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What causes a low TSH level with a normal free T4 level?
Subclinical hyperthyroidism (SCH) is defined as a low thyroid-stimulating hormone (TSH) level with normal free T4 and free T3 levels in patients without specific symptoms of hyperthyroidism. There is no evidence that treating SCH results in improved cardiovascular outcomes and evidence is insufficient that it improves neuropsychiatric outcomes (strength of recommendation [SOR]: C).
Bone mineral density may be increased with treatment of SCH (SOR: B, based on one randomized clinical trial).
Early detection and management of SCH is important
Jae Ho Lee, MD
Department of Family and Community Medicine, Baylor College of Medicine, Houston, Tex; Catholic University Medical College of Korea
SCH is one of those subclinical diseases commonly encountered in primary care; it is more common in women than men, in blacks than whites, and in the elderly. It is less common, however, than subclinical hypothyroidism. Early detection and management of SCH is important for several reasons. First of all, with careful history taking and a thorough laboratory follow-up, other hidden thyroid diseases and medication problems may be found and prevented. Second, the cardiovascular abnormalities related to this disease may precede the onset of a more severe cardiovascular disease. Third, it is becoming apparent that this disease may accelerate the development of osteoporosis, particularly in postmenopausal women. Finally, as I have learned from my clinical experience, if patient and family are not counseled properly, they may become confused and abandon follow-up or treatment.
Evidence summary
The decreased TSH level seen in SCH results from the pituitary’s response to minor elevations in serum or tissue T4 and T3 levels.1 Although these level remain within the normal range, the increases are sufficient to decrease the serum TSH level. The prevalence of SCH depends on the level of TSH used as a threshold. When the lower limit of TSH is set at 0.4 mIU/L, the prevalence was 3.2%.2 When followed up at 1 year, 40% to 60% of subjects with suppressed TSH levels will have normal TSH values.3 Progression to overt hyperthyroidism is uncommon, occurring in 4.3% of subjects at 4 years.4 It is worth noting that individuals treated with levothyroxine have a prevalence of iatrogenic SCH from 14% to 21%.5
In patients with SCH aged >60 years, the cumulative incidence of atrial fibrillation after 10 years varied with the serum TSH level: it was 28% in those with serum TSH <0.1 mIU/L; 16% in those with values between 0.1 and 0.4 mIU/L, and 11 % in those with normal values.6 Patients with SCH have been reported to have increased heart rate, contractility, left ventricular mass, and increased risk of diastolic dysfunction and atrial arrhythmias.7 Patients aged >60 years with at least 1 suppressed TSH value have an increase in mortality over 5 years (standardized mortality ratio [SMR]=1.8; 95% confidence interval [CI], 1.2–2.7). At 10 years, the SMR was 1.2 (95% CI, 0.9–1.7). It appears that this is primarily related to cardiovascular mortality.8
There are little data on the effects of treating SCH. One study of postmenopausal women with endogenous SCH (defined as TSH <0.1 mIU/L) randomly assigned women to take methimazole (Tapazole) or placebo. Both groups were followed for 2 years and none received any medication with known effects on bone metabolism in the past or during the study period. The untreated patients with SCH had significantly higher bone mineral density loss (>5%) at both 18 and 24 months.9
Recommendations from others
A systematic review suggests the following regarding the evaluation and treatment of SCH.10
- Exclude other causes of subnormal serum TSH concentration (TABLE)
- Retest patients. Patients with atrial fibrillation, and cardiac disease, or a TSH <0.1 mIU/L should be retested in 2 to 4 weeks. Other patents can be retested in 3 months.
- Patients whose TSH remains <0.1 mIU/L should undergo a radioactive iodine uptake scan. If the uptake is high (consistent with Graves’s disease or a focal nodule), treat as appropriate for that disease.
Younger patients (<60 years), with mild TSH suppression (0.1–0.45 mIU/L) or low radioactive iodine uptake can be followed with serial TSH testing at 3- to 12-month intervals. However, for these patients who also have cardiac disease, decreased bone mineral density, or symptoms suggestive of hyperthyroidism, thyroid suppression is recommended.
In patients aged >60 years with TSH <0.1 mIU/L, antithyroid treatment should be considered to decrease cardiac and bone loss complications.
Patients receiving thyroid replacement therapy should have their dose adjusted to maintain a normal serum TSH concentration. However, when thyroid hormone therapy is used for TSH suppression to prevent or reduce goiter growth or prevent recurrence of thyroid cancer, then a lower TSH may be unavoidable. The adverse effects can be minimized by treatment with the least level of suppression necessary to meet the desired goal.
1. Toft AD. Clinical practice. Subclinical hyperthyroidism. N Engl J Med 2001;345:512-516.
2. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489-499.
3. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf) 1991;34:77-83.
4. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM. Low serum thyrotropin (thyroid stimulating hormone) in older persons without hyperthyroidism. Arch Intern Med 1991;151:165-168.
5. Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. Br J Gen Pract 1993;43:107-109.
6. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;331:1249-1252.
7. Biondi B, Fazio S, Carella C, et al. Cardiac effects of long term thyrotropin suppressive therapy with levothyroxine. J Clin Endocrinol Metab 1993;77:334.
8. Parle JV, Maisonneuve P, Sheppard MC, et al. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001;358:861-865.
9. Mudde AH, Houben AJ, Nieuwenhuijzen Kruseman AC. Bone metabolism during anti-thyroid drug treatment of endogenous subclinical hyperthyroidism. Clin Endocrinol (Oxf) 1994;41:421-424.
10. Surks MI, Oritz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228-238.
Subclinical hyperthyroidism (SCH) is defined as a low thyroid-stimulating hormone (TSH) level with normal free T4 and free T3 levels in patients without specific symptoms of hyperthyroidism. There is no evidence that treating SCH results in improved cardiovascular outcomes and evidence is insufficient that it improves neuropsychiatric outcomes (strength of recommendation [SOR]: C).
Bone mineral density may be increased with treatment of SCH (SOR: B, based on one randomized clinical trial).
Early detection and management of SCH is important
Jae Ho Lee, MD
Department of Family and Community Medicine, Baylor College of Medicine, Houston, Tex; Catholic University Medical College of Korea
SCH is one of those subclinical diseases commonly encountered in primary care; it is more common in women than men, in blacks than whites, and in the elderly. It is less common, however, than subclinical hypothyroidism. Early detection and management of SCH is important for several reasons. First of all, with careful history taking and a thorough laboratory follow-up, other hidden thyroid diseases and medication problems may be found and prevented. Second, the cardiovascular abnormalities related to this disease may precede the onset of a more severe cardiovascular disease. Third, it is becoming apparent that this disease may accelerate the development of osteoporosis, particularly in postmenopausal women. Finally, as I have learned from my clinical experience, if patient and family are not counseled properly, they may become confused and abandon follow-up or treatment.
Evidence summary
The decreased TSH level seen in SCH results from the pituitary’s response to minor elevations in serum or tissue T4 and T3 levels.1 Although these level remain within the normal range, the increases are sufficient to decrease the serum TSH level. The prevalence of SCH depends on the level of TSH used as a threshold. When the lower limit of TSH is set at 0.4 mIU/L, the prevalence was 3.2%.2 When followed up at 1 year, 40% to 60% of subjects with suppressed TSH levels will have normal TSH values.3 Progression to overt hyperthyroidism is uncommon, occurring in 4.3% of subjects at 4 years.4 It is worth noting that individuals treated with levothyroxine have a prevalence of iatrogenic SCH from 14% to 21%.5
In patients with SCH aged >60 years, the cumulative incidence of atrial fibrillation after 10 years varied with the serum TSH level: it was 28% in those with serum TSH <0.1 mIU/L; 16% in those with values between 0.1 and 0.4 mIU/L, and 11 % in those with normal values.6 Patients with SCH have been reported to have increased heart rate, contractility, left ventricular mass, and increased risk of diastolic dysfunction and atrial arrhythmias.7 Patients aged >60 years with at least 1 suppressed TSH value have an increase in mortality over 5 years (standardized mortality ratio [SMR]=1.8; 95% confidence interval [CI], 1.2–2.7). At 10 years, the SMR was 1.2 (95% CI, 0.9–1.7). It appears that this is primarily related to cardiovascular mortality.8
There are little data on the effects of treating SCH. One study of postmenopausal women with endogenous SCH (defined as TSH <0.1 mIU/L) randomly assigned women to take methimazole (Tapazole) or placebo. Both groups were followed for 2 years and none received any medication with known effects on bone metabolism in the past or during the study period. The untreated patients with SCH had significantly higher bone mineral density loss (>5%) at both 18 and 24 months.9
Recommendations from others
A systematic review suggests the following regarding the evaluation and treatment of SCH.10
- Exclude other causes of subnormal serum TSH concentration (TABLE)
- Retest patients. Patients with atrial fibrillation, and cardiac disease, or a TSH <0.1 mIU/L should be retested in 2 to 4 weeks. Other patents can be retested in 3 months.
- Patients whose TSH remains <0.1 mIU/L should undergo a radioactive iodine uptake scan. If the uptake is high (consistent with Graves’s disease or a focal nodule), treat as appropriate for that disease.
Younger patients (<60 years), with mild TSH suppression (0.1–0.45 mIU/L) or low radioactive iodine uptake can be followed with serial TSH testing at 3- to 12-month intervals. However, for these patients who also have cardiac disease, decreased bone mineral density, or symptoms suggestive of hyperthyroidism, thyroid suppression is recommended.
In patients aged >60 years with TSH <0.1 mIU/L, antithyroid treatment should be considered to decrease cardiac and bone loss complications.
Patients receiving thyroid replacement therapy should have their dose adjusted to maintain a normal serum TSH concentration. However, when thyroid hormone therapy is used for TSH suppression to prevent or reduce goiter growth or prevent recurrence of thyroid cancer, then a lower TSH may be unavoidable. The adverse effects can be minimized by treatment with the least level of suppression necessary to meet the desired goal.
Subclinical hyperthyroidism (SCH) is defined as a low thyroid-stimulating hormone (TSH) level with normal free T4 and free T3 levels in patients without specific symptoms of hyperthyroidism. There is no evidence that treating SCH results in improved cardiovascular outcomes and evidence is insufficient that it improves neuropsychiatric outcomes (strength of recommendation [SOR]: C).
Bone mineral density may be increased with treatment of SCH (SOR: B, based on one randomized clinical trial).
Early detection and management of SCH is important
Jae Ho Lee, MD
Department of Family and Community Medicine, Baylor College of Medicine, Houston, Tex; Catholic University Medical College of Korea
SCH is one of those subclinical diseases commonly encountered in primary care; it is more common in women than men, in blacks than whites, and in the elderly. It is less common, however, than subclinical hypothyroidism. Early detection and management of SCH is important for several reasons. First of all, with careful history taking and a thorough laboratory follow-up, other hidden thyroid diseases and medication problems may be found and prevented. Second, the cardiovascular abnormalities related to this disease may precede the onset of a more severe cardiovascular disease. Third, it is becoming apparent that this disease may accelerate the development of osteoporosis, particularly in postmenopausal women. Finally, as I have learned from my clinical experience, if patient and family are not counseled properly, they may become confused and abandon follow-up or treatment.
Evidence summary
The decreased TSH level seen in SCH results from the pituitary’s response to minor elevations in serum or tissue T4 and T3 levels.1 Although these level remain within the normal range, the increases are sufficient to decrease the serum TSH level. The prevalence of SCH depends on the level of TSH used as a threshold. When the lower limit of TSH is set at 0.4 mIU/L, the prevalence was 3.2%.2 When followed up at 1 year, 40% to 60% of subjects with suppressed TSH levels will have normal TSH values.3 Progression to overt hyperthyroidism is uncommon, occurring in 4.3% of subjects at 4 years.4 It is worth noting that individuals treated with levothyroxine have a prevalence of iatrogenic SCH from 14% to 21%.5
In patients with SCH aged >60 years, the cumulative incidence of atrial fibrillation after 10 years varied with the serum TSH level: it was 28% in those with serum TSH <0.1 mIU/L; 16% in those with values between 0.1 and 0.4 mIU/L, and 11 % in those with normal values.6 Patients with SCH have been reported to have increased heart rate, contractility, left ventricular mass, and increased risk of diastolic dysfunction and atrial arrhythmias.7 Patients aged >60 years with at least 1 suppressed TSH value have an increase in mortality over 5 years (standardized mortality ratio [SMR]=1.8; 95% confidence interval [CI], 1.2–2.7). At 10 years, the SMR was 1.2 (95% CI, 0.9–1.7). It appears that this is primarily related to cardiovascular mortality.8
There are little data on the effects of treating SCH. One study of postmenopausal women with endogenous SCH (defined as TSH <0.1 mIU/L) randomly assigned women to take methimazole (Tapazole) or placebo. Both groups were followed for 2 years and none received any medication with known effects on bone metabolism in the past or during the study period. The untreated patients with SCH had significantly higher bone mineral density loss (>5%) at both 18 and 24 months.9
Recommendations from others
A systematic review suggests the following regarding the evaluation and treatment of SCH.10
- Exclude other causes of subnormal serum TSH concentration (TABLE)
- Retest patients. Patients with atrial fibrillation, and cardiac disease, or a TSH <0.1 mIU/L should be retested in 2 to 4 weeks. Other patents can be retested in 3 months.
- Patients whose TSH remains <0.1 mIU/L should undergo a radioactive iodine uptake scan. If the uptake is high (consistent with Graves’s disease or a focal nodule), treat as appropriate for that disease.
Younger patients (<60 years), with mild TSH suppression (0.1–0.45 mIU/L) or low radioactive iodine uptake can be followed with serial TSH testing at 3- to 12-month intervals. However, for these patients who also have cardiac disease, decreased bone mineral density, or symptoms suggestive of hyperthyroidism, thyroid suppression is recommended.
In patients aged >60 years with TSH <0.1 mIU/L, antithyroid treatment should be considered to decrease cardiac and bone loss complications.
Patients receiving thyroid replacement therapy should have their dose adjusted to maintain a normal serum TSH concentration. However, when thyroid hormone therapy is used for TSH suppression to prevent or reduce goiter growth or prevent recurrence of thyroid cancer, then a lower TSH may be unavoidable. The adverse effects can be minimized by treatment with the least level of suppression necessary to meet the desired goal.
1. Toft AD. Clinical practice. Subclinical hyperthyroidism. N Engl J Med 2001;345:512-516.
2. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489-499.
3. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf) 1991;34:77-83.
4. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM. Low serum thyrotropin (thyroid stimulating hormone) in older persons without hyperthyroidism. Arch Intern Med 1991;151:165-168.
5. Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. Br J Gen Pract 1993;43:107-109.
6. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;331:1249-1252.
7. Biondi B, Fazio S, Carella C, et al. Cardiac effects of long term thyrotropin suppressive therapy with levothyroxine. J Clin Endocrinol Metab 1993;77:334.
8. Parle JV, Maisonneuve P, Sheppard MC, et al. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001;358:861-865.
9. Mudde AH, Houben AJ, Nieuwenhuijzen Kruseman AC. Bone metabolism during anti-thyroid drug treatment of endogenous subclinical hyperthyroidism. Clin Endocrinol (Oxf) 1994;41:421-424.
10. Surks MI, Oritz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228-238.
1. Toft AD. Clinical practice. Subclinical hyperthyroidism. N Engl J Med 2001;345:512-516.
2. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489-499.
3. Parle JV, Franklyn JA, Cross KW, Jones SC, Sheppard MC. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf) 1991;34:77-83.
4. Sawin CT, Geller A, Kaplan MM, Bacharach P, Wilson PW, Hershman JM. Low serum thyrotropin (thyroid stimulating hormone) in older persons without hyperthyroidism. Arch Intern Med 1991;151:165-168.
5. Parle JV, Franklyn JA, Cross KW, Jones SR, Sheppard MC. Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. Br J Gen Pract 1993;43:107-109.
6. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;331:1249-1252.
7. Biondi B, Fazio S, Carella C, et al. Cardiac effects of long term thyrotropin suppressive therapy with levothyroxine. J Clin Endocrinol Metab 1993;77:334.
8. Parle JV, Maisonneuve P, Sheppard MC, et al. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001;358:861-865.
9. Mudde AH, Houben AJ, Nieuwenhuijzen Kruseman AC. Bone metabolism during anti-thyroid drug treatment of endogenous subclinical hyperthyroidism. Clin Endocrinol (Oxf) 1994;41:421-424.
10. Surks MI, Oritz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291:228-238.
Evidence-based answers from the Family Physicians Inquiries Network
Is the long-term use of proton pump inhibitors safe?
Long-term use of proton pump inhibitors (PPIs) appears safe, resulting in no clinically relevant adverse effects (strength of recommendation: B, based on nonsystematic reviews, cohort studies, or low-quality randomized controlled trials). No evidence clearly links PPIs to gastric cancer or carcinoid, enteric infections, or significant nutrient malabsorption.
Evidence summary
The long-term safety of PPIs is not completely known. There are 5 PPIs on the US market. Clinical experience with these medications ranges from 3 to 20 years. All of the identified studies addressing long-term use have follow-up of 10 years or less (Table). Studies of longer duration are warranted. We reviewed the possible adverse effects of these medications.
Gastric carcinoid. PPIs cause predictable and sustained hypergastrinemia in response to acid suppression. In rats, this causes enterochro-maffin-like cell (ECL) hyperplasia and carcinoid tumors, raising a safety concern in humans. In a nonsystematic review of 11 studies of 1800 patients who used PPIs from 6 months to 8 years, there were no neoplastic ECL changes or carcinoid tumors.1 Three other nonsystematic reviews support these findings.2-4 In a randomized controlled trial comparing efficacy and safety of rabeprazole with omeprazole for gastro-esophageal disease, 123 (51%) out of 243 patients completed 5 years of the study; no patients had neoplastic ECL changes.5
Atrophic gastritis and gastric cancer. Atrophic gastritis with intestinal metaplasia is associated with gastric adenocarcinoma. Because PPIs can theoretically cause atrophic gastritis, there is a concern that this could lead to gastric cancer. The evidence regarding atrophic gastritis is contradictory. A nonsystematic review identified 1 cohort study and 1 randomized controlled trial of patients taking omeprazole from 1 to 4 years, which showed no association between PPI use and atrophic gastritis.1 The same review reported that another cohort study of patients using omeprazole for 1 year showed an increase in atrophic gastritis. None of the studies reviewed showed an association between omeprazole use and intestinal metaplasia or its progression to gastric adenocarcinoma.1 Three other nonsystematic reviews support these findings.2,3,5 The available evidence indicates that PPI use is not clearly associated with atrophic gastritis, or with progression from gastritis to metaplasia or cancer.
Enteric infections. Because hypochlorhydria is associated with bacterial enteric infections, bacterial enteritis is a theoretical risk of long-term PPI use. A large case-control study of 54,461 patients using omeprazole for 1 year showed no association with such infections.6
Mineral malabsorption. Dietary calcium, phosphorus, magnesium, zinc, and iron depend on gastric acid for absorption. Two separate non-systematic reviews showed no problems with malabsorption of these micronutrients.1,3
B12 malabsorption. Two nonsystematic reviews showed a decrease in vitamin B12 absorption among patients on high-dose (up to 80 mg of omeprazole daily), long-term PPI therapy (eg, patients with Zollinger-Ellison syndrome).1,2 This has not been demonstrated for patients taking more typical doses of omeprazole. The clinical significance of this is unknown; however, the authors of these reviews suggested monitoring B12 levels of patients on long-term, high-dose PPI therapy.
TABLE
Potential proton pump inhibitor safety concerns
| Safety concern | PPI studied | Duration of studies | Evidence |
|---|---|---|---|
| Gastric carcinoids | Omeprazole, lansoprazole, pantoprazole, rabeprazole | 1–8 years | No increased risk1-5 |
| Gastric metaplasia/adenocarcinoma | Omeprazole | 1–5 years | No increased risk1-3,5 |
| Enteric infections | Omeprazole | 1 year | No increased risk6 |
| Mineral malabsorption | Omeprazole | 6 months–2 years | No increased risk1,3 |
| B12 malabsorption | Omeprazole | 10 years | Decreased B12 levels with high-dose therapy1,2 |
Recommendations from others
A Federal Drug Commission report indicates that labeling PPIs for cancer risk is not warranted.7 The American College of Gastroenterology and the University of Michigan Health System guidelines for treatment of gastroesophageal disease recommend long-term PPI therapy as an option without any warning against their use.8,9
No evidence of long-term adverse health effects from PPIs, but cost still a problem
Richard A. Guthmann, MD
Illinois Masonic Family Practice Residency, University of Illinois at Chicago
Proton pump inhibitors work. They effectively treat the symptoms and reduce the complication involved with peptic ulcer disease. The lack of evidence suggesting any long-term adverse health effects, even if not definitive, is very encouraging, but the cost of these medicines remains a problem. Both patients and third-party payers continue to object to their cost, and for this reason, as well as longer safety track records, less expensive medicines such as H2 blockers and over-the-counter antacids should be tried for longer-term treatment.
1. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000;14:651-668.
2. Garnett WR. Considerations for long-term use of protonpump inhibitors. Am J Health Syst Pharm 1998;55:2268-2279.
3. Freston JW. Long-term acid control and proton pump inhibitors: interactions and safety issues in perspective. Am J Gastroenterol 1997;92(4 Suppl):51S-57S.
4. Freston JW, Rose PA, Heller CA, Haber M, Jennings D. Safety profile of Lansoprazole: the US clinical trial experience. Drug Saf 1999;20:195-205.
5. Thjodleifsson B, Rindi G, Fiocca R, et al. A randomized double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years. Aliment Pharmacol Ther 2003;17:343-351.
6. Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid-sup-pressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology 1997;8:571-574.
7. Proton pump inhibitor relabeling for cancer risk not warranted; long-term studies recommended. FDC Rep 1996;58(Nov 11)T&G:1-2.
8. Management of gastroesophageal reflux disease (GERD). Ann Arbor, Mich: University of Michigan Health System; last updated 2002 March. Available at: cme.med.umich.edu/iCME/gerd/default.asp. Accessed on March 16, 2004.
9. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1999;94:1434-1442.
Long-term use of proton pump inhibitors (PPIs) appears safe, resulting in no clinically relevant adverse effects (strength of recommendation: B, based on nonsystematic reviews, cohort studies, or low-quality randomized controlled trials). No evidence clearly links PPIs to gastric cancer or carcinoid, enteric infections, or significant nutrient malabsorption.
Evidence summary
The long-term safety of PPIs is not completely known. There are 5 PPIs on the US market. Clinical experience with these medications ranges from 3 to 20 years. All of the identified studies addressing long-term use have follow-up of 10 years or less (Table). Studies of longer duration are warranted. We reviewed the possible adverse effects of these medications.
Gastric carcinoid. PPIs cause predictable and sustained hypergastrinemia in response to acid suppression. In rats, this causes enterochro-maffin-like cell (ECL) hyperplasia and carcinoid tumors, raising a safety concern in humans. In a nonsystematic review of 11 studies of 1800 patients who used PPIs from 6 months to 8 years, there were no neoplastic ECL changes or carcinoid tumors.1 Three other nonsystematic reviews support these findings.2-4 In a randomized controlled trial comparing efficacy and safety of rabeprazole with omeprazole for gastro-esophageal disease, 123 (51%) out of 243 patients completed 5 years of the study; no patients had neoplastic ECL changes.5
Atrophic gastritis and gastric cancer. Atrophic gastritis with intestinal metaplasia is associated with gastric adenocarcinoma. Because PPIs can theoretically cause atrophic gastritis, there is a concern that this could lead to gastric cancer. The evidence regarding atrophic gastritis is contradictory. A nonsystematic review identified 1 cohort study and 1 randomized controlled trial of patients taking omeprazole from 1 to 4 years, which showed no association between PPI use and atrophic gastritis.1 The same review reported that another cohort study of patients using omeprazole for 1 year showed an increase in atrophic gastritis. None of the studies reviewed showed an association between omeprazole use and intestinal metaplasia or its progression to gastric adenocarcinoma.1 Three other nonsystematic reviews support these findings.2,3,5 The available evidence indicates that PPI use is not clearly associated with atrophic gastritis, or with progression from gastritis to metaplasia or cancer.
Enteric infections. Because hypochlorhydria is associated with bacterial enteric infections, bacterial enteritis is a theoretical risk of long-term PPI use. A large case-control study of 54,461 patients using omeprazole for 1 year showed no association with such infections.6
Mineral malabsorption. Dietary calcium, phosphorus, magnesium, zinc, and iron depend on gastric acid for absorption. Two separate non-systematic reviews showed no problems with malabsorption of these micronutrients.1,3
B12 malabsorption. Two nonsystematic reviews showed a decrease in vitamin B12 absorption among patients on high-dose (up to 80 mg of omeprazole daily), long-term PPI therapy (eg, patients with Zollinger-Ellison syndrome).1,2 This has not been demonstrated for patients taking more typical doses of omeprazole. The clinical significance of this is unknown; however, the authors of these reviews suggested monitoring B12 levels of patients on long-term, high-dose PPI therapy.
TABLE
Potential proton pump inhibitor safety concerns
| Safety concern | PPI studied | Duration of studies | Evidence |
|---|---|---|---|
| Gastric carcinoids | Omeprazole, lansoprazole, pantoprazole, rabeprazole | 1–8 years | No increased risk1-5 |
| Gastric metaplasia/adenocarcinoma | Omeprazole | 1–5 years | No increased risk1-3,5 |
| Enteric infections | Omeprazole | 1 year | No increased risk6 |
| Mineral malabsorption | Omeprazole | 6 months–2 years | No increased risk1,3 |
| B12 malabsorption | Omeprazole | 10 years | Decreased B12 levels with high-dose therapy1,2 |
Recommendations from others
A Federal Drug Commission report indicates that labeling PPIs for cancer risk is not warranted.7 The American College of Gastroenterology and the University of Michigan Health System guidelines for treatment of gastroesophageal disease recommend long-term PPI therapy as an option without any warning against their use.8,9
No evidence of long-term adverse health effects from PPIs, but cost still a problem
Richard A. Guthmann, MD
Illinois Masonic Family Practice Residency, University of Illinois at Chicago
Proton pump inhibitors work. They effectively treat the symptoms and reduce the complication involved with peptic ulcer disease. The lack of evidence suggesting any long-term adverse health effects, even if not definitive, is very encouraging, but the cost of these medicines remains a problem. Both patients and third-party payers continue to object to their cost, and for this reason, as well as longer safety track records, less expensive medicines such as H2 blockers and over-the-counter antacids should be tried for longer-term treatment.
Long-term use of proton pump inhibitors (PPIs) appears safe, resulting in no clinically relevant adverse effects (strength of recommendation: B, based on nonsystematic reviews, cohort studies, or low-quality randomized controlled trials). No evidence clearly links PPIs to gastric cancer or carcinoid, enteric infections, or significant nutrient malabsorption.
Evidence summary
The long-term safety of PPIs is not completely known. There are 5 PPIs on the US market. Clinical experience with these medications ranges from 3 to 20 years. All of the identified studies addressing long-term use have follow-up of 10 years or less (Table). Studies of longer duration are warranted. We reviewed the possible adverse effects of these medications.
Gastric carcinoid. PPIs cause predictable and sustained hypergastrinemia in response to acid suppression. In rats, this causes enterochro-maffin-like cell (ECL) hyperplasia and carcinoid tumors, raising a safety concern in humans. In a nonsystematic review of 11 studies of 1800 patients who used PPIs from 6 months to 8 years, there were no neoplastic ECL changes or carcinoid tumors.1 Three other nonsystematic reviews support these findings.2-4 In a randomized controlled trial comparing efficacy and safety of rabeprazole with omeprazole for gastro-esophageal disease, 123 (51%) out of 243 patients completed 5 years of the study; no patients had neoplastic ECL changes.5
Atrophic gastritis and gastric cancer. Atrophic gastritis with intestinal metaplasia is associated with gastric adenocarcinoma. Because PPIs can theoretically cause atrophic gastritis, there is a concern that this could lead to gastric cancer. The evidence regarding atrophic gastritis is contradictory. A nonsystematic review identified 1 cohort study and 1 randomized controlled trial of patients taking omeprazole from 1 to 4 years, which showed no association between PPI use and atrophic gastritis.1 The same review reported that another cohort study of patients using omeprazole for 1 year showed an increase in atrophic gastritis. None of the studies reviewed showed an association between omeprazole use and intestinal metaplasia or its progression to gastric adenocarcinoma.1 Three other nonsystematic reviews support these findings.2,3,5 The available evidence indicates that PPI use is not clearly associated with atrophic gastritis, or with progression from gastritis to metaplasia or cancer.
Enteric infections. Because hypochlorhydria is associated with bacterial enteric infections, bacterial enteritis is a theoretical risk of long-term PPI use. A large case-control study of 54,461 patients using omeprazole for 1 year showed no association with such infections.6
Mineral malabsorption. Dietary calcium, phosphorus, magnesium, zinc, and iron depend on gastric acid for absorption. Two separate non-systematic reviews showed no problems with malabsorption of these micronutrients.1,3
B12 malabsorption. Two nonsystematic reviews showed a decrease in vitamin B12 absorption among patients on high-dose (up to 80 mg of omeprazole daily), long-term PPI therapy (eg, patients with Zollinger-Ellison syndrome).1,2 This has not been demonstrated for patients taking more typical doses of omeprazole. The clinical significance of this is unknown; however, the authors of these reviews suggested monitoring B12 levels of patients on long-term, high-dose PPI therapy.
TABLE
Potential proton pump inhibitor safety concerns
| Safety concern | PPI studied | Duration of studies | Evidence |
|---|---|---|---|
| Gastric carcinoids | Omeprazole, lansoprazole, pantoprazole, rabeprazole | 1–8 years | No increased risk1-5 |
| Gastric metaplasia/adenocarcinoma | Omeprazole | 1–5 years | No increased risk1-3,5 |
| Enteric infections | Omeprazole | 1 year | No increased risk6 |
| Mineral malabsorption | Omeprazole | 6 months–2 years | No increased risk1,3 |
| B12 malabsorption | Omeprazole | 10 years | Decreased B12 levels with high-dose therapy1,2 |
Recommendations from others
A Federal Drug Commission report indicates that labeling PPIs for cancer risk is not warranted.7 The American College of Gastroenterology and the University of Michigan Health System guidelines for treatment of gastroesophageal disease recommend long-term PPI therapy as an option without any warning against their use.8,9
No evidence of long-term adverse health effects from PPIs, but cost still a problem
Richard A. Guthmann, MD
Illinois Masonic Family Practice Residency, University of Illinois at Chicago
Proton pump inhibitors work. They effectively treat the symptoms and reduce the complication involved with peptic ulcer disease. The lack of evidence suggesting any long-term adverse health effects, even if not definitive, is very encouraging, but the cost of these medicines remains a problem. Both patients and third-party payers continue to object to their cost, and for this reason, as well as longer safety track records, less expensive medicines such as H2 blockers and over-the-counter antacids should be tried for longer-term treatment.
1. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000;14:651-668.
2. Garnett WR. Considerations for long-term use of protonpump inhibitors. Am J Health Syst Pharm 1998;55:2268-2279.
3. Freston JW. Long-term acid control and proton pump inhibitors: interactions and safety issues in perspective. Am J Gastroenterol 1997;92(4 Suppl):51S-57S.
4. Freston JW, Rose PA, Heller CA, Haber M, Jennings D. Safety profile of Lansoprazole: the US clinical trial experience. Drug Saf 1999;20:195-205.
5. Thjodleifsson B, Rindi G, Fiocca R, et al. A randomized double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years. Aliment Pharmacol Ther 2003;17:343-351.
6. Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid-sup-pressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology 1997;8:571-574.
7. Proton pump inhibitor relabeling for cancer risk not warranted; long-term studies recommended. FDC Rep 1996;58(Nov 11)T&G:1-2.
8. Management of gastroesophageal reflux disease (GERD). Ann Arbor, Mich: University of Michigan Health System; last updated 2002 March. Available at: cme.med.umich.edu/iCME/gerd/default.asp. Accessed on March 16, 2004.
9. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1999;94:1434-1442.
1. Laine L, Ahnen D, McClain C, Solcia E, Walsh JH. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2000;14:651-668.
2. Garnett WR. Considerations for long-term use of protonpump inhibitors. Am J Health Syst Pharm 1998;55:2268-2279.
3. Freston JW. Long-term acid control and proton pump inhibitors: interactions and safety issues in perspective. Am J Gastroenterol 1997;92(4 Suppl):51S-57S.
4. Freston JW, Rose PA, Heller CA, Haber M, Jennings D. Safety profile of Lansoprazole: the US clinical trial experience. Drug Saf 1999;20:195-205.
5. Thjodleifsson B, Rindi G, Fiocca R, et al. A randomized double-blind trial of the efficacy and safety of 10 or 20 mg rabeprazole compared with 20 mg omeprazole in the maintenance of gastro-oesophageal reflux disease over 5 years. Aliment Pharmacol Ther 2003;17:343-351.
6. Garcia Rodriguez LA, Ruigomez A. Gastric acid, acid-sup-pressing drugs, and bacterial gastroenteritis: how much of a risk? Epidemiology 1997;8:571-574.
7. Proton pump inhibitor relabeling for cancer risk not warranted; long-term studies recommended. FDC Rep 1996;58(Nov 11)T&G:1-2.
8. Management of gastroesophageal reflux disease (GERD). Ann Arbor, Mich: University of Michigan Health System; last updated 2002 March. Available at: cme.med.umich.edu/iCME/gerd/default.asp. Accessed on March 16, 2004.
9. DeVault KR, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. The Practice Parameters Committee of the American College of Gastroenterology. Am J Gastroenterol 1999;94:1434-1442.
Evidence-based answers from the Family Physicians Inquiries Network
What medication best prevents migraine in children?
Propranolol, valproic acid, and amitriptyline are effective prophylaxis for migraine in children to varying degrees, are widely available, and have a reasonable safety profile (strength of recommendation [SOR]: B, based on either single randomized controlled trial, prospective or retrospective cohort studies, or trials with conflicting evidence).
Flunarizine and nimodipine have the best evidence of benefit in children; however, availability, cost, and side effects limit their usefulness (SOR: B, based on multiple small randomized controlled trials).
Evidence summary
Amitryptyline was moderately efficacious in 3 small nonblinded trials.1,2 The largest and best-designed prospective cohort trial studied 192 children. Of the 146 patients available for the first follow-up visit, 84% noted subjective improvement of symptoms. Headache frequency decreased from 17.1 ± 10.1 to 9.2 ± 10.0 days/month (P<.001).1
Propranolol, although widely used in children, has conflicting evidence regarding effectiveness. One small randomized controlled trial showed reduced headache frequency in children when compared with placebo.3 However, these results were not duplicated in a larger randomized controlled trial using slightly smaller doses.4
A comparative randomized controlled trial with multiple crossovers involving 33 children found that a self-hypnosis placebo decreased mean headache frequency from 13.3 per 3-month interval to 5.8 (P=.045), but found propranolol no different than placebo.5 Propranolol was also studied in a 3-armed randomized controlled trial in comparison with flunarizine—a drug likely to be efficacious—and placebo. Both drugs were equally efficacious and superior to placebo according to reviews; however, these results were not published in English and could not be critiqued by this author.2
In 2 small retrospective case studies, valproic acid demonstrated >50% improvement in symptoms in 65%6 and 78%7 of subjects. A single uncontrolled interventional trial of valproic acid in 10 children showed a significant trend of improvement in frequency (mean of 6 attacks/month to 0.8 attacks/month) and duration (mean 5.5 hours per attack to 1.1 hour).8
Two similar vasodilatory calcium channel blockers, flunarizine and nimodipine, have the best evidence as migraine prophylactics in children. Flunarizine was found to be effective in multiple well-designed randomized controlled trials and case series, as well as in multiple comparative trials with other agents.2
In a double-blinded, placebo-controlled randomized controlled trial of 48 children, flunarizine decreased mean headache frequency (3.0 attacks/3 months vs 6.5 [P<.001]).9 A repeat randomized controlled trial in 70 children had similar outcomes.10
Nimodipine, in a single randomized controlled trial with crossover design in 37 children decreased headache frequency from a mean of ~2.7 attacks/month to ~1.9 vs. no change for placebo (P<.05).11 A small, prospective, nonblinded comparative trial found that nimodipine and flunarizine have similar efficacy and are superior to placebo.12
Cyproheptadine is widely used in children but is not as effective as amitriptyline and propranolol.2 In adults it is not considered a first-line agent due to lack of evidence of efficacy.13 Nonsteroidal anti-inflammatory drugs have insufficient data to recommend them as prophylactic medications in children.2
RECOMMENDATIONS FROM OTHERS
Nelson Textbook of Pediatrics recommends propranolol as a first-line agent for prevention.14
A recent review article15 recommends cyproheptadine as an initial agent in children <10 years of age. This article also has a patient handout discussing nonpharmacologic prophylactics such as regular sleep, exercise, stress reduction, and avoiding certain foods.
UpToDate recommends propranolol, cyproheptadine, valproate, and amitriptyline as prophylactic options based on patient parameters such as age, sex, and comorbid conditions.16
Propranolol has fewest side effects
Ra Nae Stanton, MD
Southern Illinois University, Carbondale; Quincy Family Practice Residency, Quincy, Ill
Migraines in children are not as well studied as the same problem in adults. I like to stick with older medications known to have fewer side effects. Propranolol is my first choice for any age, since it has been well studied and has very few side effects. Amitriptyline would be second because it is well known, but it does have a sedating effect. If both of these fail to control the migraines, I would consider calcium channel blockers, which are newer in the prevention of migraines.
1. Hershey AD, Powers SW, Vockell AL, et al. Effectiveness of amitriptyline in the prophylactic management of childhood headaches. Headache 2000;40:539-549.
2. Evers S. Drug treatment of migraine in children. Paediatr Drugs 1999;1:7-18.
3. Ludvigsson J. Propranolol used in prophylaxis of migraine in children. Acta Neurol Scand 1974;50:109-115.
4. Forsythe W, Gillies D, Sills M. Propranolol (‘Inderal’) in the treatment of childhood migraine. Dev Med Child Neurol 1984;26:737-741.
5. Olness K, MacDonald JT, Uden DL. Comparison of self-hypnosis and propranolol in the treatment of juvenile classic migraine. Pediatrics 1987;79:593-597.
6. Pakalnis A, Greenburg G, Drake ME, Jr, Paolichi J. Pediatric migraine prophylaxis with divalproex. J Child Neurol 2001;16:731-734.
7. Caruso JM, Brown WD, Exil G, Gascon GG. The efficacy of divalproex sodium in the prophylactic treatment of children with migraine. Headache 2000;40:672-676.
8. Serdaroglu G, Erhan E, Tekgul H, et al. Sodium valproate prophylaxis in childhood migraine. Headache 2002;42:819-822.
9. Sorge F, Marano E, Flunarizine v. placebo in childhood migraine. A double-blind study. Cephalagia. 1985;5(suppl 2):145-148.
10. Sorge F, De Simone R, Marano E, Nolana M, Orefice G, Carrieri P. Flunarizine in prophylaxis of childhood migraine. A double-blind, placebo-controlled, crossover study. Cephalagia 1988;8:1-6.
11. Battistella PA, Ruffilli R, Moro R, et al. A placebo-controlled crossover trial of nimodipine in pediatric migraine. Headache 1990;30:264-268.
12. Castellana M, Carini U, Capirci G, Mazzocchi B. Calcium entry blockers in the treatment of primary headache in children: our experience with flunarizine and nimodipine. In: Lanzi G, Balottin U, Cernibori A, eds. Headache in children and adolescents. Amsterdam: Elsevier; 1989;349-352.
13. Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. American College of Neurology, April 2000. Available at: www.aan.com/professionals/practice/pdfs/gl0090.pdf. Accessed on August 7, 2003.
14. Behrman RE, Kliegman R, Jenson HB. Nelson Textbook of Pediatrics. 16th ed. Philadelphia: W.B. Saunders; 2000;16:1832-1834.
15. Lewis DW. Headaches in children and adolescents. Am Fam Physician 2002;65:625-632.
16. Cruse, RP. Management of migraine headache in children. UpToDate. Last update October 15, 2002. Available at: www.uptodate.com. Accessed on July 22, 2003.
Propranolol, valproic acid, and amitriptyline are effective prophylaxis for migraine in children to varying degrees, are widely available, and have a reasonable safety profile (strength of recommendation [SOR]: B, based on either single randomized controlled trial, prospective or retrospective cohort studies, or trials with conflicting evidence).
Flunarizine and nimodipine have the best evidence of benefit in children; however, availability, cost, and side effects limit their usefulness (SOR: B, based on multiple small randomized controlled trials).
Evidence summary
Amitryptyline was moderately efficacious in 3 small nonblinded trials.1,2 The largest and best-designed prospective cohort trial studied 192 children. Of the 146 patients available for the first follow-up visit, 84% noted subjective improvement of symptoms. Headache frequency decreased from 17.1 ± 10.1 to 9.2 ± 10.0 days/month (P<.001).1
Propranolol, although widely used in children, has conflicting evidence regarding effectiveness. One small randomized controlled trial showed reduced headache frequency in children when compared with placebo.3 However, these results were not duplicated in a larger randomized controlled trial using slightly smaller doses.4
A comparative randomized controlled trial with multiple crossovers involving 33 children found that a self-hypnosis placebo decreased mean headache frequency from 13.3 per 3-month interval to 5.8 (P=.045), but found propranolol no different than placebo.5 Propranolol was also studied in a 3-armed randomized controlled trial in comparison with flunarizine—a drug likely to be efficacious—and placebo. Both drugs were equally efficacious and superior to placebo according to reviews; however, these results were not published in English and could not be critiqued by this author.2
In 2 small retrospective case studies, valproic acid demonstrated >50% improvement in symptoms in 65%6 and 78%7 of subjects. A single uncontrolled interventional trial of valproic acid in 10 children showed a significant trend of improvement in frequency (mean of 6 attacks/month to 0.8 attacks/month) and duration (mean 5.5 hours per attack to 1.1 hour).8
Two similar vasodilatory calcium channel blockers, flunarizine and nimodipine, have the best evidence as migraine prophylactics in children. Flunarizine was found to be effective in multiple well-designed randomized controlled trials and case series, as well as in multiple comparative trials with other agents.2
In a double-blinded, placebo-controlled randomized controlled trial of 48 children, flunarizine decreased mean headache frequency (3.0 attacks/3 months vs 6.5 [P<.001]).9 A repeat randomized controlled trial in 70 children had similar outcomes.10
Nimodipine, in a single randomized controlled trial with crossover design in 37 children decreased headache frequency from a mean of ~2.7 attacks/month to ~1.9 vs. no change for placebo (P<.05).11 A small, prospective, nonblinded comparative trial found that nimodipine and flunarizine have similar efficacy and are superior to placebo.12
Cyproheptadine is widely used in children but is not as effective as amitriptyline and propranolol.2 In adults it is not considered a first-line agent due to lack of evidence of efficacy.13 Nonsteroidal anti-inflammatory drugs have insufficient data to recommend them as prophylactic medications in children.2
RECOMMENDATIONS FROM OTHERS
Nelson Textbook of Pediatrics recommends propranolol as a first-line agent for prevention.14
A recent review article15 recommends cyproheptadine as an initial agent in children <10 years of age. This article also has a patient handout discussing nonpharmacologic prophylactics such as regular sleep, exercise, stress reduction, and avoiding certain foods.
UpToDate recommends propranolol, cyproheptadine, valproate, and amitriptyline as prophylactic options based on patient parameters such as age, sex, and comorbid conditions.16
Propranolol has fewest side effects
Ra Nae Stanton, MD
Southern Illinois University, Carbondale; Quincy Family Practice Residency, Quincy, Ill
Migraines in children are not as well studied as the same problem in adults. I like to stick with older medications known to have fewer side effects. Propranolol is my first choice for any age, since it has been well studied and has very few side effects. Amitriptyline would be second because it is well known, but it does have a sedating effect. If both of these fail to control the migraines, I would consider calcium channel blockers, which are newer in the prevention of migraines.
Propranolol, valproic acid, and amitriptyline are effective prophylaxis for migraine in children to varying degrees, are widely available, and have a reasonable safety profile (strength of recommendation [SOR]: B, based on either single randomized controlled trial, prospective or retrospective cohort studies, or trials with conflicting evidence).
Flunarizine and nimodipine have the best evidence of benefit in children; however, availability, cost, and side effects limit their usefulness (SOR: B, based on multiple small randomized controlled trials).
Evidence summary
Amitryptyline was moderately efficacious in 3 small nonblinded trials.1,2 The largest and best-designed prospective cohort trial studied 192 children. Of the 146 patients available for the first follow-up visit, 84% noted subjective improvement of symptoms. Headache frequency decreased from 17.1 ± 10.1 to 9.2 ± 10.0 days/month (P<.001).1
Propranolol, although widely used in children, has conflicting evidence regarding effectiveness. One small randomized controlled trial showed reduced headache frequency in children when compared with placebo.3 However, these results were not duplicated in a larger randomized controlled trial using slightly smaller doses.4
A comparative randomized controlled trial with multiple crossovers involving 33 children found that a self-hypnosis placebo decreased mean headache frequency from 13.3 per 3-month interval to 5.8 (P=.045), but found propranolol no different than placebo.5 Propranolol was also studied in a 3-armed randomized controlled trial in comparison with flunarizine—a drug likely to be efficacious—and placebo. Both drugs were equally efficacious and superior to placebo according to reviews; however, these results were not published in English and could not be critiqued by this author.2
In 2 small retrospective case studies, valproic acid demonstrated >50% improvement in symptoms in 65%6 and 78%7 of subjects. A single uncontrolled interventional trial of valproic acid in 10 children showed a significant trend of improvement in frequency (mean of 6 attacks/month to 0.8 attacks/month) and duration (mean 5.5 hours per attack to 1.1 hour).8
Two similar vasodilatory calcium channel blockers, flunarizine and nimodipine, have the best evidence as migraine prophylactics in children. Flunarizine was found to be effective in multiple well-designed randomized controlled trials and case series, as well as in multiple comparative trials with other agents.2
In a double-blinded, placebo-controlled randomized controlled trial of 48 children, flunarizine decreased mean headache frequency (3.0 attacks/3 months vs 6.5 [P<.001]).9 A repeat randomized controlled trial in 70 children had similar outcomes.10
Nimodipine, in a single randomized controlled trial with crossover design in 37 children decreased headache frequency from a mean of ~2.7 attacks/month to ~1.9 vs. no change for placebo (P<.05).11 A small, prospective, nonblinded comparative trial found that nimodipine and flunarizine have similar efficacy and are superior to placebo.12
Cyproheptadine is widely used in children but is not as effective as amitriptyline and propranolol.2 In adults it is not considered a first-line agent due to lack of evidence of efficacy.13 Nonsteroidal anti-inflammatory drugs have insufficient data to recommend them as prophylactic medications in children.2
RECOMMENDATIONS FROM OTHERS
Nelson Textbook of Pediatrics recommends propranolol as a first-line agent for prevention.14
A recent review article15 recommends cyproheptadine as an initial agent in children <10 years of age. This article also has a patient handout discussing nonpharmacologic prophylactics such as regular sleep, exercise, stress reduction, and avoiding certain foods.
UpToDate recommends propranolol, cyproheptadine, valproate, and amitriptyline as prophylactic options based on patient parameters such as age, sex, and comorbid conditions.16
Propranolol has fewest side effects
Ra Nae Stanton, MD
Southern Illinois University, Carbondale; Quincy Family Practice Residency, Quincy, Ill
Migraines in children are not as well studied as the same problem in adults. I like to stick with older medications known to have fewer side effects. Propranolol is my first choice for any age, since it has been well studied and has very few side effects. Amitriptyline would be second because it is well known, but it does have a sedating effect. If both of these fail to control the migraines, I would consider calcium channel blockers, which are newer in the prevention of migraines.
1. Hershey AD, Powers SW, Vockell AL, et al. Effectiveness of amitriptyline in the prophylactic management of childhood headaches. Headache 2000;40:539-549.
2. Evers S. Drug treatment of migraine in children. Paediatr Drugs 1999;1:7-18.
3. Ludvigsson J. Propranolol used in prophylaxis of migraine in children. Acta Neurol Scand 1974;50:109-115.
4. Forsythe W, Gillies D, Sills M. Propranolol (‘Inderal’) in the treatment of childhood migraine. Dev Med Child Neurol 1984;26:737-741.
5. Olness K, MacDonald JT, Uden DL. Comparison of self-hypnosis and propranolol in the treatment of juvenile classic migraine. Pediatrics 1987;79:593-597.
6. Pakalnis A, Greenburg G, Drake ME, Jr, Paolichi J. Pediatric migraine prophylaxis with divalproex. J Child Neurol 2001;16:731-734.
7. Caruso JM, Brown WD, Exil G, Gascon GG. The efficacy of divalproex sodium in the prophylactic treatment of children with migraine. Headache 2000;40:672-676.
8. Serdaroglu G, Erhan E, Tekgul H, et al. Sodium valproate prophylaxis in childhood migraine. Headache 2002;42:819-822.
9. Sorge F, Marano E, Flunarizine v. placebo in childhood migraine. A double-blind study. Cephalagia. 1985;5(suppl 2):145-148.
10. Sorge F, De Simone R, Marano E, Nolana M, Orefice G, Carrieri P. Flunarizine in prophylaxis of childhood migraine. A double-blind, placebo-controlled, crossover study. Cephalagia 1988;8:1-6.
11. Battistella PA, Ruffilli R, Moro R, et al. A placebo-controlled crossover trial of nimodipine in pediatric migraine. Headache 1990;30:264-268.
12. Castellana M, Carini U, Capirci G, Mazzocchi B. Calcium entry blockers in the treatment of primary headache in children: our experience with flunarizine and nimodipine. In: Lanzi G, Balottin U, Cernibori A, eds. Headache in children and adolescents. Amsterdam: Elsevier; 1989;349-352.
13. Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. American College of Neurology, April 2000. Available at: www.aan.com/professionals/practice/pdfs/gl0090.pdf. Accessed on August 7, 2003.
14. Behrman RE, Kliegman R, Jenson HB. Nelson Textbook of Pediatrics. 16th ed. Philadelphia: W.B. Saunders; 2000;16:1832-1834.
15. Lewis DW. Headaches in children and adolescents. Am Fam Physician 2002;65:625-632.
16. Cruse, RP. Management of migraine headache in children. UpToDate. Last update October 15, 2002. Available at: www.uptodate.com. Accessed on July 22, 2003.
1. Hershey AD, Powers SW, Vockell AL, et al. Effectiveness of amitriptyline in the prophylactic management of childhood headaches. Headache 2000;40:539-549.
2. Evers S. Drug treatment of migraine in children. Paediatr Drugs 1999;1:7-18.
3. Ludvigsson J. Propranolol used in prophylaxis of migraine in children. Acta Neurol Scand 1974;50:109-115.
4. Forsythe W, Gillies D, Sills M. Propranolol (‘Inderal’) in the treatment of childhood migraine. Dev Med Child Neurol 1984;26:737-741.
5. Olness K, MacDonald JT, Uden DL. Comparison of self-hypnosis and propranolol in the treatment of juvenile classic migraine. Pediatrics 1987;79:593-597.
6. Pakalnis A, Greenburg G, Drake ME, Jr, Paolichi J. Pediatric migraine prophylaxis with divalproex. J Child Neurol 2001;16:731-734.
7. Caruso JM, Brown WD, Exil G, Gascon GG. The efficacy of divalproex sodium in the prophylactic treatment of children with migraine. Headache 2000;40:672-676.
8. Serdaroglu G, Erhan E, Tekgul H, et al. Sodium valproate prophylaxis in childhood migraine. Headache 2002;42:819-822.
9. Sorge F, Marano E, Flunarizine v. placebo in childhood migraine. A double-blind study. Cephalagia. 1985;5(suppl 2):145-148.
10. Sorge F, De Simone R, Marano E, Nolana M, Orefice G, Carrieri P. Flunarizine in prophylaxis of childhood migraine. A double-blind, placebo-controlled, crossover study. Cephalagia 1988;8:1-6.
11. Battistella PA, Ruffilli R, Moro R, et al. A placebo-controlled crossover trial of nimodipine in pediatric migraine. Headache 1990;30:264-268.
12. Castellana M, Carini U, Capirci G, Mazzocchi B. Calcium entry blockers in the treatment of primary headache in children: our experience with flunarizine and nimodipine. In: Lanzi G, Balottin U, Cernibori A, eds. Headache in children and adolescents. Amsterdam: Elsevier; 1989;349-352.
13. Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine. American College of Neurology, April 2000. Available at: www.aan.com/professionals/practice/pdfs/gl0090.pdf. Accessed on August 7, 2003.
14. Behrman RE, Kliegman R, Jenson HB. Nelson Textbook of Pediatrics. 16th ed. Philadelphia: W.B. Saunders; 2000;16:1832-1834.
15. Lewis DW. Headaches in children and adolescents. Am Fam Physician 2002;65:625-632.
16. Cruse, RP. Management of migraine headache in children. UpToDate. Last update October 15, 2002. Available at: www.uptodate.com. Accessed on July 22, 2003.
Evidence-based answers from the Family Physicians Inquiries Network