Transcript Anxiety and Pain Control 2007 Part 1 - February 9

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
 Special topics in patient evaluation for oral
sedation
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
Standard approaches to oral
sedation (single dose)
 Adults
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Diazepam 2-15 mg
Lorazepam 1-4 mg
Triazolam 0.125-0.5 mg
Alprazolam 0.25-1 mg
 Children
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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
Oral Premedicants/Anxiolytics
of Choice
 Criteria
 High safety margin
 Reversible
 Fast onset, mixed durations
 Specific agents
 Benzodiazepines
 Specific w1 agonists: zolpidem
Mechanism of action
 Binding to specific benzodiazepine
receptors:
Increased binding of GABA to GABAA
receptors
 Increased responsiveness of chloride
channels to GABA binding
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Benzodiazepines
GABAA 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
Benzodiazepines
Adverse effects
 Loss of airway and respiratory depression
 Paradoxical reactions (excitement,
disinhibition)
 Sexual fantasies
 Modest dependence liability
 Narrow-angle glaucoma risk
 Teratogenesis potential
Benzodiazepines
Pharmacokinetics of
benzodiazepines
 Diazepam (2-15 mg)
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Onset: 1 hr
Duration: 3 hr
Terminal half-life 25-50 hr (with long-acting
metabolite)
 Lorazepam (1-4 mg)
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Onset: 1.5-2 hr
Duration: 6 hr
Terminal half-life 10-16 hr
 Triazolam (0.125-0.5 mg)
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Onset: 45 min
Duration: 2 hr
Terminal half-life 2-5 hr
Table 13-3.
Metabolism of benzodiazepines

-Hydroxy
metabolites
Long-acting
metabolites
3-Hydroxy
compounds
Glucuronide
conjugates
Chlordiazepoxide
Lorazepam
Desmethylchlordiazepoxide
Demoxepam
Temazepam
Clorazepate
Diazepam
Halazepam
Prazepam
Nordazepam
Oxazepam
N-Hydroxyethylflurazepam
N-desalkylflurazepam
3-Hydroxy
derivatives
Flurazepam
Quazepam
2-Oxo-quazepam
Estazolam
Alprazolam
Midazolam
Triazolam
-Hydroxy
derivatives
Drugs available for clinical use are listed in bold type. With the exception of the prodrugs clorazepate
and prazepam, only the glucuronide conjugates are inactive.
Triazolam (Halcion)
 Primary therapeutic use: insomnia
 Adverse effects: CNS depression, amnesia
 Precautions: myasthenia gravis, pulmonary disease, narrowangle 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
Benzodiazepine structures
CH3
H3C
O
N
N
N
Cl
N
N
Cl
N
Cl
Diazepam
Triazolam
Triazolam metabolism
- or 1´-hydroxylation
N
H3C
H3C
N
N
Cl
N
N
N
N
Cl
Cl
Triazolam
4-hydroxylation
N
Cl
Hydroxy metabolites
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
Triazolam
Pharmacokinetic drug
interactions (cont.)
 With 3A4 metabolic enzyme inducers
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Rifampin (Rifadin)
Phenytoin (Dilantin)
Glucocorticoids
Carbamazepine (Tegretol)
Phenobarbital (and other barbiturates)
Modafinil (Provigil)
St. John’s wort (hypericum)
Cigarette smoke (aryl hydrocarbons)
Triazolam
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
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
Scavone et al: J Clin Pharmacol 26:208-10, 1986
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
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)
Triazolam (ng/mL)
Stacked oral dosing (0.25 mg)
every 30 min
Time (hr)
Comparative Kinetics and Response to
Triazolam (0.25 mg)
Data from
Greenblatt et al:
J Pharmacol Exp
Ther 293:435-43,
2000.
8
2.5
7
SDS Triazolam
SDS Placebo
Triazolam (ng/mL)
6
5
4
3
2
1.5
1
2
0.5
1
0
Triazolam (ng/mL)
Symbol Digit Substitution Latency (sec)
Acute tolerance to triazolam
0
0
1
2
3
4
5
6
7
8
Data from Kroboth et al: J Pharmacol Exp Ther 264:1047-55, 1993
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
Scavone et al: J Clin Pharmacol 26:208-10, 1986
Fatalities with oral
benzodiazepines
 Adult cases
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Most involve suicide attempts
Several involve triazolam alone
Very rare in a therapeutic setting
Fatalities with oral benzodiazepines (2)
 Overweight teenage football player received
multiple doses of alprazolam (Xanax) for
oral sedation
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Leaves the office awake, ambulatory with
assistance
Cardiac arrest at home
Fatalities with oral benzodiazepines (3)
 Man receives multiple doses of triazolam
(Halcion) for oral sedation
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Leaves the office awake, ambulatory
Argues with wife and drives home
Fatal car crash
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
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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
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
Age-related differences in midazolam responsiveness
Potency ratio 4
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
Study Design and Measures
time
T0
T30
T60
T90
T120
T150
T180
T185
T190
T200
T240
triaz olam
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
psychomo
tor
self-report
(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
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.
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
Jackson et al: J Clin Psychopharmacol
26:4-8, 2006
OAA/S Score
4
3
569
570
571
572
573
574
575
576
577
578
AVERAGE
2
1
0
0
0.25 mg
30
60
0.5 mg
90
120
0.25 mg
Time (minutes post-1st SL triazolam dose)
150
180
Bispectral Analysis During Incremental Triazolam Dosing
by Subject
Jackson et al: J Clin Psychopharmacol
26:4-8, 2006
100
90
BIS Score
80
569
570
571
572
573
574
575
576
577
578
AVERAGE
70
60
50
40
30
0
0.25 mg
30
60
0.5 mg
90
120
0.25 mg
Time (minutes post-1st SL triazolam dose)
150
180
Psychomotor Function Assessment
(Digit Symbol Substitution Test)
DSST Raw Score
100
Jackson et al: J Clin Psychopharmacol
26:4-8, 2006
80
60
subject #
#569
#570
#571
#572
#573
#574
#575
#576
#577
#578
40
20
0
0
60
0.25 mg
triazolam
0.5 mg
triazolam
120
0.25 mg
triazolam
Time (minutes)
Time-Dependent Changes in Plasma Concentrations of Triazolam
by Subject
Plasma Concentration of Triazolam (ng/ml)
8
7
Jackson et al: J Clin Psychopharmacol
26:4-8, 2006
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
Time (minutes post-1st SL triazolam dose)
180
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