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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