Anxiolytic Activity of Chloral Hydrate and Hydroxyzine

SCIENTIFIC ARTICLE

Anxiolytic activity of chloral hydrate and hydroxyzine

M. Gladney, DMD,MS R.T. Stanley, DDSS.E. Hendricks, PhD Abstract The combinationof chloral hydrate and hydroxyzineis given frequently to anxious pediatric dental patients. In order to observe and quantify the anxiolytic effects of these drugs given alone and in combination,highly explorative male C57/black mice weretested using the light~dark test box after injecting subhypnoticdoses for increased transitions betweenthe light and dark side of the test box. Fifty-one mice weresubjected individually to a l O-mintest in the box for dose responsesfollowing the i.p. administration of 32-, 64-, and 132-mg/kgdoses of chloral hydrate; 1-, 4-, 7-, and lO-mg/kgdoses of hydroxyzine; or a combinationof each of these doses of hydroxyzineand chloral hydrate. The automatedtest box recordedthe numberof times a mousecrossed betweenthe two chambers.Doses of chloral hydrate 132 mg/kgand hydroxyzineI mg/kgresulted in significantly increased transitions. Noneof the combinationsstudied producedsignificantly increased transitions whencompared with the effective doses identified for each individual drug. The paradigmdid not support the hypothesis that the anxiolytic effects of chloral hydrate and hydroxyzine are additive or synergistic. (Pediatr Dent 16:183-89,1994)

Introduction and literature review this study. Many of the modern benzodiazepine-type 1 anxiolytic agents were tested prior to clinical use in the Antianxiety drugs are referred to by many terms 1° including "anxiolytic," which refers to drugs that have light/dark test box utilized in this study. No readily more specific anxiety reduction properties than CNS available reports evaluate the antianxiety effects of depression properties. Anxiolytics allow a patient to hydroxyzine hydrochloride and chloral hydrate in a maintain near-normal motor function while sedatives modern mouse anxiety paradigm. Many physiologic (or sedative doses) severely impede motor and cogni- and behavioral clinical studies have appeared in the tive function. pediatric dental literature, but clinical use and research Dentists have long sought a single, safe, orally ad- have not clearly established the anxiolytic effective- ministered drug that would reliably reduce anxiety in ness of the combination. children and adults when administered prior to dental Justifiably or not, anxiety reduction is often alluded treatment. No single drug has all the effects desired by to in clinical studies, texts, lectures, and case reports on manydental practitioners, therefore there is consider- the use of combinations. There appears to be a collec- able use of combinations of orally administered sedative opinion amongpediatric dentists who have stud- tive agents. 2-~ Somecombinations were initially used ied anxiolytic agents that an effective agent for uncoop- on an empirical basis. Few basic animal studies were erative dental patients would have a primary effect done on these combinations prior to their use in den- against anxiety21 tistry.6 One notable animal study was done by Pruhs, Chloral hydrate whoinvestigated the effects of adding nitrous oxide to The efficacy of chloral hydrate as an anxiolytic agent chloral hydrate. Pruhs’ study, like this one, attempted has been questioned frequently. The pharmacological to provide a basic understanding of some narrow part and medical literature frequently cites only limited of the activity of a popular combination used in pediat- anxiolytic9 effectiveness in old clinical reports. ric dentistry. There are a few animal studies of the Chloral hydrate has been used by 25 to 40%of Ameri- sedative and antianxiety effects of chloral hydrate and 7 can and Canadian pediatric dentists surveyed between hydroxyzine as single agents. Stuphel studied the ef- 1973 and 1987 to calm fearful or uncooperative pediat- fect of hydroxyzine on aggressiveness of mice and ric dental patients.2, 4, 5,12,13 Lenegre8 used mice to find that amnesia induction was not a property of subhypnotic doses of hydroxyzine. Hydroxyzinehydrochloride Pollard9 reviewed studies of pigeons and rats that tested Hydroxyzine has an excellent safety record and has the effects of many drugs, including chloral hydrate, been widely used by dentists for many years2-~4 Pedia- on punished responses. tricians have also used hydroxyzine to sedate mildly Most of the antianxiety studies of the currently popu- anxious children for less threatening medical proce- lar dental combinations like chloral hydrate and dures and for anxiety states such as those associated hydroxyzine were done approximately 20 years ago with school refusal. 15 The anxiolytic activity of and used a more aversive test than the one utilized in hydroxyzine, like chloral hydrate, has been questioned

Pediatric Dentistry: May/June1994 - Volume16, Number3 183 frequently. The medical literature on hydroxyzine con- subjective behavior evaluation criteria makes it diffi- sists mostly of old clinical reports that cite limited ef- cult for practitioners to gain a good understanding of fectiveness as an anxiolytic. 9 Hydroxyzine’s popular- the indications, dosing, and realistic expectations of ity as an anxiolytic has been described as "surprising in achievable results when using the combination of chlo- view of studies that suggest that it is not an effective ral hydrate and hydroxyzineo antianxiety agent unless it is given in doses that pro- Animalstudies duced"16 marked sedation. Although little is written about the pharmacologic In contrast to the manywidely varying and difficult effects of the combination of chloral hydrate and to control clinical studies, few studies have examined hydroxyzine, the dental literature contains manystud- the efficacy of the combination of chloral hydrate and ies and clinical reports on the use of the combination. hydroxyzine in the more controllable animal popula- Several studies involve the popular combination of tion. The widely varying clinical conclusions and study chloral hydrate and the antihistamine promethazine, criteria demonstrate a need to retreat and seek to an- which could be expected to possess activity similar to swer basic questions: Can the anxiolytic effects of chlo- those associated with the combination of chloral hy- ral hydrate or hydroxyzine be demonstrated in a mod- drate and hydroxyzine.17,18 The available clinical stud- ern, simple animal model? Does the addition of weakly ies involving the combination of chloral hydrate and anxiolytic hydroxyzine produce a synergistic or addi- hydroxyzine and the individual drugs alone, though tive effect on the weakly anxiolytic properties of chlo- numerous, present conflicting findings. The clinical ral hydrate? studies conducted by Epstein 19 and Kopel2° did not The pharmacologic effects in which pediatric den- produce evidence of hydroxyzine efficacy in reducing tists are most interested are anxiety reduction, arousable dental apprehension. Linnenburg and Lang’s studies sleep induction, and physiologic tolerance. Physiologic claimed that hydroxyzine has value as premedication tolerance measurement in children has been adequately for anxious dental patients. R1, 22 Shapira rated defined for oral sedatives including chloral hydrate hydroxyzine as "successful" in a majority of pediatric and hydroxyzine by clinical studies and reports22, 27-33 dental patients studied when he evaluated the effects Objectivity and control of variables are well established of23 combining nitrous oxide and hydroxyzine. Shapira in such studies. Anxiety reduction and therapeutic ef- found that a combination of the two agents made the ficacy, on the other hand, are difficult to measure and sedation more "successful." Smith24 found chloral hy- have been associated with contamination and with in- drate to be no more effective than a placebo in a double- vestigator and rater bias. Poorly controlled clinical stud- blind study of handicapped pediatric dental patients. ies have often proclaimed impressive efficacy, while Houpt~7 rated as successful 72%of the sedations of an controlled clinical studies have yielded inconsistent experimental group of children receiving chloral hy- findings.34 drate. Badalaty, 25 in a study that comparedchloral hy- There are a number of animal paradigms that can be drate and diazepam, rated 46.6% of a group of chloral specifically designed to test the anxiolytic versus seda- hydrate sedations to be excellent or good, which was tive actions of drugs. In the strictest sense, anxiolytic not significantly different from that of diazepam. activity occurs without producing sedation. Because The dental literature rarely makes any specific refer- anxiety reduction is mentioned in manydental articles ence to the early use of combinations of oral anxiolytic/ about conscious sedation, it warrants study. Drugs that sedatives agents used in dentistry. Several popular affect anxiety are often subjected to preclinical evalua- dental texts recommendand describe using the combi- tion in rodents utilizing the light/dark transition box, nation of chloral hydrate and hydroxyzine, although the elevated plus maze and other paradigms2°, 35-40 numerousclinical studies describe conflicting and vary- Specific studies involving the combination of chlo- ing degrees of efficacy of these drugs alone or in com- ral hydrate and hydroxyzine were not done before clini- bination.14,26 cal use of the combination became popular. Because Despite a lack of consistent, unchallenged clinical humanbehavior is subject to a host of environmental, research, chloral hydrate alone or in combination with psychological, social, and metabolic variables that af- another agent is the most frequently used oral fect a child’s cooperation level, this study makes no premedicationfor difficult patients. R, 3 The literature is attempt to make conclusions other than those concern- replete with studies indicating success rates ranging ing the synergism, additive effects, or lack of effective- from less than 30% to more than 85%when the combi- ness of the component drugs when they are used alone nation is used to calm anxious dental patients. These or combined, insofar as they can be demonstrated in a studies evaluate the combination of chloral hydrate at scientifically° verified mouse antianxiety paradigm2 varying doses, patient ages, pretreatment behaviors, The primary purpose of the experiment was to de- mental capacities, environmental settings and concomi- termine if chloral hydrate alone, hydroxyzine alone, or tant use of other agents. The lack of consistency of combinations of two drugs could be tested for anxiolytic variables and the use of inconsistent and sometimes activity in the light/dark test box. The secondary pur-

184 Pediatric Dentistry: May/June 1994 -Volume 16, Number3 pose of the experiment was to determine if additive fying the exploratory behavior of mice isolated and anxiolytic activity could be demonstrated when the placed in an aversivelighted environment of the light/ two drugs were combined. dark test box after administration of: 1. Chloral hydrate (Geneva Pharmaceuticals-- Methods and materials Bloomfield, CO) alone. Fifty-one male C57/Black mice, 6-8 weeks old, 2. Hydroxyzine hydrochloride (Warner Chilcott weighing from 21-25 g, (Jackson Laboratory, Bar Har- Labs--Morris Plains, NJ) alone. bor, ME) were housed in the animal care unit of the 3. Combinations of subsedative doses of chloral National Institute of Dental Research in four groups of hydrate and hydroxyzine hydrochloride. ten and one group of 11. The mice were randomly 4. USPSaline for Injection (Abbott Laboratories) selected for the first of up to four tests using different used for both placebo and diluent. Placebo treat- treatment regimens resulting in a total of 195 10-min ments were given throughout the experiment tests in the light/dark test box. Subsequent treatments and formed the baseline value to compare in- selectively excluded repeating the test with the same creases or decreases in transitions. drug regimen on any mouse. A constant temperature of 21°C and a controlled The research described in this article was reviewed lighting schedule of 0600 to 01800 hrs in the housing and approved by University of Nebraska Institutional unit were maintained. The mice were fed ad lib with Animal Care and Use Committee and the National standard laboratory chow. Between 0700 and 1400 Institute of Dental Research Animal Care and Use Com- hours, a group of mice were brought to an animal mittee. procedure room. The mice were given a minimumof 1 Anxiety reduction in mice was measured by quanti- hr to acclimate to the test room before receiving an intraperitoneal injection of Table.Results of all treatments the test drugs or placebo. A 0.5-cc, 28-gauge ultrafine HO mg/kg H1 mg/kg H4 mg/kg H7 mg/kg HIO mg/kg needle, insulin syringe was used to inject the small vol- COmg/kg C0+H0(Sal) °C0+H1 C0+H4 C0+H7 C0+H10 umes of medication needed. N=25 N = 8 N = 8 N = 8 N = 8 The intraperitoneal route Tr = 55.04 Tr = 69 Tr = 57.75 Tr = 50.75 Tr = 46.63 was selected to facilitate SD = 7.07 SD = 9.74 SD = 11.65 SD = 11.23 SD = 6.93 more accurate dosing. Iden- SE = 1.41 SE = 3.44 SE = 4.12 SE = 3.97 SE = 2.45 tification marks were placed on the tails of the mice im- C32 mg/kg C32+H0 C32+H1 *C32+H~ *C32+H7 tC32+H10 mediately after injection. N=8 N=8 N=8 N=8 N=8 The injected mouse was then Tr -- 61 Tr = 64.75 Tr = 40.1 Tr = 41.14 Tr = 27.5 returned to the housing SD = 6.87 SD = 7.40 SD = 9.80 SD = 12.33 SD = 17.19 cage. After 30 min the mouse SE = 2.43 SE = 2.62 SE = 3.47 SE = 4.36 SE = 6.08 was removed from the housing cage and placed in the C64 mg{kg C64+H0 C64+H1 C64+H4 C64+H7 C64+H10 center of the lighted part of N=8 N=8 N=8 N=8 N=8 the light/dark test box. The Tr = 54.25 Tr -- 49.88 Tr = 57.25 Tr = 50.88 Tr = 43 number of times the animal SD = 14.46 SD = 12.21 SD = 13.70 SD = 16.60 SD = 27.75 would cross between the lit SE = 5.11 SE = 4.32 SE = 4.84 SE = 5.87 SE = 9.81 and darkened side of the test box in a 10-min period was C132 mg/kg "C132+H0 C132+H1 C132+H4 *C132+H7 ~C132+H10 recorded. N = 10 N = 8 N = 8 N---- 8 N = 8 Tr = 74.8 Tr = 52.25 Tr = 50.25 Tr = 37.00 Tr = 33.25 Testing apparatus SD = 14.66 SD = 11.13 SD = 18.27 SD= 15.1 SD= 24.89 The light/dark test box SE = 4.64 SE-- 3.94 SE = 6.46 SE = 5.37 SE = 8.80 consists of a polypropylene cage (44x21x21 cm) divided C0+H0.5 ~C200+H0 into a large uncovered trans- Dosesused for doseresponses only. N-~8 N=8 parent compartment and a Not used in combinations. Tr = 53.00 Tr = 28.13 painted and covered dark SD= 12.75 SD= 20.22 compartment half the size of SE = 4.51 SE = 7.15 the larger compartment. The Abbreviations: Saline (Sal) Chloral hydrate(C),Hydroxyzine (H), Transitions (Tr), Standarddeviation dimensions were selected (SD), Standarderror (SE). because mice prefer dark, ¯ Dosesthat significantly increasedtransitions. * Dosesthat significantly decreasedtransitions.

Pediatric Dentistry: May/June1994 -Volume 16, Number3 185 ~oo ] mg/kg) or saline revealed a significant overall effect for drug treatment (F = 17.29, P < 0.0001). Meantransi- 8O tions for each dose of chloral hydrate are presented in Fig 1. Dunnett’s t-test (alpha = 0.05, confidence = 0.95) 60 revealed that a 132-mg/kg dose of chloral hydrate resulted in significantly increased transitions compared 40 to saline. A 200-mg/kg dose of chloral hydrate resulted in significantly decreased transitions compared with 2O the saline. Similarly, ANOVAapplied to mean transitions for 0 32 64 132 200 mice receiving hydroxyzine alone (0.5, 1, 4, 7, or 10 Chloral Hydrate DosesMG/KG mg/kg) or saline revealed a significant overall effect for drug treatment (F = 7.45, P < 0.0001). Meanvalues Fig 1. Chloral hydrate dose response. for each dose of hydroxyzine are presented in Fig 2. Dunnett’s t-test (alpha = 0.05, confidence = 0.95) revealed that only a 1-mg/kg dose of hydroxyzine resulted in significantly increased transitions compared with saline. No doses of hydroxyzine alone caused O significantly decreased mean transitions. ,~ 40 Analysisof chloral hydrate/hydroxyzine drug treatments ~ 2O ANOVAapplied to mean transitions for mice receiving 32 mg/kg of chloral hydrate combined with either 1, 4, 7, or 10 mg/kg of hydroxyzine or saline 0.5 1 4 7 10 revealed significant overall effect for drug treatment (F Hydroxyzine Doses MG/KG = 18.52, P < 0.0001). Mean values for each dose are presented in Fig 3. Dunnett’s t-test (alpha = 0.05, confi- ~--ITransitions + +SEMI dence = 0.95) revealed that doses of 4, 7, and 10 mg/kg of hydroxyzine added to 32 mg/kg of chloral hydrate Fig 2. Hydroxyzine dose response. resulted in significantly decreased transitions compared with saline. small areas to larger, brightly lit areas whenin an unfa- ANOVAapplied to mean transitions for mice re- miliar environment. The two compartments were sepa- ceiving 64 mg/kg of chloral hydrate alone, chloral hy- rated by a Plexiglass (Plakolite Inc., Columbus, OH) drate 64 mg/kg combined with either 1, 4, 7, or 10 mg/ partition with a 13x5-cm-high passageway. The num- kg of hydroxyzine, or saline revealed no significant ber of transitions between the light and dark side and overall effect for drug treatment (F = 1.36, P > 0.2602). time spent on the dark side (seconds) were electroni- Meanvalues for each dose are presented in Fig 4. cally measured by programming a set of photoelectric ANOVAapplied to mean transitions for mice re- cells to sequentially exclude head pokes and count only ceiving 132 mg/kg of chloral hydrate alone, chloral full body transitions. The electronic circuitry included a timer that was set at the beginning of the experiment to stop counting light/dark transitions and time spent 70 on the dark side automatically after 10 min. 60 P=50 Results O The table summarizes all treatment results. Note ~: 40 that the doses of 0.5 mg/kg of hydroxyzine and 200 t- 30 mg/kg of chloral hydrate were used to define anxiolytic dose response endpoints, and hence were not used in the combinations. None of the combinations produced ~0 an increase in mean baseline transitions significantly 0 greater than that produced by chloral hydrate alone at 0 1 4 7 10 a dose of 132 mg/kg. MG/KGof Hydroxyzine Added to CH 32MG/KG

Analysisof single-drugtreatments []Transitions + +SEM] Analysis of variance applied to mean transitions for mice receiving chloral hydrate alone (32, 64, 132, or 200 Fig 3. Chloral hydrate 32 mg/kg + hydroxyzine.

186 Pediatric Dentistry: May/June1994 - Volume16, Number3 test box have been shownto be particularly sensitive to anxiolytics. It has been postulated that this highly ac- 60 tive and exploratory species as well as several other ~ 5o O species with high baseline exploratory activity, may be particularly responsive to the test due to a genetically determined substrate for spontaneous exploratory be- ~- ~0 haviors.41.45 Paradigmrationale 10 The fundamental premise of this paradigm and several other currently accepted methods for using mice to 0 1 4 7 10 evaluate the effects of drugs on anxiety is that mice MG/KGof Hydroxyzine Added to CH 64MG/KG tend to explore new environments unless an aversive situation causes anxiety that limits this natural activ- [~Transitions + +SEM I ity. 1°’42 If a mouseis removed from the population with that it is housed and placed in a new lighted environ- Fig 4. Chloralhydrate 64 mg/kg+ hydroxyzine. ment an aversion is created that is loosely analogous to anxiety states which inhibit the mouse’s natural in- hydrate 132 mg/kg combined with either 1, 4, 7, or 10 stinct to explore a new environment. The aversive na- mg/kg of hydroxyzine or saline revealed a significant ture of light in an unknown environment causes the overall effect for drug treatment (F = 5.18, P < 0.0014). mouse to seek a smaller and darker area and inhibits Dunnett’s t-test (alpha = 0.05, confidence = 0.95) re- the normal exploratory transitions between the light vealed significantly decreased transitions when the mice and dark side that the mouse would instinctively make received 132 mg/kg of chloral hydrate plus 7 or 10 mg/ in a uniformly darker unknown environment. A num- kg of hydroxyzine when compared with saline. Mean ber of antianxiety agents -- when given at an effective values for each dose are represented in Fig 5. dose -- mitigate the aversion and cause the mouse to travel between the dark and light sides of the test box significantly more than it would if given just a placebo. 100 Increased transitions in the testing apparatus compared with a control group are associated with 80 anxiolytic activity; decreased transitions are associated 60 with sedation. Dose response curves were generated for the doses of chloral hydrate, hydroxyzine, and the 40 combinations used in the study. The subhypnotic doses of chloral hydrate that didn’t cause a significant de- 20 crease in mean transitions were used in combination with selected doses of hydroxyzine to study the exist- 0 ence and magnitude of antianxiety response (increase 0 1 4 7 10 in transitions) due to combining the two drugs. MG/KGof Hydroxyzine Added to CH 132MG/KG Doseselection ~ [~]Transitions + +SEMI Initial hydroxyzine doses were selected based on prior experiments that evaluated anxiolytic activity in Fig 5. Chloralhydrate 132 mg/kg + hydroxyzine. mice. Similarly, initial doses of chloral hydrate were selected based on prior studies 6, 46 using foot shock disinhibition of explorative mouseactivity. Additional Discussion doses were included in the study to the extent that each Speciesspecificity mousecould be tested four times with at least one day The strains of mice most suitable for testing of rest between each test. Blumstein45 confirmed that a antianxiety agents in the light/dark test box are the limited numberof repeat trials with as little as one day C57/Black mice and the Swiss Webster (NIH-- of rest between them was not associated with drug Bethesda, MD)mice. 41 Selecting the species and strain tolerance, circadian variability, and test learning when to be used in the light/dark test box was a critical factor the C57/Black mouse was tested in the light/dark test in the design of this study. Although rats and mice are box. good choices for antianxiety tests, rats and some spe- Chloral hydrate doses of 132 mg/kg simulated cies of mice don’t exhibit any consistent antianxiety anxiolytic activity in this study. Doses of 64-128 mg/ effects of exploration that are measurable in this para- kg of chloral hydrate in other classical tests simulated digm.41-~5 Male C57/Black mice tested in the light/dark anxiolytic6’46 activity using different mouseparadigms.

Pediatric Dentistry: May/June1994 - Volume16, Number3 187 Pruhs6 investigated the effect of adding nitrous oxide clinician keys as to which specific regimen will consis- inhalation to chloral hydrate administration in a mouse tently produce the desired results in specific patients. staircase test that associated an increased number of rears with anxiolytic activity. His study found that Conclusions individually, both drugs produced antianxiety effects The light/dark test paradigm demonstrates that at as simulated by the mouse staircase test and that subhypnotic doses: coadministration of nitrous oxide with chloral hydrate 1. Chloral hydrate has anxiolytic activity. produced an enhanced anxiolytic activity. Pruhs’6 study 2. Hydroxyzine has weaker anxiolytic activity than produced results that paralleled those obtained in a chloral hydrate. clinical study conducted by Houpt,47 which found that 3. The combinations of chloral hydrate and nitrous oxide augments the effects of chloral hydrate hydroxyzine tested did not demonstrate addi- sedation. 32 This linked pharmacologic activity between tive anxiolytic activity. humansand mice at least partially confirms the appli- The authors thank Dr. J.N. Crawley of the National Institute of Mental cability of animal paradigms for the study of combina- Health and Dr. Joseph Bryant of the National Institute of Dental tions used or contemplated for pediatric dental seda- Research for their assistance. tion. Our study sought to determine if coadministration Dr. Gladney is an active duty commissioned officer in the USPublic of chloral hydrate and hydroxyzine would produce a Heath Service, currently assigned as Oklahoma City Area Pediatric similar additive or synergistic action. This was at- Dentistry Consultant. Dr. Stanley is assistant professor, department tempted despite the historically poor response of the of pediatric dentistry, University of Nebraska Medical Center, Omaha, Nebraska. Dr. Hendricks is associate professor, department of psy- hydroxyzine component to the other "classical" chology, University of Nebraska, Omaha. disinhibitorys tests, The animal model studied indicates that there was 1. Felpel LP: Antianxiety drugs and centrally acting muscle relax- ants. In Pharmacology and therapeutics for dentistry. Neidle no advantage in using a combination of chloral hydrate EA, Kroeger DC, Yagiela JA, EDS. St. Louis: CV Mosby Co, and hydroxyzine to increase anxiolytic activity with- 1985, pp 193-209. out producing sedation. Admittedly, there may be an 2. Houpt MI: Pharmacological methods and research issues in the effective dose between those selected that may show management of child patients. Anesth Prog 33:25-29, 1986. 3. NathanJE: Managementof the difficult child: asurveyofpedi- additive anxiolytic activity. The limited range of that atric dentists’ use of restraints, sedation and general anesthe- effective dose may not prove to be practical consider- sia. ASDCJ Dent Child 56:293-301, 1989. ing variable metabolisms in any species tested. No claim 4. Nathan JE: Management of the refractory young child with is made that there is or is not any anxiolytic activity chloral hydrate: dosage selection. ASDCJ Dent Child 54:93- concurrent with the obvious sedation produced by sev- 100, 1987. 5. Wright GZ, Chiasson RC: The use of sedation by Canadian eral treatments. The light/dark test box is not designed pediatric dentists. Pediatr Dent 9:308-11, 1987. to quantify concurrent sedation when it occurs with 6. Pruhs RJ, Kalbfleisch JE, Quock RM: Combination effects of anxiolytic activity. chloral hydrate and nitrous oxide/oxygen in the mouse stair~ It is apparent from the data and consistent with our case test. Anesth Prog 35:116-20, 1988. previous knowledge that additive sedation activity does 7. Stuphel M, Masse H, Dague C: Action of physcoactive drugs on sex-related differences in of 1 mice: intraspecific aggressive- occur when the two CNS drugs are combined. The ness and acute hypoxia survival. Physchopharmacology 63:103- additive sedation observed was not spectacular be- 11, 1979. cause it was no different than the sedating dose of 200 8. Lenegre A, Fromage S, Milinkevitch D, Porsolt RD: Absence of mg/kg of chloral hydrate alone. Unless the 200-mg/kg amnesia induction in mice with hydroxyzine in comparison with three other minor tranquilizers. Arzneim-Forcsch/Drug dose causes physiologic compromise for the mouse, Res 38:558-60, 1988. single-drug therapy is likely the more prudent seda- 9. Pollard GT, Howard JL: Effects of drugs on punished behavior: tive regimen. This finding is consistent with the current pre-clinical test for anxiolytics. PharmacTher 45:403-23, 1990. medical studies involving the use of high doses of chlo- 10. Costall BJ, Kelly ME, Naylor RJ, Tomkins DM:Exploration of ral hydrate alone for the sedation of young children mice in a black and white test box: validation as a model of 4~5° anxiety. Pharmacol Biochem Behav 32:777-85, 1989. undergoing medical procedures. 11. Anderson JE: Pain and anxiety control. In Pediatric Dentistry: More animal studies may be needed to define the Infancy Through Adolescence. Pinkham JR, ED. New York: specific properties of the various combination agents WBSaunders Co, 1988, pp 81-87. that have been used clinically for many years without 12. Wright GZ, McAulay DJ: Current Premedicating trends in ever being preclinically evaluated. Such studies could pedodontics. ASDCJ Dent Child 40:185-87, 1973. 13. Duncan WK, Pruhs RJ, Ashrafi MH, Post AC: Chloral hydrate lead to more narrowly focused antianxiety clinical stud- and other drugs used in sedating young children: a survey of ies than the present clinical studies. Dentists, psycholo- American Academy of Pedodontic Diplomates. Pediatr Dent gists, physicians, and pharmacologists need to clearly 4:252-56, 1983. define the role of anxiety (if one exists) in the uncoop- 14. Troutman KC: Pharmacologic management of pain and anxi- erative pediatric dental patient. The knowledge gained ety for pediatric patients. In Pediatric Dentistry, Total Patient Care. Wei SH, ED. Philadelphia: Lea and Febiger, 1988, pp 156- by then merging exhaustive animal, narrowly focused 85. clinical, and psychological investigations maygive the 15. White JH: Pharmacology of individual drug categories. In Pe-

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