Transcript Halcion: Yesterday, Today, and Tomorrow

Halcion: Yesterday,
Today, and Tomorrow
Sean G. Boynes, DMD, MS
University 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 receptor
drug 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, 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
Pharmacokinetic Drug Interactions
With CYP3A4 metabolic enzyme inhibitors
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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 inducers
Rifampin (Rifadin)
 Phenytoin (Dilantin)
 Glucocorticoids
 Carbamazepine (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 1977
Marketed 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
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
Responses
Halcion’s high complaint rate not unique to
America
French and Italian regulators forced the halfmilligram 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 Sedation
 35% - IV
 17% - Nitrous Oxide
 6% - 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
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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
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
Bad publicity…
again
Great deal of negativity surrounding
“sleep dentistry”
Reports of deaths and adverse events
begin to surface
Fatalities with
triazolam
Adult cases
Most involve suicide attempts
 Several involve triazolam alone
 Very rare in a therapeutic setting
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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 dentistry
Difficult (if not impossible) to obtain good
funding
Off-labeled use
Safety
Reversal Agents
The Research
Dr. David Greenblatt
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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.
Triazolam (ng/mL)
Stacked oral dosing (0.25 mg)
every 30 min
Time (hr)
The Research
Dr. Scavone
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Enhanced bioavailability of sublingual triazolam
(0.5 mg)
Peak plasma concentrations, times
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SL: 4.7 ng/mL, 1.22 hr
Oral: 3.9 ng/mL, 1.25 hr
Metabolic half-lives
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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 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.
The Research
Flumazenil
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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 minutes
 Sublingual – 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
triazolam
J Clin Psychopharmacol 2006;26(1):4-8
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.
Study Design and
Measures
time
T0
T30
T60
T90
T120
T150
T180
T185
T190
T200
T240
triazolam
admin.
flumazenil
admin.
0.25 mg
0.5 mg
0.25 mg
0.2 mg
blood
sample
(5 ml)
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
vital signs
(BP, HR,
RR, SaO2)
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sedation
rating
(observer)
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bispectral
analysis
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cognitive/
sedation
self-report psychomotor
(DSST)
(participant)
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Jackson et al: J Clin Psychopharmacol 26:4-8, 2006
Observer’s Assessment of
Alertness/Sedation (OA/AS)
Scale
Responsiveness
Speech
Facial
Expression
Eyes
Score
Readily/
Normal tone
Normal
Normal
No ptosis
5
Lethargic
Mild
slurring
Mild
relaxation
Glazed
4
Responds after
loud calling
Slurring
Marked
relaxation
Marked
ptosis
3
Responds after
mild prodding
Few words
recognizable
Marked
relaxation
Marked
ptosis
2
No response to
prodding/shaking
No words
Marked
relaxation
Marked
ptosis
1
Jackson et al: J Clin Psychopharmacol 26:4-8, 2006
Clinical Interpretation of Bispectral Analysis
BIS Score
100
Clinical State
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
Observer Rating of Sedation During Incremental Triazolam Dosing
by Subject
5
OAA/S Score
4
3
569
570
571
572
573
574
575
576
577
578
AV E RAGE
2
1
0
0
0.25 mg
30
60
0.5 mg
90
120
0.25 mg
T ime (minutes post-1st SL triazolam dose)
150
180
Bispectral Analysis During Incremental Triazolam Dosing
by Subject
100
90
BIS Score
80
569
570
571
572
573
574
575
576
577
578
AV E RAGE
70
60
50
40
30
0
0.25 mg
30
60
0.5 mg
90
120
0.25 mg
T ime (minutes post-1st SL triazolam dose)
150
180
Time-Dependent Changes in Plasma Concentrations of Triazolam
by Subject
Plasma Concentration of Triazolam (ng/ml)
8
7
6
5
4
569
570
571
572
573
574
575
576
577
578
AVERAGE
3
2
1
0
0
0.25 mg
30
60
90
0.5 mg
0.25 mg
120
150
T ime (mi nutes pos t-1s t SL tri azolam dos e)
180
Observer Rating of Sedation Post Flumazenil (0.2 mg) Administration
Sedation Score
5
4
3
2
Tongue (n=5)
IM (n=3)
IV (n=2)
flumazenil
admin.
1
150
180
210
240
Time (minutes post-1st SL triazolam dose)
Bispectral Analysis Post Flumazenil (0.2 mg) Administration
100
Bispectral Score
90
80
70
60
50
40
30
150
tongue (n=5)
IM (n=3)
IV (n=2)
flumazenil
admin.
180
210
time (minutes post-1st SL triazolam dose)
240
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
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 courses
Focus more on safety – emergency
management, airway techniques, stress
proper monitoring, stress BLS/ACLS
 From anxiolysis to oral conscious sedation
 State techniques only for 18 years of age
and older
 Eliminate a large portion of course being
dedicated to marketing
 Try 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.
60
50
40
30
20
10
0
0
Cases
11-20
Cases
31 or
More
Valid
Percent
Rate the quality of education at the institution you
graduated in the following categories by circling
the number that corresponds to your rating.
50
45
40
35
30
25
20
15
10
5
N2O
0
Oral
Sed
IV
Excellent
Average
Poor
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
Conclusion: Safeguards for oral
sedation beyond anxiolysis
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

Thank You