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Abstract

Background and objective: Cyclic vomiting syndrome (CVS) is associated with migraine. This study aimed to evaluate the efficacy of sumatriptan in treating CVS.

Methods: Twelve patients were enrolled in this trial. Sumatriptan was administered either subcutaneously [(age × 4 + 20)/100 × 3 mg] or by nasal spray (NS; 20 mg). Response to the treatment was classified as complete, effective, or noneffective.

Results: Eleven patients, who presented with 35 attacks, were treated by subcutaneous injection of sumatriptan. The treatment was responsive in 19 attacks. The efficacy of sumatriptan was high in attacks that occurred in cases with a family history of migraine compared to those without (p = .0482). Five patients were treated with sumatriptan NS for six attacks. The treatment was completely responsive in two of six attacks. We observed no adverse effects associated with sumatriptan treatment in this trial.

Conclusion: We conclude that sumatriptan has potential efficacy in treating of patients with CVS.

Keywords

International headache classification cyclic vomiting syndrome (CVS)migraine sumatriptan

Introduction

Cyclic vomiting syndrome (CVS) is characterized by severe, recurrent episodes of vomiting in otherwise healthy children (1) and some adults (2).

CVS is believed to be a variant of migraine (3), and has been classified in the subgroup of childhood periodic syndromes that are common precursors of migraine (4). Sumatriptan is effective in the acute treatment of migraine in children and adults (5–7). This study aimed to evaluate the efficacy of sumatriptan in treating CVS in children and adults.

Methods

After obtaining informed consent, 12 patients (11 children and 1 adult) referred to Teikyo University Hospital and diagnosed with severe CVS by a pediatric neurologist were enrolled in this trial. Detailed history and results of previous physical examinations of all patients, including reports of complete neurologic examinations, were obtained from their medical records. Additional diagnostic tests were performed to rule out the possibility of organic causes such as gastrointestinal, neurological or metabolic diseases.

All patients were diagnosed with CVS based on the International Classificaton of Headache Disorders, second edition (ICHD-II), criteria (4). In all patients, vomiting was severe enough to cause dehydration requiring hospitalization and intravenous rehydration. All patients were admitted to our hospital for sumatriptan treatment by subcutaneous injection (SI), and were carefully observed for response and adverse effects. Sumatriptan was administered by SI [(age × 4 + 20)/100 × 3 mg] (8) or nasal spray [(NS; 20 mg)]. Patients were individually instructed on using the NS. For each attack, patient response to the treatment was classified as follows: complete (no vomiting after treatment), effective (frequency of vomiting after treatment reduced by at least half compared to last attack before initiating the treatment) or noneffective (the treatment was not effective in preventing vomiting).

We performed statistical analysis only for the SI trial. For statistical analysis, responses of the 35 attacks to SI were classified into two categories: response attack comprising (i) complete and (ii) effective responses, and non-response attack comprising (iii) no response. Data were analyzed using JMP software version 8 (SAS Institute, Cary, NC, USA); Wilcoxon’s rank-sum test was used to correlate the age of patients during the trial with attacks that responded/did not respond to the treatment.

The likelihood ratio test was used to correlate the family history of migraine among attacks that responded/did not respond to the treatment. p values < .05 were considered statistically significant.

The use of sumatriptan for treating CVS attacks in children and adults was approved by the Ethics Committee of the Teikyo University School of Medicine (no. 07078).

Results

The therapeutic responses of all patients treated with sumatriptan are outlined in Table 1. Eleven patients were administered sumatriptan subcutaneously. Of these 11 patients, four showed complete resolution (including seven complete and one noneffective response for eight attacks) and five patients showed an effective response (including 12 effective and 10 noneffective responses for 22 attacks). In total, 19 of 35 (54%) attacks were classified as responsive.

Table 1.

Results of sumatriptan treatment in patients with cyclic vomiting

					Subcutaneous injection				Nasal spray
Case	Sex	Family history of migraine	Age at onset (months)	Age at initiation of sumatriptan trial (month)	Doses of sumatriptan (mg)	Complete	Effective	Noneffective	Complete	Effective	Noneffective
1	M		3	106	1.5	3		1
2	M		15	42	1			3
3	M		22	127	1.8		1	3		1
4	F		24	39	1		3	4
5	F		36	50	1.1		2	1			1
6	M	Mother	36	116	1.7	1
7	F		36	65	1.2		5	2
8	M		37	73	1.3	2
9	F	Mother	60	115	1.7						1
10	F	Father, mother	72	117	1.7	1					2
11	M		120	293	3			2
12	M	Mother	132	139	1.9		1		1

Complete = no vomiting after treatment with sumatriptan. Effective = less than half the frequency (compared with the last attack before initiating sumatriptan treatment) of vomiting after treatment with sumatriptan.

Five patients were also treated for six attacks with sumatriptan NS. Of these, one patient showed complete resolution (one complete response), one patient showed effective resolution (one effective response) and three patients showed noneffective resolution (four noneffective responses).

A family history of migraine in a first-degree relative was identified in 33% (4 of 12) patients. The efficacy of sumatriptan was high in attacks that occurred in cases with a family history of migraine compared to those without (p = .0482). No statistically significant relationship was observed between the efficacy of sumatriptan and age during the trial (p = .640).

We observed no adverse effects associated with sumatriptan treatment.

Discussion

Sumatriptan is a serotonin agonist that has been approved for the treatment of migraine (5–7). It is believed to act by binding to one of the 5-HT₁ receptor subclasses (probably 5-HT_1D) in the dura mater, resulting in constriction of distended dural blood vessels (9). In ICHD-II, CVS has been classified in the subgroup of childhood periodic syndromes that are common precursors of migraine (Table 2) (4).

Table 2.

Childhood periodic syndromes in ICHD-II

1.3 Childhood periodic syndromes that are commonly precursors of migraine

1.3.1 cyclical vomiting

1.3.2 abdominal migraine

1.3.3 Benign paroxysmal vertigo of childhood

ICHD-II = International Classification of Headache Disorders, second edition.

The clinical efficacy of sumatriptan in migraine is related in part to the multiple mechanisms of action at vascular, neural and central physiologic sites implicated in the pathophysiology of migraine. The pathogenesis of CVS symptoms is not well understood. In this study, nine patients with CVS were responsive to sumatriptan administration. Sumatriptan may act at vascular, neural and central physiologic sites implicated in the pathophysiology of CVS. In 11 of our patients, sumatriptan was administered subcutaneously between one and 24 hours after vomiting commenced. Vomiting reduced after SI in nine patients, and two patients did not respond to the injection. Nasal sumatriptan has been found to be effective in most children with migraine (6,7). Of the five patients with CVS treated with sumatriptan in the NS form, one showed complete resolution and one showed an effective response; however, the treatment was noneffective in three patients.

The efficacy of sumatriptan in CVS has been reported in three studies (Table 3) (10–12). Sumatriptan was administered by SI in only one adult patient (10). The patient required 6 mg sumatriptan. An internationally accepted subcutaneous sumatriptan dose is 6 mg. However, a standard subcutaneous sumatriptan dose for a Japanese adult is 3 mg. In this study, the dose of sumatriptan administered by SI was calculated by the following formula: [(age × 4 + 20)/100 × 3 mg] (8). The coefficient value of the 3-mg sumatriptan dose may be relatively small. Our future studies may involve higher doses of sumatriptan for noneffective cases. In two other reported cases of CVS, sumatriptan was administered in the NS form using the same dose (20 mg) as used in our study (11,12). The efficacy of sumatriptan has also been reported for abdominal migraine (AM), a condition classified in the subgroup of childhood periodic syndromes (Table 3) (13,14). In two cases of AM, sumatriptan was administered orally in one case (13) and in the NS form in the other case (14). Although, three of five childhood periodic syndrome cases reported no family history of migraine, presence or absence of a family history of migraine was not described in two of the five cases in these studies.

Table 3.

Previous reports of CVS and AM patients treated with sumatriptan

Case	Author (year)	Diagnosis	Sex	Family history of migraine*	Age at onset (years)	Age during sumatriptan trial (years)	Subcutaneous injection dose (mg)	Nasal spray dose (mg)	Oral dose (mg)
1	Benson (1995)	CVS	M	Not described	15	19	6
3	Kakisaka (2009)	CVS	F	None	5	14		20
2	Kowalczyk (2010)	CVS	F	None	46	47		20
4	Moran (1998)	AM & M	F	Not described	39	48			100
5	Kakisaka (2010)	AM	F	None	9	12		20

CVS = cyclic vomiting syndrome. AM & M = abdominal migraine with migraine. AM = abdominal migraine.

Not described = no family history of migraine described in the report. None = no family history of migraine.

Li et al. reported that antimigraine therapy is effective for CVS (3). The authors classified the affected patients into migraine- and nonmigraine-associated CVS subgroups with either a positive family history of migraine or subsequent migraine development. In our study, the efficacy of sumatriptan treatment was high in cases with a family history of migraine compared to cases without a family history of migraine. However, patients with no family history of migraine responded to sumatriptan treatment for 50% of attacks. In addition, three previous cases of CVS and AM were treated successfully with sumatriptan (11,12,14). Based on these combined findings, our future studies may involve sumatriptan treatment in patients with no family history of migraine.

In the first stage of this study, treatment response was classified into three categories as complete, effective or noneffective. However, due to the small sample size, the statistical analysis for the SI trial only used two categories: response attack and nonresponse attack. Differences in the therapeutic response with sumatriptan between adult and pediatric migraines have also been documented (15,16). We believe that sumatriptan is more effective in older patients. However, no statistically significant relationship was observed between the efficacy of sumatriptan and age in this study.

These results demonstrate the efficacy of SI administration of sumatriptan in treating CVS, particularly in attacks that occur in cases with a family history of migraine. However, randomized placebo-controlled studies investigating the efficacy of sumatriptan in CVS attacks are needed to confirm these effects.

Conclusion

Vomiting was reduced after administration of sumatriptan in at least nine patients (75%) in this study. We conclude that sumatriptan has potential efficacy in treating of patients with CVS. However, larger and placebo-controlled studies are needed to confirm our results.

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