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The effects of the psychotherapeutic drugs, glutethimide, meprobamate and ectylurea on dental patients
Th e effects o f th e p sy ch o th e ra p e u tic d ru gs, glu tethim ide, m e p ro b a m a te a n d ectyiurea on dental p a tie n ts
W illiam J. C a rter,* D .D .S ., M .S ., and D e W a y n e H u n te r , f D .D .S ., K an sas C ity, M o .
A d ou b le blind study was c o n d u cted to co m p a r e th e 2 4 h our p rem ed ica tion e f fe c ts o f m ep ro b a m a te, ectyiu rea , g lu te th im id e and p la ceb o in 196 den tal p a tients. E valu ation s w ere b oth su b jectiv e and o b je c tiv e . G lu teth im id e was th e m ost e ffe c tiv e in allaying th e p a tien t’s a n xiety, bu t also was th e m ost to x ic. E ctyiu rea and m ep ro b a m a te than
th e
w ere
p la ceb o .
no
m o re
The
e ffe c tiv e
in vestigators
ju d g e d th e p la ceb o to be m o re e ffe c tiv e than eith er m ep rob a m a te o r ectyiu rea , and on ly slightly less e ffe c tiv e (5 4 p er c e n t ) than glu teth im id e (6 2 p er c e n t ). N o n e o f th e drugs tested is th e final a n sw er to p retrea tm en t a n x iety in d en tal patients.
ings toward impending dental treatment, and these include hypnosis, sedation, gen eral anesthesia and the ataraxic drugs. A recent survey1 shows that almost 50 per cent o f dentists are giving their pa tients some form of tranquilizing agent, primarily on an empirical basis. H o w ever, several well-controlled studies have been reported.2"9 Studies on dental pa tients were reported by Lund and Anholm,6 Lefkow itz7 and Szmyd, M cC all and Enright8 with varying results. This study attempts to assess the effects o f 24 hour premedication with ataraxic drugs on apprehensive dental patients. Because o f the known difficulties in evalu ating ataraxic drugs, a double blind test was used comparing glutethimide, m e probamate and ectyiurea with a placebo. MATERIALS
Excitability and anxiety are almost uni versal characteristics o f dental patients. These emotional symptoms are more pronounced in patients visiting a dentist than in patients in almost any other area o f health service. W ith i;'the advent of new technics, methods and instruments, much of this apprehension is needless. Nevertheless, because o f previous knowl edge and vicarious experiences, fears continue to persist. Various methods cur rently are being used to allay such feel
Glutethimide ( alpha-ethyl-alpha-phenylglu tarim ide)10 is a nonbarbiturate seda tive whose principal effect is depression o f the central and autonomic nervous system. The electroencephalographic sleep patterns are similar to those seen with secobarbital and chloral hydrate. Th ere is no analgesic effect even in large doses. Th e effects on the cardiorespiratory system are nominal even in large doses, and there is no hypotension or respiratory depression with a therapeutic dose o f 0.5
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pear in children and in adult patients to 1.0 Gm. Th e action o f glutethimide on high dosage levels. Allergic manifesta when given by mouth begins in 5 to 25 tions have been reported to range from minutes, and the maximum effect is m ild skin rash to syncope. T h e agent is achieved in 30 minutes. Th e duration o f approximately one fifth as toxic as the action is four to six hours.2 barbiturates. Isaacs3 used this agent in normal pa Lund and Anholm 6 studied 53 dental tients and found that 500 mg. o f glu patients (33 were children 2 to 15 years tethimide was equivalent to 1.5 grains old ) who had received meprobamate as pentobarbital in producing hypnosis. Th e premedication or fo r relief o f nervous principal side reactions at this dosage tension during denture adjustment. Th e level were unusual fatigue and sleepi authors reported that improvement in ness, lightheadedness and dizziness, behavior and in submission to treatment ataxia, lack o f concentration and apathy. was good to excellent in 82 per cent of T o x ic responses were reported in four cases by K ier, Whitehead and W hite.4 the patients. Drowsiness was noted in a few o f the smaller children, one adoles These patients had consumed amounts cent and one adult, but caused no incon varying from 5 to 10 Gm. of glutethimide venience. T h e authors concluded that in combination with alcohol or a barbi meprobamate is a valuable adjunct to turate. A ll patients recovered follow ing dental practice. lavage and dialysis. Drugs such as al Lefkow itz7 studied 423 patients over cohol and barbiturates which are central 18 years o f age, using a double blind nervous system depressants react synertechnic with patients categorized as ex gistically with glutethimide. A llergic re citable, apprehensive or normal. Th e actions have been reported consisting of first two groups were those requiring pre rubelliform rashes and exanthems which medication prior to dental treatment. disappeared when the drug was discon Lefkow itz used a 400 mg. meprobamate tinued. tablet which was given three times a Branch and Pastorello2 advocate the day prior to treatment. His conclusions use of glutethimide in combination with scopolamine or meperidine as a safe and were that the majority o f apprehensive and excitable patients may be expected effective premedication regimen for chil to accept dental care with more compo dren undergoing general anesthesia. It sure after receiving meprobamate. was found to decrease fear and anxiety Szmyd, M cC all and Enright8 made a in these children and made them more clinical evaluation o f promazine hydro susceptible to suggestion. chloride and meprobamate in the control Meprobamate ( 2-methyl-2-n-propyl-1, o f postoperative sequelae in patients un 3-propanediol dicarbam ate)11 is a non dergoing oral surgery. Th e results with barbiturate interneuronal blocking agent these drugs, as compared to a placebo, belonging to the group of drugs known indicated that there was no significant as substituted propanediols. Th e com effect on the postoperative sequelae of pound is known to possess definite relax pain, swelling and trismus. These agents ant properties which relieve both psychic also failed to influence the postoperative stress and muscular spasm without sig narcotic demand, and the number of nificant effect on the circulatory, respira tory or other autonomic functions. Berger5 days lost because o f convalescence was significantly increased. Th e authors con found meprobamate more effective than clude that neither promazine hydrochlo the barbiturates for alleviation o f emo ride nor meprobamate can be recom tional stress. mended for the control o f postoperative T h e side reaction most commonly seen sequelae in oral surgery. is drowsiness. This is most likely to ap
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• T H E J O U R N A L O F T H E A M E R IC A N D E N T A L A S S O C IA T IO N
Ectyiurea (2-ethyl-cis crotonylurea)12 is an agent that produces m ild depres sion o f the central nervous system, an action shared with other substituted urea compounds. It does not influence blood pressure, pulse, respiration, gastric acid ity or motility, nor does it produce skeletal muscle relaxation, analgesia or anticon vulsant effects. Th e potential use o f the drug is as a neurosedative or calming agent, and it is not considered a hypnotic. Th e toxicity of ectyiurea is extremely low. Side reactions to the drug have been mostly skin rashes o f m ild effect and short duration. Bauer and others9 reported the use o f ectyiurea in 172 patients with tension, anxiety and insomnia. They concluded that this agent is of very low toxicity, permits daytime sedation without mental depression and induces normal sleep by alleviating tension and anxiety. There is one report o f jaundice after two weeks of ectyiurea therapy.13 It was suggested that this syndrome o f cholangiolytic hepatitis was a rare allergic mechanism apparently induced by ectyiurea. PRO CEDURE
A double blind clinical study was estab lished to compare the 24 hour premedi cation effects o f meprobamate, ectyiurea, glutethimide and placebo on 196 dental patients with symptoms o f anxiety and tension. This study initially comprised two groups of patients as follow s: Group A : 90 patients, mostly adults from pri vate practices. A ll received 24 hour pre medication with either glutethimide or placebo. Seventy-one patients, or 80 per cent, were women between the ages o f 12 and 85 years. T h e average age was 33 years. Group B: 106 patients from the Chil dren’s M ercy Hospital and the U niver sity o f Kansas City Pedodontic Clinic. A ll children received treatment from a single investigator (D .H .). A ll received 24 hour premedication with meproba
mate, ectyiurea or placebo. Sixty o f the patients, or 56 per cent, were girls be tween the ages o f 10 and 17 years. T h e average age was 11.5 years. Th e three drugs and the placebo were placed in capsules o f identical size and color and each drug and placebo then was individually packaged in identical packets o f four capsules. Each capsule contained 400 mg. o f the active agent except ectyiurea ( 300 mg. ). A ll o f the packets were randomized by the manu facturer in a box containing 120 packets per box. Each packet was coded and the code list was entrusted to the com pounding pharmacist and to the project coordinator (W .J .C .). Th e code list was not to be opened unless serious side re actions should develop in the patient taking one o f the agents. A record sheet was kept for each pa tient receiving the packet o f four cap sules. Th e top half o f the sheet was for recording the packet code number, name, age, sex, type o f dental treatment plan and the emotional status o f the individ ual. T h e bottom half of the record sheet was completed on the return visit. It contained spaces for recording the tak ing of capsules, the effect o f the agent on the patient, side effects, the desirabil ity of repeating the prescription and the dentist’s observation o f the person as a dental patient. O bjective signs such as sweating o f the forehead and palms were noted as was the ease o f patient care. A single packet containing four cap sules was given to the patient or, in the case o f a child, to his parent w ith instruc tions that one capsule should be taken at each o f three times during the day preceding the dental appointment and on the morning o f the appointment. The patients were told that the capsules were intended as an aid for them prior to their appointments. Th ey were given no in formation as to the type o f medication and also no mention was made o f the possibility of side reactions. I f there was any problem concerning the taking o f the
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capsules, they were to call the attending dentist. Several o f the Kansas City practitioners (M id-Century Dental Study Club mem bers)14 who were evaluating glutethimide and a placebo noted early in the studies severe side reactions such as drowsiness, vertigo and emotional upsets in their pa tients. It was thought best to halt this part o f the study, and accordingly, fur ther evaluation o f glutethimide and placebo on patients in Group A was dis continued. Th e method of evaluating subjective and objective symptoms are here outlined. T h e subjective symptoms were derived from the patients’ own words as to how they felt about the im pending dental appointments and how they reacted to the procedures at hand. Some o f these conditions are abstract in nature and some are more applicable to a specific age group. T h e symptoms include hesitancy in being seated, a negativistic attitude, resistance toward simple procedures such as the oral examination or having roentgenograms taken, obvious fear o f local anesthetic procedures and, in general, a resentment toward the dentist. T h e objective signs were those ob served by the dentist treating the patient. During the first appointment each pa tient was checked for reaction to anxiety and apprehension. Those patients se lected expressed a fear o f most dental procedures, used excuses to postpone the appointment and related “ bad experi ences” in other dental offices. They usual ly hesitated in allowing an immediate thorough examination and refused to co operate fully in any o f the routine pro cedures. O n the second appointment, after a 24 hour premedication period, all positive signs and symptoms previously recorded were reviewed with the patient. T h e patient was asked if his feeling to ward the appointment was different or better than before. Th e dentist looked also for an increase or decrease in “ ner vousness” and a greater or lesser willing
ness to cooperate and to have routine operative procedures performed. Patient improvement was recorded only when there was pronounced change or when a completely uncooperative patient per mitted some constructive treatment. Th e dentist noted also the presence of para sympathetic sweating o f both the fore head and the palms o f the hands during the visit. RESU LT S
Th e results o f this clinical study are pre sented in the table. T h e agent glutethi mide, although too reactive for complete comparison, was found to be the most effective in rendering the patient more susceptible to dental treatment. As may be noted in the table, 72 per cent o f the patients believed that this drug made them feel less apprehensive toward their impending dental appointment. It was also noted that the investigators were slightly less impressed with the results achieved with glutethimide and gave it a score of 62 per cent. Th e side reactions, as mentioned earlier, were more numer ous with glutethimide and more intense. Seventy-eight per cent o f the patients ex perienced some form o f reaction to the drug and five patients felt they were worse for having taken the agent. Most o f the reactions were due to drowsiness, but some had more severe symptoms. One patient felt depressed, four had signs of vertigo and four maintained that they were too sleepy to return for the ap pointment. T h e results for the drugs ectyiurea and meprobamate and for the placebo were identical as regards the patients’ feelings o f improvement and the dentists’ obser vations of their effects. T h e reactions which patients experienced were consid erably less frequent and severe in the placebo group than in the two experi mental groups, but reactions such as drowsiness were recorded in all three groups. A chi square test performed on
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TH E J O U R N A L O F T H E A M E R IC A N D E N T A L A S S O C IA T IO N
Table • Results o f clinical trials using a d o u b le blind technic on d en tal
patients with a g e n ts glutethim ide,
ectylurea and m e p ro b a m a te O b je c tiv e sym ptom s*
Su b jective sym ptom s*
D ru gs used
Glutethim ide Ectylurea M e p r o b a m a te P la ce b o
Im prove d
Sa m e
W o rse
No. p a tie n t s
Per cent
No. p a tie n t s
Per cent
36 16 13 34
72 44 41 46
9 19 18 40
18 S3 56 54
No. p a tie n t s 5 1 1 —
Im proved
Sam e
W o rse
Per cent
No. p a tie n t s
Per cent
No. p a tie n t s
Per cent
No. p a tie n ts
Per cent
10 3 3
31 16 13 40
62 44 41 54
14 19 18 34
28 53 56 46
5 1 1
10 3 3
—
—
—
‘ Subjective sym ptom s: the patient's description of his feelings of anxiety or tension tow ards the dental appoin t- • ment. O bjective sym ptom s: tne dental practitioner's observations of persons as dental patients, Including evalua tion of signs such as sw eating of the forehead and palms.
these two agents and compared with the results with the placebo showed no sig nificant differences. One patient taking meprobamate had emesis after taking the first capsule and another patient became more excited after taking the series. Three patients taking ectylurea had minor side effects such as stomach-ache, hyperexcitability and tinnitis. Th ere were no severe side reactions reported in the placebo group. It was interesting to note that the placebo was more effective than either meprobamate or ectylurea as seen by the investigators. In fact, it was only slightly less effective (54 per cent) than glutethimide (62 per cen t). This tends to reduce the level o f significance o f glutethimide as an effective antiapprehensive agent. Th e dentist’s observation on the ease o f handling patients is the major point under consideration in this study, especially in the adolescent patient. A n swers to the question as to whether the patient would like the prescription re peated, were evenly divided between “ yes” and “ no” for glutethimide, ecty lurea and for the placebo. However, only one third o f the group taking meproba mate desired renewal o f the drug. DISCUSSION
Th e need for an agent to be used to re duce the anxiety and tension of dental
patients toward an impending dental appointment has been established. H o l lister13 has stated that tranquilizing drugs have established, fo r better or worse, a place in medical therapy. This does not preclude the need for additional studies, especially those that are well-controlled and include placebo comparison. Shapiro and T en g 16 emphasize that the nonpharmacological variables such as the doctorpatient relationship and the impact o f psychologic changes in the patient which tend to mimic and occasionally mask the pharmacological effect o f a drug make the placebo a necessity in clinical inves tigations. In regard to pain experienced by the patient, M aurice17 has found that it may be intensified by psychic factors. Beecher,18 commenting on the powerful placebo effect, observed that the placebo was effective in 35.2 per cent of cases when used in conjunction with other agents for relief o f pain, headache, anx iety and tension. H e maintains that the placebos are more effective when stress is greatest and can also produce thera peutic and toxic reactions. W o lf and Pinsky,19 studying the effect o f placebo and mephenesin, founds almost the same amount o f improvement of certain pa tient symptoms with each agent. Glutethimide, with the exception o f its high percentage o f side reactions, comes nearer to being an effective agent in the calming o f dental patients. This
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seems to be a characteristic common to this group o f drugs, in that the more effective they are, the more toxic they become in many o f the patients receiv ing the drug. It is interesting to note the dissimilarity between the objective symp toms recorded by the dentist and the subjective symptoms reported by the pa tients fo r glutethimide. Th e objective symptoms are only slightly greater (62 per cent) than those for the placebo (54 per c e n t). Redish and Ping20 also noted a divergence between subjective and ob jective symptoms when they evaluated ethinamate (V a lm id ) in a double blind study. Th e divergence was slight in the improved groups but became greater in the questionable or “ no help” categories. Th e patient’s feelings toward the dental appointment certainly should be consid ered, but if the practitioner’s observations are considered as at least equally reli able, results with glutethimide become less significant. In a comparison o f ectylurea, mepro bamate and the placebo in this study, there is little divergence between the subjective or objective responses. A com parison o f ectylurea and meprobamate favors ectylurea slightly but not to a degree that is clinically significant. Both drugs were found to be neither very toxic nor especially objectionable to the patient. However, unless the psychic changes manifested in these patients are more elusive than was supposed, these drugs are apparently no more effective than placebo. This study does not prove any o f the tested drugs to be the final answer to pretreatment anxiety in dental patients. Further analysis o f these agents should take into consideration an in creased dosage for ectylurea and mepro bamate and a lengthened premedication period. CONCLUSION
A double blind study was conducted to compare the effects o f glutethimide, ecty lurea, meprobamate and placebo in 196
dental patients. Glutethimide proved the most effective in allaying patients’ emo tional conditions but was also the most frequently toxic. Ectylurea and mepro bamate were no more effective than the placebo and were only slightly more re active than the placebo. This study does not provide an answer to the treatment o f anxiety in dental patients in reference to the afore-mentioned drugs.
This study was supported ¡n part by a research grant from the A m es C o ., Inc., Elkhart, Ind. *Professor of pedodontics, University of Kansas City School of Dentistry, and chief of dental service, C h il dren's M ercy H o sp ita l. tPedodontic - resident, C h ild ren 's M ercy H ospital. 1. Tranquilizers are prescribed by 44.5% of dentists, usually preoperatively. D. Survey 34:780 June 1958. 2. Branch, D. R., and Pastorello, R. R. Use of g lu tethim ide for preoperative m edication in children. New Eng. J. M e d . 257:125 July i8, 1957. 3. Isaacs, B. H ypn otic effect of glutethim ide in nor mal human subjects. Lancet 272:558 M arch 16, 1957. 4. Kier, L. C .; W hitehead, R. W., and White* W . C. Blood and urine levels in glutethim ide (doriden) in toxication. J .A .M .A . 166:1861 A p ril 12, 1958. 5. Berger, F. M . M eprobam ate, its pharm aceutical properties and clinical uses. Internat. Rec. M ed . 169:184 A p ril 1956. , 6. Lund, L., an d Anholm , J. M . C lin ic a l observations on the use of m eprob am ate in dental procedures. O ra l Surg., O ra l M e d . & O ra l Path. 10:1281 Dec. 1957. 7. Lefkowitz, W . Use of m eprobam ate before o pe r ative procedures. A preliminary report. J. O h io D. A . 32:27 W in ter 1958. 8. Szmyd, L.; M c C a ll, C . M., and Enright, E. T. Tranquilizing d ru gs in oral surgery. J. O r a l Surg. 16:310 July 1958. 9. Bauer,H. G ., and others. A clinical evaluation of ectylurea {nostyn). N . Y. State M . J. 58:520 Feb. 15, 1958. 10. G lutethim ide (D oriden), C ib a Pharmaceutical Products, Jnc., Sum mit, N. J. 11. M e p ro b a m a te (Equanil), W yeth Laboratories, Philadelphia. / 12. Ectylurea (Nostyn), A m e s C om pany, Inc., Elk hart, Ind. 13. Hochm an, R., and Robins, J. J. Jaundice due to ectylurea. New Eng. J. M ed . 259:583 Sept. 18, 1958. 14. M em bers of the M id -C e ntu ry Dental Study C lu b are: H . D. Buell, W . H. Cottrel, W . C lifton, W . G . Dennis, R. W . Edwards, Jr., J. I. Hense, C . R. M c C le l lan, W . D. Milter, C . V. Neath, W . H. Poyser, H . R. Skoog, J. D. Stanton, C . Stout, H. G . W r ig h t and H. Forbes. 15. Hollister, L. E. C o m p lic atio n s from the use of tranquilizing dru gs. New Eng. J. M e d . 257:170 July 25, 1957. 16. Shapiro, A . P., and Teng, H. C . Technic o f co n trolled dru g assay illustrated by a com parison study of rauwolfia serpentina, phenobarbital and place b o In the hypertensive patient. New Eng. J. M e d . 256:970 M a y 23, f957. 17. M aurice, C . G . Differential d iagn o sis of dental pain. J .A .D .A . 50:316 M arch 1955. 18. Beecher, H. K. Powerful placebo. J .A .M .A . 159:1602 Dec. 24, 1955. 19. W o lf, S., and Pinsky, R. H. Effects of placebo adm inistration and occurrence of toxic reactions. J .A .M .A . 155:339 M a y 22, 1954. 20. Redish, C . H., and Ping, R.S. Ethinamate (V a l m id) in dentistry. O ra l Surg., O ra l M e d . & O ra l Path. 11:742 July 1958.
W illiam J. C a rter,* D .D .S ., M .S ., and D e W a y n e H u n te r , f D .D .S ., K an sas C ity, M o .
A d ou b le blind study was c o n d u cted to co m p a r e th e 2 4 h our p rem ed ica tion e f fe c ts o f m ep ro b a m a te, ectyiu rea , g lu te th im id e and p la ceb o in 196 den tal p a tients. E valu ation s w ere b oth su b jectiv e and o b je c tiv e . G lu teth im id e was th e m ost e ffe c tiv e in allaying th e p a tien t’s a n xiety, bu t also was th e m ost to x ic. E ctyiu rea and m ep ro b a m a te than
th e
w ere
p la ceb o .
no
m o re
The
e ffe c tiv e
in vestigators
ju d g e d th e p la ceb o to be m o re e ffe c tiv e than eith er m ep rob a m a te o r ectyiu rea , and on ly slightly less e ffe c tiv e (5 4 p er c e n t ) than glu teth im id e (6 2 p er c e n t ). N o n e o f th e drugs tested is th e final a n sw er to p retrea tm en t a n x iety in d en tal patients.
ings toward impending dental treatment, and these include hypnosis, sedation, gen eral anesthesia and the ataraxic drugs. A recent survey1 shows that almost 50 per cent o f dentists are giving their pa tients some form of tranquilizing agent, primarily on an empirical basis. H o w ever, several well-controlled studies have been reported.2"9 Studies on dental pa tients were reported by Lund and Anholm,6 Lefkow itz7 and Szmyd, M cC all and Enright8 with varying results. This study attempts to assess the effects o f 24 hour premedication with ataraxic drugs on apprehensive dental patients. Because o f the known difficulties in evalu ating ataraxic drugs, a double blind test was used comparing glutethimide, m e probamate and ectyiurea with a placebo. MATERIALS
Excitability and anxiety are almost uni versal characteristics o f dental patients. These emotional symptoms are more pronounced in patients visiting a dentist than in patients in almost any other area o f health service. W ith i;'the advent of new technics, methods and instruments, much of this apprehension is needless. Nevertheless, because o f previous knowl edge and vicarious experiences, fears continue to persist. Various methods cur rently are being used to allay such feel
Glutethimide ( alpha-ethyl-alpha-phenylglu tarim ide)10 is a nonbarbiturate seda tive whose principal effect is depression o f the central and autonomic nervous system. The electroencephalographic sleep patterns are similar to those seen with secobarbital and chloral hydrate. Th ere is no analgesic effect even in large doses. Th e effects on the cardiorespiratory system are nominal even in large doses, and there is no hypotension or respiratory depression with a therapeutic dose o f 0.5
C A R T E R — H U N T E R . . . V O L U M E 61, O C T O B E R I960 •
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pear in children and in adult patients to 1.0 Gm. Th e action o f glutethimide on high dosage levels. Allergic manifesta when given by mouth begins in 5 to 25 tions have been reported to range from minutes, and the maximum effect is m ild skin rash to syncope. T h e agent is achieved in 30 minutes. Th e duration o f approximately one fifth as toxic as the action is four to six hours.2 barbiturates. Isaacs3 used this agent in normal pa Lund and Anholm 6 studied 53 dental tients and found that 500 mg. o f glu patients (33 were children 2 to 15 years tethimide was equivalent to 1.5 grains old ) who had received meprobamate as pentobarbital in producing hypnosis. Th e premedication or fo r relief o f nervous principal side reactions at this dosage tension during denture adjustment. Th e level were unusual fatigue and sleepi authors reported that improvement in ness, lightheadedness and dizziness, behavior and in submission to treatment ataxia, lack o f concentration and apathy. was good to excellent in 82 per cent of T o x ic responses were reported in four cases by K ier, Whitehead and W hite.4 the patients. Drowsiness was noted in a few o f the smaller children, one adoles These patients had consumed amounts cent and one adult, but caused no incon varying from 5 to 10 Gm. of glutethimide venience. T h e authors concluded that in combination with alcohol or a barbi meprobamate is a valuable adjunct to turate. A ll patients recovered follow ing dental practice. lavage and dialysis. Drugs such as al Lefkow itz7 studied 423 patients over cohol and barbiturates which are central 18 years o f age, using a double blind nervous system depressants react synertechnic with patients categorized as ex gistically with glutethimide. A llergic re citable, apprehensive or normal. Th e actions have been reported consisting of first two groups were those requiring pre rubelliform rashes and exanthems which medication prior to dental treatment. disappeared when the drug was discon Lefkow itz used a 400 mg. meprobamate tinued. tablet which was given three times a Branch and Pastorello2 advocate the day prior to treatment. His conclusions use of glutethimide in combination with scopolamine or meperidine as a safe and were that the majority o f apprehensive and excitable patients may be expected effective premedication regimen for chil to accept dental care with more compo dren undergoing general anesthesia. It sure after receiving meprobamate. was found to decrease fear and anxiety Szmyd, M cC all and Enright8 made a in these children and made them more clinical evaluation o f promazine hydro susceptible to suggestion. chloride and meprobamate in the control Meprobamate ( 2-methyl-2-n-propyl-1, o f postoperative sequelae in patients un 3-propanediol dicarbam ate)11 is a non dergoing oral surgery. Th e results with barbiturate interneuronal blocking agent these drugs, as compared to a placebo, belonging to the group of drugs known indicated that there was no significant as substituted propanediols. Th e com effect on the postoperative sequelae of pound is known to possess definite relax pain, swelling and trismus. These agents ant properties which relieve both psychic also failed to influence the postoperative stress and muscular spasm without sig narcotic demand, and the number of nificant effect on the circulatory, respira tory or other autonomic functions. Berger5 days lost because o f convalescence was significantly increased. Th e authors con found meprobamate more effective than clude that neither promazine hydrochlo the barbiturates for alleviation o f emo ride nor meprobamate can be recom tional stress. mended for the control o f postoperative T h e side reaction most commonly seen sequelae in oral surgery. is drowsiness. This is most likely to ap
48/446
• T H E J O U R N A L O F T H E A M E R IC A N D E N T A L A S S O C IA T IO N
Ectyiurea (2-ethyl-cis crotonylurea)12 is an agent that produces m ild depres sion o f the central nervous system, an action shared with other substituted urea compounds. It does not influence blood pressure, pulse, respiration, gastric acid ity or motility, nor does it produce skeletal muscle relaxation, analgesia or anticon vulsant effects. Th e potential use o f the drug is as a neurosedative or calming agent, and it is not considered a hypnotic. Th e toxicity of ectyiurea is extremely low. Side reactions to the drug have been mostly skin rashes o f m ild effect and short duration. Bauer and others9 reported the use o f ectyiurea in 172 patients with tension, anxiety and insomnia. They concluded that this agent is of very low toxicity, permits daytime sedation without mental depression and induces normal sleep by alleviating tension and anxiety. There is one report o f jaundice after two weeks of ectyiurea therapy.13 It was suggested that this syndrome o f cholangiolytic hepatitis was a rare allergic mechanism apparently induced by ectyiurea. PRO CEDURE
A double blind clinical study was estab lished to compare the 24 hour premedi cation effects o f meprobamate, ectyiurea, glutethimide and placebo on 196 dental patients with symptoms o f anxiety and tension. This study initially comprised two groups of patients as follow s: Group A : 90 patients, mostly adults from pri vate practices. A ll received 24 hour pre medication with either glutethimide or placebo. Seventy-one patients, or 80 per cent, were women between the ages o f 12 and 85 years. T h e average age was 33 years. Group B: 106 patients from the Chil dren’s M ercy Hospital and the U niver sity o f Kansas City Pedodontic Clinic. A ll children received treatment from a single investigator (D .H .). A ll received 24 hour premedication with meproba
mate, ectyiurea or placebo. Sixty o f the patients, or 56 per cent, were girls be tween the ages o f 10 and 17 years. T h e average age was 11.5 years. Th e three drugs and the placebo were placed in capsules o f identical size and color and each drug and placebo then was individually packaged in identical packets o f four capsules. Each capsule contained 400 mg. o f the active agent except ectyiurea ( 300 mg. ). A ll o f the packets were randomized by the manu facturer in a box containing 120 packets per box. Each packet was coded and the code list was entrusted to the com pounding pharmacist and to the project coordinator (W .J .C .). Th e code list was not to be opened unless serious side re actions should develop in the patient taking one o f the agents. A record sheet was kept for each pa tient receiving the packet o f four cap sules. Th e top half o f the sheet was for recording the packet code number, name, age, sex, type o f dental treatment plan and the emotional status o f the individ ual. T h e bottom half of the record sheet was completed on the return visit. It contained spaces for recording the tak ing of capsules, the effect o f the agent on the patient, side effects, the desirabil ity of repeating the prescription and the dentist’s observation o f the person as a dental patient. O bjective signs such as sweating o f the forehead and palms were noted as was the ease o f patient care. A single packet containing four cap sules was given to the patient or, in the case o f a child, to his parent w ith instruc tions that one capsule should be taken at each o f three times during the day preceding the dental appointment and on the morning o f the appointment. The patients were told that the capsules were intended as an aid for them prior to their appointments. Th ey were given no in formation as to the type o f medication and also no mention was made o f the possibility of side reactions. I f there was any problem concerning the taking o f the
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capsules, they were to call the attending dentist. Several o f the Kansas City practitioners (M id-Century Dental Study Club mem bers)14 who were evaluating glutethimide and a placebo noted early in the studies severe side reactions such as drowsiness, vertigo and emotional upsets in their pa tients. It was thought best to halt this part o f the study, and accordingly, fur ther evaluation o f glutethimide and placebo on patients in Group A was dis continued. Th e method of evaluating subjective and objective symptoms are here outlined. T h e subjective symptoms were derived from the patients’ own words as to how they felt about the im pending dental appointments and how they reacted to the procedures at hand. Some o f these conditions are abstract in nature and some are more applicable to a specific age group. T h e symptoms include hesitancy in being seated, a negativistic attitude, resistance toward simple procedures such as the oral examination or having roentgenograms taken, obvious fear o f local anesthetic procedures and, in general, a resentment toward the dentist. T h e objective signs were those ob served by the dentist treating the patient. During the first appointment each pa tient was checked for reaction to anxiety and apprehension. Those patients se lected expressed a fear o f most dental procedures, used excuses to postpone the appointment and related “ bad experi ences” in other dental offices. They usual ly hesitated in allowing an immediate thorough examination and refused to co operate fully in any o f the routine pro cedures. O n the second appointment, after a 24 hour premedication period, all positive signs and symptoms previously recorded were reviewed with the patient. T h e patient was asked if his feeling to ward the appointment was different or better than before. Th e dentist looked also for an increase or decrease in “ ner vousness” and a greater or lesser willing
ness to cooperate and to have routine operative procedures performed. Patient improvement was recorded only when there was pronounced change or when a completely uncooperative patient per mitted some constructive treatment. Th e dentist noted also the presence of para sympathetic sweating o f both the fore head and the palms o f the hands during the visit. RESU LT S
Th e results o f this clinical study are pre sented in the table. T h e agent glutethi mide, although too reactive for complete comparison, was found to be the most effective in rendering the patient more susceptible to dental treatment. As may be noted in the table, 72 per cent o f the patients believed that this drug made them feel less apprehensive toward their impending dental appointment. It was also noted that the investigators were slightly less impressed with the results achieved with glutethimide and gave it a score of 62 per cent. Th e side reactions, as mentioned earlier, were more numer ous with glutethimide and more intense. Seventy-eight per cent o f the patients ex perienced some form o f reaction to the drug and five patients felt they were worse for having taken the agent. Most o f the reactions were due to drowsiness, but some had more severe symptoms. One patient felt depressed, four had signs of vertigo and four maintained that they were too sleepy to return for the ap pointment. T h e results for the drugs ectyiurea and meprobamate and for the placebo were identical as regards the patients’ feelings o f improvement and the dentists’ obser vations of their effects. T h e reactions which patients experienced were consid erably less frequent and severe in the placebo group than in the two experi mental groups, but reactions such as drowsiness were recorded in all three groups. A chi square test performed on
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TH E J O U R N A L O F T H E A M E R IC A N D E N T A L A S S O C IA T IO N
Table • Results o f clinical trials using a d o u b le blind technic on d en tal
patients with a g e n ts glutethim ide,
ectylurea and m e p ro b a m a te O b je c tiv e sym ptom s*
Su b jective sym ptom s*
D ru gs used
Glutethim ide Ectylurea M e p r o b a m a te P la ce b o
Im prove d
Sa m e
W o rse
No. p a tie n t s
Per cent
No. p a tie n t s
Per cent
36 16 13 34
72 44 41 46
9 19 18 40
18 S3 56 54
No. p a tie n t s 5 1 1 —
Im proved
Sam e
W o rse
Per cent
No. p a tie n t s
Per cent
No. p a tie n t s
Per cent
No. p a tie n ts
Per cent
10 3 3
31 16 13 40
62 44 41 54
14 19 18 34
28 53 56 46
5 1 1
10 3 3
—
—
—
‘ Subjective sym ptom s: the patient's description of his feelings of anxiety or tension tow ards the dental appoin t- • ment. O bjective sym ptom s: tne dental practitioner's observations of persons as dental patients, Including evalua tion of signs such as sw eating of the forehead and palms.
these two agents and compared with the results with the placebo showed no sig nificant differences. One patient taking meprobamate had emesis after taking the first capsule and another patient became more excited after taking the series. Three patients taking ectylurea had minor side effects such as stomach-ache, hyperexcitability and tinnitis. Th ere were no severe side reactions reported in the placebo group. It was interesting to note that the placebo was more effective than either meprobamate or ectylurea as seen by the investigators. In fact, it was only slightly less effective (54 per cent) than glutethimide (62 per cen t). This tends to reduce the level o f significance o f glutethimide as an effective antiapprehensive agent. Th e dentist’s observation on the ease o f handling patients is the major point under consideration in this study, especially in the adolescent patient. A n swers to the question as to whether the patient would like the prescription re peated, were evenly divided between “ yes” and “ no” for glutethimide, ecty lurea and for the placebo. However, only one third o f the group taking meproba mate desired renewal o f the drug. DISCUSSION
Th e need for an agent to be used to re duce the anxiety and tension of dental
patients toward an impending dental appointment has been established. H o l lister13 has stated that tranquilizing drugs have established, fo r better or worse, a place in medical therapy. This does not preclude the need for additional studies, especially those that are well-controlled and include placebo comparison. Shapiro and T en g 16 emphasize that the nonpharmacological variables such as the doctorpatient relationship and the impact o f psychologic changes in the patient which tend to mimic and occasionally mask the pharmacological effect o f a drug make the placebo a necessity in clinical inves tigations. In regard to pain experienced by the patient, M aurice17 has found that it may be intensified by psychic factors. Beecher,18 commenting on the powerful placebo effect, observed that the placebo was effective in 35.2 per cent of cases when used in conjunction with other agents for relief o f pain, headache, anx iety and tension. H e maintains that the placebos are more effective when stress is greatest and can also produce thera peutic and toxic reactions. W o lf and Pinsky,19 studying the effect o f placebo and mephenesin, founds almost the same amount o f improvement of certain pa tient symptoms with each agent. Glutethimide, with the exception o f its high percentage o f side reactions, comes nearer to being an effective agent in the calming o f dental patients. This
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seems to be a characteristic common to this group o f drugs, in that the more effective they are, the more toxic they become in many o f the patients receiv ing the drug. It is interesting to note the dissimilarity between the objective symp toms recorded by the dentist and the subjective symptoms reported by the pa tients fo r glutethimide. Th e objective symptoms are only slightly greater (62 per cent) than those for the placebo (54 per c e n t). Redish and Ping20 also noted a divergence between subjective and ob jective symptoms when they evaluated ethinamate (V a lm id ) in a double blind study. Th e divergence was slight in the improved groups but became greater in the questionable or “ no help” categories. Th e patient’s feelings toward the dental appointment certainly should be consid ered, but if the practitioner’s observations are considered as at least equally reli able, results with glutethimide become less significant. In a comparison o f ectylurea, mepro bamate and the placebo in this study, there is little divergence between the subjective or objective responses. A com parison o f ectylurea and meprobamate favors ectylurea slightly but not to a degree that is clinically significant. Both drugs were found to be neither very toxic nor especially objectionable to the patient. However, unless the psychic changes manifested in these patients are more elusive than was supposed, these drugs are apparently no more effective than placebo. This study does not prove any o f the tested drugs to be the final answer to pretreatment anxiety in dental patients. Further analysis o f these agents should take into consideration an in creased dosage for ectylurea and mepro bamate and a lengthened premedication period. CONCLUSION
A double blind study was conducted to compare the effects o f glutethimide, ecty lurea, meprobamate and placebo in 196
dental patients. Glutethimide proved the most effective in allaying patients’ emo tional conditions but was also the most frequently toxic. Ectylurea and mepro bamate were no more effective than the placebo and were only slightly more re active than the placebo. This study does not provide an answer to the treatment o f anxiety in dental patients in reference to the afore-mentioned drugs.
This study was supported ¡n part by a research grant from the A m es C o ., Inc., Elkhart, Ind. *Professor of pedodontics, University of Kansas City School of Dentistry, and chief of dental service, C h il dren's M ercy H o sp ita l. tPedodontic - resident, C h ild ren 's M ercy H ospital. 1. Tranquilizers are prescribed by 44.5% of dentists, usually preoperatively. D. Survey 34:780 June 1958. 2. Branch, D. R., and Pastorello, R. R. Use of g lu tethim ide for preoperative m edication in children. New Eng. J. M e d . 257:125 July i8, 1957. 3. Isaacs, B. H ypn otic effect of glutethim ide in nor mal human subjects. Lancet 272:558 M arch 16, 1957. 4. Kier, L. C .; W hitehead, R. W., and White* W . C. Blood and urine levels in glutethim ide (doriden) in toxication. J .A .M .A . 166:1861 A p ril 12, 1958. 5. Berger, F. M . M eprobam ate, its pharm aceutical properties and clinical uses. Internat. Rec. M ed . 169:184 A p ril 1956. , 6. Lund, L., an d Anholm , J. M . C lin ic a l observations on the use of m eprob am ate in dental procedures. O ra l Surg., O ra l M e d . & O ra l Path. 10:1281 Dec. 1957. 7. Lefkowitz, W . Use of m eprobam ate before o pe r ative procedures. A preliminary report. J. O h io D. A . 32:27 W in ter 1958. 8. Szmyd, L.; M c C a ll, C . M., and Enright, E. T. Tranquilizing d ru gs in oral surgery. J. O r a l Surg. 16:310 July 1958. 9. Bauer,H. G ., and others. A clinical evaluation of ectylurea {nostyn). N . Y. State M . J. 58:520 Feb. 15, 1958. 10. G lutethim ide (D oriden), C ib a Pharmaceutical Products, Jnc., Sum mit, N. J. 11. M e p ro b a m a te (Equanil), W yeth Laboratories, Philadelphia. / 12. Ectylurea (Nostyn), A m e s C om pany, Inc., Elk hart, Ind. 13. Hochm an, R., and Robins, J. J. Jaundice due to ectylurea. New Eng. J. M ed . 259:583 Sept. 18, 1958. 14. M em bers of the M id -C e ntu ry Dental Study C lu b are: H . D. Buell, W . H. Cottrel, W . C lifton, W . G . Dennis, R. W . Edwards, Jr., J. I. Hense, C . R. M c C le l lan, W . D. Milter, C . V. Neath, W . H. Poyser, H . R. Skoog, J. D. Stanton, C . Stout, H. G . W r ig h t and H. Forbes. 15. Hollister, L. E. C o m p lic atio n s from the use of tranquilizing dru gs. New Eng. J. M e d . 257:170 July 25, 1957. 16. Shapiro, A . P., and Teng, H. C . Technic o f co n trolled dru g assay illustrated by a com parison study of rauwolfia serpentina, phenobarbital and place b o In the hypertensive patient. New Eng. J. M e d . 256:970 M a y 23, f957. 17. M aurice, C . G . Differential d iagn o sis of dental pain. J .A .D .A . 50:316 M arch 1955. 18. Beecher, H. K. Powerful placebo. J .A .M .A . 159:1602 Dec. 24, 1955. 19. W o lf, S., and Pinsky, R. H. Effects of placebo adm inistration and occurrence of toxic reactions. J .A .M .A . 155:339 M a y 22, 1954. 20. Redish, C . H., and Ping, R.S. Ethinamate (V a l m id) in dentistry. O ra l Surg., O ra l M e d . & O ra l Path. 11:742 July 1958.