Halcion: Yesterday, Today, and Tomorrow

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  • 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 receptor drug 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 forsleep 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. Johns 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 1970s, ideal and revolutionary in the treatmentof 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 drugs 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 benzos of the time (Dalmane and Restoril) even-though less used.

Source:Halcion:Its the Most Widely Prescribed Sleeping Pill in the World.But is it Safe?NewsweekAug 19, 1991 13. Responses

  • Halcions 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 FDAs 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

  • Halcions first chapter with unhappy ending
  • Halcion falls out of favor for insomnia as the 1990s 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 dentistrys 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.com 2006 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 1990s- 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 patients ability to independently and continuously maintain an airway and respond appropriately to physical stimulation.

25. Semantics andExtremeMarketing

  • As negative publicity surrounds sleep dentistry, DOCS attempts to dissociatefrom 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 aTitratedOral 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 Res