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

Chanpong et al., Anesth Prog 2005; 52:3-11

• Canadian telephone survey

• n=1100• 5.5% felt very nervous

or terrified

Standard approaches to oral sedation (single dose)

Adults Diazepam 2-15 mg Lorazepam 1-4 mg Triazolam 0.125-0.5 mg Alprazolam 0.25-1 mg

Children 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/Anxiolyticsof Choice

Criteria High safety margin Reversible Fast onset, mixed durations

Specific agents Benzodiazepines Specific 1 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

BenzodiazepinesBenzodiazepines

GABAA receptordrug binding sites

Pharmacologic effects

Anxiety relief CNS depression with high doses Relatively shallow dose response Anticonvulsant activity Anterograde amnesia Centrally mediated muscle relaxation

BenzodiazepinesBenzodiazepines

Adverse effects

Loss of airway and respiratory depression Paradoxical reactions (excitement,

disinhibition) Sexual fantasies Modest dependence liability Narrow-angle glaucoma risk Teratogenesis potential

BenzodiazepinesBenzodiazepines

Pharmacokinetics of benzodiazepines

Diazepam (2-15 mg) Onset: 1 hr Duration: 3 hr Terminal half-life 25-50 hr (with long-acting

metabolite) Lorazepam (1-4 mg)

Onset: 1.5-2 hr Duration: 6 hr Terminal half-life 10-16 hr

Triazolam (0.125-0.5 mg) Onset: 45 min Duration: 2 hr Terminal half-life 2-5 hr

Chlordiazepoxide

Desmethylchlor-

diazepoxide

Demoxepam

Nordazepam Oxazepam

Clorazepate

Diazepam

Halazepam

Prazepam

Flurazepam

Lorazepam

Alprazolam

Midazolam

Triazolam

α - Hydroxy

derivatives

Glucuronide

conjugates

13-3.Table Metabolism of benzodiazepines

Quazepam

Estazolam

- -N Hydroxyethyl

flurazepam

2- -Oxo quazepam

Temazepam

- Long acting

metabolites

3- Hydroxy

compounds

- Hydroxy

metabolites

α

- -N desalkyl

flurazepam

3-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,

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

N

Cl N

OCH3

N

Cl N

H3C

Cl

N

Diazepam Triazolam

Benzodiazepine structures

N

Triazolam Hydroxy metabolites

Triazolam metabolism

Cl

N

Cl N

H3CNN

N

Cl N

H3CNN

Cl

α- or 1´-hydroxylation

4-hydrox-ylation

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

TriazolamTriazolam

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)

TriazolamTriazolam

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 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

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)

Time (hr)

Stacked oral dosing (0.25 mg)every 30 min

Triazolam (ng/mL)

Comparative Kinetics and Response to Triazolam (0.25 mg)

Data from Greenblatt et al:J Pharmacol ExpTher 293:435-43, 2000.

Acute tolerance to triazolam

0

1

2

3

4

5

6

7

8

0 1 2 3 4 5 6 7 8

SDS TriazolamSDS PlaceboTriazolam (ng/mL)

Data from Kroboth et al: J Pharmacol Exp Ther 264:1047-55, 1993

2.5

2

1.5

1

0.5

0Symbol Digit Substitution Latency

(sec)

Triazolam (ng/mL)

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

Scavone et al: J Clin Pharmacol 26:208-10, 1986

Fatalities with oral benzodiazepines

Adult cases Most involve suicide attempts Several involve triazolam alone Very rare in a therapeutic setting

Fatalities with oral benzo-diazepines (2)

Overweight teenage football player received multiple doses of alprazolam (Xanax) for oral sedation Leaves the office awake, ambulatory with

assistance Cardiac arrest at home

Fatalities with oral benzo-diazepines (3)

Man receives multiple doses of triazolam (Halcion) for oral sedation 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 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

Potency ratio 4

Age-related differences in midazolam responsiveness

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

0.2 mg

0.25 mg

0.5 mg

0.25 mg

Study Design and Measures

timetriazolam

admin.flumazenil

admin.

bloodsample(5 ml)

vital signs(BP, HR,

RR, SaO2)

sedationrating

(observer)

bispectralanalysis

sedationself-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

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 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

1801501209060300

0

1

2

3

4

5

569

570

571

572

573

574

575

576

577

578

AVERAGE

Time (minutes post-1st SL triazolam dose)

OAA/S Score

0.25 mg 0.25 mg0.5 mg

Observer Rating of Sedation During Incremental Triazolam Dosing by Subject

Jackson et al: J Clin Psychopharmacol26:4-8, 2006

1801501209060300

30

40

50

60

70

80

90

100

569

570

571

572

573

574

575

576

577

578

AVERAGE

Time (minutes post-1st SL triazolam dose)

BIS Score

0.25 mg 0.25 mg0.5 mg

Bispectral Analysis During Incremental Triazolam Dosing by Subject

Jackson et al: J Clin Psychopharmacol26:4-8, 2006

1206000

20

40

60

80

100

#569#570#571#572#573#574#575#576#577#578

Psychomotor Function Assessment (Digit Symbol Substitution Test)

Time (minutes)

DSST Raw Score

subject #

0.25 mgtriazolam

0.25 mgtriazolam

0.5 mgtriazolam

Jackson et al: J Clin Psychopharmacol26:4-8, 2006

1801501209060300

0

1

2

3

4

5

6

7

8

569

570

571

572

573

574

575

576

577

578

AVERAGE

Time (minutes post-1st SL triazolam dose)

Plasma Concentration of Triazolam (ng/ml)

0.25 mg 0.25 mg0.5 mg

Time-Dependent Changes in Plasma Concentrations of Triazolam by Subject

Jackson et al: J Clin Psychopharmacol26:4-8, 2006

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