Anxiety and Pain Control 2007

1. Anxiety and Pain Control 2007 John A. Yagiela, DDS, PhD Utah Dental Association Salt Lake City February 9, 2007

2. 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

3. 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

4. CH CH 3 3 H H 3 3 Articaine (Septocaine, Zorcaine): a thiophene derivative O O H H NHC CH N NHC CH N S C H C H 3 7 3 7 C C COOCH 3 Articaine Prilocaine

5. Mean Sensory Voltage: First Premolar 300 F B F B F 250 F B F F B B A B B A J A F F J F A J F J F E J E A B E F J J B E J A A A J A F E 200 E J B J F J F J E E J J J A B B B J J E B F E A E A B B B A ∆ Voltage (V) F A A A E E 150 A E Lid-2%-H E A E F E B B E Ult-2%-L E 100 Ult-2%-H J Ult-4%-L A 50 Ult-4%-H F 0 E A F B J 0 10 20 30 40 50 60 70 80 90 Time (min)

6. VAS pain scores 4% A + Epi 2% L + Epi Malamed SF, et al. J Am Dent Assoc 131:635-42, 2000

7. 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%)

8. 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

9. Local anesthesia use in Germany (1996) 2% 3% Articaine 4% 91% Lidocaine Mepivacaine Others

10. Local anesthesia use in Canada (1999) Articaine 12% Prilocaine 46% 32% Lidocaine Mepivacaine 6% 4% Bupivacaine

11. 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

12. Reported cases of paresthesiaby year Articaine marketed Haas DA, Lennon D: J Can Dent Assoc 61:297-304, 1995

13. Incidence data • Articaine and prilocaine: 91% of cases • 1993 incidence by agent • Articaine: 1/440,000 • Prilocaine: 1/588,000 • Lidocaine: none • Mepivacaine: none Haas DA, Lennon D: J Can Dent Assoc 61:297-304, 1995

14. 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

15. Cases of nerve injury by year Articaine marketed Hillerup S, Jensen R: Int J Oral Maxillofac Surg 35:437-43, 2006

16. 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

17. 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

18. Effect of lidocaine on intracellular Ca2+ Johnson: Anesthesiology 97:1466-76, 2002

19. Effect of lidocaine on neuronal survival Johnson: Anesthesiology 97:1466-76, 2002

20. 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

21. Comparative spinal neurotoxicity of prilocaine and lidocaine Kishimoto et al: Anesthesiology 97:1250-3, 2002

22. Postulated mechanism for nerve injury

24. 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

25. 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

26. 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

27. Local Anesthetic Metabolism Role of cytochrome P450 enzymes

28. Principal drug metabolizing enzymes

29. Lidocaine metabolism

30. 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.

31. 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.

32. Effect of fluvoxamine on lidocaine pharmacokinetics Healthy subjects Cirrhotic patients Orlando et al. Clin Pharmacol Ther 2004;75:80-8.

33. Effect of erythromycin on lidocaine pharmacokinetics Healthy subjects Cirrhotic patients Orlando et al. Br J Clin Pharmacol 2003;55:86-93.

34. 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.

35. Lidocaine pharmacokinetics influenced by stress Saranteas et al. J Oral Maxillofac Surg 2004;62:858-62.

36. Anesthetic efficacy of ropivacaine without vasoconstrictor for inferior alveolar nerve block El-Sharrawy EA, Yagiela JA. Anesth Prog 2006;53:3-7.

37. 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.

38. Onset time (soft-tissue)

39. Quality of anesthesia

40. Quality of anesthesia (2)

41. Duration of anesthesia

42. Duration of analgesia

43. Lidocaine and prilocaine periodontal gel (Oraqix)

44. 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

45. 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

47. 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

48. Oraqix delivery syringe

49. Oraqix cartridge contents • Lidocaine/prilocaine 2.5%/2.5% • Poloxamers 188 and 407 • HCl for pH adjustment • Purified water • pH 7.5-8.0