Doi:10.1016/s0887-8994(03)00410-7

Physician Preference for Antiepileptic Drug
Concentration Testing
Robert J. Baumann, MD*†, Melody Ryan, PharmD*‡, and Aaron Yelowitz, PhD§
A four-item questionnaire asked active U.S. members
Monitoring antiepileptic concentrations is also useful of the Child Neurology Society to value painless anti-
in evaluating patient adherence to the treatment plan epileptic drug concentration monitoring, whether
and for monitoring the variations induced by changes in members had ordered a saliva level (the best estab-
weight and metabolism as children grow The review lished painless method) in the last year, and whether
articles that guide American physicians mention using such levels were available. Value was quantified by
other tissues to monitor antiepileptic drug concentrations, time per patient that the physician would willingly
but virtually all guidance and usual therapeutic values are expend to arrange for the test. Of 945 questionnaires
given for blood and thus require a venipuncture sent, 544 (58%) were returned. When asked the value
This bias exists in part because of good evidence corre- of a painless method for children, 286/522 (55%)
lating the effects of the commonly used antiepileptic drugs reported willingness to expend 10 to 30 minutes to
with serum concentrations. Interestingly, there is also arrange the test; 498/522 (95%) would use a painless
good evidence correlating the effects of the commonly method if available. When asked the value of an
used antiepileptic drugs, phenobarbital, phenytoin, and immediate sample at home during a seizure or adverse
carbamazepine with concentrations as measured in saliva.
event, a substantial majority, 370/526 (70%), would
Saliva is the alternative body fluid, available without make an important donation of their own time to
causing the patient pain, that is best suited for therapeutic arrange for the sample. Only 5% would not use it. Just
drug monitoring Nevertheless, neither review articles 2/544 respondents had obtained a painless (saliva)
nor discussions with colleagues suggest that saliva levels concentration, and merely 33/544 (6%) perceived such
tests as being available. We conclude that child neu-
Monitoring with serum antiepileptic concentrations in- rologists put a high value on painless antiepileptic
volves some obvious disadvantages. There is the discom- monitoring. These data suggest that a painless method
fort and fear associated with the venipuncture necessary to of measuring antiepileptic drug concentrations— espe-
obtain serum. Additionally there is the cost and inconve- cially if it could be performed at home—would fulfill
nience of going to a clinic or hospital to have the blood an unmet need in the care of children with epilepsy.
2004 by Elsevier Inc. All rights reserved.
drawn. The problem of discomfort is magnified withchildren whose age or limited intellectual ability makes it Baumann RJ, Ryan M, Yelowitz A. Physician preference impossible for them to understand why this pain is “for for antiepileptic drug concentration testing. Pediatr Neurol their own good”. Moreover, parents may not want to subject a child to this discomfort and thus neglect havingtheir child tested and then miss subsequent clinic appoint-ments Introduction
None of these disadvantages occur with saliva monitor- ing. There is no pain, and no special skill is required to Successful treatment of epilepsy often requires the monitoring of antiepileptic drug concentrations. Within We have been puzzled by the apparent lack of use of a the usual therapeutic ranges for these drugs, most children painless method of therapeutic monitoring. One hypothe- have good seizure control with minimum adverse effects sis is that the adoption of new technology is dependent From the Departments of *Neurology and †Pediatrics, College of Medicine, University of Kentucky; ‡Division of Pharmacy Practice and Dr. Baumann; Kentucky Clinic L445; University of Kentucky; Science, College of Pharmacy, University of Kentucky; and §Department of Economics, University of Kentucky, Lexington, Received April 10, 2003; accepted June 5, 2003.
2004 by Elsevier Inc. All rights reserved.
Baumann et al: Preference for AED Testing doi:10.1016/S0887-8994(03)00410-7 ● 0887-8994/04/$—see front matter Responses to questions 3 and 4 about perceived value of
Of 1006 mailed surveys, 57 were returned by the postal Question #4
service as undeliverable and four went to members of our Immediate
research group, giving a denominator of 945 patients.
Question #3
Sample at Home
Painless
at Time of
After three mailings, 544/945 questionnaires had been Method for
Seizure or
returned (58%). We compared responders and nonre- Responses
Routine Care
Adverse Event
sponders, dividing them into the four regions defined bythe U.S. Census Bureau We could find no statisti- cally significant geographic differences between respond- ers and nonresponders. Only 2/544 (0.4%) respondents indicated having obtained a saliva level in the last year (question #1), and just 33/544 (6%) indicated that saliva levels were available to them (question #2). 187/544 (34%) replied that no such levels were available to their practice, and 312/544 (57%) “didn’t know” (question #2).
Of the 33 positive respondents, 12 were located in the Midwest, 8 in the South, 7 in the East, and 6 in the West with no predominance in any specific cities.
Question #3 asked: “How valuable to the care of your pediatric patients would be the ability to obtain anticon- vulsant drug levels by a painless method as opposed to serum which requires a venipuncture?” There were 522 * Phrase in parenthesis only used in question 4.
usable responses 286/522 or 55% of respondingphysicians thought such an innovation valuable enoughthat they would expend 10 to 30 minutes of their own time upon physician attitudes and behavior. Thus if saliva to arrange the test, and 498/522 or 95% stated that they monitoring is not being used, this hypothesis posits that would use a painless method if it were available. Question physicians are uninterested in the advantages presented by #4 asked: “How valuable to the care of selected patients saliva testing, such as reducing discomfort, and further would be the ability to obtain an immediate sample at posits that physicians, by not requesting saliva levels, are home for anticonvulsant level determination at the time of preventing the adoption of this technology. We investi- a seizure or adverse event—without the delay necessitated gated these issues by questionnaire, surveying American by a trip to a laboratory or emergency department?” A substantial majority of the sample, 370/526, 70% of thephysicians, would make a significant donation of their own time to arrange for such a test. Only 5% believed itwas not of value With permission of the Medical Institutional Review Board, we mailed a questionnaire to each active United States member of the Child Discussion
Neurology Society. To be an active member, a physician needs to be“certified in Neurology with Special Qualification in Child Neurology bythe American Board of Psychiatry and Neurology” or “eligible to take the Our survey indicates that child neurologists place a high examination for certification” The vast majority of these physicians value on a painless method of monitoring antiepileptic are also eligible for certification by the American Board of Pediatrics.
drug concentrations We sought a value judg- We had Medical Institutional Review Board permission to identify ment from the respondents and avoided the traditional respondents and to send two follow-up questionnaires to physicians who responses “strongly agree”, “agree”, “neither agree nor did not respond initially. The questionnaire consisted of four questions.
To encourage responses and to limit the burden on the surveyed disagree”, and “strongly disagree”. The reason we avoided physicians, the questionnaire was limited to a single page. The first two those responses is that the questions involved pain vs no questions asked whether respondents had ordered one or more saliva pain. We were concerned that respondents would believe levels in the last year and whether the respondents believed that such that for social reasons they were obligated to “agree” with levels were available to them. Two additional questions inquired about any method that reduced pain whatever their true feelings.
the perceived value of painless monitoring to their patients in routinepractice and at home monitoring in crisis situations. For these last two Money is commonly used in such surveys to measure questions, respondents could choose between the four responses listed in value—respondents are asked how much they would be willing to pay to achieve a given outcome. In our opinion, Excluded from the survey were the investigators and their colleagues because doctors do not personally finance the care of their patients, this measure would be unrealistic for a physician In advance of the survey, we telephoned 10 national testing laborato- ries and inquired whether they would perform salivary antiepileptic drug survey. On the other hand, it is common for physicians to levels. Five laboratories replied affirmatively.
expend their time without additional remuneration in the care of patients. So we asked physicians to what extent Our data suggest that saliva antiepileptic monitoring has they would be willing to spend their time “to obtain not been widely adopted. Among U.S. child neurologists, anticonvulsant levels by a painless method” To the patients of this survey, only two respondents had our surprise 11% of physicians chose the most expensive ordered a saliva antiepileptic level in the last year as part option, one half hour of their time. Another 44% offered of their routine office practice and less than 7% (37/544) 10 minutes of time, the second option. These two groups reported even knowing of a laboratory which could per- outnumbered the 212 physicians (41%) who would use the form the test. The child neurologists are the pediatric test but did not believe it warranted an additional time subspecialists with the greatest experience in managing epilepsy. Children with epilepsy constitute a large percent- A number of physicians who chose the third answer, age of their patients. If they do not use an epilepsy-related “. . . I might use the test but would not spend extra time test and don’t even know where to obtain it, in our per patient”, wrote notes on the margin asking if we didn’t opinion, it is doubtful if any other group of U.S. physicians understand how busy physicians were, didn’t we know caring for children with epilepsy uses it.
that there was no extra time in the day to do things such as Our survey suggests that a painless method of measur- arrange for tests. They indicated that they actually would ing antiepileptic drug concentrations, especially if the value the test highly but could not see how they could technique would lend itself to obtaining samples at home invest one half hour or even 10 additional minutes. These or school, would fill an important and unmet need in the responses have encouraged us to believe that the surveyed management of children with epilepsy. Using saliva in doctors took the questionnaire seriously and that respon- place of serum might fill that need. Data supporting saliva dents who volunteered to expend their own time placed a measurements for phenobarbital, phenytoin, and carbam- high value in avoiding subjecting children to painful tests.
azepine have been available for over 10 years We also asked respondents how valuable the ability “to Recent studies have demonstrated close correlations be- obtain an immediate sample at home . . . at the time of a tween serum and saliva concentrations for lamotrigine seizure or adverse event” would be. The positive response levetiracetam and topiramate It is possible was overwhelming. Seventy percent would invest 10 to 30 that some clinicians also routinely monitor hepatic, hema- minutes per patient of their own time “to make advance topoietic, and other factors that require blood samples.
Given the lack of value of such monitoring with the above We have no clear explanation why 70% of physicians antiepileptic drugs, it is difficult to see that this will be a were willing to expend their own time (question #4) vs 55% for the preceding question. Perhaps the phrase The technique for obtaining saliva is easy enough; the “adverse event” in this last question triggered a stronger child simply spits into a plastic cup For infants or response than the routine situation described in question children who are unable to cooperate, a simple, disposable #4. The differing responses between the questions lends pipette can be used to obtain saliva. A drop of citric acid credibility to our impression that the child neurologists will stimulate saliva production if the child’s mouth is dry who responded read each questions carefully and at- without altering the assay The major technological tempted to give an answer that reflected their best clinical problem is obtaining saliva too close in time to oral administration of medication—traces of medication may The ability to obtain an immediate sample in the home remain in the mouth and contaminate the sample. A 3-hour is a potential advantage of saliva monitoring This interval is sufficient to avoid this problem use has not been widely explored, but the simplicity of Our survey data strongly suggest that there is an unmet sample collection and the stability of specimens at room need for obtaining antiepileptic drug concentrations with- temperature suggests it could be practical Especially out causing pain, especially if this method could be used at with epilepsy where seizures can occur infrequently and home or school. It is clear that the current leading remembering to adhere to medication schedules can be technology which could meet this need, saliva concentra- difficult this option could be especially valuable tion determinations, has not been adopted. This circum- In the event that a child has a seizure or possible adverse stance does not appear to reflect a lack of physician effect, physicians often need an antiepileptic drug concen- interest. We do not have data regarding other factors that tration before suggesting a medication adjustment. With might inhibit the adoption of this technology. It is possible serum this entails a visit to a laboratory, or during nights that economic factors which are beyond physician control, and weekends it means either an emergency department such as the loss of revenue from phlebotomy or the cost to visit or waiting until the laboratory resumes operation. The the laboratory of switching from one test to another, have emergency department visit may not be clinically neces- favored the status quo. The lack of proprietary methods sary and incurs further expense. Delaying collection of the that would be promoted by patent holders could also be a sample allows the serum concentration to change so that the measured serum concentration will no longer represent Assuming there were no commercial barriers, a pathway the concentration that existed when the event occurred for expanding the use of salivary antiepileptic drug con- centrations would include demonstrating: (1) The exis- Baumann et al: Preference for AED Testing tence of high and replicable correlations between salivary fancy, childhood, and adolescence. In: Wyllie E, ed. The treatment of levels, serum levels, and dose. (2) The ability of families epilepsy: Principles and practice. Philadelphia: Lippincott Williams & to secure salivary samples at home. (3) That when stored Kriel RL, Birnbaum AK, Cloyd JC. Antiepileptic drug therapy in
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Source: http://gatton.uky.edu/faculty/yelowitz/BaumannRyanYelowitz.pdf