study drug (min)

Pro

port

ion

of P

atie

nts

Re

cove

red

Sham (n = 120)median = 132.5 min

NV-101 (n = 120)median = 50 min

Relationship between time-to-event functions forefficacy endpoints ( Weibull AFT model)

P<0.0001

Phentolamine (OraverseTM) - mandible

98

Phentolamine (OraVerseTM) Safety

Vital Signs-Systolic Blood Pressure - mandible

100

105

110

115

120

125

130

135

140

145

150

Anesth

etic*

Anesth

etic

(sta

nding

)

Prior t

o Ran

dom

izatio

n*

5 (s

tand

ing)**

10-2

0 (s

tand

ing)** 15

*30

*45

*60

*12

0*18

0*24

0*30

0*

Discha

rge*

Time (minutes)

Sys

tolic

Blo

od

Pre

ssu

re (

mm

Hg

)

Sham (N=122)

OraVerseTM (N=122)

* Supine or Sitting**5 (standing) is the standing value within 5 minutes of study drug administration. 10-20 (standing) is the standing value between 10 and 20 minutes of study drug administration

99

60

65

70

75

80

85

90

95

Anest

hetic

*

Anest

hetic

(sta

nding

)

Prior t

o Ran

dom

izatio

n*

5 (s

tand

ing)**

10-2

0 (s

tand

ing)**

15*

30*

45*

60*

120*

180*

240*

300*

Discha

rge*

Time (minutes)

Dia

sto

lic B

loo

d P

ress

ure

(m

mH

g)

Sham (N=122)

OraVerseTM

(N=122)

*

Supine or Sitting

**5 (standing) is the standing value within 5 minutes of study drug administration. 10-20 (standing) is the standing value between 10 and 20 minutes of study drug administration

Phentolamine (OraVerseTM) Safety

Vital Signs-Diastolic Blood Pressure - mandible

100

55

60

65

70

75

80

85

90

95

Anesth

etic*

Anesth

etic

(sta

nding

)

Prior t

o Ran

dom

izatio

n*

5 (s

tand

ing)**

10-2

0 (s

tand

ing)**

15*

30*

45*

60*

120*

180*

240*

300*

Discha

rge*

Time (minutes)

Pu

lse

(bea

ts p

er m

inu

te)

Sham (N=122)

OraVerseTM

(N=122)

* Supine or Sitting**5 (standing) is the standing value within 5 minutes of study drug administration. 10-20 (standing) is the standing value between 10 and 20 minutes of study drug administration

Phentolamine (OraVerseTM) Safety

Vital Signs-Pulse - mandible

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.

0

10

20

30

40

50

60

70

80

90

100

110

120

130

140

150

160

170

Imm

ediat

ely a

fter L

ocal

Anesth

etic

Prior t

o Ran

dom

izatio

n

Imm

ediat

ely a

fter S

tudy

Dru

g

30 M

inute

s

1 Hou

r

1 Hou

r 30

Minu

tes

2 Hou

rs

3 Hou

rs

4 Hou

rs

5 Hou

rs

Timepoint

Hef

t-P

arke

r V

AS

Sco

re (

0 -

170)

Sham (N=122)

OraVerse (N=122)

102

Conclusions of Phase 3 Adult/Adolescent Studies

• Mandibular procedures– Efficacy: Phentolamine (OraVerseTM) 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 (OraVerseTM) 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

0

50

100

0 60 120 180 240

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

Pro

po

rtio

n o

f P

atie

nts

wit

h N

orm

al S

ensa

tio

n