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Anxiety and Pain Control 2007

Anxiety and Pain Control 2007. John A. Yagiela, DDS, PhD Utah Dental Association Salt Lake City February 9, 2007. Oral Sedation Topics. Review of oral sedation The continuing debate over multiple dosing techniques with triazolam ADA guidelines review Reversal of triazolam with flumazenil

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Anxiety and Pain Control 2007

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

  2. Oral Sedation Topics • Review of oral sedation • The continuing debate over multiple dosing techniques with triazolam • ADA guidelines review • Reversal of triazolam with flumazenil • Special topics in patient evaluation for oral sedation

  3. Preference for Sedation/GA • Canadian telephone survey • n=1100 • 5.5% felt very nervous or terrified Chanpong et al., Anesth Prog 2005; 52:3-11

  4. Standard approaches to oral sedation (single dose) • Adults • Diazepam 2-15 mg • Lorazepam 1-4 mg • Triazolam 0.125-0.5 mg • Alprazolam 0.25-1 mg • Children • Chloral hydrate 50 mg/kg up to 1 gm • Hydroxyzine 25-100 mg (up to 1 mg/lb) • Midazolam 0.25-1 mg/kg (up to 20 mg) • Diazepam 0.25-0.6 mg/kg (up to 15 mg) • Combinations with or without opioids

  5. Oral Premedicants/Anxiolyticsof Choice • Criteria • High safety margin • Reversible • Fast onset, mixed durations • Specific agents • Benzodiazepines • Specific w1 agonists: zolpidem

  6. Mechanism of action • Binding to specific benzodiazepine receptors: • Increased binding of GABA to GABAA receptors • Increased responsiveness of chloride channels to GABA binding Benzodiazepines

  7. GABAA receptordrug binding sites

  8. Pharmacologic effects • Anxiety relief • CNS depression with high doses • Relatively shallow dose response • Anticonvulsant activity • Anterograde amnesia • Centrally mediated muscle relaxation Benzodiazepines

  9. Adverse effects • Loss of airway and respiratory depression • Paradoxical reactions (excitement, disinhibition) • Sexual fantasies • Modest dependence liability • Narrow-angle glaucoma risk • Teratogenesis potential Benzodiazepines

  10. Pharmacokinetics of benzodiazepines • Diazepam (2-15 mg) • Onset: 1 hr • Duration: 3 hr • Terminal half-life 25-50 hr (with long-acting metabolite) • Lorazepam (1-4 mg) • Onset: 1.5-2 hr • Duration: 6 hr • Terminal half-life 10-16 hr • Triazolam (0.125-0.5 mg) • Onset: 45 min • Duration: 2 hr • Terminal half-life 2-5 hr

  11. Triazolam (Halcion) • Primary therapeutic use: insomnia • Adverse effects: CNS depression, amnesia • Precautions: myasthenia gravis, pulmonary disease, narrow-angle glaucoma, C-IV controlled substance, pregnancy category X • Dosage forms: tablets: 0.125 and 0.25 mg • Directions: 0.25 (0.125-0.5) mg 30 min before bedtime or 45 min before treatment • Clinical duration: 2 hr

  12. Benzodiazepine structures N CH3 H3C N O N N N N Cl Cl Cl Diazepam Triazolam

  13. N H3C N N H3C N N N N Cl N Cl Cl Triazolam metabolism a-or 1´-hydroxylation 4-hydrox- ylation Cl Triazolam Hydroxy metabolites

  14. Pharmacokinetic drug interactions • With CYP3A4 metabolic enzyme inhibitors • Erythromycin (EES) and clarithromycin (Biaxin) • Ketoconazole (Nizoral) and related antifungal drugs • Fluvoxamine (Luvox) and related antidepressants • Ritonavir (Norvir) and related anti-AIDS drugs • Verapamil (Isoptin), diltiazem (Cardizem) and related Ca+-channel blockers • Amiodarone (Cordarone), cimetadine (Tagamet), nefazodone (Serzone), zafirlukast (Accolate), ergotamine • Quinupristin/dalfopristin (Synercid), rifabutin (Mycobutin), isoniazid (Nydrazid), • Aprepitant (Emend), imatinib (Gleevec), cyclosporine (Sandimmune) • Grapefruit juice Triazolam

  15. Pharmacokinetic drug interactions (cont.) • With 3A4 metabolic enzyme inducers • Rifampin (Rifadin) • Phenytoin (Dilantin) • Glucocorticoids • Carbamazepine (Tegretol) • Phenobarbital (and other barbiturates) • Modafinil (Provigil) • St. John’s wort (hypericum) • Cigarette smoke (aryl hydrocarbons) Triazolam

  16. Enhanced efficacy of sublingual triazolam • SL triazolam (0.25 mg) more effective than oral triazolam in reducing anxiety and pain during oral surgery • SL triazolam resulted in higher peak plasma concentrations but no difference in recovery rate or side effects Berthold et al: Oral Surg 84:119-24, 19997

  17. Enhanced bioavailability of sublingual triazolam (0.5 mg) • Peak plasma concentrations, times • SL: 4.7 ng/mL, 1.22 hr • Oral: 3.9 ng/mL, 1.25 hr • Metabolic half-lives • SL: 4.1 hr • Oral: 3.7 hr • SL has 28% greater bioavailability Scavone et al: J Clin Pharmacol 26:208-10, 1986

  18. DOCS: Dental Organization for Conscious Sedation • Brainchild of Dr. Mark Silverman • Aim was to provide the benefits of conscious sedation without impediments of state regulations, advanced training requirements • Early courses to the profession touted “Sleep Dentistry” using multiple doses of triazolam (Halcion) Introduction

  19. Main Concerns of Dental Organizations and Regulatory Agencies • “Sleep dentistry” was either misleading advertising or promoted unlawful drug administration • Weekend courses largely devoted to marketing have resulted in inadequately educated clinicians • Giving additional doses before the full effects of the first dose have occurred may result in oversedation • “Titration of oral medication for the purposes of sedation is unpredictable. Repeated dosing of orally administered sedative agents may result in an alteration of the state of consciousness beyond the intent of the practitioner.” (ADA Guidelines)

  20. Stacked oral dosing (0.25 mg) every 30 min Triazolam (ng/mL) Time (hr)

  21. Comparative Kinetics and Response to Triazolam (0.25 mg) Data from Greenblatt et al: J Pharmacol Exp Ther 293:435-43, 2000.

  22. Acute tolerance to triazolam 2.5 2 1.5 Symbol Digit Substitution Latency (sec) Triazolam (ng/mL) 1 0.5 0 Data from Kroboth et al: J Pharmacol Exp Ther 264:1047-55, 1993

  23. Enhanced bioavailability of sublingual triazolam (0.5 mg) • Peak plasma concentrations, times • SL: 4.7 ng/mL, 1.22 hr • Oral: 3.9 ng/mL, 1.25 hr • Metabolic half-lives • SL: 4.1 hr • Oral: 3.7 hr • SL has 28% greater bioavailability Scavone et al: J Clin Pharmacol 26:208-10, 1986

  24. Fatalities with oral benzodiazepines • Adult cases • Most involve suicide attempts • Several involve triazolam alone • Very rare in a therapeutic setting

  25. Fatalities with oral benzo-diazepines (2) • Overweight teenage football player received multiple doses of alprazolam (Xanax) for oral sedation • Leaves the office awake, ambulatory with assistance • Cardiac arrest at home

  26. Fatalities with oral benzo-diazepines (3) • Man receives multiple doses of triazolam (Halcion) for oral sedation • Leaves the office awake, ambulatory • Argues with wife and drives home • Fatal car crash

  27. Nonfatal reaction to oral triazolam • 30 y.o. woman in good health receives 2 mg of triazolam (Halcion) (eight 0.25 mg tablets) for oral sedation over 6 hr period • Prescribed Vicodin (500 mg acetaminophen/ 5 mg hydrocodone) for postoperative pain to take 1 tab every 4-6 hr • Husband notices patient taking four tablets in 15 min • Patient has no memory of entire evening

  28. Prescription for Fatality Large doses of multiple medications Lack of appropriate monitoring Lack of effective emergency response Premature discharge home Discharge shortly after reversal of sedation Operation of dangerous machinery Failure to remember postoperative instructions, drug use Elderly, frail patients

  29. Age-related differences in midazolam responsiveness Potency ratio 4

  30. Pharmacokinetics and Clinical Effects of Multidose Sublingual Triazolam in Healthy Volunteers Jackson DL, Milgrom P, Heacox GA, Kharasch ED J Clin Psychopharmacol 2006;26(1):4-8

  31. Study Design and Measures 0.25 mg 0.5 mg 0.25 mg 0.2 mg Jackson et al: J Clin Psychopharmacol 26:4-8, 2006

  32. Observer’s Assessment of Alertness/Sedation (OA/AS) Scale Jackson et al: J Clin Psychopharmacol 26:4-8, 2006

  33. Objectives • To evaluate the CNS depression evoked by the repeated dosing of sublingual triazolam, to a total dose of 1.0 mg, in healthy adults, • To determine the time-dependent plasma concentrations of triazolam in a repeated dosing paradigm, • To compare the efficacy of a single intraoral submucosal (SL, tongue), intramuscular (IM), and intravenous (IV) injection of flumazenil (0.2 mg) at reversing the sedative effects of triazolam.

  34. Clinical Interpretation of Bispectral Analysis BIS Score Clinical State 100 awake sedated 60 moderate hypnotic level 40 deep hypnotic level 0 isoelectric EEG, total suppression Rosow C - Anesthesiol Clin North America - 01-DEC-2001; 19(4): 947-66, xi

  35. Observer Rating of Sedation During Incremental Triazolam Dosing by Subject Jackson et al: J Clin Psychopharmacol 26:4-8, 2006

  36. Bispectral Analysis During Incremental Triazolam Dosing by Subject Jackson et al: J Clin Psychopharmacol 26:4-8, 2006

  37. 100 80 60 #569 #570 #571 40 #572 #573 #574 #575 #576 20 #577 #578 0 0 60 120 Psychomotor Function Assessment (Digit Symbol Substitution Test) Jackson et al: J Clin Psychopharmacol 26:4-8, 2006 subject # DSST Raw Score 0.25 mg 0.5 mg 0.25 mg triazolam triazolam triazolam Time (minutes)

  38. Time-Dependent Changes in Plasma Concentrations of Triazolam by Subject Jackson et al: J Clin Psychopharmacol 26:4-8, 2006

  39. Risk-benefit considerations • There is a strong need and demand for sedation services not currently met by available resources for general dentistry • Safety is of paramount concern • Safety of enteral sedation should be at least as good as alternative methods of anesthesia care USP Workshop

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