Prophylactic Cyproheptadine to Control Paroxysmal Hemicrania Attacks: A Preliminary Investigation

Abstract

Background:

Paroxysmal hemicrania (PH) is a severe short-lasting headache usually localized around the eye. It might occur in conjunction with ipsilateral autonomic manifestations of trigeminal nerve stimulation. PH responds well to indomethacin treatment; however, considering the adverse effects of indomethacin, its long-term use is a matter of question and investigations about other prophylactic medications are going on, but they are inconclusive. The current study aims to investigate the efficacy of prophylactic use of cyproheptadine to control PH symptoms.

Materials and Methods:

The current clinical trial was conducted on 20 children diagnosed with PH undergoing prophylactic treatment with cyproheptadine syrup at a dosage of 0.2–0.4 mg/kg twice daily for a period of 3 months. The duration, frequency, and severity of headaches were assessed at baseline and then monthly for 3 months.

Results:

Significantly shorter duration, less frequency, and less severity of headaches were observed in the postintervention assessments of the patients (P < 0.001). The effect size analysis showed that the greatest effect of the treatment was on the intensity of the headache (effect size: 0.866) and the least effect was on duration of the headache (effect size: 0.775). Drowsiness (5%) and increased appetite (30%) were the only adverse effects of treatment with cyproheptadine.

Conclusion:

Findings of this study showed that short-term prophylactic cyproheptadine in divided doses of 0.2–0.4 mg/kg could appropriately improve PH in terms of frequency, duration, and the intensity of the attacks. Nevertheless, further investigations are strongly recommended.

INTRODUCTION

Headache is one of the common complaints of children referring to outpatient pediatric clinics. This disorder is generally divided into two subcategories: primary, originating from the brain structure, and secondary, caused by an underlying condition. Migraine and tension headaches are the most frequent and disabling type of headache in childhood; however, another form of this disabling condition, trigeminal autonomic cephalalgia (TAC), is 100 times less prevalent.[1] The International Classification of Headache Disorders, 3^rd edition (ICHD-3) has classified this primary headache, TAC, into four categories including cluster headache, paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform headache with conjunctival injection and tearing syndrome, and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms.[2]

TAC is generally represented by severe unilateral short episodes of pain accompanying ipsilateral autonomic manifestations of trigeminal nerve stimulation, such as ptosis, miosis, eye tearing, conjunctival injection, nasal obstruction, or rhinorrhea. The headaches of this group differ regarding their duration, frequency, and treatments.[3] PH is one of the severe short-lasting subtypes of TAC, which is described as sharp, stabbing, or agonizing pain, usually localized around the eye and lasting for 2–30 min. This characteristic differentiates it from cluster headaches. This headache can occur many dozens of times per day.[4] Typically, PH occurs in adulthood; however, pediatric cases with this diagnosis have been explained as well. Agitation or restlessness has been reported as the significant manifestation of PH in children. This primary headache is divided into two subtypes of chronic and episodic, which differ in terms of their duration and headache-free periods. One of the core diagnostic criteria in PH is its dramatic response to indomethacin; however, the long-term use of this agent is an issue of debate because of paucity of knowledge in this regard as well as the potential adverse effects of indomethacin.[3]

Cyproheptadine is a first-generation antihistamine agent widely being used for prevention of childhood paroxysmal neurologic events such as benign paroxysmal vertigo, migraine-associated cyclic vomiting syndrome, and benign paroxysmal torticollis.[5,6,7,8] Recently, attention has been turned to this medication for TAC; however, the knowledge in this regard is remarkably limited.[9] Accordingly, the current study was conducted with an aim to investigate the utility of cyproheptadine to prevent PH in children.

MATERIALS AND METHODS

Study population

The current clinical trial was conducted on 20 children diagnosed with PH in neurology outpatient clinic of Imam Hossein Hospital affiliated with Isfahan University of Medical Sciences from January 2021 to March 2022. Figure 1 shows the consort diagram of the study population.

Figure 1.

Consort diagram of the study population

The study protocol was designed based on the tenets of Helsinki declaration, proposed to the ethics committee of Isfahan University of Medical Sciences and approved via code number IR.MUI.MED.REC.1400.819. Besides, it has been registered in the Iranian Registry of Clinical Trials, encoded as “IRCT20190208042654N5.” The study was entirely explained to the legal guardians of the patients. They were reassured regarding the confidentiality of personal information and they signed written consent.

Children aged 2–15 years with episodic PH diagnosis based on ICHD-3,[2] who had the least headache attacks of once a week were included. The criterion for prophylactic management of PH was the incidence of paroxysmal attacks for more than once a week. Diagnoses other than PH, hypersensitivity to cyproheptadine or the incidence of significant drug-related adverse effects, withdrawal from the study during the intervention, epileptic headaches or other epileptic disorders, major psychiatric disorders such as major depressive disorders, anxiety disorders, and attention deficit hyperactivity disorders, anatomical or structural brain disorders in magnetic resonance imaging (MRI), failure to participate in follow-up visits or inappropriate study checklist completion, and obesity (more than 95% percentile according to age and gender) were the exclusion criteria.

The study was a census trial, and all the patients meeting the criteria entered the study through convenience sampling.

Data collection

The patients referring with the complaint of headache compatible with PH were primarily assessed to rule out seizures and structural abnormalities. Accordingly, an electroencephalography (EEG) and an MRI were performed for them. PH diagnosis was primarily made by a pediatric neurologist and then confirmed by the other two members of the panel who were responsible for the current study.

Other data collected included the patients’ age, gender, weight, the interval between symptom initiation and treatment application, gestational age at birth, and the route of delivery.

Intervention

Prophylactic treatment with cyproheptadine syrup (Alhavi Pharmacy, Tehran, Iran) at a dosage of 0.2–0.4 mg/kg twice daily was initiated for the patients. The treatment continued for 3 months.

Outcomes

The primary outcome of the study was to investigate the frequency, duration, and severity of headaches in children.

The pain severity was assessed using visual analog scale, a 0–10 scoring system, with 0 indicating no pain and 10 indicating the most severe pain.

The patients were primarily visited in advance for medication initiation and then followed for a period of 3 months through monthly visits. During the visits, the parents were asked about the incidence, duration, and intensity of pain in the previous month; if the child had any paroxysmal attack, it was recorded.

Statistical analysis

The obtained data were entered into the Statistical Package for Social Sciences (Released 2009 PASW statistics for Windows; SPSS Inc., Chicago, IL, USA) version 18. The categorical variables were presented as absolute numbers and percentages, while the continuous variables were presented as mean ± standard deviation. Kolmogrov–Smirnov test was used to determine data distribution normality. Considering the abnormal distribution of the data, Friedman’s test was used to assess the trend of changes in headache characteristics and then, Bonferroni correction test was utilized as the post hoc test. A P value less than 0.05 was considered as the level of significance.

RESULTS

In the current study, the eligibility of 31 patients was assessed, among whom five did not meet the study criteria (a patient with epileptic discharge in EEG and seizure and four because of obesity or overweight). The remaining 26 patients entered the study, while six others discontinued the intervention because of significant increase in their appetite and weight gain. Eventually, 20 children with documented PH diagnosis fulfilled the study criteria. The mean age of the study population was 6.94 ± 1.52 years (range: 3–10 years), and the study population consisted of boys (50%) and girls (50%) equally. All the patients had normal MRIs, while 95% of them had normal EEGs. The one who had abnormal EEG and remained in the study had epileptic discharge but without seizure. Demographic and clinical variables are presented in detail in Table 1.

Table 1.

Demographic and clinical characteristics of the study population

Variable	Descriptive statistics
Age (years), mean±standard deviation	1.52±6.94
Gender (boys), n (%)	10 (50)
Weight (kg), mean±standard deviation	4.39±24.60
The interval between symptom initiation and treatment application (days), mean±standard deviation	86.18±88.85
Gestational age (≥37 weeks), n (%)	19 (95)
Route of delivery (cesarean section), n (%)	14 (70)
Electroencephalography (normal), n (%)	19 (95)
Magnetic resonance imaging (normal), n (%)	20 (100)

The results of Friedman’s test presented in Table 2 showed that the duration, frequency, and severity of the headaches were significantly different in at least one of the investigated times (P < 0.001). The results of Bonferroni correction test showed that the duration of the headaches was statistically less significant in all the postintervention assessments compared to the baseline, within a month (P = 0.005), in 2 months (P < 0.001), and in 3 months (P < 0.001). Besides, the headaches’ frequencies in children in the first (P = 0.006), second (P < 0.001), and third (P < 0.001) months of cyproheptadine use were significantly lesser in comparison to the study baseline. Also, the headaches’ severity scores were remarkably less in all the assessed intervals compared to the baseline (P = 0.007 for the first month, P < 0.001 for the second month, and P < 0.001 for the third month). Comparison of the intervals with each other revealed insignificant differences (P > 0.05). The effect size analysis showed that the greatest effect of the treatment was on the intensity of the headache (effect size: 0.866) and the least effect was on the duration of the headache (effect size: 0.775). Figure 2 shows the trend of headache changes in the assessed categories.

Table 2.

The effects of cyproheptadine on paroxysmal hemicrania

Variables	Baseline	Within a month	Within 2 months	Within 3 months	P a	Effect size
Duration (min)	2.5 [0, 2]	1 [0, 2]	1 [0, 2]	0 [2, 10]	<0.001	0.775
Frequency (per week)	16 [8, 32]	1.5 [0, 8]	1 [0, 2]	0 [0, 1]	<0.001	0.861
Severity (VAS)	8 [8, 9]	6 [0, 7.75]	2.5 [0, 6]	0 [0.5, 50]	<0.001	0.866

VAS=Visual analog scale. ^aFriedman’s test

Figure 2.

The trend of changes in headache characteristics brought about by prophylactic cyproheptadine

Drowsiness was the only adverse effect of the medication, which was experienced by one of the patients (5%). Increased appetite was noticed in six patients (30%); however, none of them gained weight significantly.

DISCUSSION

To the best of our knowledge, the current study is the first one assessing the use of cyproheptadine for PH prophylaxis. Findings of our study revealed that short-term cyproheptadine use in divided doses of 0.2–0.4 mg/kg twice daily could successfully lead to improved PH in terms of all characteristics including the frequency, duration, and severity of the headaches. Moreover, cyproheptadine use was accompanied by negligible adverse effects, which were limited to drowsiness in only one of the patients and increased appetite in 30% of them; however, weight gain was not remarkable.

Even though the term PH that has been categorized as one of the subtypes of TAC and has been explained since long time ago, its management has remained a matter of debate. Besides, the long-term use of indomethacin as a definite treatment for PH has not been well studied, while even with short-term use, one-third of the patients showed dose-limiting side effects and one-fifth of them discontinued indomethacin because of intolerability.[10] The other matter in this issue refers to the prophylactic approaches in contrast to therapeutic ones. The short period of the paroxysmal attacks might lead to inability to treat the patient as the headache might finish earlier than applying any medication.[1]

Cyproheptadine is an antagonist at the 5-hydroxytryptamine (5-HT2), histamine H1, and muscarinic cholinergic receptors, and is widely used for the prophylaxis of various conditions such as migraine, benign paroxysmal vertigo, migraine-associated cyclic vomiting syndrome, and benign paroxysmal torticollis.[5,6,7,8,11,12,13] The most significant adverse effects of this agent are sedation and weight gain.

Migraine prophylaxis is the most popular application of cyproheptadine, considering its serotonin-antagonizing and calcium channel-blocking properties. Drowsiness and weight gain are the major adverse effects limiting its use; nevertheless, a major body of evidence in the literature has favored this medication due to its significant impact on the frequency and intensity of the headaches. For migraine prevention, this agent has been used in diverse doses such as 0.25–1.5 mg/kg/day in divided doses, which is higher than that prescribed in our study.[14,15,16] Further investigations not only reveal the positive impact of cyproheptadine on usual migraines, but also its impact on the other subtypes such as abdominal migraine and vestibular migraine. In this regard, Cokyaman and Cetin[17] evaluated the efficacy of cyproheptadine on vestibular migraine in a study and found that over 85% of the patients showed remarkable decrease in the incidence and severity of their symptoms including vomiting and vertigo. The diagnosis of abdominal migraine is one of the challenging conditions for the pediatricians; nevertheless, numerous studies in the literature have reported dramatic alleviation of symptoms among those who received prophylactic treatment with cyproheptadine.[18,19]

As mentioned above, benign paroxysmal vertigo and torticollis are two other conditions that might be potentially prevented by using cyproheptadine. The paroxysmal and short-lasting nature of these disorders, characteristics that are similar to PH, has limited the therapeutic interventions; therefore, prophylaxis seems to be more logical when the attacks are short, frequent, and painful.[6,7,20] Given that, similar hypothesis inspired us to apply this prophylactic intervention for PH, as well.

Despite the paucity of knowledge regarding prophylactic use of cyproheptadine for PH, it has been examined for different types of TAC. Barløse et al.[21] reported promising outcomes after using this agent for the prophylactic management of patients suffering from cluster headaches, while Klapper et al.[22] opposed them due to lack of response of patients diagnosed with cluster headache to cyproheptadine. Similarly, a study by Qaiser et al.[9] reported insignificant impact of cyproheptadine use on three patients with TAC. Although the antiserotonin property of cyproheptadine has been considered, the key point for its application in TACs, as well as for PH in our study, the real pharmacodynamics and pharmacokinetics of this agent for PH remain unanswered. Besides, knowledge about the use of cyproheptadine in PH is not adequate and further longitudinal studies are required to generalize the data.

Limitations

The small study sample population and the short follow-up period are the major limitations of the current study. Furthermore, it is better to conduct a double-blinded study with a parallel group receiving placebo. Accordingly, further evaluations with a larger sample size, longer follow-up period, and double-blinded design can provide better views for headache control in children.

CONCLUSION

Findings of this study showed that short-term prophylactic cyproheptadine in two divided doses of 0.2–0.4 mg/kg could appropriately improve PH in terms of frequency, duration, and the intensity of the attacks. Nevertheless, further investigations are strongly recommended to generalize the study outcomes.

Financial support and sponsorship

Isfahan University of Medical Sciences sponsored the study with the grant number 3400889.

Conflicts of interest

There are no conflicts of interest.