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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

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Anxiety and pain control 2007

Anxiety and Pain Control 2007

John A. Yagiela, DDS, PhD

Utah Dental Association

Salt Lake City

February 9, 2007


Oral sedation topics
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
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
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 anxiolytics of choice
Oral Premedicants/Anxiolyticsof Choice

  • Criteria

    • High safety margin

    • Reversible

    • Fast onset, mixed durations

  • Specific agents

    • Benzodiazepines

    • Specific w1 agonists: zolpidem


Mechanism of action
Mechanism of action

  • Binding to specific benzodiazepine receptors:

    • Increased binding of GABA to GABAA receptors

    • Increased responsiveness of chloride channels to GABA binding

Benzodiazepines


Gaba a receptor drug binding sites
GABAA receptordrug binding sites


Pharmacologic effects
Pharmacologic effects

  • Anxiety relief

  • CNS depression with high doses

  • Relatively shallow dose response

  • Anticonvulsant activity

  • Anterograde amnesia

  • Centrally mediated muscle relaxation

Benzodiazepines


Adverse effects
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
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


Triazolam halcion
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


Benzodiazepine structures
Benzodiazepine structures

N

CH3

H3C

N

O

N

N

N

N

Cl

Cl

Cl

Diazepam Triazolam


Triazolam metabolism

N

H3C

N

N

H3C

N

N

N

N

Cl

N

Cl

Cl

Triazolam metabolism

a-or 1´-hydroxylation

4-hydrox-

ylation

Cl

Triazolam Hydroxy metabolites


Pharmacokinetic drug interactions
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

Triazolam


Pharmacokinetic drug interactions cont
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)

Triazolam


Enhanced efficacy of sublingual 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
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
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
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)


Anxiety and pain control 2007

Stacked oral dosing (0.25 mg) Agencies

every 30 min

Triazolam (ng/mL)

Time (hr)


Anxiety and pain control 2007

Comparative Kinetics and Response to Triazolam (0.25 mg) Agencies

Data from Greenblatt et al:

J Pharmacol Exp

Ther 293:435-43, 2000.


Acute tolerance to triazolam
Acute tolerance to triazolam Agencies

2.5

2

1.5

Symbol Digit Substitution Latency (sec)

Triazolam (ng/mL)

1

0.5

0

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


Enhanced bioavailability of sublingual triazolam 0 5 mg1
Enhanced bioavailability of sublingual triazolam (0.5 mg) Agencies

  • 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
Fatalities with oral benzodiazepines Agencies

  • Adult cases

    • Most involve suicide attempts

    • Several involve triazolam alone

    • Very rare in a therapeutic setting


Fatalities with oral benzo diazepines 2
Fatalities with oral benzo-diazepines (2) Agencies

  • 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
Fatalities with oral benzo-diazepines (3) Agencies

  • 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
Nonfatal reaction to oral triazolam Agencies

  • 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
Prescription for Fatality Agencies

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



Pharmacokinetics and clinical effects of multidose sublingual triazolam in healthy volunteers

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
Study Design and Measures Sublingual Triazolam

0.25 mg

0.5 mg

0.25 mg

0.2 mg

Jackson et al: J Clin Psychopharmacol 26:4-8, 2006


Observer s assessment of alertness sedation oa as scale
Observer’s Assessment of Alertness/Sedation (OA/AS) Scale Sublingual Triazolam

Jackson et al: J Clin Psychopharmacol 26:4-8, 2006


Objectives
Objectives Sublingual Triazolam

  • 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
Clinical Interpretation of Bispectral Analysis Sublingual Triazolam

BIS Score

Clinical State

100

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


Anxiety and pain control 2007

Observer Rating of Sedation During Incremental Triazolam Dosing

by Subject

Jackson et al: J Clin Psychopharmacol

26:4-8, 2006


Anxiety and pain control 2007

Bispectral Analysis During Incremental Triazolam Dosing Dosing

by Subject

Jackson et al: J Clin Psychopharmacol

26:4-8, 2006


Anxiety and pain control 2007

100 Dosing

80

60

#569

#570

#571

40

#572

#573

#574

#575

#576

20

#577

#578

0

0

60

120

Psychomotor Function Assessment

(Digit Symbol Substitution Test)

Jackson et al: J Clin Psychopharmacol

26:4-8, 2006

subject #

DSST Raw Score

0.25 mg

0.5 mg

0.25 mg

triazolam

triazolam

triazolam

Time (minutes)


Anxiety and pain control 2007

Time-Dependent Changes in Plasma Concentrations of Triazolam

by Subject

Jackson et al: J Clin Psychopharmacol

26:4-8, 2006


Risk benefit considerations
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