Halcion: Yesterday, Today, and Tomorrow

1. Halcion: Yesterday, Today, and Tomorrow Sean G. Boynes, DMD, MS University of Pittsburgh School of Dental Medicine Department of Anesthesiology

2. Halcion (Triazolam) • Triazolam is a benzodiazepine with a very short elimination half-life and metabolized via hepatic microsomal oxidation or glucorondidation.

3. Mechanism of action • Binding to specific benzodiazepine receptors: • Increased binding of GABA to GABA-A receptors • Increased responsiveness of chloride channels to GABA binding

4. GABA-A receptordrug binding sites

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

6. Triazolam (Halcion) • Primary therapeutic use: insomnia: Halcion is labeled for sleep problems that are usually temporary, requiring treatment for only a short time, usually 1 or 2 days and no more than 1 to 2 weeks. • 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

7. 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

8. 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)

9. Side Effects • Common side effects include: Coordination problems, dizziness, drowsiness, headache, light-headedness, nausea/vomiting, nervousness • Traveler's amnesia" has been reported by patients who took Halcion to induce sleep while traveling. To avoid this condition, it is recommended to not take Halcion on an overnight flight of less than 7 to 8 hours.

10. In the Beginning… • When the first benzodiazepines hit the market in the early 1970’s, ideal and revolutionary in the treatment of sleep disorders (barbiturates) • The Upjohn produced, Halcion approved at doses of up to a full milligram in 1977 • Marketed as ultimate sleep aid and hits America in 1983

11. Yesterday… • Issues with Halcion in Belgium and Holland… August 1979 Dutch authorities suspended the drug’s license for six months • In early 1980, the Dutch government reauthorized 0.25mg dose but banned higher ones- Upjohn leaves not to be reintroduced until 1990

12. 1984 • Half milligram doses of Halcion hit U.S. market • Turbulent first years: In a report, the FDA noted that Halcion racked up 8 to 30 times as many adverse-reaction reports as mainstay benzo’s of the time (Dalmane and Restoril) even-though less used. Source: Halcion: It’s the Most Widely Prescribed Sleeping Pill in the World. But is it Safe? Newsweek Aug 19, 1991

13. Responses • Halcion’s high complaint rate not unique to America • French and Italian regulators forced the half-milligram from their market • Upjohn voluntarily lowered the recommended starting dose from a half milligram to a quarter in the U.S. and under FDA pressure, the company also acknowledged a revised package insert (“bizarre or abnormal behavior, agitation and hallucinations”)

14. Responses • 1989 – FDA’s Psychopharmacological Drugs Advisory Committee agreed that Halcion needed stronger amnesia warnings but after hearing several Upjohn reps voted not to require any other special measures • Issues with rebound ensue

15. Bad Publicity • Cindy Ehrlich – Fall of 1989, California magazine told story of depression and anxiousness (“ [I was] convinced that the world was on the brink of nuclear war or invasion from space.” • Piece prompted a flurry of publicity

16. Bad Publicity • 1991 Newsweek article tells a story of murder, severe depression, and the elderly waking up in town squares across the country

17. Fall from Grace • Halcion’s first chapter with unhappy ending • Halcion falls out of favor for insomnia as the 1990’s conclude • Alternative treatments: Ambien (new controversy); ProSom; Lunesta; Melontonin; Benadryl; etc…

18. Today…

19. New Beginnings • New use (off-label) in dental offices {Initial standard of 0.25mg with Nitrous Oxide} • “Sleep Dentistry” begins to seep into dentistry’s mainstream vernacular • Dental Anxiety becomes a main topic of discussion

20. Dental Anxiety • 23 million people with dental fear are more willing to see a dentist if a form of sedation is offered.1 • The use of sedation techniques are progressively important as a safe and successful method of anxiolysis for use by dental professionals.2 • Dionne, RA et al. Assessing the need for anesthesia and sedation in the general population. JADA. 1998; 129: 167-73. • Girdler NM, Hill CM. Sedation in Dentistry. Oxford: Butterworth Heinemann, 1998.

21. Dental Anxiety • A public opinion poll demonstrated that 79% of the polled public preferred to “sleep” during dental treatment. • This same population was then asked what type of sedation they preferred. • 40% - Oral Sedation • 35% - IV • 17% - Nitrous Oxide • 6% - Other Source: www.dentalpolls.com2006

22. Dental Anxiety • In a recent survey, 93.7% of 2003 graduates responded that they perceive a need from there dental population for sedation services. Source: Boynes SG, Lemak AL, Close J. A Survey of Anesthesia Sedation Education in Dental Schools of the United States. (ADEA-In Press)

23. “Sleep Dentistry” • Mid 1990’s- sleep dentistry is marketed as a dental appointment while you sleep • Stacked dose technique introduced • DOCS organization officially formed in 2000 (major marketing) • A heavy anesthetic?

24. Anxiolysis Vs. Conscious Sedation • Concern with what level of sedation is being achieved with this new technique • Anxiolysis - Drug induced state of consciousness in which a patient still has the capability to respond to verbal command with a sustained cognitive function. • Conscious Sedation – A minimally depressed level of consciousness retaining the patient’s ability to independently and continuously maintain an airway and respond appropriately to physical stimulation.

25. Semantics and Extreme Marketing • As negative publicity surrounds “sleep dentistry”, DOCS attempts to dissociate from the term • DOCS initiates impressive marketing campaign • Becomes major focus of new dental controversy

26. In the mainstream… • At the start of the new millennium, the DOCS technique was a well known entity in the dental profession • Issues with DOCS marketing education • Stacked dose technique initially marketed as a Titrated Oral Sedation

27. Methodology • Begins with 0.25mg of triazolam orally at one hour prior to appointment • Followed with another 0.25mg orally at the time of appointment • Then, 0.125mg sublingually 45 minutes into the procedure • Continued additional doses of 0.125mg sublingually as patient sedation need merits • Note: There is much variation with the stacked-dose method -As presented at the Anesthesia Research Foundation Workshop on Enteral Sedation in Dentistry. Washington D. C. 2003

28. Bad publicity… again • Great deal of negativity surrounding “sleep dentistry” • Reports of deaths and adverse events begin to surface

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

30. 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)

31. Organized Dentistry Responds • ADA reiterates guidelines • AGD takes stance it feels supports general practitioner • Anesthesia Research Foundation Workshop on Enteral Sedation in Dentistry takes place in Washington D.C.

32. Anesthesia Research Foundation Workshop on Enteral Sedation in Dentistry: Washington D.C. • In 2003, really the first time all sides of the controversy were together • Ideas for guidelines and management • Publish findings: April 2006 JADA • Opened discussions for proper research and ways to obtain funding

33. The Research • Very little data with triazolam in dentistry • Difficult (if not impossible) to obtain good funding • Off-labeled use • Safety • Reversal Agents

34. The Research • Dr. David Greenblatt • In an estimated representation of plasma concentrations, with stacked dosing every 30 minutes, presented data to suggest a plasma concentration that would increase approximately two-fold (ng/mL) with each 0.25mg dose • The terminal peak plasma level of the stacked dose, when compared with the single dose technique, suggests a plasma level difference at an estimated increase of approximately 4ng/mL Source: Greenblatt et al: J Pharmacol Exp Ther 293:435-43, 2000.

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

36. The Research • Dr. Scavone • 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 Source: Scavone et al: J Clin Pharmacol 26:208-10, 1986

37. The Research • Reversal Agents • Flumazenil (Romazicon) benzodiazepine reversal agent • When administered through IV, reverses sedation and psychomotor impairment within 5 minutes of administration and demonstrates an onset time of approximately one minute with the recommended dosage Source: Bloom JW et al. Clin Ther. 1992 Nov-Dec;14(6):910-23.

38. The Research • Flumazenil • Recommended initial dose of Romazicon is 0.2 mg administered intravenously over 15 seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds, a second dose of 0.2 mg can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL). The dosage should be individualized based on the patient’s response. • Resedation Source: Morgan GE, Mikhail MS, Murray MJ. Clinical Anesthesiology, ed. 3. New York; McGraw-Hill, 2002.

39. The Research • Flumazenil (continued) • Additional Routes of Administration (Sublingual, Intramuscular, [Intranasal]?) • 1997- Heniff et al. presented an analysis of flumazenil • Intramuscular – 5.17 minutes • Sublingual – 4.37 minutes • Intravenous – 120 seconds Source: Heniff et al. Acad Emerg Med. 4: 1115-8: 1997

40. The Research • Dr.’s Doug Jackson and Peter Milgrom • Most current research available • Evaluated the sedation level of ten patients administered a stacked dose of triazolam • J Clin Psychopharmacol 2006;26(1):4-8

41. 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.

42. 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

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

44. 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

45. Observer Rating of Sedation During Incremental Triazolam Dosing by Subject

46. Bispectral Analysis During Incremental Triazolam Dosing by Subject

47. Time-Dependent Changes in Plasma Concentrations of Triazolam by Subject

48. 5 4 3 2 Tongue (n=5) IM (n=3) IV (n=2) 1 150 180 210 240 Observer Rating of Sedation Post Flumazenil (0.2 mg) Administration Sedation Score flumazenil admin. Time (minutes post-1st SL triazolam dose)

49. flumazenil admin.

50. Rebound Sedation at the Time of Discharge • Four subjects required an additional dose of flumazenil (0.2 mg, IV) 60 minutes after the initial dose: • IV: 1 subject • IM: 1 subject • SL: 2 subjects Jackson et al: J Clin Psychopharmacol 26:4-8, 2006