John E. Kalachnik, M.Ed., Thomas E. Hanzel, M.A.
Behavioral side effects of antiepileptic drugs (AEDs) are an often overlooked and underrecognized problem for individuals with mental retardation and developmental disabilities (MRDD). The recognition of AED behavioral side effects is imperative because these side effects can be easily confused with other behavioral, mental, or physical problems. In situations where these side effects are not correctly identified, quality of life activities and active treatment programs may be potentially compromised, psychopharmacologic medication inadvertently prescribed, and aversive, restraint, or deprivation procedures used. Because the behavioral side effects associated with barbiturate AEDs are of particular concern (Coulter, 1988a), the purpose of this article is to review barbiturate AED behavioral side effects, exemplify potential consequences of non-detection through clinical cases, and provide a set of clinical profiles prompting further inquiry.
Review of Barbiturate AED Behavioral Side Effects Drugs Involved
Phenobarbital (Luminal) and primidone (Mysoline) are the primary barbiturate AEDs prescribed. Occasionally, mephobarbital (Mebaral) is prescribed. Barbiturate AEDs are prescribed for approximately 21% to 42% of individuals with MRDD who have epilepsy (Branford, 1994; Harper & Wadsworth, 1993; Pary, 1993; Poindexter, 1993; Singh & Towle, 1993; Zaharia & Struxness, 1991)1 . Overall, barbiturate AEDs are prescribed for approximately 4% to 9% of all individuals with MRDD (Branford, 1994; Harper & Wadsworth, 1993; Pary, 1993; Poindexter, 1993; Zaharia & Struxness, 1991).1
Specific Behavioral Side Effects
Barbiturate AED behavioral side effects reported for adults or children with MRDD include aggression, property destruction, hyperactivity, frustration or irritability, disruptive vocalizations, noncompliance, self-injurious behavior, verbal threats, depressive symptoms, and abusiveness (Barnhill & Carlos, 1997; Burd, Kereshian, & Fisher, 1987; Campbell & McNamara, 1993; Coulter, 1988b; Gay, 1984; Hanzel, Bauernfeind, Kalachnik, & Harder, 2000; Hanzel, Kalachnik, Harder, 1992; Kalachnik, Hanzel, Harder, Bauernfeind, & Engstrom, 1995; Mayhew, Hanzel, Ferron, Kalachnik, & Harder, 1992; Poindexter, Berglund, & Kolstoe, 1993; Poindexter & Kolstoe, 1992). Temper tantrums, disobedience, and sleep disturbance have also been reported as behavioral side effects among children without MRDD (Herranz, Armijo, & Arteaga, 1988; Wolfe & Forsythe, 1978).
These behavioral side effects require objective definition and measurement for an individual (Stores, 1975). Specific examples reported in the aforementioned literature include tipping over furniture, tearing clothing, biting ones arms or hands, tearfulness or unprovoked crying, hitting or kicking others, banging testing apparatus, slamming doors, and throwing objects.
Possible Risk Factors
Phenobarbital and primidone generally exacerbate pre-existing behavior problems (Wolf & Forsythe, 1978). Consequently, individuals with pre-existing behavior problems are believed to be at higher risk for barbiturate AED behavioral side effects (Trimble & Cull, 1988). Organic brain damage, psychomotor epilepsy, and multiple AEDs may also place an individual at higher risk (Rivinus, 1982).
Some authorities and clinicians consider individuals with MRDD to be more susceptible to barbiturate AED behavioral side effects, especially those individuals with behavior problems per se, or behavior problems associated with a chronic psychiatric condition (Alvarez, 1998; Barnhill & Carlos, 1997; Gay, 1984). Not an uncommon occurrence, behavior problems are displayed by 47% to 60% of individuals with MRDD (Hill & Bruinicks, 1984; Jacobson, 1982). A prevalence of approximately 71% was reported based upon the 1987 National Medical Expenditure Survey, but the list of problem behaviors from which this figure was derived included inappropriate dressing and inability to avoid danger (Cunningham & Mueller, 1991). These two behaviors are not typically classified as behavior problems (aka maladaptive or challenging behavior) because they relate more to activities of daily living or skill level.
One explanation offered for the increased risk of barbiturate AED behavioral side effects in individuals with MRDD, as well as children, is that these medications impair inhibitory control (Gay, 1984). For example, instead of pointing and asking for another persons possession, one is more likely to push the other person away and grab the desired object without permission. This disinhibition is more likely to occur in individuals who have poor self-control due either to developmental level (the person has not yet learned socially acceptable methods) or neurological impairment.
Barbiturate behavioral side effects occur in approximately 20% to 40% of children (Camfield, Camfield, Smith, & Tibbles, 1985; McGowan, Neville, & Reynolds, 1983; Wolfe & Forsythe, 1978) and in approximately 34% of individuals with MRDD (Gay, 1984).
In terms of the number of individuals with MRDD who may have barbiturate AED behavioral side effects, there are 379,847 individuals living in residential settings in the United States who receive Intermediate Care Facilities for the Mentally Retarded (ICF/MR) services or Home and Community Based Waiver Services (HCBS) (Anderson, Prouty, & Lakin, 2000). If barbiturate AEDs are prescribed for 4% to 9%, approximately 15,194 to 34,186 individuals are at risk for these side effects. If 30% actually develop the side effects, approximately 4,558 to 10,256 individuals may be experiencing barbiturate AED behavioral side effects to varying degrees.
Reasons for Non-Recognition
It is easy to overlook barbiturate AED behavioral side effects among individuals with MRDD for a number of reasons. First, compared to the general population, individuals with MRDD may be less able to discern or effectively communicate the presence of these side effects (Poindexter & Kolstoe, 1992). Second, barbiturate AED behavioral side effects often resemble behavior problems commonly associated with MRDD or mental illness. As a result, behavioral side effects may be inadvertently assumed to be part of an underlying psychiatric or behavioral condition (Stores, 1975; Wilkinson, Murphy, & Georgeson, & DSouza, 1982). Third, an individual may initially tolerate barbiturate AEDs and then subtly develop the side effects over time (Ferrari, Barabas, & Matthews, 1983), such that, when combined with an existing behavior problem which may vary over time, an association with the barbiturate AED may not be made. Fourth, barbiturate AED behavioral side effects may occur within normal therapeutic serum ranges and are not necessarily detected through serum level monitoring alone (Beardsley, Freeman, & Appel, 1983; Ferrari et al., 1983; Stores, 1975; Withdrawing antiepileptic drugs, 1989). Fifth, seizure control concerns may limit systematic inquiry (Fischbacher, 1982). And sixth, lack of adequately sensitive detection instruments may contribute (Beghi, et al., 1987; Cramer, et al., 1983; Stores, 1975).
Potential Consequences of Non-Detection
The potential consequences of not recognizing barbiturate AED behavioral side effects generally fall into three categories.
The first potential consequence is that antipsychotic medication may be inadvertently prescribed or prescribed at doses higher than necessary in an effort to control barbiturate AED behavioral side effects (Brodtkorb, Sand, & Strandjord, 1993; Hanzel et al., 1992; Hanzel et al., 2000). This, in turn, may cause other side effects. For example, antipsychotic medication may cause tardive dyskinesia (TD), a potentially persistent movement disorder. Similarly, antipsychotic medication, especially at higher doses, may cause akathisia as well as other movement disorders such as pseudoparkinsonism. Efforts to minimize antipsychotic medication, even through gradual reductions, may fail because barbiturate AED behavioral side effects increase when antipsychotic medication is decreased (Hanzel et al, 1992).
It has also been suggested that psychopharmacologic medication in general may be inadvertently prescribed or used at doses higher than necessary when barbiturate AEDs are prescribed (Coulter, 1988b). Although necessary to qualify, there is some evidence to support this suggestion. Wilkinson et al. (1982) reported that the mean number of psychotropic drugs per patient decreased significantly from 1.03 to 0.83 when AEDs were reduced for individuals with MRDD and epilepsy. This data must be qualified, however, because other AEDs such as phenytoin (Dilantin) and clonazepam (Klonopin) which can cause behavioral side effects were included, behavioral data was not reported, and psychotropic medication was not defined (i.e., the reduction may have primarily or only represented antipsychotic drugs). Beghi et al. (1987), in addition to reporting a decrease in antipsychotic medication when AEDs were reduced for individuals with MRDD and epilepsy, reported that other psychotropic medications, consisting primarily of benzodiazepines for behavioral or psychiatric purposes, decreased from 47 to 35 prescriptions (1.00 to 0.75 drugs per patient). This data must be qualified because a statistical analysis was not conducted and, like the Wilkinson et al. (1982) report, other AEDs which may cause behavioral side effects were involved. Silver et al. (1999) included four individuals (three with MRDD) who were prescribed phenobarbital in a study of high dose propranolol (Inderal) for aggression. Poindexter (2000) observed that these four individuals aggression, thought to be part of a behavioral or psychiatric condition and for which high dose propranolol was prescribed, may have instead represented phenobarbital behavioral side effects. This possibility must be qualified because phenobarbital was not manipulated, and, as both the authors and Poindexter observed, akathisia from the coinciding use of antipsychotic medication at high doses may have been involved.
The second potential consequence is that educational or positive behavioral procedures may be repeatedly attempted in an effort to manage barbiturate AED behavioral side effects. Unsuccessful efforts to manage these side effects may eventually lead to living with the problem and a resignation that the problem is an unchangeable characteristic of the individual. In more severe cases, aversive, restraint, or deprivation procedures may be used. Valuable time and resources may be allocated, and unintended consequences or a high level of restrictiveness may occur (Hanzel et al., 1992). For example, social interactions between the individual and others may be avoided or strained. Efforts to discontinue the aversive, restraint, or deprivation procedure may prove unsuccessful because barbiturate AED behavioral side effects may increase when the procedure is removed.
The third potential consequence is that quality of life indices may be affected. Barbiturate AED behavioral side effects may be associated with injury to self or others of such severity that medical treatment is required (Kalachnik et al., 1995). Removal from a less restrictive living environment such as a group home or other community placement may occur with diminished opportunity to engage in activities of normal daily living (Coulter, 1988b; Barnhill & Carlos, 1997). An individual may be re-admitted or transferred to an institutional setting, or, alternatively, an individual residing in an institutional setting may not be considered for community residential services.
Clinical Cases Exemplifying the Potential Consequences of Non-Recognition
The Table presents the cases of barbiturate AED behavioral side effects the authors have published (Hanzel et al., 1992; 2000; Kalachnik et al., 1995; Mayhew et al., 1992). These cases exemplify to various degrees the potential consequences of non-recognition. The overall decrease of behavior problems after barbiturate AED discontinuation was 82%.
In regard to the inadvertent use of antipsychotic medication or the use of higher doses than necessary, antipsychotic medication was reduced or discontinued for six individuals after barbiturate AEDs were discontinued (Cases 1, 6-10). The overall mean dose of antipsychotic medication for all six individuals was reduced from 213 mg/day to 130 mg/day while the mean dose for the four individuals without full discontinuation (Cases 1, 6, 8, and 9) was reduced from 306 mg/day to 195 mg/day. This primarily occurred because problem behaviors for these six individuals decreased by an average of 82% after barbiturate AEDs were discontinued. Analyses for Cases 6-10 showed that both dose and problem behavior decreases were significant and confirmed that improved behavior after barbiturate AED discontinuation was not adversely affected by subsequent antipsychotic medication decreases (Hanzel et al., 2000).
In regard to the potential for increased AED behavioral side effects when antipsychotic medication is decreased, three individuals had unsuccessful antipsychotic medication reduction attempts while barbiturate AEDs were prescribed (Cases 1, 7, 10). Case 1 is particularly relevant in that two gradual antipsychotic medication reduction attempts adhering to all lowest optimal effective dose methodological recommendations (Kalachnik, 1988; 1999) failed, and data was mistakenly interpreted as confirmation that the individual required 550 mg/day of chlorpromazine.
In regard to tardive dyskinesia, three individuals, including the two individuals for whom antipsychotic medication was completely discontinued, developed tardive dyskinesia as a result of the long-term prescription of antipsychotic medication (Cases 1, 7, 10).
In regard to the inadvertent use or the use of higher doses than necessary of psychopharmacologic medications other than antipsychotic drugs, doxepin was discontinued for one individual (Case 1). Another individual (Case 5) had a history of numerous attempts to treat physical aggression with various antipsychotic and other psychopharmacologic medications which the involved clinician was certain would not have occurred if barbiturate AEDs had not been in the regimen.
Behavioral and Educational Programs
Restraint procedures which had been in place for an extended period of time for two individuals were successfully discontinued after barbiturate AEDs were withdrawn (Cases 1 and 7). The individual in Case 2 is perhaps most illustrative of the potential ramifications of repeated unsuccessful positive behavioral interventions and educational attempts. Combined with the failure of psychopharmacologic medication, professional and direct care staff concluded the behavior was an unchangeable characteristic of the individual. Because behavioral data was not reviewed within a formal multi-disciplinary team process as usually occurs when a psychopharmacologic medication is prescribed or a restraint procedure used, one set of professionals reviewed the behavioral data while another set reviewed seizure data. As a result, behavioral data was not analyzed in relation to barbiturate AEDs, and the possibility of AED behavioral side effects was overlooked.
Quality of Life
Infection and scar tissue, a quality of life health issue, occurred for one individual who required medical attention due to periodic lacerations from self-injurious and disruptive behavior (Case 4).
Successful community placement occurred for six individuals as a result of improved behavior after barbiturate AED discontinuation (Cases 5-10). This was noteworthy because the individuals had resided in public residential facilities for extended periods of time. Indeed, community placement occurred before further antipsychotic medication reductions could be achieved for three of the individuals (Cases 6, 8 and 9). The individual in Case 9 best illustrated a totally unexpected and successful community placement which few, if any, people believed was possible given the individual,s history. Part of this individuals improved quality of life included a renewed interest in playing recognizable tunes on the piano.
A Brief Comment on the Strengths and Limitations of the Cases
In terms of strengths, the behavioral side effects in these cases were not caused by high or toxic serum levels because all individuals were well within the normal therapeutic range of 15-40 microg/ml for phenobarbital or 5-12 microg/ml for primidone. Measurement of behavior for all individuals occurred on a daily basis and used frequency count, 30-minute time sample, or 15 or 30-minute partial interval recording. Barbiturate AED and psychopharmacologic drug changes were gradual, data analysis took into account the time to reach drug steady-state levels, and analysis eliminated phenytoin as the cause of behavior problems (Cases 6-10).
In terms of limitations, while real-time clinical decisions in all cases were based upon the working hypothesis that barbiturate AED behavioral side effects were present, retrospective case analysis, nonetheless, occurred. Clinical ethics prevented a barbiturate AED re-challenge to formally confirm the presence of the behavioral side effects. Eight individuals may have had problem behavior successfully treated when carbamazepine (Tegretal) or valproate (Depakote) replaced barbiturate AEDs for seizure control (Cases 2, 3, and 5-10). This is, problem behavior thought to represent barbiturate behavioral side effects may have instead represented an undiagnosed mood disorder. Although barbiturate AED behavioral side effects were methodologically established before carbamazepine was increased for one individual (Case 2), methodologically established when these drugs were not prescribed for one individual (Case 1), and methodologically established when coinciding valproic acid was decreased for one individual (Case 4), these cases do not necessarily apply to Cases 5-10. This illustrates a common clinical reality. When seizure control is paramount and a barbiturate AED suspected of causing behavioral side effects cannot be reduced or discontinued before initiating another AED with potential psychopharmacologic properties, it may not be possible to conclude with clinical certainty whether the original AED was causing a behavioral side effect or whether the second AED is treating an undiagnosed affective disorder.
Overall, it must be stressed that all 10 individuals had a history of problem behavior and that problem behavior was not completely eliminated when barbiturate AEDs were discontinued. As a result, barbiturate AEDs were thought to have been exacerbating pre-existing behavior problems (state exacerbated) rather than causing new behavior problems (state dependent).
Clinical Profiles Suggesting Case Review
Clinicians, parents or guardians, and members of the multidisciplinary team should remain alert to the following clinical profiles which may suggest the possibility of barbiturate AED behavioral side effects. It is essential to remember these profiles do not diagnosis or confirm the presence of barbiturate AED behavioral side effects. Rather, they are intended to serve only as indicators or red flags prompting further review with appropriate medical and neurological personnel.
The individual is prescribed a barbiturate AED and displays a behavior problem (as listed under the Specific Behavioral Side Effects section) especially if ...
An antipsychotic medication is currently prescribed, especially if a reduction attempt has failed in the presence of the barbiturate AED, or
A restraint, deprivation, or aversive procedure is currently in place, especially if the procedure has been used for an extended period of time, or
Positive behavioral or educational intervention procedures are repeatedly attempted and fail or are minimal because the behavior is accepted as an unchangeable characteristic of the individual, or
A non-antipsychotic psychopharmacologic medication is currently prescribed and a psychopathology was not clearly diagnosed before the barbiturate AED was prescribed and the problem behavior or symptoms worsened after the barbiturate AED was prescribed.
The individual is prescribed a barbiturate AED and does not display a behavior problem (as listed under the Specific Behavioral Side Effects section) but is prescribed...
Two psychopharmacologic medications from the same class (intraclass polypharmacy or duplicate therapy), especially antipsychotic medication, or
Three or more psychopharmacologic medications (interclass polypharmacy) unless a clearly diagnosed psychopathology such as treatment resistant bipolar disorder has been diagnosed, or
A mega-dose of a psychopharmacologic medication clearly above the recommended range contained in the manufacturer,s package insert.
Complicating Clinical Issues
If a clinical profile is present and formal review with appropriate medical and neurological personnel suggests barbiturate AED behavioral side effects may be present, several complicating clinical issues may be involved. These can make the assessment and evaluation of barbiturate AED behavioral side effects difficult.
First and foremost, there is no absolute test for confirming suspected barbiturate AED behavior side effects. In most cases, the only confirmation may be the reduction and removal of the barbiturate AED.
Second, withdrawal effects may occur during barbiturate AED discontinuation (Withdrawing antiepileptic drugs, 1989). These may include seizures, irritability, sleep problems, and even the temporary increase of the very behaviors suspected of being barbiturate AED behavioral side effects. Unless the individual is treated in a specialized inpatient program, barbiturate AED reductions should proceed slowly (Coulter, 1988b; Fischbacher, 1982) and may take a number of months to complete. Even with gradual reductions, withdrawal effects may still occur in some cases (Coulter, 1988a). It is important not to overreact to temporary behavioral increases.
Third, seizure control is a complex process. Other AEDs may need to be adjusted or initiated prior to or during the barbiturate AED withdrawal process. This may be a difficult and extended endeavor since most AEDs affect blood levels of other AEDs. While barbiturate AEDs may no longer be necessary for some individuals, other individuals may require barbiturate AEDs for seizure control despite behavioral side effects.
The use of the clinical profiles to identify individuals with potential barbiturate AED behavioral side effects combined with comprehensive medical and neurological review can help minimize these side effects. Given that these behavioral side effects are present (or likely present) and given that the benefit of barbiturate AED reduction for the individual outweighs the risk, gradual reductions may help to increase the likelihood of long-term success and minimize withdrawal effects. The measurement of the suspected behavioral side effect using techniques such as frequency count, time sample, or interval recording may be extremely helpful within this process because these methods are sensitive to change. Since phenobarbital takes approximately 21 days to reach steady-state serum levels after a dose change (Garnett, 1989), analysis should consider the possibility that the behavior may not correlate with the new dose until steady-state is reached. Graphically organizing behavioral and seizure data by drug and dose condition by the multi-disciplinary team during this process can greatly contribute to structured physician review.
Overall, the profiles and information presented are not intended to imply that barbiturate AEDs should never be prescribed. Indeed, barbiturate AEDs may be the only medication which controls seizures for some individuals. Not everyone develops barbiturate AED behavioral side effects, and problem behaviors may not be explained by these side effects. Rather, the purpose of the profiles and information presented is to alert clinicians, parents or guardians, and members of the multidisciplinary team about the possibility of these behavioral side effects, especially for those cases where little else seems to explain a behavior problem or a behavior problem continues despite great efforts to treat it. As exemplified by the cases reviewed, the lack of recognition of barbiturate AED behavioral side effects may potentially compromise the quality of an individuals life.
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For further information:
John E. Kalachnik, M.Ed.
University of South Carolina School of Medicine
Center for Disability Resources
Columbia, SC 29208