Comparison of triazolam, diazepam, and placebo as outpatient oral premedication for endodontic patients

0099-2399/97/2303-0181 $03.00/0 JOURNALOF ENDODONTICS Copyright © 1997 by The American Association of Endodontists

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VOL. 23, No. 3, MARCH1997

Comparison of Triazolam, Diazepam, and Placebo as Outpatient Oral Premedication for Endodontic Patients Daniel G. Ehrich, DDS, MS, John P. Lundgren, DDS, MS, Raymond A. Dionne, DDS, PhD, Brian K. Nicoll, DDS, and Jeffrey W. Hutter, DMD, M.Ed

a result, endodontic patients normally do not have access to parenteral premedication. The use of oral premedication as an alternative to the parenteral route of administration is limited by prolonged onset of activity, inability to titrate the dose on the basis of the patient's response, limited efficacy because of lower blood levels, and delayed recovery. Nevertheless, it enjoys a long history of success as a means of decreasing preoperative and intraoperative anxiety. Since its introduction in 1963, diazepam (valium) has been the most popular choice among oral anxiolytics. Although effective, its long plasma half-life of greater than 50 h and its conversion to active metabolites may result in prolonged impairment. Given these limitations, a need exists for an oral agent that provides onset appropriate for the outpatient dental environment, effective anxiety reduction, safety, and relatively rapid recovery. Triazolam (Halcion) was developed to meet the need for a fast-acting, short-duration hypnotic with minimal effects on motor or intellectual performance. Early clinical trials supported the safety and efficacy of the drug, and it was first approved in Holland in 1977 as a treatment for sleep disorders (2). Since 1985 triazolam has ranked first in the United States for outpatient prescriptions of sedative hypnotic drugs (3). Onset of hypnotic activity after oral administration occurs in less than 1 h (4) because of rapid absorption; peak plasma levels are achieved within 1'/2 h (5). A dose of 0.25 to 0.5 mg is used for sleep induction, resulting in increased total sleep time and decreased number of awakenings (6). The sleep effect does not carry into the following day. No impairment in morning alertness, ambulatory function, coordination, or equilibrium are found after a 0.25 mg dose (7). As seen on standardized tests of psychomotor impairment, triazolam' s effect is short-acting, with return to base line performance within 4 h after 0.125 or 0.25 mg doses (8). Side effects of triazolam are a direct extension of its pharmacological properties and include drowsiness, dizziness, and incoordination (9). The medication has also been shown to reduce cardiovascular response to stress and anxiety. In a case-control study of patients presenting for removal of impacted third molars, those who received oral triazolam the morning of surgery had significantly less cardiac dysrhythmias and lower resting heart rate than did the placebo patients (10). An important quality of the drug has been the lack of respiratory depression at the highest doses used clinically (0.25 to 0.5 rag) (4).

Triazolam and diazepam were compared as oral antianxiety agents in a randomized double-blind, placebo-controlled clinical study of 79 endodontic patients with elevated anxiety regarding endodontic treatment. Patients who scored >-10 on the Corah Dental Anxiety Survey received oral formulations of triazolam (0.25 mg), diazepam (5 mg), or placebo. Before, during, and after the endodontic procedure, patients completed psychomotor tests and anxiety scales, and were evaluated for 24-h postoperative recall. In comparison with diazepam and placebo, triazolam was significantly better for decreased anxiety (p < 0.05), impaired cognitive function (p < 0.05), patients' rating of drug effectiveness (p < 0.05), and amnesia to clinical events (p < 0.02) and pictures (p < 0.03). Diazepam showed similar trends compared with placebo, but to a lesser degree. Diazepam also had a much longer recovery period. No adverse effects were noted with either drug. These findings suggest that orally administered triazolam (0.25 mg) is a safe and more effective anxiolyUc agent than diazepam (5.0 mg) for endodontic patients.

Although there have been considerable improvements in dentistry in the area of pain control, there still exist patients who are fearful of dental treatment. The prospect of "root canal" treatment introduces an even greater degree of anxiety in these individuals. Despite efforts by clinicians to alleviate anxiety through nonpharmacologic means, some patients still require anxiolytic medication. Although general anesthesia is the most effective method of treatment, intravenous conscious sedation has become a standard alternative to it largely because of increased concern regarding anesthetic safety. General anesthesia and intravenous conscious sedation, however, are used primarily by oral surgeons and only a limited number of other dentists have appropriate training (1). As

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Its rapid onset, short duration of action, and lack of active metabolites have made triazolam a useful premedication for surgical cases. In patients scheduled for elective surgery, the effectiveness of 0•5 mg of triazolam administered 60 rain before surgery was found to be equivalent to 10 to 15 mg of diazepam for decreasing anxiety and producing amnesia (11). In a study of patients presenting for minor urological surgery, 0.25 mg of triazolam, 10 mg of diazepam and 15 mg of midazolam were compared as oral premedicants (12). The lowest anxiety scores were recorded for the triazolam and midazolam groups, with triazolam being perceived by the patients as more anxiolytic. Triazolam, as a premedication before dental procedures, has been evaluated in several clinical trials. Anxious patients scheduled for extraction of an impacted mandibular third molar who received 0.25 mg of triazolam the morning of surgery showed a tendency toward decreased anxiety immediately preoperatively (10). A dose-response evaluation demonstrated that 0.25 mg of triazolam in combination with nitrous oxide produced a therapeutic effect equal to 0.5 mg of triazolam and nitrous oxide, but with a more rapid recovery (13). In the second phase of the study, 0.25 mg of triazolam in combination with 40% nitrous oxide produced anxiety relief comparable with 19.3 mg of intravenous diazepam, again with a more rapid postoperative recovery. Although the aforementioned studies suggest that triazolam is an effective anxiolytic medication, no published study directly compares triazolam with other orally administered benzodiazepine anxiolytic drugs for dental procedures. The purpose of the present study was to compare oral premedication with 0.25 mg of triazolam, 5 mg of diazepam, or placebo administered in a double-blind fashion to patients undergoing endodontic treatment•

MATERIALS AND METHODS Endodontic patients with heightened anxiety were identified using the Corah Dental Anxiety Survey, which consists of four questions focusing on the patient's level of anxiety related to an anticipated dental procedure (14). A total of 263 patients requiring endodontic treatment were screened; of these, 79 met the entry criteria (a score of ->10 of 16 on the anxiety survey) and participated in the study. Exclusion criteria included pregnant or lactating females, current use of cimetidine, erythromycin, any psychoactive drug, or any central nervous system depressant medication. One hour before the appointment (at the -60-rnin interval), base line information (including age, height, weight, blood pressure, heart rate, respiratory rate, and responses to a battery of psychomotor and anxiety measurement questionnaires) was collected. The questionnaires consisted of the Digit Symbol Substitution Test (DSST) to evaluate cognitive function (4), and vertical and horizontal visual analogue scales (VVAS and HVAS) to measure anxiety (13, 15, 16). To evaluate memory impairment, the patient was shown the first of seven simple drawings of common items, such as a chair or clock. The DSST is a psychomotor test, wherein the subject matches geometric figures to numbers according to a key, and it is scored as the number of characters correctly written during 90 s. The VVAS, used to measure the degree of anxiety, is a 20-cm scale on which the patient indicates current level of anxiety along a continuum of 12 levels of anxiety ranging from "not nervous" to "extremely nervous" (13, 15, 16). The 10-cm HVAS is a similar scale, with only the phrases "no nervousness" and "as nervous as can be" at opposite ends (17)•

On completion of the base line data, the patient received (in a double-blind fashion) 0.25 mg of triazolam, 5 mg of diazepam, or placebo in identically appearing gelatin capsules. The DSST, VVAS, and HVAS were repeated at 10 intervals: - 4 5 min (45 min before starting the endodontic procedure), - 3 0 min, - 1 5 rain, 0 time (start of procedure), + 15 rain, +30 min, +60 min, +90 min, +120 rain, and + 180 min. Six additional memory cards were shown at - 4 5 rain, - 3 0 min, - 15 rain, 0 time, + 15 min, and +30 rain. Pain was measured at +60 rain to determine if it contributed to the level of anxiety reported by the patient. It consisted of a 10-cm HVAS, wherein one end of the scale read "no pain" and the opposite end read "as painful as can be" (17). At + 15 rain and +90 rain, the endodontist and a neutral observer rated patient cooperation based on body movement and verbalization of discomfc~t. Possible scores ranged from completely cooperative (0 points) to major interference with the procedure (12 points). Patients were dismissed in the company of a responsible adult and were contacted by telephone the next morning. At this time they were asked to recall specific events and respond to a written questionnaire, on which they indicated pictures they remembered and rated their evaluation of the medication as poor (0), fair (1), good (2), very good (3), or excellent (4). Parametric data (VVAS, HVAS, and DSST) were analyzed by analysis of variance and the Duncan Multiple Range Test. Nonparametric data (clinical observations and global evaluation) were analyzed by the Kruskal-Wallis test. Recall of picture cards and clinical events was evaluated using 9(2 tests. RESULTS As measured in millimeters on the VVAS at +30 and +60 rain, the triazolam group had a significantly (p < 0.05) greater decrease in anxiety from base line measurement than did the placebo group (Fig. 1). Patients rated triazolarn significantly (p < 0.05) better than both diazepam or placebo (Fig. 2). There was no difference among the three groups as assessed by the patient pain rating (which was low across groups) or observer ratings of patient cooperation. As measured by DSST, the triazolam group evidenced significant impairment at times +30, +60, and +90 min, then recovered by + 180 rnin (Fig. 3) The placebo and diazepam groups tended to improve their score earlier, then remain at a high cognitive skill level throughout the remainder of the study period.

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FIG 1. Change in patient self-report of anxiety (VVAS) from base tine observation to intraoperative observation. *Significantly different from placebo, p < 0.05.

Vol. 23, No. 3, M a r c h 1 9 9 7

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FIG 4. Patient's 24-h postoperative recall of clinical events and picture cards. *Significantly different from placebo and diazepam, p < 0.05.

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FIG 3. Impairment of cognitive-psychomotor function as measured by the DSST. *Significantly different from placebo and diazepam, p < 0.05.

The triazolam group had significantly (p < 0.02) more amnesia to clinical events (receiving local anesthetic or the actual endodontic procedure) than either the placebo or diazepam groups (Fig. 4). Only 55% of the patients from the triazolam group recalled the endodontic procedure. In comparison with the other groups, the triazolam patients also had significant (p < 0.03) amnesia for the picture cards shown at + 15 and +30 min (the last two pictures shown to the patient)• No significantly adverse side effects were seen in any patient either during or after the procedure. At the follow-up telephone interview conducted 24 h postoperatively, six patients from the triazolam group reported symptoms of tiredness, whereas three patients reported lightheadedness or dizziness the evening after the procedure.

DISCUSSION These results demonstrate that, when administered as an oral premedication for endodontic patients, 0.25 mg of triazolam significantly decreases anxiety from base line when compared with 5 mg of diazepam or placebo. Patients judged triazolam as much more effective than diazepam or placebo. They gave triazolam an average rating of 3.2 (excellent = 4; poor = 0), whereas diazepam and placebo received ratings <2. The effectiveness and short

duration of action of triazolam were substantiated by the DSST. Between 30 and 90 rain intraoperatively, the triazolam group experienced difficulty in completing the psychomotor test. Several fell asleep during the endodontic procedure, and three patients actually fell asleep as they were writing the DSST symbols on the form. These same patients, however, were alert and well oriented by completion of the endodontic appointment. Triazolam also produced significant amnesia for intraoperative events, as evidenced by lack of recall of the local anesthetic, the actual procedure, and picture cards. The other groups readily recalled intraoperative events and procedures. Controversy has surrounded the use of triazolam. Adverse reactions with this medication were first reported in 1979 by a Dutch psychiatrist who prescribed the drug to patients with serious sleep disorders that could not be treated with other hypnotics (2). His reports were anecdotal, but since that time there have been similar reports elsewhere in Europe and in the United States. In 1988, the manufacturer withdrew the 0.5 mg of triazolam, but the Food and Drug Administration has continued to approve the use of a 0.25 mg dose for most adults and a 0.125 mg dose for the elderly and the debilitated (18). In an attempt to quantify the association of triazotam with adverse behavioral reactions, Wysowski and Barash (3) made a statistical comparison of reactions associated with triazolam and temazepam as reported through the Food and Drug Administration Spontaneous Reporting System. Temazepam was used for comparison because it is also a short-acting hypnotic and was marketed in the United States (in 1981), at about the same time as triazolam (in 1983). Reactions were categorized as confusion, amnesia, bizarre behavior, agitation, and hallucinations. There were 19 reports per 1 million prescriptions for triazolam. When, however, the reports in which there was concomitant alcohol, opioid, psychoactive drug use, concomitant psychiatric or neurologic disorders, or where doses >0.5 mg were used were excluded, the number of reports per 1 million prescriptions was nearly halved. The average age of patients with adverse reactions was over 60 yr. Nearly all reported cases of adverse reactions associated with triazolam have been in cases of long-term use for sleep disorders. Even among studies evaluating the use of triazolam for insomnia, side effects are normally limited to withdrawal, sleeplessness, amnesia, headache, dizziness, and drowsiness (6, 19, 20). In stud-

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ies of triazolam as a preoperative sedative before oral surgical procedures, no adverse reactions of any significance have been reported (10, 13). The current study, likewise, found no adverse reactions in the sample of 25 triazolam and 26 diazepam subjects. It seems that, in the outpatient dental setting presented herein, wherein a single oral dose of 0.25 mg of triazolam [0.125 mg dose for the elderly (8)] is administered preoperatively to anxious endodontic patients, the medication is both safe and highly effective. The assertions contained herein are those of the authors and are not to be construed as official or as reflecting the views of the Department of the Navy, Department of Defense, or the U.S. government. Dr. Ehrich is a former endodontic resident at the Naval Dental School, Bethesda, MD, and is now a staff endodontist at the Naval Dental Center, San Diego, CA. Dr. Lundgren is a former endodontic resident at the Naval Dental School, Bethesda, MD, and is now a staff endodontist at the Naval Dental Center, Parris Island, SC. Dr. Dionne is a Captain in the Public Health Service, and Chief, Clinical Pharmacology Unit, National Institute of Dental Research, National Institutes of Health, Bethesda, MD. Dr. Nicoll, is a board-certified periodontist at the Naval Dental Research Institute, Detachment Bethesda, MD. Dr. Hutter is Director, Advanced Specialty Education Program in Endodontics, Baltimore College of Dental Surgery School, University of Maryland, Baltimore, MD. He is the former Chair, Endodontics Department and Director, Advanced Specialty Education Program in Endodontics, Naval Dental School, Bethesda, MD. Address requests for reprints to Dr. Jeffrey W. Hutter, Department of Endodontics, Baltimore College of Dental Surgery Dental School, University of Maryland, 666 West Baltimore Street, Baltimore, MD 21201-1586.

References 1. American Dental Association, Council on Dental Education. Sedation and Anesthesia Survey: Preliminary Report. ADA/ADSA Workshop on Dental Anesthesiology Education. Chicago, March 1989. 2. Ladimer I. Commentary: trials and tribulations of triazolam. J Clin Pharmacol 1980;Feb-Mar:159-61. 3. Wysowski DK, Barash D. Adverse behavioral reactions attributed to triazolam in the Food and Drug Administration's Spontaneous Reporting System. Arch Intern Med 1991 ;151:2003-8.

4. Longbottom RT, Pleuvry BJ. Respiratory and sedative effects of triazelam in volunteers. Br J Anaesth 1984;56:179-85. 5. Eberts FS, Philopoulos Y, Reineke LM, Vliek RW. Triazolam disposition. Clin Pharmacol Ther 1981 ;29:81-93. 6. Chaudoir PJ, Bodkin NL, O'Donnell J, Anderson A, Holland RL. A comparative study of zopiclone and triazolam in patients with insomnia. Int Clin Psychopharmacol 1991;5:21-7. 7. Fleming JA, McClure DJ, Mayes C, Phillips R, Bourgouin J. A comparison of the efficacy, safety and withdrawal effects of zopiclone and triazolam in the treatment of insomnia. Int Clin Psychopharmacol 1990;5:29-37. 8. Greenblatt DJ, Harmatz JS, Shapiro L, Engelhardt N, Gouthro TA, Shader RI. Sensitivity to triazolam in the elderly. N Engl J Meal 1991;324: 1691-8. 9. Physicians' Desk Reference. 49th ed. Oradell, NJ: Medical Economics Co., Inc., 1995. 10. Lieblich SE, Horswell B. Attenuation of anxiety in ambulatory oral surgery patients with oral triazolam. Oral Maxillofac Surg 1991;49:792-6. 11. Baughman VL, Becker GL, Ryan CM, Glazer M, Abenstein JP. Effectiveness of triazolam, diazepam, and placebo as preanesthetic medications. Anesthesiology 1989;71:196-200. 12. Forrest P, Galletly DC, Yee P. Placebo controlled comparison of midazolam, triazolam and diazepam as oral premedicants for outpatient anaesthesia. Anaesth Intens Care 1987;15:296-304. 13. Kaufman E, Hargreaves KM, Dionne RA. Comparison of oral triazolam and nitrous oxide with placebo and intravenous diazepam for outpatient premedication. Oral Surg 1993;75:156-64. 14. Corah NL, Gale EN, Illig SJ. Assessment of a dental anxiety scale. J Am Dent Assoc 1978;97:816-9. 15. Gracely RH, Dubner R. Reliability and validity of verbal descriptor scales of painfulness. Pain 1987;29:175-85. 16. Walther DJ, Gracely RH. Ratio scales of pleasantness and unpleasantness affective descriptors. Am Pain Soc Abstr 1986;6:34. 17. Wilson J. A preliminary evaluation of analogue scoring in sedation. Br J Anaesth 1969;41:792-3. 18. Ayd FJ (ed). Triazolam 0.125 mg: risks vs. benefits. Int Drug Ther Newsletter 1992;27(April):13-6. 19. Kales A, Kales JD, Bixler EO, Scharf MB, Russek E. Hypnotic efficacy of trJazotam: sleep laboratory evaluation of intermediate-term effectiveness. J Clin Pharmacol 1976;16:399-406. 20. Shugars KD, Linet OI, Metzler CM, Rudzik AD. A multiclinic comparison of the hypnotic efficacy of triazolam and placebo in insomniac outpatients. Clin Ther 1980;2:390-8.

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