Halcion: Yesterday, Today, and Tomorrow
Sean G. Boynes, DMD, MSUniversity of Pittsburgh School of Dental Medicine
Department of Anesthesiology
Halcion (Triazolam)
Triazolam is a benzodiazepine with a very short elimination half-life and metabolized via hepatic microsomal oxidation or glucorondidation.
Mechanism of action
Binding to specific benzodiazepine receptors: Increased binding of GABA to GABA-A
receptors Increased responsiveness of chloride
channels to GABA binding
GABA-A receptordrug binding sites
Pharmacologic effects
Anxiety relief
CNS depression with high doses
Relatively shallow dose response
Anticonvulsant activity
Anterograde amnesia
Centrally mediated muscle relaxation
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, amnesiaPrecautions: myasthenia gravis, pulmonary disease, narrow-angle glaucoma, C-IV controlled substance, pregnancy category XDosage forms: tablets: 0.125 and 0.25 mgDirections: 0.25 (0.125-0.5) mg 30 min before bedtime or 45 min before treatmentClinical duration: 2 hr
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
Pharmacokinetic Drug Interactions (cont.)
With 3A4 metabolic enzyme inducersRifampin (Rifadin)Phenytoin (Dilantin)GlucocorticoidsCarbamazepine (Tegretol)Phenobarbital (and other barbiturates)Modafinil (Provigil)St. John’s wort (hypericum)Cigarette smoke (aryl hydrocarbons)
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.
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 1977Marketed as ultimate sleep aid and hits America in 1983
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
1984Half milligram doses of Halcion hit U.S. marketTurbulent 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
ResponsesHalcion’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”)
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
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
Bad Publicity
1991 Newsweek article tells a story of murder, severe depression, and the elderly waking up in town squares across the country
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…
Today…
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
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
1. Dionne, RA et al. Assessing the need for anesthesia and sedation in the general population. JADA. 1998; 129: 167-73.
2. Girdler NM, Hill CM. Sedation in Dentistry. Oxford: Butterworth Heinemann, 1998.
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 Sedation35% - IV17% - Nitrous Oxide6% - Other
Source: www.dentalpolls.com 2006
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)
“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?
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.
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
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
MethodologyBegins with 0.25mg of triazolam orally at one hour prior to appointmentFollowed with another 0.25mg orally at the time of appointmentThen, 0.125mg sublingually 45 minutes into the procedureContinued additional doses of 0.125mg sublingually as patient sedation need meritsNote: 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
Bad publicity… again
Great deal of negativity surrounding “sleep dentistry”
Reports of deaths and adverse events begin to surface
Fatalities with triazolam
Adult casesMost involve suicide attemptsSeveral involve triazolam aloneVery rare in a therapeutic setting
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)
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.
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
The Research
Very little data with triazolam in dentistryDifficult (if not impossible) to obtain good fundingOff-labeled useSafetyReversal Agents
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.
Time (hr)
Stacked oral dosing (0.25 mg)every 30 min
Triazolam (ng/mL)
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
The Research
Reversal AgentsFlumazenil (Romazicon) benzodiazepine
reversal agentWhen 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.
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.
The Research
Flumazenil (continued)Additional Routes of Administration
(Sublingual, Intramuscular, [Intranasal]?)1997- Heniff et al. presented an analysis of
flumazenil Intramuscular – 5.17 minutesSublingual – 4.37 minutes Intravenous – 120 seconds
Source: Heniff et al. Acad Emerg Med. 4: 1115-8: 1997
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 triazolamJ Clin Psychopharmacol 2006;26(1):4-8
ObjectivesTo 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.
0.2 mg
0.25 mg
0.5 mg
0.25 mg
Study Design and Measures
time triazolam admin.
flumazenil admin.
blood sample (5 ml)
vital signs (BP, HR, RR, SaO2)
sedation rating
(observer)
bispectral analysis
sedation self-report
(participant)
cognitive/ psychomotor
(DSST)
T0 T30 T60 T90 T120 T150 T180 T185 T190 T200 T240
Jackson et al: J Clin Psychopharmacol 26:4-8, 2006
Observer’s Assessment of Alertness/Sedation (OA/AS) Scale
Responsiveness SpeechFacial
ExpressionEyes Score
Readily/
Normal toneNormal Normal No ptosis 5
LethargicMild
slurring
Mild
relaxationGlazed 4
Responds after
loud callingSlurring
Marked
relaxation
Marked
ptosis 3
Responds after
mild prodding
Few words
recognizable
Marked
relaxation
Marked
ptosis 2
No response to
prodding/shakingNo words
Marked
relaxation
Marked
ptosis 1
Jackson et al: J Clin Psychopharmacol 26:4-8, 2006
Clinical Interpretation of Bispectral Analysis BIS Score Clinical State
100
0
60
40
awake
sedated
moderate hypnotic level
deep hypnotic level
isoelectric EEG, total suppression
Rosow C - Anesthesiol Clin North America - 01-DEC-2001; 19(4): 947-66, xi
18015012090603000
1
2
3
4
5
569570571572573574575576577578AVERAGE
Time (minutes post-1st SL triazolam dose)
OA
A/S
Sco
re
0.25 mg 0.25 mg0.5 mg
Observer Rating of Sedation During Incremental Triazolam Dosing by Subject
180150120906030030
40
50
60
70
80
90
100
569570571572573574575576577578AVERAGE
Time (minutes post-1st SL triazolam dose)
BIS
Sco
re
0.25 mg 0.25 mg0.5 mg
Bispectral Analysis During Incremental Triazolam Dosing by Subject
18015012090603000
1
2
3
4
5
6
7
8
569570571572573574575576577578AVERAGE
Time (minutes post-1st SL triazolam dose)
Pla
sma C
oncentr
ation o
f Tr
iazo
lam
(ng/m
l)
0.25 mg 0.25 mg0.5 mg
Time-Dependent Changes in Plasma Concentrations of Triazolam by Subject
2402101801501
2
3
4
5
Tongue (n=5)IM (n=3)IV (n=2)
Observer Rating of Sedation Post Flumazenil (0.2 mg) Administration
Time (minutes post-1st SL triazolam dose)
Sedation Score
flumazeniladmin.
24021018015030
40
50
60
70
80
90
100
tongue (n=5)IM (n=3)IV (n=2)
Bispectral Analysis Post Flumazenil (0.2 mg) Administration
time (minutes post-1st SL triazolam dose)
Bis
pect
ral S
core
flumazeniladmin.
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 subjectsJackson et al: J Clin Psychopharmacol 26:4-8, 2006
The Research
Conclusions (Jackson et al.)
“Given the considerable inter-subject variability in triazolam concentrations and effects, additional research is needed to assess this multidosing strategy before it can be endorsed as a useful and safe sedation sedation technique for managing fearful and anxious patients in dental practice.”
Meanwhile… Back at the Batcave
Individual State Dental Boards begin to determine new anesthesia regulations
Variation (as usual) with how the new regulations were set up
Minimum and Maximum requirements set depending on which state
State Regulations
Oral conscious sedation permits are issued
Requirements needed in order to obtain permit
State’s vary in definition and needed requirements
Change…Again
DOCS changes format of CE coursesFocus more on safety – emergency
management, airway techniques, stress proper monitoring, stress BLS/ACLS
From anxiolysis to oral conscious sedationState techniques only for 18 years of age
and olderEliminate a large portion of course being
dedicated to marketingTry to produce research
Tomorrow…
The Future
Need more research
What is the role of the general practitioner in anxiolysis?
A need for more organized regulation
Guideline and Accreditation Change
What is the role of the dental schools?
Specify how many demonstrations and/or hands-on sedation cases you participated in
during your dental school career.
0
10
20
30
40
50
60
0
Cases
11-20
Cases
31 or
More
ValidPercent
Rate the quality of education at the institution you graduated in the following categories by circling
the number that corresponds to your rating.
05
101520253035404550
Excellent Average Poor
N2O
OralSedIV
Conclusion: Safeguards for oral sedation beyond anxiolysis
Continual monitoring of patient for consciousness
Continuous monitoring of pulse oximetry, heart rate
Continual monitoring of blood pressure
Use of reversal agent if patient drifts into unconsciousness and cannot be aroused
Staying within your (comfortable) training level
Prescription for fatalityLarge doses of multiple medicationsLack of appropriate monitoringLack of effective emergency responsePremature discharge homeDischarge shortly after reversal of sedation Operation of dangerous machineryFailure to remember postoperative
instructions, drug useElderly, frail patients
Conclusion: Safeguards for oral sedation beyond anxiolysis
Thank You
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