Pediatric Psychophannacologic Uses of Propranolol Review and Case Illustrations

JENNIFER SIMS, MSN, RN, and MATTHEW R. GALVIN, MD

This article introduces child and adolescent psychiatric nurses to the use of propranolol for aggression in children and adoles- cents. The use of propranolol is relatively new in the area of psychiatry. A retrospective chart review of patients who had received propranolol was conducted in an intermediate care hospital. Case illustrations are presented.

NCLUDED IN THE GROUP OF CHILDREN AND ADOLESCENTS who require psychiatric hospitalization are those who so I poorly modulate their aggressiveness that they seriously

disrupt the home, the classroom, and their relationships with others. Aggression is used to describe various behaviors that harm, or that are intended to h m , another. Aggression is inherent in human biological organization, yet widely varied in its manifestations depending upon developmental stage and other individual and familial factors, as well as cultUrai influences (Eisenberg, 1980). Some specific examples of aggression include physical attacks on property, on other people, or upon oneself. Mastering aggressive impulses and modulating and directing them is an ongoing developmental @k throughout the aggressive individual’s life. Poorly modulated aggression occurs in conditions commonly en- countered by the psychiatric nurse working with children and adolescents. These conditions include conduct disorder, organic brain syndrome (organic personality disorder), and post-traumatic stress disorder (PTSD).

A child who bites, kicks, hits, or threatens with s h q objects poses difficulties in therapeutic management. Early interventions that allow the child to calm down before behavior becomes out of control are preferable to other more restrictive interventions. Nevertheless, nurses, unit staff members, and physicians find themselves resorting to seclu- sion and restraint or therapeutic holds, when opportunities for less restrictive interventions are not recognized or when

Reprint requests: Jennifer Sims, 33% Sherbume Circle, Indianapolis, IN

Accepted for publication September 7, 1989 46222.

From the LaRue D. Carter Memorial Hospital, Indianapolis, Indiana

early measures simply are not successful. When restrictive intervention is frequently required with a particular child, staff members often experience their own mounting frustra- tion, anger, and anxiety. Often the child is frightened by his own aggressive behavior, although the anxiety may not be recognized by the clinician in the presence of the child’s anger.

Frequently, much can be accomplished through interdis- ciplinary communication, treatment planning, and in-service training to reduce these feelings and to provide a safe, secure environment for the child (Kalogjera, Bedi, Watson, & Meyer, 1989). Sometimes, pharmacotherapy is a necessary adjunctive treatment modality that will allow the child to learn how to control maladaptive behaviors. In this article, the pediatric pharmacotherapy of aggression is briefly re- viewed. Propranolol is discussed in detail because it may be an agent with which psychiatric nurses are less familiar. Case illustrations are provided for the use of propranolol in conduct disorder, organic personality disorder, and ETSD.

Review of the Literature Aggression itself has been linked in animal studies with

testosterone, progesterone, luteinizing hormone, renin , B-endorphin, prolactin, melatonin, norepinephrine, dopa- mine, epinephrine, acetylcholine, serotonin, 5-hydroxyindol- acetic acid, and phenylacetic acid, among others (Kaplan & Sadock, 1988). The noradrenergic system may play a role in reward systems, awntion, and cognitive integration (Coyle, 1987). With so many neuronal systems, neuromodulators, and neurotransmitters being implicated, it is not surprising that medications employed in assisting children to manage aggression are diverse. The list of medications includes lithium carbonate, anticonvulsants, neuroleptics, antidepres- sants, and B-adrenergic blockers.

18

PEDIATRIC PSYCHOPHARMACOLOGIC USES OF PROPRANOLOL SIMS & GALVIN 19 Lithium

Although lithium carbonate is the drug of choice for the management of bipolar disorder, it also has been used for children and adolescents with a variety of dignoses and behavioral problems, including aggressive and explosive behavior. Campbell, Small, and others (1982) performed a double-blind study of 15 boys between the ages of 6 and 12 years who were hospitalized for chronic aggressive and explosive behavior. The boys were randomly assigned to one of three groups: haloperidol, lithium carbonate, and chlor- promazine (which served as the control drug). Results of this study indicated that all three drugs were effective in decreas- ing aggressiveness in children; however, relatively low doses of chlorpromazine led to excessive sedation. Campbell, Cohen, and Small (1982) also did a double-blind, placebo- controlled study involving 66 men aged 16-24 in a correc- tional institution for crimes of aggressive behavior. The study showed that the progressive reduction of aggressive- ness by the end of a 4 month period was significant for lithium compared with placebo.

Anticonvulsants

Anticonvulsants, particularly carbamazepine (CMZ), also have been reported effective in treating rage outbursts. Mattes ( 1986a) reported several uncontrolled studies done on adults in which CMZ reduced aggressiveness. Evans, Clay, and Gualtieri (1987) also reported open studies with the conclusion that CMZ may prove efficacious against the following symptoms, regardless of etiology: hyper- or hypo- activity, diminished concentration, aggressive behavior, and dysphoric mood. It appears that CMZ may be of benefit in reducing aggressiveness; however, there remains a need for

'

, additional controlled studies to confirm this.

Neuroleptics

Neuroleptics have been an important treatment in manag- ing the symptoms of aggression. As Campbell, Small, et al. ( 1982) reported, haloperidol and chlorpromazine were effec- tive in reducing aggression in children. Thioridazine hydro- chloride also has been reported as useful in improving aggressive and destructive behavior in children (Aman & Singh, 1980). Antidepressants also may be effective in reducing violence in some depressed patients. Imipramine was found to be effective in hostile and retarded adolescent patients, while amitriptyline was effective in agitated, ag- gressive, and/or depressed adult patients (Itil & Wadred, 1975).

Beta-adrenergic Blockers with Adults Beta-adrenergic blocking agents also have been cited in

recent literature as being effective in the control of aggres- sion and rage outbursts in adults (Mattes, 1986b). Mattes (1985) discussed case reports with the use of metaprolol for

intermittent explosive disorder in adult patients. Both of the case reports indicated a decrease in frequency and intensity of aggression after the administration of metaprolol.

Greendyke and Kanter (1986) conducted a double-blind, placebo-controlled study to examine the influences of pin- dolol on 11 patients (aged 28-76) with explbsive and impul- sive behaviors secondary to organic brain disease. The 11 patients were randomly assigned to w i v e pindolol or placebo capsules. Results of the study revealed that assaul- tive episodes and hostility were reduced while patients were receiving pindolol.

Another B-blocker that has been cited as effective in the management of aggression is propranolol. Yudofsky, Williams, and Gorman ( 198 1) discussed four case reports of adult patients with central nervous system (CNS) lesions and rage outbursts. The patients were given propranolol in dosages of 320-520 mglday in combination with their current medication. After administration of propranolol, the rage and violent outbursts were controlled. Greendyke, Schuster, and Wooten (1984) completed a study on six adult male patients with organic brain disease manifesting in assaultive and violent behavior. Twenty milligrams of Pro- pranolol was given 4 times per day (QID) with the daily dosage being increased by 40 mg every 3-5 days if no complications were observed. The maximum dosage of propranolol was 520 mg/day. The results of this study indicated a reduction in assaultive behavior and oufbursts of uncontrolled rage by the patients. The authors also suggested that an advantage of propranolol in the treatment of assaul- tive behavior in patients with organic brain disease is its lack of sedative effects.

Ratey, Manill, and Oxenkrug (1983) reported three cases of patients with brain damage who also had a history of provoked and unprovoked episodes of rage. All three pa- tients were treated with propranolol and responded with either a decrease or cessation of episodic aggressive out- bursts. Ratey and others (1986) also discussed an open trial of 19 mentally retarded patients (aged 24-29) who exhibited assaultive or self-abusive behavior. These patients were treated with propranolol after other treatment measures had failed. Eight of the patients improved with a mean dosage of 1 16 mg/day , while 1 1 patients improved with a mean Qsage of 130 mg/day. These authors also found that propranolol was useful in treating akathisia. Mattes (1986a) conducted an open study with 13 adults (aged 17-33) who had temper outbursts and residual attention deficit disorder (ADD). The subjects were given propranolol initially at 10 mg QID and increased daily by 10 mg per dose to a maximum dosage of 160 mg QID. Results of the study revealed that 11 of the patients improved in temper, and symptoms of ADD were reduced.

Sorgi, Ratey, and Polakoff (1986) conducted a chart review on seven adult patients with a DSM-Ill-R diagnosis of chronic schizophrenia who had aggressive behaviors. The

20 JCPN VOLUME3 NUMBER 1 1990

patients continued to take their prescribed neuroleptic drug in addition to propranolol. The chart review indicated a 70% reduction in assaultive behavior after administration of pro- pranolol. The chart review also suggested the usefulness of propranolol in decreasing aggressive behavior, and that the combination of neuroleptics and B-blockers may be more effective than the use of each of these drugs alone. Greendyke, Kanter, Schuster, Verstriate, and Wooten (1986) completed a double-blind, placebo-controlled study on nine patients with organic brain disease and assaultive behavior. The patients were randomly assigned to receive propranolol (520 mg/day) or placebo capsules for eleven weeks. Pmpranolol was initiated at 80 mg/day and increased by 80 mg every 3-4 days until the daily dosage reached 520 mg/day. The results of this double blind study showed fewer assaults during the 1 1-week period by those treated with propranolol. Five out of the nine patients showed marked improvement, two showed moderate improvement, and two showed little or no improvement in assaultive behavior. During the 1 1-week period, the number of assaults decreased from 88 (placebo period) to 52 (propranolol period), and the intensity and duration of outbursts lessened during the propranolol treatment.

Propranolol in Children and Adolescents

Recent studies have appeared in the literature on the efficacy of propranolol with children. Williams, Mehl, Yudofsky, Adams, and Roseman (1982) reported a retro- spective study of 30 patients with uncontrolled rage outbursts and organic brain dysfunction over a 2%-year period. The patients (11 children, 15 adolescents, and 4 adults), aged 7-35, were treated with propranolol for at least 1 month. Propranolol was started at either 10 or 20 mg, 3 or 4 times per day, and titrated upward every 3 days in increments of 30-80 mg. The maximum dosage of propranolol was 50-1600 muday in some patients. Results of the retrospective study indicated that more than 75% of the patients showed either a marked or moderate improvement in control of rage out- bursts after propranolol. Kuperman and Stewart (1987) conducted a study of 16 children and adolescents who had demonstrated physically aggressive behavior. The mean age of the children was 13.4 years; eight patients were diagnosed as mildly to severely mentally retarded. All children were started on propranolol, 20 mg , twice per day, with the dosage being increased every four days. The progress of the children was followed up for 3 months, and changes in behavior were rated as no change, slight improvement, moderately im-

and gradually increased over a 2-week period until a maxi- mum dosage of 2.5 mgikgiday was reached. Prior to propra- nolol administration, the children were rated on the Reaction Index (including autonomic hyperarousal). The results showed a significant improvement in the rating scores during propranolol treatment and a significant gradual decrease after propranolol treatment.

Thus, there is increasing evidence for the efficacy of B-blockers in the control of aggression, assaultive behavior, and rage outbursts. There also were decreases in somatic symptoms of anxiety, autonomic overarousal and neurolep tic-induced akathisia.

Method

The purpose of the retrospective chart review was to determine the clinical efficacy of the use of propranolol.

Treatment Setting

The chart review was conducted in an intermediate care hospital serving youths. The hospital provides services to children aged 5-12 and adolescents aged 13-17. The treat- ment modalities offered include individual and group psy- chotherapy, milieu therapy, occupational therapy, recre- ational therapy, and pharmacotherapy. The patients tend to be chronically impaired in their adaptive level of function- ing, with an average current global assessment functioning (CGAF) of 36. Children average approximately 91 on the full scale intelligence quotient (FSIQ). Most DSM-III-R diagnos- tic groups are represented except principal diagnosis of substance abuse and mental retardation.

Subjects

The total number of charts reviewed was seven. Subjects were between the ages of 5 and 14. Table 1 characterizes the subject population in terms of age, diagnoses, target symp- toms, timing of propranolol trial and dosages employed, concurrent medications, and treatmentemergent side ef- fects. The propranolol protocol used followed the guidelines identified by Yudofsky, Williams, and Gordon (1981). The protocol consisted of obtaining the patient’s pulse and blood pressure before each dose of propranolol. The dose was maintained if the pulse was >50 and the blood pressure was >80/50. Both the pulse and blood pressure were measured M hour later, and if they remained below acceptable levels that dose of propranolol was skipped.

proved, or much improved. Results of this open study revealed that 10 of the 16 children were recorded either as moderately or much improved.

Famularo, Kenscherff, and Fenton (1988) conducted a pilot study on eleven children diagnosed with PTSD. The children were aged 6-12, four boys and seven girls. Propra- nolol was given 3 times per day at a dosage of 0.8 mg/kg/day

Procedures The procedure involved reviewing the charts (after dis-

charge in all cases but one) of children or adolescent patients tried on propranolol. The target behavior for implementing propranolol was identified. The authors determined the clinical efficacy of propranolol on the basis of reviews of

PEDIATRIC PSYCHOPHARMACOUXiIC USES OF PROPRANOLOL SIMS & GALVIN 21

aggression severity ratings (on a scale of 0-10) by unit staff twice daily, frequency with which restrictive interventions were used, the patient’s pass privilege level, ability to have home visits, nurses’ progress notes, and physician’s clinical global impression. Each chart was rated in terms of efficacy and treatment-emergent side effects. The results are reported in Table 1. No improvement after administration of propra- nolol was assigned a score of 0, minimal improvement in target symptoms a 1, moderate improvement in target symp- toms a 2, and marked improvement a 3.

Case Review Case I-Intermittent Explosive Disorder

A 14-year-old overweight male had long-standing prob- lems of poorly controlled bouts of anger in which he became physically aggressive. He also had a history of myoclonic seizure disorder since age four. He had past aggressive outbursts at home and school in which he would tear up inanimate objects, destroy property, and threaten physical harm to others with sharp objects. His behavior would become increasingly violent at home. While in the hospital he would become physically aggressive and oppositional with staff to the point where physical restraint and separation from his peers were required.

Prior to hospitalization he had received Mellaril (Sandoz Pharmaceuticals, E. Hanover, NJ). The child was initially started on 10 mg of propranolol orally, three times per day (TID), and achieved a peak dosage of 90 mg orally per day. Teachers and nursing staff reported him to be doing better overall, although he did continue to exhibit some attention- seeking behavior and immaturity. During this time, the patient’s behavior improved to the point of his receiving additional privileges of a building pass and a home visit. The use of propranolol was associated with an increase in his dilantin level. Propranolol was eventually decreased to 20 mg, four times per day (QID), when the patient’s pulse rate became 48. Aggression rating reports showed a gradual decline, and reports from nursing staff cited the patient as handling frustration better and having fewer incidents of anger. On the propranolol dosage of 20 mg QID, the patient no longer seemed to lose control or become physically aggressive when angered. The patient was discharged home on 20 mg of propranolol QID, 100 mg of Dilantin TID, (Parke-Davis, Moms Plains, NJ) 50 mg of Dilantin infatab at bedtime and 1 mg of Klonopin (Roche Laboratories, Nutley, NJ) TID.

Case 2 4 r g a n i c Brain Syndrome

An 1 1 -year-old boy was provisionally diagnosed as having tuberous sclerosis and a history of mixed seizure disorder since 9 months of age. He also had a history of disruptive, oppositional, aggressive behavior at home and school. He tended to become more explosive and aggressive at home, where he would cause physical harm to others. Prior to

hospitalization, the patient had at various times received a neuroleptic and several anticonvulsants.

While hospitalized, the patient had temper outbursts and aggressive impulses towards younger peers, necessitating the use of seclusion. He temporarily responded well to tokens and social rewards. While hospitalized, he was given a neuroleptic with sedating effects. He also was admitted for partial hospitalization, but became physically aggressive and experienced cognitive disorganization with paranoia. He was re-admitted for full hospitalization. The patient’s aggression ratings ranged from moderate to severe. A dosage of propra- nolol at 10 mg TID was started. After administration of propranolol, the patient had a significant reduction in the frequency of aggressive behavior. He enjoyed multiple home visits without episodes of aggressive outbursts. The nursing staff and teachers’ reports reflected better control of aggres- sive impulses. The patient was discharged on propranolol.

Case 3-Conduct Disorder: Undersocialized Aggressive

A 5-year-old boy with a previous medical history of failure to thrive and brain concussion presented to the facility with noncompliance with adult directions and discipline, destruc- tion of objects, hyperactivity, and short attention span. At various times prior to hospitalization the patient had been given a psychostimulant without benefit, a neuroleptic with an initially favorable but unsustained response, and a sedat- ing neuroleptic with treatment-emergent side effects.

During hospitalization, the child’s disruptive and aggres- sive behavior toward peers and adults prompted one-to-one coverage in order for him to participate in school and activities. A dosage of 10 mg of propranolol TID was initiated, gradually increasing to 160 mg/day (60 mg each at morning and night, and 40 mg at noon). Propranolol proved effective with modest but definite improvement, evidenced by a decrease in total hours of seclusion. Conners Teachers Rating Scales and global assessment after propranolol ad- ministration indicated some improvement in his aggressive- ness and agitation. The patient was discharged home on 160 mg of propranolol per day.

Case W r g a n i c Personality Disorder

A 13-year-old male diagnosed with toxocariasis and enco- presis also displayed impulsive, distractible, and aggressive behavior (verbally towards adults, physically towards peers). Because of his behavioral and emotional problems, he had been placed in classes for the severely emotionally handicapped at school. Prior to hospitalization, the patient, had received psychostimulants, anticonvulsants, and several neuroleptics at various times with little benefit. Navane (Roerig, New York, NY) appeared to have the best effect, but due to parental noncompliance with his medication regimen, his behavior continued to deteriorate. While hospi- talized, the patient displayed aggressive behavior. Due to his

TAB

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23 PEDIATRIC PSYCHOPHARMACOLOGIC USES OF PROPRANOLOL . SIMS & GALVIN

soiling and poor social skills, he was frequently the center of teasing, which he would respond to aggressively (i.e., gouging the skin of his tormenter, leaving multiple abra- sions). This behavior would require physical restraint of the patient. His aggression ratings ranged from moderate to severe. The patient had been tried on several pharmacother- apeutic agents throughout his hospitalization. These agents included Stelazine (Smith Kline Beckman Corporation, Phil- adelphia, PA) and dextroamphetamine and had no significant benefit, but rather treatment-emergent side effects of slurred speech and thickened tongue (he was also on prednisolone for macular edema). He then was given a dosage of 10 mg of propranolol TID, which was then titrated to a peak dosage of 60 mg TID. He had begun missing doses because of de- creased blood pressure and heart rate, so propranolol was decreased to 40 mg TID. While receiving 40 mg of propran- 0101 TID, L-tryptophan at 500 mg TID was introduced. Although there was areduction in frequency of seclusion, his aggression ratings remained moderate to severe. He was continued on propranolol, but the L-tryptophan was discon- tinued. Now being given a combination of propranolol(40 mg, TID) and Navane (4 mg daily), he has shown some positive response, with a decrease in intensity of aggressive behavior and an increase in privileges and responsibilities.

Case S--Conduct Disorder: Solitary, Aggressive

A 14-year-old seventh grade male with encopresis also exhibited assaultive and destructive behavior. He would become aggressive with peers and bite their hands. He had also bitten his own hands.

He was given Ritalin without any positive effect. As his behavior became more violent during hospitalization, requir- ing physical restraint, he was put on a dosage of propranolol at 10 mg TID, which was titrated gradually to 40 mg, TID. He showed some positive reaction to propranolol by a decrease in his aggressive behavior, but dosage was limited by negative cardiovascular effects.

Case 7-Dost-traumti~ Stress Disorder

A 13-year-old boy with oppositional defiant disorder, well established in chronicity, had been informed of a life- threatening illness. In response, he developed a post-trau- matic stress disorder, which further aggravated his disruptive behavior disorder and also resulted in difficulty sleeping, irritability, autonomic hyperarousal (flushing, tachycardia, and marked anxiety), recurrent distressing dreams, ‘and repetitive play in which themes or aspects of the trauma were expressed.

By the time of hospitalization he was taking a psychostim- ulant, an antidepressant, and a sedating neuroleptic in com- bination. His rapid escalations into out-of-control behavior were an obstacle to individual psychotherapy, as well as participation in the milieu and activities. He frequently

required interventions including restraints and one-to-one nursing coverage. The phannacotherapeutic strategy was to simplify his regimen to a nonsedative neuroleptic and intro- duce propranolol, initiated at 10 mg orally, TID and titrated to 50 mg orally, TID. L-tryptophan also was used for insomnia as well as for its putative effect upon aggression. The neuroleptic was discontinued. Judged by serial Conners Teachers Rating Scales, Clinical Global Impressions, and frequency with which restrictive interventions were re- quired, the pharmacotherapeutic strategy proved effective. The patient was able to make considerable progress in dealing with reactions to a catastrophic stressor. All medica- tions were eventually discontinued. While intensive work was still required for his oppositional defiant disorder, he was able to return to his local community.

Discussion

The chart review is consistent with literature citing the efficacy of propranolol in decreasing aggressive behavior in younger patients. The cases illustrate the various uses of propranolol. That some of these patients were especially treatment-resistant is additional evidence suggesting the efficacy of propranolol. Based on the retrospective review of the previously identified indicators, two patients were found to have marked improvement, two to have moderate im- provement, two to have minimal improvement, and one to have no improvement. None were judged worse. In terms of side effects leading to discontinuation of the medicine, there was no one who required discontinuation of this medication. However, side effects did impose a limit upon the dosage of propranolol in many subjects.

Of course, retrospective chart reviews or the open studies mentioned in the literature review do not substitute for double-blind, plaqebo-controlled studies in children and adolescents. This retrospective chart review was limited by the small sample size, and the aggression rating scale was subjective by the raters. Nevertheless, beta-blockers can be expected to be used more often in the future, alone or in combination with other medications (e.g., neuroleptics or anticonvulsants). An advantage of propranolol over neuro- leptics in treating younger patients with aggressive behavior is the infrequency of sedative effects and involuntary move- ment disorders. A disadvantage is the necessity for monitor- ing blood pressure and heart rate. Since nurses are primarily responsible for administering medications and observing their influences on behavior as well as their side effects, they are in a position to assist in evaluating alternative phannaco- therapies. The nurse also is able to assist in teaching family members to monitor pulse prior to administration of propra- nolol and to be alert to side effects of the medication. Some side effects of propranolol are bradycardia, hypotension, drowsiness, lethargy, wheezing, dyspnea, toxic psychosis, confusion, disorientation, and hallucination. The long term

24 JCPN . VOLUME 3 . NUMBER 1 1990

effects of propranolol are not known and require further study.

No medication should be considered as more than an adjunct to other nonpharmacologic interventions. However, if the limitations of any psychopharmacologic intervention in children and adolescents are kept in mind, propranolol may be a useful addition to agents that allow the child to learn control of maladaptive behaviors.

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Campbell, M., Cohen, I., & Small. A. (1982). Drugs in aggressive behavior. Journal of the American Academy of Child Psychiatry,

Campbell. M., Small, A., Green, W., Jennings, S., Perry, R., Bennet, W., Padron-Gayal, M., &Anderson, L. (1982). Lithium and haloperidol in hospitalized aggressive children. Psychopharmacology Bulletin.

Coyle, J. (1987). Biochemical development of the brain. In C. Popper (Ed.), Psychiatric phannacosciences of children and adolescents (pp. 3-23). Washington, DC: American Psychiatric Press.

Eisenberg, L. (1980). Normal child development. In H.I. Kaplan, A.M. Freedman, & B.J. Saddock (Eds.). Comprehensive textbook of psychiatry Ill (p. 103). Baltimore: Williams & Wilkins.

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