anxiety and pain control 2007 john a. yagiela, dds, phd utah dental association salt lake city...
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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