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Theophylline compliance in adolescent patients with chronic asthma
JOURNAL OF ADOLESCENT HEALTH CARE 3:177-179, 1982
BRIEF SCIENTIFIC REPORT
Theophylline Compliance in Adolescent Patients With Chronic Asthma K I M B A L L A. MILLERI M . D .
Twen~-one chronic asthma patients ages 12 to 17 years were studied to determine their compliance in taking medication. Serum theophyiline concentrations were determined and theOphyUine doSage (milligrams per kilogram body weight pe r day) was calculated in participants who had allegedly followed their medication regimen. Although the theophylline dosage followed the guidelines in the literature, only 10% ofthe patients had serum levels in the [herapeutic range. This study suggests that noncompliance among adolescent asthmatics is similar to the noncompliance found in adolescents with other chronic illnesses and that physicians should use drug levels in designing optimal short' and long-term management programs. Further, it emphasizes the need for physicians to educate their patients as to the therapeutic actions of the medication they are taking and the necessity of medication compliance. KEY WORDS:
Patient compliance Asthma Theophylline Adolescent chronic illness Asthma is a major chronic illneSs of adolescents. Several studies show that with appropriate bronchodilator management these patients can have a normal life; yet in spite of these medical regimens, asthma is the most common cause of school absence due to a chronic illness (1,2). Theophylline is the basic drug used in managing chronic asthma in adolescents, and there is a direct From the Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan. Address reprint requests to: Kimball A. Miller, M.D., Departmen t of Pediatrics, Mayo Clinic, Rochester, Minnesota 55905. Manuscript accepted June 25, 1982.
relationship between serum concentration and therapeutic effect (3-5). The pharmacologic action of the drug results from an inhibition of the phOsphodiesterase enzyme, which converts adenosine 3',5'monophosphate (cyclic adenosine monoph0sphate) to adenosine 5'-monophosphate in the bronchial smooth muscle. This inhibition leads to an increase in intracellular cyclic adenosine monophosphate concentration, resulting in relaxation of bronchial smooth muscle. In the clinical management of adolescent asthmatics, the lack of response to theophylline is commonly taken as an indication to change medication or to add additional therapeutic modalities. Although this may be the case in some situations, the lack of medication response may also be the result of prescription error, inadequate education about administration of medication, increased drug metabolism, or noncompliance. This article addresses noncompliance as a cause of poor clinical response to theophylline. A review of the literature shows two major methods for measuring compliance: direct and indirect measures (6,7). Direct measures involve the analysis of body fluids for qualitative or quantitative determination of the presence of prescribed medication in the b o d y compartment analyzed. Indirect measures of compliance are usually less objective and include a pill count, patient self-repOrting, and analysis of treatment outcomes. Overall noncompliance for the pediatric population is approximately 50% with a range from 20% to 80% (6,7). More specifically, rates of noncompliance are reported to be higher among adolescents taking chronic medications (79). The purpose of this study is to estimate, by using the direct method of measuring serum theophylline concentrations, the incidence of medication compli-
© Society for Adolescent Medicine, 1982 Published by Elsevier Science Publishing Co., Inc, 52 Vanderbilt Ave., New York, NY 10017
177 0197-0070/82/030177 + 03502.75
178
MILLER
J O U R N A L OF A D O L E S C E N T H E A L T H CARE Vol. 3, No. 3
ance in adolescents allegedly taking therapeutiC doses of theophylline.
Methods Adolescents with a chart-documented diagnosis of chronic asthma (history of repeated episodes of wheezing responsive to bronchodilator medication) w h o came to our university walk-in clinic for treatm e n t of acute bronchospasm and who had allegedly complied with prescribed theophylline doses were Selected to take part in this study. Only patients whose prescriptions for long-acting theophylline preparations followed the guidelines in the literature for therapy were included in the study (10-12). During the period of medical management, the patients were questioned about their theophylline medication, its use during th e past 24 hours, and their recent use of other medications. All adolescent patients who had a history of theophylline compliance and were not taking medications known to affect the0phylline metabolism had serum sample obtained for theophyliine concentration as measured by high-pressure chromotography. During the study period July 1979 through June 1980, 21 patients aged 12-17 years fulfilled the above criteria and were included in this study. Each patient's prescribed the-
Table 1. Theophylline Dosage and Serum Levels in Adolescents Reportedly Following Their Prescribed Regimen Dosage
S e r u m level
Patient
(mg/kg body wt/day)
Oxg/ml)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 M e a n _+ SD
38 26 16 17 16 16 16 16 19 28 19 26 22 22 16 16 16 24 27 19 16 21.5 _+ 3.6
1.5 0.0 7.1 5.3 3.5 0.0 0.0 8.3 9.1 9.8 3.7 3.7 1.3 1.4 1.2 5.5 8.0 5.2 13.4 12.9 9.0 5.2 + 4.2
ophylline dosage (in milligrams per kilogram of body weight per day) was calculated, and the dosage along with the serum theophylline concentration was recorded on the patient's chart for subsequent use by the physician responsible for continuity of care. In patients with more than one acute illness, only the first alleged theophylline dosage and serum concentration were used for data analysis.
Results In the adolescents allegedly compliant with their theophylline medication regimen, there was a range of serhm concentrations from 0 to 13.4/xg/ml. As s h o w n in Table 1, the sera of 86% of the patients contained theophylline. The mean serum theophylline ~concentration in the adolescent studies (5.2 /xg/ml) was subtherapeutic, and only 10% of the patient~ were found to have serum concentrations in the therapeutic zone (10-20/xg/ml). The calculated dosage of theophylline ranged from 16-38 mg/kg per day with a mean of 21.5 mg/kg per day.
Discussion In our adolescent chronic asthma patients who had theophylline prescribed in dosages consistent with current literature recommendations and a history of medication compliance, only a small percentage (10%) had serum levels in the therapeutic range. Although the metabolism of the0phylline varies widely among patients, recent pharmacologic studies suggest that adolescents receiving the dosages prescribed should, in general, have levels in the therapeutic range (11,12). Therefore, one can postulate that for a significant number, the cause of low serum levels was noncompliance with the prescribed medication regimen. The results suggest that adolescent patients with chronic asthma may have noncompliance rates similar to those reported in adolescents with other chronic conditions such as epilepsy and rheumatic fever (6=-9). Moreover, our results are consistent with the findings reported in the pediatric asthma population (13,!4). Therefore, it cannot be assumed that patients whose chronic asthma is uncontrolled, even though pharmacologic doses of theophylline have been prescribed, are theophylline resistant and require additional types of bronchodilator therapy. Furthermore, the results reinforce the need for obtaining serum drug levels in designing optimal short- and long-term medical management regimens for adolescents. To accomplish the goal of a normal life
December 1982
THEOPHYLLINE COMPLIANCE IN ADOLESCENT CHRONIC ASTHMATICS
without dySpnea, restriction Of physical activity, or absence from school, the physician should make a special effort to emphasize the importance of compliance with the medication regimen. Management Programs for patients with chronic asthma might be more effective if they stressed to the patient the medication's therapeutic action, duration of action, and the need for continuous usage.
References 1. Blair H: Natural history of childhood asthma. Arch Dis Child 52:613-619, 1977 2. Parcel GS, Gilman SC, Nader PR, et al.: A comparison of absentee rates of elementary school children with asthma and nonasthmatic schoolmates. Pediatrics 64:878-881, 1979 3. Weinberger M: Theophylline for treatment of asthma. J Pediatr 92:1-7, 1978 4. Levy G, Koysooko R: i~harmacokinetic analysis of the effect o~ theophylline on pulmonary function in asthmatic children, J Pediatr 86:789-793, 1975 5. Leffert F: The management of chronic asthma. J Pediatr 97:875885, 1980
179
6. Ha ggerty RJ, Roghmann ;KJ: Noncompliance and Self medication: TWO neglected aspects of pediatric pharmacology. Pediatr Clin N Am 19:101-115, 1972 7. Litt IF, Cuskey WR: Compliance with medical regimens during adolescence. Pediatr Clin N Am 27:3-15, 1980 8. wilson JT: Compliance with insffuctions iti the evaluation of therapeutic efficacy: A common but frequently unrecognized major variabl~. Clin Pediatr 12:333-340, 1973 9. Korsch BM, Fine RN, Negrete VF: Noncompliance in children with renal transplants. Pediatrics 61:972-976, 1978 10. Kelly H, Murphy S: Efficacy of a i2-hour sustained-i*elease preparation in maintaining therapeutic Serum theophylline levels in asthmatic children. Pediatrics 66:97-102, 1980 11. Wyatt R, WMnberger M, Hendeles L: Oral theophylline dosage for the m~inagement of chronic asthma. J Pediatr 92:125130, 1978 12. Hendeies L, Weinberger M, Wyatt R: Guide to oral theophylline therapy for the treatment of chronic asthma. Am J Dis Child 132:876-880, 1978 13. Eney RD, Goldstein EO: Compliance of chronic asihmatics with oral administration.of theophylline as measured by serum and salivary levels. Pediatrics 57:513-517, 1976 14. Sublett FL, Pollard SJ, Kadlec GJ, et al.: Non-compliance in asthmatic children: A study of theophylline levels in a pediatric emergency room population. Ann Allergy 43:95-97, 1979
BRIEF SCIENTIFIC REPORT
Theophylline Compliance in Adolescent Patients With Chronic Asthma K I M B A L L A. MILLERI M . D .
Twen~-one chronic asthma patients ages 12 to 17 years were studied to determine their compliance in taking medication. Serum theophyiline concentrations were determined and theOphyUine doSage (milligrams per kilogram body weight pe r day) was calculated in participants who had allegedly followed their medication regimen. Although the theophylline dosage followed the guidelines in the literature, only 10% ofthe patients had serum levels in the [herapeutic range. This study suggests that noncompliance among adolescent asthmatics is similar to the noncompliance found in adolescents with other chronic illnesses and that physicians should use drug levels in designing optimal short' and long-term management programs. Further, it emphasizes the need for physicians to educate their patients as to the therapeutic actions of the medication they are taking and the necessity of medication compliance. KEY WORDS:
Patient compliance Asthma Theophylline Adolescent chronic illness Asthma is a major chronic illneSs of adolescents. Several studies show that with appropriate bronchodilator management these patients can have a normal life; yet in spite of these medical regimens, asthma is the most common cause of school absence due to a chronic illness (1,2). Theophylline is the basic drug used in managing chronic asthma in adolescents, and there is a direct From the Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, Michigan. Address reprint requests to: Kimball A. Miller, M.D., Departmen t of Pediatrics, Mayo Clinic, Rochester, Minnesota 55905. Manuscript accepted June 25, 1982.
relationship between serum concentration and therapeutic effect (3-5). The pharmacologic action of the drug results from an inhibition of the phOsphodiesterase enzyme, which converts adenosine 3',5'monophosphate (cyclic adenosine monoph0sphate) to adenosine 5'-monophosphate in the bronchial smooth muscle. This inhibition leads to an increase in intracellular cyclic adenosine monophosphate concentration, resulting in relaxation of bronchial smooth muscle. In the clinical management of adolescent asthmatics, the lack of response to theophylline is commonly taken as an indication to change medication or to add additional therapeutic modalities. Although this may be the case in some situations, the lack of medication response may also be the result of prescription error, inadequate education about administration of medication, increased drug metabolism, or noncompliance. This article addresses noncompliance as a cause of poor clinical response to theophylline. A review of the literature shows two major methods for measuring compliance: direct and indirect measures (6,7). Direct measures involve the analysis of body fluids for qualitative or quantitative determination of the presence of prescribed medication in the b o d y compartment analyzed. Indirect measures of compliance are usually less objective and include a pill count, patient self-repOrting, and analysis of treatment outcomes. Overall noncompliance for the pediatric population is approximately 50% with a range from 20% to 80% (6,7). More specifically, rates of noncompliance are reported to be higher among adolescents taking chronic medications (79). The purpose of this study is to estimate, by using the direct method of measuring serum theophylline concentrations, the incidence of medication compli-
© Society for Adolescent Medicine, 1982 Published by Elsevier Science Publishing Co., Inc, 52 Vanderbilt Ave., New York, NY 10017
177 0197-0070/82/030177 + 03502.75
178
MILLER
J O U R N A L OF A D O L E S C E N T H E A L T H CARE Vol. 3, No. 3
ance in adolescents allegedly taking therapeutiC doses of theophylline.
Methods Adolescents with a chart-documented diagnosis of chronic asthma (history of repeated episodes of wheezing responsive to bronchodilator medication) w h o came to our university walk-in clinic for treatm e n t of acute bronchospasm and who had allegedly complied with prescribed theophylline doses were Selected to take part in this study. Only patients whose prescriptions for long-acting theophylline preparations followed the guidelines in the literature for therapy were included in the study (10-12). During the period of medical management, the patients were questioned about their theophylline medication, its use during th e past 24 hours, and their recent use of other medications. All adolescent patients who had a history of theophylline compliance and were not taking medications known to affect the0phylline metabolism had serum sample obtained for theophyliine concentration as measured by high-pressure chromotography. During the study period July 1979 through June 1980, 21 patients aged 12-17 years fulfilled the above criteria and were included in this study. Each patient's prescribed the-
Table 1. Theophylline Dosage and Serum Levels in Adolescents Reportedly Following Their Prescribed Regimen Dosage
S e r u m level
Patient
(mg/kg body wt/day)
Oxg/ml)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 M e a n _+ SD
38 26 16 17 16 16 16 16 19 28 19 26 22 22 16 16 16 24 27 19 16 21.5 _+ 3.6
1.5 0.0 7.1 5.3 3.5 0.0 0.0 8.3 9.1 9.8 3.7 3.7 1.3 1.4 1.2 5.5 8.0 5.2 13.4 12.9 9.0 5.2 + 4.2
ophylline dosage (in milligrams per kilogram of body weight per day) was calculated, and the dosage along with the serum theophylline concentration was recorded on the patient's chart for subsequent use by the physician responsible for continuity of care. In patients with more than one acute illness, only the first alleged theophylline dosage and serum concentration were used for data analysis.
Results In the adolescents allegedly compliant with their theophylline medication regimen, there was a range of serhm concentrations from 0 to 13.4/xg/ml. As s h o w n in Table 1, the sera of 86% of the patients contained theophylline. The mean serum theophylline ~concentration in the adolescent studies (5.2 /xg/ml) was subtherapeutic, and only 10% of the patient~ were found to have serum concentrations in the therapeutic zone (10-20/xg/ml). The calculated dosage of theophylline ranged from 16-38 mg/kg per day with a mean of 21.5 mg/kg per day.
Discussion In our adolescent chronic asthma patients who had theophylline prescribed in dosages consistent with current literature recommendations and a history of medication compliance, only a small percentage (10%) had serum levels in the therapeutic range. Although the metabolism of the0phylline varies widely among patients, recent pharmacologic studies suggest that adolescents receiving the dosages prescribed should, in general, have levels in the therapeutic range (11,12). Therefore, one can postulate that for a significant number, the cause of low serum levels was noncompliance with the prescribed medication regimen. The results suggest that adolescent patients with chronic asthma may have noncompliance rates similar to those reported in adolescents with other chronic conditions such as epilepsy and rheumatic fever (6=-9). Moreover, our results are consistent with the findings reported in the pediatric asthma population (13,!4). Therefore, it cannot be assumed that patients whose chronic asthma is uncontrolled, even though pharmacologic doses of theophylline have been prescribed, are theophylline resistant and require additional types of bronchodilator therapy. Furthermore, the results reinforce the need for obtaining serum drug levels in designing optimal short- and long-term medical management regimens for adolescents. To accomplish the goal of a normal life
December 1982
THEOPHYLLINE COMPLIANCE IN ADOLESCENT CHRONIC ASTHMATICS
without dySpnea, restriction Of physical activity, or absence from school, the physician should make a special effort to emphasize the importance of compliance with the medication regimen. Management Programs for patients with chronic asthma might be more effective if they stressed to the patient the medication's therapeutic action, duration of action, and the need for continuous usage.
References 1. Blair H: Natural history of childhood asthma. Arch Dis Child 52:613-619, 1977 2. Parcel GS, Gilman SC, Nader PR, et al.: A comparison of absentee rates of elementary school children with asthma and nonasthmatic schoolmates. Pediatrics 64:878-881, 1979 3. Weinberger M: Theophylline for treatment of asthma. J Pediatr 92:1-7, 1978 4. Levy G, Koysooko R: i~harmacokinetic analysis of the effect o~ theophylline on pulmonary function in asthmatic children, J Pediatr 86:789-793, 1975 5. Leffert F: The management of chronic asthma. J Pediatr 97:875885, 1980
179
6. Ha ggerty RJ, Roghmann ;KJ: Noncompliance and Self medication: TWO neglected aspects of pediatric pharmacology. Pediatr Clin N Am 19:101-115, 1972 7. Litt IF, Cuskey WR: Compliance with medical regimens during adolescence. Pediatr Clin N Am 27:3-15, 1980 8. wilson JT: Compliance with insffuctions iti the evaluation of therapeutic efficacy: A common but frequently unrecognized major variabl~. Clin Pediatr 12:333-340, 1973 9. Korsch BM, Fine RN, Negrete VF: Noncompliance in children with renal transplants. Pediatrics 61:972-976, 1978 10. Kelly H, Murphy S: Efficacy of a i2-hour sustained-i*elease preparation in maintaining therapeutic Serum theophylline levels in asthmatic children. Pediatrics 66:97-102, 1980 11. Wyatt R, WMnberger M, Hendeles L: Oral theophylline dosage for the m~inagement of chronic asthma. J Pediatr 92:125130, 1978 12. Hendeies L, Weinberger M, Wyatt R: Guide to oral theophylline therapy for the treatment of chronic asthma. Am J Dis Child 132:876-880, 1978 13. Eney RD, Goldstein EO: Compliance of chronic asihmatics with oral administration.of theophylline as measured by serum and salivary levels. Pediatrics 57:513-517, 1976 14. Sublett FL, Pollard SJ, Kadlec GJ, et al.: Non-compliance in asthmatic children: A study of theophylline levels in a pediatric emergency room population. Ann Allergy 43:95-97, 1979