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Oral dihydroergotamine for therapy-resistant migraine attacks in children
ELSEVIER
Oral Dihydroergotamine for Therapy-Resistant Migraine Attacks in Children M i r j a L. H~im~il~iinen, M D * * , Kalle H o p p u , M D * , a n d P i r k k o R. S a n t a v u o r i , M D *
Twelve children with migraine symptoms that did not respond to conventional analgesics completed a double-blind, placebo-controlled, cross-over study of two doses of oral dihydroergotamine (DHE) for acute treatment. The primary endpoint was reduction of headache by I>2 grades on a 5-grade scale at 2 hours. After DHE, 7 of the 12 children reached the primary endpoint, and 2 reached the primary endpoint after placebo [difference 42%; 95% confidence interval (CI) 14%-70%]. Five of the 7 were pain-free after DHE (3 with 20 /ag/kg; 2 with 40 lag/kg); none was pain-free after placebo. Headache recurred in 2 of the 5. Although headache recurrence limits the efficacy of oral DHE, it may be useful in the acute treatment of migraine in selected children. © 1997 by Elsevier Science Inc. All rights reserved. H~im~il~iinen ML, Hoppu K, Santavuori PR. Oral dihydroergotamine for therapy-resistant migraine attacks in children. Pediatr Neurol 1997; 16:114-117.
Introduction Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are effective, but do not benefit all children with migraine. Dihydroergotamine (DHE) has been used for migraine since the 1940s [1]. Receptor pharmacology revived interest in DHE and led to controlled trials which suggested that intranasal spray and subcutaneous injection are useful in adults [2,3]. In children, the three previous studies of DHE or ergotamine as acute treatment were inconclusive [4-6]. In adults, because of the poor and variable bioavailability of oral DHE, effective doses are difficult to determine [7]. Because pain study in children
From the *Departments of Pediatrics and Pediatric Neurology; Children's Hospital; and the *Department of Clinical Pharmacology; University of Helsinki; Helsinki, Finland.
114
PEDIATRIC NEUROLOGY
Vol. 16 No. 2
has advanced since the early trials of DHE, we evaluated the efficacy of oral DHE for the acute treatment of migraine in a pilot study.
Patients and Methods The study was conducted in three pediatric hospitals in the greater Helsinki area between March 1993 and December 1994 as part of a larger investigation project on drug treatment of migraine in children. Eligible for this study were children who had at least two migraine attacks a month, meeting the International Headache Society criteria for migraine [8]. They had undergone a run-in period and investigation by the same doctor (M.LH.) to rule out headache of other etiologies. Most of the children, before entering the present trial, then completed a trial with acetaminophen and ibuprofen [9]. Children with renal, hepatic, or cardiovascular disease and those receiving continuous oral drug therapy were excluded. At the time of study, none of the children was receiving prophylactic drug therapy for migraine. The study was a randomized, double-blind, placebo-controlled, fourway cross-over trial. Each patient received two identical bottles, one containing DHE mesylate oral solution 2 mg/ml, and the other containing placebo of similar appearance, and was asked to swallow a dose, mixed with a small volume of water or other liquid, at the onset of a headache attack. Dosing was demonstrated at the entry to the trial. Thus, in each child, one migraine attack was treated at home with DHE 20 ixg/kg (DHE solution 2 drops/10 kg) and one was treated with placebo. If the first dose provided any relief, a second dose could be taken after 1 hour. If neither treatment produced an adequate response, the plan was to treat, after contact with the investigator, one further migraine attack with DHE 40 txg/kg and one with placebo. With estimated response rates of 60% for DHE and 10%-20% for placebo (a risk of 5%, 13 risk of 20%, bilateral testing), 11-20 children were required for the study sample. The children were asked to self-report the intensity of each headache on a 5-point scale [10] (5 = severe, 3-4 = moderate, 2 = mild, and 1 = no pain) before treatment, and at 30 and 60 rain thereafter, continuing hourly for as long as 5 hours unless the child fell asleep. The reliability and validity of this scale has been demonstrated in children >4 years of age, and its correlation with behavioral assessment of pain was demonstrated to be independent of the age of the child [ 10]. Nausea, mobility, and complaints of pain were assessed with a questionnaire. The primary endpoint of clinical efficacy was reduction of severe or moderate pain (~>grade 3) by at least 2 grades at 2 hours. Children who
Communications should be addressed to: Dr. H~n~ilainen; Children's Hospital; University of Helsinki; Stenb~ickinkatu 11, 00290 Helsinki, Finland. Received July 1, 1996; accepted September 13, 1996.
© 1997 by Elsevier Science Inc. All rights reserved. PII S0887-8994(96)00289-5 • 0887-8994/97/$17.00
fell asleep in ~<1 hour were classified as responders. Children who took rescue medication (acetaminophen or NSAIDs) before assessment were classified as nonresponders. Each child was asked to indicate the preferred treatment in the diary. The code was then broken for the preference because it was considered ethically unacceptable to withhold adequate treatment until the entire study was completed. Frequency differences were analyzed with McNemar test. For the main results, 95% confidence intervals (CI) are given; P < .05 was considered statistically significant. The protocol was approved by the ethics committee of each hospital. Informed consent from parents and assent from the children were obtained before entry into the study, which was conducted in accordance with the Declaration of Helsinki. After a median run-in period of 6 months (range 1-15 months), including the foregoing drug trial with acetaminophen and ibuprofen, 16 children (median age 10 years 9 months) entered the study. Three patients were excluded before analysis: 2 took no test drugs (1 because of the unpleasant taste; 1 because of infrequent headaches), and 1 was lost to follow-up. Table 1 presents demographic data of the 13 children. They had experienced migraine for a median of 41 months, and all had experienced the maximal intensity of headache indicated on the pain scale. Their migraine episodes lasted a median of 12 hours and occurred once or twice a month in 31%, three to four times a month in 46%, and weekly in 23%. Physical and neurologic examination of all children was normal. One patient (Patient 5) had paroxysmal mild proteinuria and EEG background abnormality, and in another (Patient 2), MRI demonstrated a small, clinically insignificant, pineal cyst. In the other children, EEG and MRI were non-hal.
Results Data sufficient for efficacy analysis were provided by 12 children after DHE and by 13 children after placebo. One patient (Patient 15), who fell asleep 1 hour after receiving placebo, did not take DHE because of infrequent migraine attacks and was excluded. Of the remaining 12 children, 7 improved by at least 2 grades in their pain intensity (primary endpoint) 2 hours after DHE, and 2 improved similarly after placebo (difference 42%; 95% C1 14%-70%, P = .06 NS). After DHE, 5 were pain-free, and 2 (Patients 13 and 16) fell asleep after the lower dose of DHE. In 2 (Patients 1 and 4) of the 5 who became painfree after DHE, headache recurred in a few hours. Neither of the children who responded to placebo after the lower dose (Patients 6 and 16) became pain-free, and 1 of them (Patient 16) fell asleep, but was awakened by headache 6 hours later. Data on the lower dose only were available for 10 of the 12 children. One (Patient 11) did not take the lower dose, and another (Patient 7) neither responded to the placebo nor recorded the pain intensity. Nine patients provided appropriate data after the higher dose. Neither of the 2 children (Patients 1 and 7) responding after DHE 40 txg/kg had responded after 20 Ixg/kg. Four of the 5 children who responded after 20 ixg/kg, nevertheless wished to try the higher dose: 2 (Patients 4 and 6) without success, 1 (Patient 13) wrongly taking acetaminophen 1.5 hours before DHE, and 1 (Patient 10) reporting a positive response without diary information. Three children preferred DHE; none preferred placebo. None of the children repeating the dose of DHE (n = 3) or placebo (n = 5) responded to either the initial or the
subsequent dose during the same headache. Six of 12 patients after DHE (Patients 7 and 14 after 20 ixg/kg, patient 11 after 40 Ixg/kg, and Patients 2, 4, and 9 after both doses) and 8 of 13 patients after placebo (Patients 5 and 13 after the lower dose; Patients 7, 9, and 11 after the higher dose; and patients 1, 2, and 4 after both doses) used escape analgesia. One child (patient 4) experienced nausea after higher doses of both DHE and placebo. Two (Patients 7 and 16) vomited 30 rain after taking the lower DHE dose and 1 (patient 11) vomited 20 min after taking the higher placebo dose. No other adverse events were observed. Eleven of the 13 children had previously completed the placebo-controlled trial with acetaminophen and ibuprofen [9], in which four of them (Patients 1, 4, 9, and 10) became pain-free with the active drug, but their later responses were unsatisfactory. Three of them (patients 1, 4, and 10) benefited from DHE, and 1 (Patient 9) did not. Three of the 7 (Patients 6, 7, and 13) who did not become pain-free with the active drugs of the previous trial benefited from DHE. One (Patient 16) of the 2 children (Patients 2 and 16) not participating in the previous trial responded to DHE. Five of the children (Patients 4, 5, 9, 11, and 14) subsequently participated in a placebo-controlled trial with sumatriptan, in which l of them (Patient 5) responded to sumatriptan [11]. Discussion The efficacy of DHE appears to be superior to that of placebo, although the conventional level of statistical significance was not reached. That most of the responders became pain-free with DHE but not with placebo, supports this conclusion. Nausea and vomiting were the only adverse events reported after both DHE and placebo. The nonresponders may have received inadequate doses, as the oral bioavailability of DHE is low. Because we did not measure the concentration of DHE, definite data are lacking; therefore, it is difficult to draw further conclusions. In an adult study, 9%-60% of the 10 mg dose was absorbed. Because of the extensive first-pass metabolism, however, the oral bioavailability was much lower, averaging 0.5%-0.6%, after the 10, 20, and 30 mg doses, and interpatient variability was sixfold [7]. Subcutaneous and intravenous injections avoid the first-pass metabolism but are not suitable for all outpatients. A rectal solution or a nasal spray could also be used to increase bioavailability. We cannot explain why 2 of the 4 children who responded to the lower DHE dose did not subsequently respond to a higher dose. The lower dose may have been high enough for them, and the higher dose might have exceeded their optimal therapeutic range. An alternative explanation may be intraindividual variation in bioavailability. Headache recurrence, possibly due to the short half-life of DHE [7], was a problem. Recurrence can be treated with repeated administration, but overdosing has caused
Ham~Riinen et al: Oral DHE for Migraine in Children
115
(yr, mo)/Sex
Demographic
Months 33 29 92 57 36 36 96’ 41* 56’ 2ot 89 21 61’
History
Hours 4 I2 20 24 12 18 48 5 24 12 12 12 96
Duration
Migraine
Abbreviation: DHE = Dihydroergotamine.
at
Response* 0 0 PFl-2 0 PM 0 0 PFI-2 REI-2 0 REl-2 -
60
-
Second Dose -60 60
DHE 20 k&k
I hour or 2 hours. REl/RE2
Per month 3S4 34 3-4 Weekly l-2 3-4 1-2 Weekly 1-2 1-2 Weekly 3-4 34
Frequency
105 --
-60
Second Dose 60 30 60
Placebo
40 -
-
Rescue 120 360 60 180 -
______ _._.__.
in pain by ~2 of 5 grades at
0 0 0 REl-2
Response* 0 0 0 0 RE2 ND 0 0
= Reduction
180
120 210 60 60 -
Rescue
data of children at randomization and their responses to study treatments ~.. ___.. --___ II__
* Response: 0 = No response, PFl/PF2 = Pain-free Second dose = Time to new dose in minutes, Rescue = Time to rescue medication in minutes. ’ Migraine with aura. ’ Pttbertat.
Patient/Age 1/9,9/M 2/12,5/M 4/l 1,8/M 5/l 0,9/F 618,Om 7/6,0/F 9/13,0/M 10/15,4VM 11/11,8/M 13/6,2/M 14/14,5*/F 15/5&F 16/&l/F
Table 1. ~.____.~.
--
-
-.
Second Dose 90 --
25
120
Rescue 240 120
_~
Response* 0 0 0 0 0 0 0 ND 0 0 -
_.._.~.~. ___-___
60
--
Second Dose 90
Placebo
1 hour or 2 hours. ND = No data, (-_) = Did not take.
0 -
Response* PFl-2 0 0 0 0 PFl-2 0 ND 0
DHE 40 pg/kg
_____.
45
210 510
Rescue 60 210 120
-.L
Preference DHE Neither Neither Neither Neither DHE Neither DHE Neither Neither Neither ND ND
____...-
concern [3], although adverse events were mild in the present study. The results of this pilot study indicate that some children may benefit from oral DHE as an acute treatment for their migraine. We suggest that a larger controlled clinical trial be conducted, preceded by a phannacokinetic study. M.L.H. was supported by grants from the Arvo and Lea Ylpp6 Foundation and the Academy of Finland. The authors thank Drs. Marketta Muttilainen of Jorvi Hospital and Veli Ylitalo of Aurora Hospital for allowing us the use of their facilities, Sandoz supplied the dihydroergotamine, and the Pharmacy of the Helsinki University Central Hospital prepared the placebo.
References It] Scott AK. Dihydroergotamine: A review of its use in the treatment of migraine and other headaches. Clin Neuropharmacol 1992;15: 289-96. [2] Ziegler D, Ford R, Kriegler J, et al. Dihydroergotamine nasal spray for the acute treatment of migraine. Neurology 1994;44:447-53. [3] Silberstein SD, Young WB. Safety and efficacy of ergotamine tartrate and dihydroergotamine in the treatment of migraine and status migrainosus. Neurology 1995;45:577-84.
[4] Congdon PJ, Forsythe WI. Migraine in childhood: A study of 300 children. Dev Med Child Neurot 1979;21:209-16. [5] Forsythe I, Hockaday JM. Management of childhood migraine. In: Hockaday JM, ed. Migraine in childhood. Cambridge: Butterworths, 1988:63-74. [6] Pothmann R, Baumann A, Besken E. Ergotaminics in childhood migraine. In: Gallai V, Guidetti V, eds. Juvenile headache, lntemational Congr Ser Excerpta Med. Amsterdam: Elsevier Science Publishers BV, 1991:409-12. [7] Little PJ, Jennings GL, Skews H, Bobik A. Bioavailability of dihydroergotamine in man. Br J Clin Pharmacol 1982:13:785-90. [8] Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(suppl 7): 1-96. [9] H~im~il~iinen ML, Hoppu K, Valkeila E, Santavuori P. lbuprofen or acetaminophen for the acute treatment of migraine in children: A double-blind, randomized, placebo-controlled, crossover' study. Neurology 1997;48:103-7. [10] Maunuksela E-L, Olkkola KT, Korpela R. Measurement of pain in children with self-reporting and behavioral assessment. Clin Pharmacol Ther 1987;42:137-41. [11] H~im~il~iinen ML, Hoppu K, Santavuori P. Sumatriptan for migraine attacks in children, a randomized, placebo-controlled study. Do children with migraine respond to oral sumatriptan differently from adults? Neurology 1997 (in press).
H~im~il~iinen et al: Oral DHE for Migraine in Children
117
Oral Dihydroergotamine for Therapy-Resistant Migraine Attacks in Children M i r j a L. H~im~il~iinen, M D * * , Kalle H o p p u , M D * , a n d P i r k k o R. S a n t a v u o r i , M D *
Twelve children with migraine symptoms that did not respond to conventional analgesics completed a double-blind, placebo-controlled, cross-over study of two doses of oral dihydroergotamine (DHE) for acute treatment. The primary endpoint was reduction of headache by I>2 grades on a 5-grade scale at 2 hours. After DHE, 7 of the 12 children reached the primary endpoint, and 2 reached the primary endpoint after placebo [difference 42%; 95% confidence interval (CI) 14%-70%]. Five of the 7 were pain-free after DHE (3 with 20 /ag/kg; 2 with 40 lag/kg); none was pain-free after placebo. Headache recurred in 2 of the 5. Although headache recurrence limits the efficacy of oral DHE, it may be useful in the acute treatment of migraine in selected children. © 1997 by Elsevier Science Inc. All rights reserved. H~im~il~iinen ML, Hoppu K, Santavuori PR. Oral dihydroergotamine for therapy-resistant migraine attacks in children. Pediatr Neurol 1997; 16:114-117.
Introduction Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) are effective, but do not benefit all children with migraine. Dihydroergotamine (DHE) has been used for migraine since the 1940s [1]. Receptor pharmacology revived interest in DHE and led to controlled trials which suggested that intranasal spray and subcutaneous injection are useful in adults [2,3]. In children, the three previous studies of DHE or ergotamine as acute treatment were inconclusive [4-6]. In adults, because of the poor and variable bioavailability of oral DHE, effective doses are difficult to determine [7]. Because pain study in children
From the *Departments of Pediatrics and Pediatric Neurology; Children's Hospital; and the *Department of Clinical Pharmacology; University of Helsinki; Helsinki, Finland.
114
PEDIATRIC NEUROLOGY
Vol. 16 No. 2
has advanced since the early trials of DHE, we evaluated the efficacy of oral DHE for the acute treatment of migraine in a pilot study.
Patients and Methods The study was conducted in three pediatric hospitals in the greater Helsinki area between March 1993 and December 1994 as part of a larger investigation project on drug treatment of migraine in children. Eligible for this study were children who had at least two migraine attacks a month, meeting the International Headache Society criteria for migraine [8]. They had undergone a run-in period and investigation by the same doctor (M.LH.) to rule out headache of other etiologies. Most of the children, before entering the present trial, then completed a trial with acetaminophen and ibuprofen [9]. Children with renal, hepatic, or cardiovascular disease and those receiving continuous oral drug therapy were excluded. At the time of study, none of the children was receiving prophylactic drug therapy for migraine. The study was a randomized, double-blind, placebo-controlled, fourway cross-over trial. Each patient received two identical bottles, one containing DHE mesylate oral solution 2 mg/ml, and the other containing placebo of similar appearance, and was asked to swallow a dose, mixed with a small volume of water or other liquid, at the onset of a headache attack. Dosing was demonstrated at the entry to the trial. Thus, in each child, one migraine attack was treated at home with DHE 20 ixg/kg (DHE solution 2 drops/10 kg) and one was treated with placebo. If the first dose provided any relief, a second dose could be taken after 1 hour. If neither treatment produced an adequate response, the plan was to treat, after contact with the investigator, one further migraine attack with DHE 40 txg/kg and one with placebo. With estimated response rates of 60% for DHE and 10%-20% for placebo (a risk of 5%, 13 risk of 20%, bilateral testing), 11-20 children were required for the study sample. The children were asked to self-report the intensity of each headache on a 5-point scale [10] (5 = severe, 3-4 = moderate, 2 = mild, and 1 = no pain) before treatment, and at 30 and 60 rain thereafter, continuing hourly for as long as 5 hours unless the child fell asleep. The reliability and validity of this scale has been demonstrated in children >4 years of age, and its correlation with behavioral assessment of pain was demonstrated to be independent of the age of the child [ 10]. Nausea, mobility, and complaints of pain were assessed with a questionnaire. The primary endpoint of clinical efficacy was reduction of severe or moderate pain (~>grade 3) by at least 2 grades at 2 hours. Children who
Communications should be addressed to: Dr. H~n~ilainen; Children's Hospital; University of Helsinki; Stenb~ickinkatu 11, 00290 Helsinki, Finland. Received July 1, 1996; accepted September 13, 1996.
© 1997 by Elsevier Science Inc. All rights reserved. PII S0887-8994(96)00289-5 • 0887-8994/97/$17.00
fell asleep in ~<1 hour were classified as responders. Children who took rescue medication (acetaminophen or NSAIDs) before assessment were classified as nonresponders. Each child was asked to indicate the preferred treatment in the diary. The code was then broken for the preference because it was considered ethically unacceptable to withhold adequate treatment until the entire study was completed. Frequency differences were analyzed with McNemar test. For the main results, 95% confidence intervals (CI) are given; P < .05 was considered statistically significant. The protocol was approved by the ethics committee of each hospital. Informed consent from parents and assent from the children were obtained before entry into the study, which was conducted in accordance with the Declaration of Helsinki. After a median run-in period of 6 months (range 1-15 months), including the foregoing drug trial with acetaminophen and ibuprofen, 16 children (median age 10 years 9 months) entered the study. Three patients were excluded before analysis: 2 took no test drugs (1 because of the unpleasant taste; 1 because of infrequent headaches), and 1 was lost to follow-up. Table 1 presents demographic data of the 13 children. They had experienced migraine for a median of 41 months, and all had experienced the maximal intensity of headache indicated on the pain scale. Their migraine episodes lasted a median of 12 hours and occurred once or twice a month in 31%, three to four times a month in 46%, and weekly in 23%. Physical and neurologic examination of all children was normal. One patient (Patient 5) had paroxysmal mild proteinuria and EEG background abnormality, and in another (Patient 2), MRI demonstrated a small, clinically insignificant, pineal cyst. In the other children, EEG and MRI were non-hal.
Results Data sufficient for efficacy analysis were provided by 12 children after DHE and by 13 children after placebo. One patient (Patient 15), who fell asleep 1 hour after receiving placebo, did not take DHE because of infrequent migraine attacks and was excluded. Of the remaining 12 children, 7 improved by at least 2 grades in their pain intensity (primary endpoint) 2 hours after DHE, and 2 improved similarly after placebo (difference 42%; 95% C1 14%-70%, P = .06 NS). After DHE, 5 were pain-free, and 2 (Patients 13 and 16) fell asleep after the lower dose of DHE. In 2 (Patients 1 and 4) of the 5 who became painfree after DHE, headache recurred in a few hours. Neither of the children who responded to placebo after the lower dose (Patients 6 and 16) became pain-free, and 1 of them (Patient 16) fell asleep, but was awakened by headache 6 hours later. Data on the lower dose only were available for 10 of the 12 children. One (Patient 11) did not take the lower dose, and another (Patient 7) neither responded to the placebo nor recorded the pain intensity. Nine patients provided appropriate data after the higher dose. Neither of the 2 children (Patients 1 and 7) responding after DHE 40 txg/kg had responded after 20 Ixg/kg. Four of the 5 children who responded after 20 ixg/kg, nevertheless wished to try the higher dose: 2 (Patients 4 and 6) without success, 1 (Patient 13) wrongly taking acetaminophen 1.5 hours before DHE, and 1 (Patient 10) reporting a positive response without diary information. Three children preferred DHE; none preferred placebo. None of the children repeating the dose of DHE (n = 3) or placebo (n = 5) responded to either the initial or the
subsequent dose during the same headache. Six of 12 patients after DHE (Patients 7 and 14 after 20 ixg/kg, patient 11 after 40 Ixg/kg, and Patients 2, 4, and 9 after both doses) and 8 of 13 patients after placebo (Patients 5 and 13 after the lower dose; Patients 7, 9, and 11 after the higher dose; and patients 1, 2, and 4 after both doses) used escape analgesia. One child (patient 4) experienced nausea after higher doses of both DHE and placebo. Two (Patients 7 and 16) vomited 30 rain after taking the lower DHE dose and 1 (patient 11) vomited 20 min after taking the higher placebo dose. No other adverse events were observed. Eleven of the 13 children had previously completed the placebo-controlled trial with acetaminophen and ibuprofen [9], in which four of them (Patients 1, 4, 9, and 10) became pain-free with the active drug, but their later responses were unsatisfactory. Three of them (patients 1, 4, and 10) benefited from DHE, and 1 (Patient 9) did not. Three of the 7 (Patients 6, 7, and 13) who did not become pain-free with the active drugs of the previous trial benefited from DHE. One (Patient 16) of the 2 children (Patients 2 and 16) not participating in the previous trial responded to DHE. Five of the children (Patients 4, 5, 9, 11, and 14) subsequently participated in a placebo-controlled trial with sumatriptan, in which l of them (Patient 5) responded to sumatriptan [11]. Discussion The efficacy of DHE appears to be superior to that of placebo, although the conventional level of statistical significance was not reached. That most of the responders became pain-free with DHE but not with placebo, supports this conclusion. Nausea and vomiting were the only adverse events reported after both DHE and placebo. The nonresponders may have received inadequate doses, as the oral bioavailability of DHE is low. Because we did not measure the concentration of DHE, definite data are lacking; therefore, it is difficult to draw further conclusions. In an adult study, 9%-60% of the 10 mg dose was absorbed. Because of the extensive first-pass metabolism, however, the oral bioavailability was much lower, averaging 0.5%-0.6%, after the 10, 20, and 30 mg doses, and interpatient variability was sixfold [7]. Subcutaneous and intravenous injections avoid the first-pass metabolism but are not suitable for all outpatients. A rectal solution or a nasal spray could also be used to increase bioavailability. We cannot explain why 2 of the 4 children who responded to the lower DHE dose did not subsequently respond to a higher dose. The lower dose may have been high enough for them, and the higher dose might have exceeded their optimal therapeutic range. An alternative explanation may be intraindividual variation in bioavailability. Headache recurrence, possibly due to the short half-life of DHE [7], was a problem. Recurrence can be treated with repeated administration, but overdosing has caused
Ham~Riinen et al: Oral DHE for Migraine in Children
115
(yr, mo)/Sex
Demographic
Months 33 29 92 57 36 36 96’ 41* 56’ 2ot 89 21 61’
History
Hours 4 I2 20 24 12 18 48 5 24 12 12 12 96
Duration
Migraine
Abbreviation: DHE = Dihydroergotamine.
at
Response* 0 0 PFl-2 0 PM 0 0 PFI-2 REI-2 0 REl-2 -
60
-
Second Dose -60 60
DHE 20 k&k
I hour or 2 hours. REl/RE2
Per month 3S4 34 3-4 Weekly l-2 3-4 1-2 Weekly 1-2 1-2 Weekly 3-4 34
Frequency
105 --
-60
Second Dose 60 30 60
Placebo
40 -
-
Rescue 120 360 60 180 -
______ _._.__.
in pain by ~2 of 5 grades at
0 0 0 REl-2
Response* 0 0 0 0 RE2 ND 0 0
= Reduction
180
120 210 60 60 -
Rescue
data of children at randomization and their responses to study treatments ~.. ___.. --___ II__
* Response: 0 = No response, PFl/PF2 = Pain-free Second dose = Time to new dose in minutes, Rescue = Time to rescue medication in minutes. ’ Migraine with aura. ’ Pttbertat.
Patient/Age 1/9,9/M 2/12,5/M 4/l 1,8/M 5/l 0,9/F 618,Om 7/6,0/F 9/13,0/M 10/15,4VM 11/11,8/M 13/6,2/M 14/14,5*/F 15/5&F 16/&l/F
Table 1. ~.____.~.
--
-
-.
Second Dose 90 --
25
120
Rescue 240 120
_~
Response* 0 0 0 0 0 0 0 ND 0 0 -
_.._.~.~. ___-___
60
--
Second Dose 90
Placebo
1 hour or 2 hours. ND = No data, (-_) = Did not take.
0 -
Response* PFl-2 0 0 0 0 PFl-2 0 ND 0
DHE 40 pg/kg
_____.
45
210 510
Rescue 60 210 120
-.L
Preference DHE Neither Neither Neither Neither DHE Neither DHE Neither Neither Neither ND ND
____...-
concern [3], although adverse events were mild in the present study. The results of this pilot study indicate that some children may benefit from oral DHE as an acute treatment for their migraine. We suggest that a larger controlled clinical trial be conducted, preceded by a phannacokinetic study. M.L.H. was supported by grants from the Arvo and Lea Ylpp6 Foundation and the Academy of Finland. The authors thank Drs. Marketta Muttilainen of Jorvi Hospital and Veli Ylitalo of Aurora Hospital for allowing us the use of their facilities, Sandoz supplied the dihydroergotamine, and the Pharmacy of the Helsinki University Central Hospital prepared the placebo.
References It] Scott AK. Dihydroergotamine: A review of its use in the treatment of migraine and other headaches. Clin Neuropharmacol 1992;15: 289-96. [2] Ziegler D, Ford R, Kriegler J, et al. Dihydroergotamine nasal spray for the acute treatment of migraine. Neurology 1994;44:447-53. [3] Silberstein SD, Young WB. Safety and efficacy of ergotamine tartrate and dihydroergotamine in the treatment of migraine and status migrainosus. Neurology 1995;45:577-84.
[4] Congdon PJ, Forsythe WI. Migraine in childhood: A study of 300 children. Dev Med Child Neurot 1979;21:209-16. [5] Forsythe I, Hockaday JM. Management of childhood migraine. In: Hockaday JM, ed. Migraine in childhood. Cambridge: Butterworths, 1988:63-74. [6] Pothmann R, Baumann A, Besken E. Ergotaminics in childhood migraine. In: Gallai V, Guidetti V, eds. Juvenile headache, lntemational Congr Ser Excerpta Med. Amsterdam: Elsevier Science Publishers BV, 1991:409-12. [7] Little PJ, Jennings GL, Skews H, Bobik A. Bioavailability of dihydroergotamine in man. Br J Clin Pharmacol 1982:13:785-90. [8] Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8(suppl 7): 1-96. [9] H~im~il~iinen ML, Hoppu K, Valkeila E, Santavuori P. lbuprofen or acetaminophen for the acute treatment of migraine in children: A double-blind, randomized, placebo-controlled, crossover' study. Neurology 1997;48:103-7. [10] Maunuksela E-L, Olkkola KT, Korpela R. Measurement of pain in children with self-reporting and behavioral assessment. Clin Pharmacol Ther 1987;42:137-41. [11] H~im~il~iinen ML, Hoppu K, Santavuori P. Sumatriptan for migraine attacks in children, a randomized, placebo-controlled study. Do children with migraine respond to oral sumatriptan differently from adults? Neurology 1997 (in press).
H~im~il~iinen et al: Oral DHE for Migraine in Children
117