Anxiety and Pain Control 2007

John A. Yagiela, DDS, PhD

Utah Dental Association

Salt Lake CityFebruary 9, 2007

Local Anesthesia Topics

Articaine: efficacy versus neurotoxicity

Advances in local anesthetic metabolism

Ropivacaine as a dental anesthetic Oraqix, the topical anesthetic for periodontics

NV-101 (phentolamine mesylate), a new reversal agent for local anesthesia

Articaine Hydrochloride (Septocaine)

Old new drug Thiophene-based amide Metabolized by plasma carboxyesterase

Low maximum dosage; low accumulation with repeated dosing

4% solution more effective than 2% lidocaine, both with epinephrine?

Increased incidence of nerve damage

Articaine

CH 3

HNHC

CH 3O

CH

H

N

C 73

S

COOCH 3

Prilocaine

CH 3

HNHC

CH 3O

CH

H

N

C 73

Articaine (Septocaine, Zorcaine): a thiophene

derivative

0 10 20 30 40 50 60 70 80 900

50

100

150

200

250

300

∆ Voltage (V)

Time (min)

Lid-2%-H Ult-2%-L Ult-2%-H Ult-4%-L Ult-4%-H

Mean Sensory Voltage: First Premolar

VAS pain scores

Parameter Simple Complex Simple Complex

Subjects (n) 674 207 338 104

Mean (mm) 3 5 4 6

Median (mm) 0 2 0 2

Range (mm) 0-90 0-73 0-90 0-64

4% A + Epi 2% L + Epi

Malamed SF, et al. J Am Dent Assoc 131:635-42, 2000

Studies showing increased efficacy of

articaine

Potocnik et al. J Dent Res 2006;85:162-6. Rat sural nerve study 2% and 4% articaine better than 2% and 4% lidocaine and 3% mepivacaine at blocking A fibers (but not C fibers)

Kanaa et al. J Endod 2006;32:296-8. Randomized double-blind cross-over study using electronic pulp tester

Articaine more effective than lidocaine after mandibular buccal infiltration anesthesia (65% vs. 39%)

The efficacy question

No proof of increased effectiveness in double-blind clinical trials using standard injections

No clinical trial with sufficient power to distinguish small differences

If 97.5% versus 95% efficacy and 40 patients per week,

one less failure per week

Local anesthesia use in Germany (1996)

2%

3%

4%91%ArticaineLidocaineMepivacaineOthers

Local anesthesia use in Canada (1999)

12%

6%4%

46% 32%

ArticainePrilocaineLidocaineMepivacaineBupivacaine

Haas, DA, Lennon D: A 21 year retrospective study of reports of paresthesia following local anesthetic administration. J Can Dent Assoc 61:319-30, 1995.

Study of reports to the Professional Liability Program of Ontario, Canada (1973-1993)

Surgery cases excluded 143 reports (lip, 42; tongue, 92; both, 9)

No significant effect of age, gender, or needle gauge

Reported cases of paresthesiaby year

0

5

10

15

20

25

1970 1980 1990 2000

Haas DA, Lennon D: J Can Dent Assoc 61:297-304, 1995

Articainemarketed

Incidence data

Haas DA, Lennon D: J Can Dent Assoc 61:297-304, 1995

Articaine and prilocaine: 91% of cases

1993 incidence by agent Articaine: 1/440,000 Prilocaine: 1/588,000 Lidocaine: none Mepivacaine: none

Hillerup S, Jensen R: Nerve injury caused by mandibular block analgesia. Int J Oral Maxillofac Surg 35:437-43, 2006.

Consecutive patients with injection injury to oral branches of trigeminal nerve 1997-2004

Referrals from colleagues and Danish Dental Association’s Patient Insurance Scheme (covering all dentists)

patients with unilateral injection injury: 40 lingual nerve; 10 inferior alveolar; 2 both

Cases of nerve injury by year

Articainemarketed

Hillerup S, Jensen R: Int J Oral Maxillofac Surg 35:437-43, 2006

Incidence data

Articaine : 55% of cases 2001-2002 incidence data

Articaine: 20 times higher incidence than other local anesthetics combined

Hillerup S, Jensen R: Int J Oral Maxillofac Surg 35:437-43, 2006

Johnson ME, Saenz JA, DaSilva AD, et al: Effect of local anesthetic on neuronal cytoplasmic calcium and plasma membrane lysis (necrosis) in a cell culture model. Anesthesiology 97:1466-76, 2002

NDE7 neurons derived from dorsal root ganglion loaded with fura-2

Cells exposed to lidocaine 0.1%-5% for 60 min

Fluorescence microscopy for Ca2+ and cell death during exposure period

Effect of lidocaine on intracellular Ca2+

Johnson: Anesthesiology 97:1466-76, 2002

Effect of lidocaine on neuronal survival

Johnson: Anesthesiology 97:1466-76, 2002

Kishimoto T, Bollen AW, Drasner K: Comparative spinal neurotoxicity of prilocaine and lidocaine. Anesthesiology 97:1250-3, 2002.

Rats received intrathecal infusions of 2.5% prilocaine, 2.5% lidocaine, or normal saline (n=30/group)

Tail-flick test day 4 Histopathologic examination day 7

Comparative spinal neurotoxicity of prilocaine and lidocaine

Kishimoto et al: Anesthesiology 97:1250-3, 2002

Postulated mechanism for nerve injury

Deficits related to anesthetic and vasoconstrictor concentrations

Selander et al. Acta Anaesthesiol Scand 1979;23:127-36. Differing concentrations of bupivacaine with and without epinephrine injected into and around sciatic nerve fascicles in rabbits

Injection beneath epineurium resulted no injury except with excessive bupivacaine concentrations

Injection beneath perineurium resulted in concentration- and vasoconstrictor-dependent axonal degeneration

Intrafascicular injection causes

neurologic deficits Hadzic et al. Reg Anesth Pain Med 2004;29:417-23. 4 mL 2% lidocaine with 1:25,000 epinephrine injected into and around sciatic nerve fascicles in dogs in 1 min

Injection beneath epineurium resulted in little injection pressure and no injury

Injection beneath perineurium resulted in high injection pressure and axonal degeneration

Summary of findings Statistical association of 4% local anesthetic solutions with higher incidence of damage

Local anesthetics are neurotoxic in clinical concentrations

Neurotoxicity is concentration dependent Clinically used local anesthetics show similar inherent neurotoxicity

The perineurium serves as a barrier to local anesthetic distribution

Intrafascicular injection appears to be required for damage

The lingual nerve has as few as 1 fascicle

Local Anesthetic Metabolism

Role of cytochrome P450 enzymes

Principal drug metabolizing enzymes

Lidocaine metabolism

Lidocaine pharmacokinetics CYP1A2 is the major determinant of lidocaine metabolism in patients with normal liver function

Liver disease reduces CYP1A2 activity

Fluvoxamine (Luvox) inhibits oxidative metabolism of lidocaine, MEGX, and GX by 60%

Orlando et al. Clin Pharmacol Ther 2004;75:80-8.

Lidocaine pharmacokinetics (2) CYP3A4 is normally a minor determinant of lidocaine metabolism in patients with normal liver function

Liver disease may not significantly reduce CYP3A4 activity

Erythromycin inhibits lidocaine metabolism by 15%-20%

Orlando et al. Br J Clin Pharmacol 2003;55:86-93.

Effect of fluvoxamine on lidocaine pharmacokinetics

ParameterPlaceb

oFluvoxami

nePlaceb

oFluvoxami

ne

CL (mL/min•k

g)12.1 4.85* 4.21* 3.65*

Vss (L/kg) 1.87 1.57 2.87* 2.55*T1/2 (hr) 2.15 4.94* 9.31† 9.17†

Healthy subjects Cirrhotic patients

Orlando et al. Clin Pharmacol Ther 2004;75:80-8.

Effect of erythromycin on lidocaine pharmacokinetics

ParameterPlaceb

oErythrom.

Placebo

Erythrom.

CL (mL/min•k

g)9.83 8.15* 5.46* 4.26*,†

Vss (L/kg) 1.47 1.34 2.44* 2.42*T1/2 (hr) 2.23 2.80* 5.77† 7.74*,†

Healthy subjects Cirrhotic patients

Orlando et al. Br J Clin Pharmacol 2003;55:86-93.

Lidocaine pharmacokinetics influenced by stress

Rats without stress compared to rats experiencing mandibular osteotomy, cold swimming stress, experimental arthritis

Lidocaine (3 mg/kg) administered every 2 hr for 5 doses.

Serum lidocaine measured 2 hr after last dose

Saranteas et al. J Oral Maxillofac Surg 2004;62:858-62.

Lidocaine pharmacokinetics influenced by stress

Saranteas et al. J Oral Maxillofac Surg 2004;62:858-62.

ControlOsteotom

y Cold

swimming

Exp. arthriti

s

Serum lidocain

e(µg/mL)

5.9 ± 1.1

9.3 ± 0.6*

8.2 ± 0.2*

8.9 ± 0.7*

Mandible (µg/g)

1.1 ± 0.1

0.6 ± 0.7*

0.6 ± 0.7*

0.8 ± 0.2*

Anesthetic efficacy of ropivacaine without vasoconstrictor for

inferior alveolar nerve block

El-Sharrawy EA, Yagiela JA. Anesth Prog

2006;53:3-7.

Study design Randomized parallel-group, dose-ranging study of 72 ASA I patients receiving mandibular 3rd molar extraction

One cartridge for inferior alveolar-lingual nerve block and buccal infiltration

Re-injection up to two times if failure of previous injections

El-Sharrawy and Yagiela. Anesth Prog 2006;53:3-7.

Onset time (soft-tissue)

Rating

Patient Response During Extraction

1 No pain throughout procedure

2 Some discomfort during procedure, but reinjection not necessary.

3 Second injection necessary, but no pain afterward.

4 Some discomfort afterward, but third injection not necessary.

5 Third injection necessary, but no pain afterward.

6 Some discomfort after third injection, but procedure completed.

7 Discomfort after third injection, and procedure postponed.

Quality of anesthesia

Quality of anesthesia (2)

Duration of anesthesia

Duration of analgesia

Lidocaine and prilocaine periodontal gel (Oraqix)

Disclaimers

Some of the information presented here was developed by Dentsply

I was a single-site principal investigator for one multisite phase 3 trial of Oraqix

Dentsply has provided a gift to UCLA for me to develop a DVD-based local anesthesia learning resource

Lidocaine and prilocaine periodontal gel 2.5%/2.5%(Oraqix)

Eutectic mixture of local anesthetics

Solution at room temperature; gel at body temperature

First topical anesthetic specifically designed for scaling and root planing

FDA approved December 19, 2003 http://www.oraqix.com

Lidocaine and prilocaine periodontal gel 2.5%/2.5%(Oraqix)

Eutectic mixture of local anesthetics

Solution at room temperature; gel at body temperature

First topical anesthetic specifically designed for scaling and root planing

FDA approved December 19, 2003

Oraqix delivery syringe

Oraqix cartridge contents

Lidocaine/prilocaine 2.5%/2.5% Poloxamers 188 and 407 HCl for pH adjustment Purified water pH 7.5-8.0