A Randomized, Double-Blind, Placebo-Controlled Study of Sumatriptan Nasal Spray in the Treatment of Acute Migraine in Adolescents
Objective. To compare the efficacy and tolerability of sumatriptan nasal spray (NS; 5 mg, 10 mg, and 20 mg) with placebo for the treatment of acute migraine in adolescents.
Methods. A randomized, double-blind, placebo-controlled, single-attack study was conducted in 653 US adolescents (12–17 years of age). Patients with at least a 6-month history of migraine, who met International Headache Society criteria for migraine (with or without aura) were eligible for participation. Headache relief 2 hours postdose, complete relief, presence or absence of associated symptoms, headache recurrence, and use of rescue medications were recorded. The primary efficacy endpoint was headache relief 2 hours postdose sumatriptan NS (20 mg) versus placebo. Safety and tolerability were assessed by examining adverse events, changes in electrocardiograms, vital signs, physical examinations, and clinical laboratory tests.
Results. Headache relief 1 hour postdose was significantly greater for patients using 10 mg (56%) and 20 mg (56%) of sumatriptan NS compared with placebo (41%). Headache relief 2 hours postdose was significantly greater for patients using 5 mg of sumatriptan NS (66%) compared with placebo (53%), and approached statistical significance for 20 mg (63%) compared with placebo (53%). Complete relief 2 hours postdose was significantly greater for patients using 20 mg of sumatriptan NS compared with placebo (36% vs 25%, respectively). Each dose of sumatriptan (5 mg, 10 mg, and 20 mg) was superior to placebo with respect to the cumulative percentages of patients first reporting headache relief within 2 hours of dosing (Kaplan-Meier). The sumatriptan 20-mg dose was superior to placebo with respect to the cumulative percentages of patients first reporting complete relief within 2 hours of dosing (Kaplan-Meier). Photophobia and phonophobia were significantly reduced 2 hours postdose for sumatriptan NS (20 mg), compared with placebo (36% vs 48% and 25% vs 44%, respectively). Taste disturbance was the most commonly reported adverse event (2%, 19%, 30%, and 26% for placebo, 5 mg, 10 mg, and 20 mg, respectively). No drug-related serious adverse events or clinically relevant changes in laboratory parameters, electrocardiograms, or vital signs were reported.
Conclusions. Sumatriptan NS is effective and well-tolerated for the treatment of acute migraine in adolescents, with the 20-mg dose providing the best overall efficacy and tolerability profiles.
- IHS =
- International Headache Society •
- NS =
- nasal spray •
- ECG =
- electrocardiogram •
- HR =
- headache recurrence
Migraine is a common cause of headache among children and adolescents, occurring in 4% to 10% of all school-aged children, when International Headache Society (IHS)1 criteria for diagnosis are applied.2–5 The prevalence of migraine in children increases proportionately with age, and ranges from ∼3%5–7 between 3 and 8 years of age to as high as 19% at the beginning of adolescence.5 Migraine occurs in equal proportions of males and females before puberty, but becomes predominately female (3:1) after puberty.3 Migraine is believed by many to have a genetic component attributable to its early onset in life and associated familial history. Scientists have mapped a genetic locus to a specific chromosome in some migraine patients; however, other scientists have proposed linkage to alternate chromosomal regions.8,9
Many criteria have been used to diagnose migraine in childhood and suggested modifications to the pediatric IHS guidelines may increase diagnostic sensitivity and specificity to more appropriately identify children and adolescents for treatment.10,11 Typically, the clinical presentation of migraine in adolescents is similar to that of adults. However, adolescent migraine pain is most often bilateral, frontal, and pulsatile with associated symptoms, such as nausea, vomiting, photophobia, or phonophobia. On average, adolescents experience shorter migraine attacks ranging from 1 to 48 hours of duration compared with an average range of 4 to 72 hours in adults.12
The impact of migraine on children and adolescents is underappreciated and extends beyond the disability associated with the migraine attack. One study demonstrated that school-aged migraineurs lost 2.8 school days per year attributable to migraine, as well as significantly more school days for other illnesses compared with non-migraineurs.5 Migraine may impair school performance through increased absenteeism, as well as reduced work productivity.13 Adolescent migraine may affect interpersonal development at a critical time by restricting sport, work, recreation, and family activities. Rapid and effective medications for the treatment of adolescent migraine would be invaluable to adolescent migraineurs and their families.
No medications, including those that provide headache relief in adults, have been proven effective in pivotal and well-controlled adolescent migraine clinical trials. The results of 2 open-label studies14,15 suggest that subcutaneous sumatriptan (Imitrex, Glaxo Wellcome Inc, Research Triangle Park, NC), a 5HT1 agonist that is available in multiple formulations, was effective in alleviating headache in migraineurs 6 to 16 years of age. Dosing varied in these studies: the first used the adult-approved dose of Imitrex (6 mg)14 and the second used a dose based on body weight (.06 mg/kg).15Currently, sumatriptan has not been approved for adolescents in any formulation. Appropriate dosages and adverse event profiles have not been identified by the Food and Drug Administration or by any other regulatory agency.
Sumatriptan nasal spray (NS) is effective in adults with rapid-onset migraine and associated symptoms.16–19 A small placebo-controlled study conducted in migraineurs <10 years of age recently demonstrated that sumatriptan NS (20 mg) provided significantly more headache relief 2 hours postdose compared with placebo, with disturbance of taste as the only adverse event.20 Sumatriptan NS has not been evaluated previously in a large-scale, placebo-controlled clinical trial involving adolescents. We present the results of the first large-scale, randomized, double-blind, placebo-controlled trial of sumatriptan NS (5 mg, 10 mg, and 20 mg) to evaluate its efficacy and tolerability in the treatment of acute migraine in adolescents.
This was a randomized, double-blind, placebo-controlled, single-attack, parallel-group study conducted in an outpatient setting to evaluate the efficacy and tolerability of sumatriptan NS (5 mg, 10 mg, and 20 mg) for the treatment of acute migraine in adolescents (protocol: SUMA3005).
Males and females 12 to 17 years of age with a diagnosis of migraine (with or without aura) meeting IHS1 criteria (1.1 and 1.2) and with at least a 6-month history of moderate or severe attacks were eligible for study participation. Patients were required to have a history of 2 to 8 moderate or severe migraine attacks per month for each of the 2 months preceding study enrollment, with a typical migraine duration of 4 or more hours. Patients were required to have ≤15 days of tension headache per month and were required to have failed at least 1 previous over-the-counter or prescription medication for the treatment of migraine.
Patients were excluded from the study if they had a history of congenital heart disease; confirmed or suspected cardiovascular disease; Prinzmetal's angina; systemic lupus erythematosus; Kawasaki disease; homozygous sickle cell anemia; recurrent syncope; cardiac arrhythmias requiring medication; atherosclerotic disease; history of cerebrovascular pathology including stroke, hypertension for age, Raynaud's syndrome, impaired hepatic, or renal function; or evidence of alcohol, drug, or substance abuse within the previous year. Females were excluded if they were pregnant, breastfeeding, or sexually active and not using adequate contraceptive measures.
Patients could not use ergotamine-containing drugs or derivatives or any other 5HT1 agonist within 24 hours before or after treatment with study medication. Opiates, simple analgesics, and antiemetic medications could not be used within 6 hours before or 2 hours after use of study medication. Monoamine oxidase inhibitors could not be used for a minimum of 2 weeks before screening and throughout the course of the study. Selective serotonin reuptake inhibitors could not be used from screening through study exit.
Forty-six US sites received institutional review board approval and enrolled patients in the study. Patients and their parents or legal guardians provided written informed consent before study enrollment.
Patients were screened in a clinic in a migraine-free state, where they provided medical and migraine histories and received a complete physical examination and assessment of vital signs, clinical laboratory tests, serum pregnancy tests (females), and a 12-lead electrocardiogram (ECG). Patients who met inclusion criteria received training in the use of the NS device, study procedures, and the patient diary. Patients were instructed that all treatment criteria must have been met before use of the study drug and were encouraged to call a toll-free telephone service that advised them regarding study medication use based on their pretreatment symptoms. Patients were contacted by study personnel approximately every 2 weeks regarding compliance with enrollment criteria, use of birth control, pregnancy status, concurrent medication use, and study procedures. Patients who had not treated a migraine attack within 4 months of randomization returned to the clinic for retraining and for reevaluation of study eligibility.
Patients were randomized after successful screening using a computer-generated, parallel design, 1:1:1:1 ratio (block size of 8) to receive single doses of sumatriptan NS (5 mg, 10 mg, and 20 mg) or identically appearing placebo NS. The allocation schedule was concealed in tamper-evident, blinded envelopes kept by the sponsor. Patients self-administered 1 dose at home, in the presence of a parent or legal guardian, to treat a moderate or severe migraine attack. Patients recorded the time of onset of migraine pain and the time of medication administration. Time to treatment was measured as the difference between those 2 time points. A second identical NS dose could be used 2 to 24 hours after the initial dose of study medication. All patients completed an exit visit typically within 2 to 10 days after treatment, during which patients were queried regarding adverse events and pregnancy status (females).
Headache pain was patient-rated using a 4-point pain scale (0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe pain) and recorded at baseline (predose) and at 15, 30, 60, and 120 minutes postdose. Headache relief was defined as a reduction in predose headache pain severity from moderate or severe to mild or no pain (pain scale of 2 or 3 reduced to 1 or 0). Complete relief was defined as a reduction from moderate or severe predose pain to no pain (pain scale of 2 or 3 reduced to 0). The primary efficacy endpoint was headache relief 2 hours postdose: sumatriptan NS (20 mg) versus placebo. Secondary efficacy parameters included headache relief and complete relief for the remaining sumatriptan doses and the 20-mg dose at 15, 30, 60, 90, and 120 minutes postdose versus placebo.
The presence or absence of nausea, vomiting, photophobia, and phonophobia was reported at baseline and 15, 30, 60, and 120 minutes after administration of study medication.
Headache Recurrence (HR)/Rescue Medication Use
HR was defined as significant worsening of pain (from no or mild to moderate or severe) 2 to 24 hours postdose, after having achieved headache relief 2 hours postdose. Use of a second dose of study drug or use of rescue medication 2 to 24 hours after the initial dose of study medication was recorded.
Safety was assessed using standard migraine methodology.21–24 Overall safety assessments included the incidence of adverse events, abnormalities in physical examinations, vital signs, clinical laboratory tests (hematology, blood chemistry, urinalysis, or pregnancy), or ECGs. An adverse event was defined as any untoward medical occurrence after the use of a study drug. A serious adverse event was defined as any medical occurrence that was fatal, life-threatening, disabling, required hospitalization, or caused congenital anomaly in the offspring of a patient. Cancer and study drug overdose were also considered serious adverse events.
Statistical efficacy analyses were performed on the intent-to-treat population that consisted of all patients who treated a migraine attack and returned evaluable data. A separate efficacy analysis was performed in the per-protocol population, a subgroup of patients from the intent-to-treat population minus those patients who did not take the study drug as the protocol required.
Assuming that the proportion of adolescent patients with relief was 40% for placebo and 60% for sumatriptan NS (20 mg), ∼110 patients per treatment group were required to detect a statistically significant difference (with a power of .80 and a significance level of .05) between groups.
All statistical tests were conducted using SAS software (SAS Institute Inc, Cary, NC). The Cochran-Mantel-Hanszel test,25adjusted for center effects, was used to compare treatment groups with respect to binary response variables. Missing values were imputed using last observation carried forward. Patients who took rescue medication within 2 hours after medication were considered treatment failures. Descriptive statistics are presented for patient demographics, HR, and safety/tolerability; no tests of statistical significance were performed on these parameters.
A Kaplan-Meier survival analysis was performed to compare the time to headache relief (headache pain score of 1 or 0) and time to complete relief (headache pain score of 0) within the 2-hour treatment window for each dose of study medication with placebo. The log-rank test was used to determine significant differences between the treatment groups.
Six hundred fifty-three patients were randomly assigned to receive study drug or placebo, of which 510 self-treated 1 migraine attack (intent-to-treat population). Three patients who used study medication did not return efficacy data and were excluded from the efficacy analyses. The per-protocol population included all subjects in the intent-to-treat population with the exception of 44 patients (9%) who were excluded primarily attributable to failure to treat migraine pain within 6 hours of onset or failure to record efficacy data from 1.5 to 2.5 hours postdose. The treatment blind remained intact throughout the conduct of the study. The disposition of all study patients is presented in Fig 1.
The treatment groups were similar in age, gender, migraine type, predose pain severity, and migraine medication history. Ninety-one percent of the patients treating migraine in this study were white; 4%, black; 4%, American Hispanic; and <1%, Asian. Adolescents in this study treated a greater proportion of moderate headache pain (65%) compared with severe pain (35%). Placebo patients treated their migraines more quickly (time from migraine onset to medication administration) than did the sumatriptan-treated patients (1.70 hours for the placebo group vs 2.09, 1.90, and 1.96 hours for the 5 mg, 10 mg, and 20 mg groups, respectively). Large proportions of adolescents in this study reported photophobia (86%) and phonophobia (79%). The proportion of patients with nausea was lower (46%), and few patients reported vomiting (5%). Fifteen percent of the adolescents in this study used prophylactic medications within 24 hours of using study drug. Table 1 summarizes the baseline and demographic characteristics of the 4 treatment groups.
Headache relief at 1 hour postdose in the intent-to-treat population was reported by significantly more patients using 10 mg (56%) and 20 mg (56%) of sumatriptan NS compared with placebo (41%;P < .05). Headache relief at 2 hours postdose in the intent-to-treat population was reported by significantly more patients using 5 mg of sumatriptan NS (66%) compared with placebo (53%;P < .05) and approached statistical significance for the 20 mg dose (63%) compared with placebo (53%; P = .059; Fig 2). The per-protocol population of patients treated with 20 mg of sumatriptan NS (64%) reported significantly more headache relief 2 hours postdose compared with placebo (53%; P < .05).
Each dose of sumatriptan (5 mg, 10 mg, and 20 mg) was superior to placebo with respect to the cumulative percentages of patients first reporting headache relief within 2 hours of dosing (Kaplan-Meier,P < .05; Fig 3). Younger patients 12 to 14 years of age reported higher efficacy rates at the lower doses of sumatriptan NS, while older patients 15 to 17 years of age reported the highest efficacy at the 20-mg dose (Table 2). Headache relief 2 hours postdose was similar between patients who were sumatriptan-naı̈ve and patients who had used 5HT1 agonists previously (Table 2). However, there were no significant differences in headache relief among the sumatriptan treatment groups at any endpoint.
Significantly greater proportions of patients treated with sumatriptan NS (20 mg) achieved complete relief 2 hours postdose compared with placebo (36% vs 25%, respectively; P < .05). The sumatriptan NS 20-mg dose was superior to placebo with respect to cumulative percentages of patients first reporting complete relief within 2 hours of dosing (Kaplan-Meier, P < .05; Fig 4).
Photophobia was significantly lower in the 20 mg of sumatriptan NS treatment group (36%) 2 hours postdose compared with placebo (48%;P < .05). Phonophobia was significantly lower in the 5 mg of sumatriptan NS (28%) and 20 mg of sumatriptan NS (25%) treatment groups 2 hours postdose compared with placebo (44%;P < .05; Table 3). In addition, phonophobia was significantly lower in the sumatriptan NS 20-mg treatment group compared with placebo at the 30- and 60-minute time points (P < .05). The baseline incidences of nausea or vomiting were low, and no significant differences were reported after treatment at any time point.
Rescue Medication Use
The percentage of patients using rescue medication was 21%, 22%, and 26% for 5 mg, 10 mg, and 20 mg of sumatriptan NS, respectively, versus 33% for placebo. The mean times to treatment with rescue medication were 4.17, 3.54, and 5.30 hours for 5 mg, 10 mg, and 20 mg of sumatriptan NS, respectively, compared with 4.87 hours for placebo. No significant differences were observed for any comparisons of rescue medication. The number of patients taking a second dose of study medication were 14, 11, and 9 patients for 5 mg, 10, and 20 mg sumatriptan NS, respectively, versus 11 placebo-treated patients. The mean times to treatment with a second dose of study medication were 8.25, 9.15, and 8.73 hours for 5 mg, 10 mg, and 20 mg of sumatriptan NS, respectively, versus 5.64 hours for placebo.
There was no difference in HR among treatment groups (18%, 20%, and 16% for 5 mg, 10 mg, and 20 mg of sumatriptan NS, respectively vs 20% placebo). The mean time to HR was longer for patients treated with all sumatriptan NS dosages compared with placebo, and seemed to be dose-related (7.2, 8.0, and 8.2 hours for 5 mg, 10 mg, and 20 mg, respectively vs 6.7 hours for placebo).
The overall incidence of adverse events, without regard to attribution to study drug, increased with increasing sumatriptan dosage. Taste disturbance was the most commonly reported adverse event, and when taste disturbance was not included in the calculations, the overall incidence of adverse events in the sumatriptan NS treatment groups was similar to or lower than that with placebo (Fig 5).
A summary of the incidence of drug-related adverse events that occurred at an incidence of ≥3% in the active treatment group by symptom is presented in Table 4.
No new adverse events were reported by those patients taking 2 doses of study drug, regardless of treatment group assignment. There were no clinically significant laboratory, vital sign, or ECG changes reported. The numbers of patients who reported an adverse event graded with the intensity of severe were 8 (6%), 5 (4%), and 15 (13%) for the sumatriptan NS 5-mg, 10-mg, and 20-mg doses compared with 13 (10%) for placebo. These adverse events included headache, migraine, disturbance of taste, nausea, and vomiting. One placebo-treated patient (<1%) reported a serious adverse event related to exacerbation of migraine symptoms that required emergency department treatment. No sumatriptan-treated patients reported a serious adverse event.
The results of this study demonstrate that sumatriptan NS is effective and well-tolerated in the treatment of moderate or severe migraine in adolescents. All 3 dosages studied provided headache relief, with patients in the 10-mg and 20-mg treatment groups reporting headache relief as early as 1 hour postdose. Interestingly, younger patients 12 to 14 years of age reported higher efficacy rates at lower doses of sumatriptan NS, while older patients 15 to 17 years of age reported the highest efficacy at the 20-mg dose. Although the lower sumatriptan NS doses may offer some therapeutic benefit to younger adolescents, sumatriptan NS (20 mg) consistently provided the most rapid and effective treatment across adolescent age groups.
Photophobia and phonophobia were significantly reduced in the sumatriptan NS (20 mg) treatment group within or at 2 hours of treatment. Associated symptoms are an integral part of adolescent migraine, contributing to the morbidity experienced by this age group, and essential to making the correct medical diagnosis. The high baseline presence of phonophobia and photophobia in our study indicates the appropriateness of patient selection and reinforces the significant reductions and benefits obtained with 20 mg of sumatriptan NS. Adolescents who must limit their school/work attendance and physical activities during a migraine attack because of the presence of photophobia or phonophobia may benefit greatly from this therapy and may return to these activities more frequently. Further study is needed to address the full impact of migraine disability as it relates to school and work in adolescents.
HR was low (≤20%) across all sumatriptan NS treatment groups in this study. Patients in the 20-mg treatment group reported the longest time to HR (>8 hours), suggesting that time to recurrence may be directly related to dosage. The HR rates reported in this clinical trial are lower than those reported in adult sumatriptan NS trials,16,17 and that may be attributable to the shorter attack duration observed in adolescent migraine. Sumatriptan NS seems to be effective in reducing HR as well as prolonging the time to recurrence in adolescent migraineurs, and when a second dose of sumatriptan was used to treat HR in this study, no additional risk was identified.
The magnitude of the treatment effect in our study varied from previous sumatriptan NS studies in adults.16–18 However, this observation should not be attributed to the efficacy of sumatriptan NS in the adolescent age group because the proportions of adolescents experiencing headache relief 2 hours postdose with sumatriptan NS were similar to those reported by adults in earlier sumatriptan NS studies.16–19 The elevated placebo response observed in this study adversely impacted the treatment effect. In general, pain studies in children have been associated with unusually high placebo response rates,26 and adolescents27 in particular have been known to report elevated placebo response rates in clinical trials.28Adolescents may be vulnerable to the effects of study participation and the anticipation of medication efficacy.28 The shorter duration of migraine attacks among adolescents and the specific instruction to wait until headache pain was moderate or severe before using study medication may have also contributed to the elevated placebo effect,11,29 because some of the responders to placebo may actually have experienced spontaneous resolution of their headache within the 2-hour efficacy window. Similar placebo effects were observed in an adolescent sumatriptan tablet study30and are not unique to our study population.
Sumatriptan NS was well-tolerated among the adolescent migraineurs in this study, with safety and adverse events similar to those reported in adult sumatriptan NS clinical trials.16–18 Disturbance of taste was reported as the most frequent adverse event, and when taste disturbance was removed from the calculations, the incidences of adverse events for the active treatment groups were similar to or lower than placebo. A recent study found that in patients who used flavored hard candies (lemon drops) after administration of sumatriptan NS the bitter taste was reduced, although taste disturbance did not discourage patients from using the NS formulation.31 Patients who report taste disturbance may benefit from coaching to keep their head upright or slightly tilted forward to facilitate appropriate deposition of medication in the nasal passage. The incidence of triptan sensations (warmth, burning/stinging sensations, or paresthesia) was low in this study compared with other sumatriptan formulations used with adolescents,14,15 and when these findings are coupled with the absence of serious adverse events in the active treatment groups, the NS formulation may be the preferred formulation for adolescent migraine.
The data presented in this study support the findings of several smaller studies of sumatriptan for the treatment of acute migraine in children and adolescents.14,15,20 Two open-label studies of subcutaneous sumatriptan demonstrated headache relief and reduced associated symptoms 2 hours postdose in children and adolescents.14,15 A more recent placebo-controlled study of sumatriptan NS (20 mg) in 14 children <10 years of age reported impressive efficacy rates (86%) 2 hours postdose20 that support and extend the evidence for our observation that efficacy may be higher in younger age. The younger children in that study also reported significant reductions in photophobia and phonophobia after treatment with sumatriptan NS, complementing our adolescent findings. Taste disturbance was the only reported adverse event, indicating uniform treatment and side-effect responses across study populations, regardless of patient age. Elevated placebo rates (43%) were also observed, demonstrating that enhanced placebo effect is not limited to the adolescent age group. These authors speculate that the rapid onset of action of sumatriptan NS (20 mg) may have increased the ability to detect statistically significant differences between active treatment and placebo in children, who characteristically have short-duration migraines. We present evidence of the rapid response of the 10-mg and 20-mg doses to support this observation. In total, the responses of younger children to sumatriptan NS (20 mg) are similar to our adolescent findings but are limited by the single dosage studied and the small patient sample.
It should be noted that although this study was aimed at examining only the acute use of sumatriptan in aborting migraine attacks, adolescents with recurrent and frequent attacks may be candidates for prophylactic treatment as part of a comprehensive migraine management plan.32 At present, there is a paucity of studies examining the effectiveness of migraine preventative treatments in this population. Although 15% of the patients in the current study remained on non-selective serotonin reuptake inhibitor prophylactic medications during the study, no other information was analyzed with regard to prophylactic medications.
This study provides the first large-scale, placebo-controlled evidence of the efficacy and tolerability of sumatriptan NS in the treatment of acute migraine and its associated symptoms in adolescents. Although sumatriptan has not been formally approved for use in adolescents, this study offers considerable evidence of efficacy, tolerability, and safety of sumatriptan in this age group. The sumatriptan NS 20-mg dose may be particularly well-suited for adolescent use because it provided consistent and effective relief of headache pain, photophobia, and phonophobia, with only mild and transient side effects. The intranasal device may be particularly useful for adolescents who desire rapid onset of relief, who do not want to use an injection, or whose migraine-associated symptoms preclude the use of oral medication.
This study was funded by Glaxo Wellcome Inc.
We thank the other clinical investigators who participated in this study: James Adelman, Greensboro, NC; Peter Ahmann, Marshfield, WI; Joan Benz, Cedar Rapids, IA; Gary Berman, Minneapolis, MN; David Bettis, Boise, ID; Mark Blatter, Pittsburgh, PA; Jeffrey Blumer, Cleveland, OH; Paul Brownstone, Boulder, CO; Roger Cady, Springfield, MO; Richard Colan, Milwaukee, WI; Ron Davis, Washington, DC; Michael Edmond, Austin, TX; Keith Edwards, Bennington, VT; Victor Elinoff, Endwell, NY; Thomas Enlow, Akron, OH; Michael Greenberg, Waldorf, MD; Michael Haugh, Tulsa, OK; James Hedrick, Bardstown, KY; Raymond Kandt, High Point, NC; Robert Kaniecki, Pittsburgh, PA; Jack Klapper, Denver, CO; Hubert Leonard, Portland, OR; Donald Lewis, Norfolk, VA; Steve Linder, Dallas, TX; Walter Molofsky, New York, NY; Joseph Maytal, New Hyde Park, NY; Robert Nahouraii, Charlotte, NC; William Patterson, Birmingham, AL; Arthur Prensky, St. Louis, MO; Anthony Puopolo, Milford, MA; Joel Rutman, San Antonio, TX; Cesar Santos, Winston-Salem, NC; Lawrence Seiden, Catonsville, MD; Susan Smietana, Detroit, MI; Fred Sheftell, Stamford, CT; Egilius Spierings, Wellesley Hills, MA; Richard Taylor, Towson, MD; Russell Walker, Phoenix, AZ; Thomas Ward, Lebanon, NH; Warren Wasiewski, Lancaster, PA; Terry Watkin, Fairfax, VA; and Jeanette Wendt, Tucson, AZ.
We also acknowledge the writing and editorial assistance of Barbara Wilson in the preparation of this manuscript.
- Received August 6, 1999.
- Accepted February 1, 2000.
- Address correspondence to Paul Winner, DO, 5205 Greenwood Ave, Suite 200, West Palm Beach, FL 33407. E-mail:
This study was presented in part at the 1999 American Association for the Study of Headache and International Headache Consortium meetings; June 11–13, 1999; Boston, MA.
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- Copyright © 2000 American Academy of Pediatrics