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Abstract

The tricyclic antidepressant amitriptyline (AMT) and the calcium channel blocker flunarizine are frequently used in the preventive treatment of migraine, but the side-effect of prominent weight gain that frequently emerges during preventive treatment of migraine with these agents often leads to the discontinuation of therapy. In this study, we aimed to investigate the possible relationship between the weight gain associated with the use of these agents and serum levels of leptin, C-peptide and insulin in patient with migraine. Forty-nine migraine patients with a body mass index (BMI) < 25 and without any endocrinological, immunological or chronic diseases were randomly divided into two groups, receiving AMT or flunarizine. There was a statistically significant increase in serum levels of leptin, C-peptide, insulin and measures of BMI in both groups when measured at the 12th week of therapy compared to their respective basal levels. To our knowledge this is the first study investigating the effects of AMT and flunarizine on serum leptin levels in preventive use of migraine treatment. A result from this study indicates that AMT and flunarizine may cause leptin resistance possibly by different mechanisms and thereby result in increase in serum leptin levels and BMI.

Keywords

Migraine leptin weight gain flunarizine amitriptyline

Introduction

Migraine headaches are primary episodic headaches, seen at a rate of 18% in women and 6% in men, and manifest themselves with various neurological, gastrointestinal and autonomic changes (1, 2). Preventive treatment is applied in migraine patients who suffer from severe and frequent attacks that lead to functional loss in work place and/or home (3). In the preventive treatment of migraine, various groups of drugs are used, primarily beta-blockers, tricyclic antidepressants, calcium channel blockers and anticonvulsants (1, 3, 4). Amitriptyline (AMT), which is a tricyclic antidepressant, is frequently used in preventive treatment of this disorder (2, 5). The mechanism of action for AMT in the preventive treatment of migraine has not been fully elucidated, but it is known to inhibit the neuronal re-uptake of norepinephrin and serotonin(5-HT) in the brain (1, 3). Increased appetite, weight gain, dry mouth and sedation are the frequently encountered side-effects (1, 3, 6). Weight gain and increased appetite are particularly responsible for the early discontinuation of the preventive treatment of migraine that is more frequently seen in the female population. Another drug that is used in migraine preventive treatment is flunarizine, which is a calcium channel blocker (1, 3, 4, 7). Although its mechanism of action in preventive treatment of migraine is not fully understood, it has been suggested to inhibit hypoxia in cerebral neurons and the contraction of vascular smooth muscles, and to block the release of 5-HT related to neurovascular inflammation (8, 9). Its most frequently reported side-effects are weight gain and drowsiness (1, 3, 10). The weight gain side-effect that emerges during its use causes the discontinuation of treatment.

Leptin is an adipocyte hormone that regulates food intake and energy balance, and that also maintains the negative feedback between the satiety centre in the hypothalamus and the adipose tissue (11–14). Fasting serum levels of the hormones insulin and C-peptide are involved in the control the energy balance and glucose consumption of the body (11, 15). Leptin, insulin and C-peptide are hormones that closely monitor the energy balance and weight gain of the body. In our study, we aimed to investigate the relationship between the weight gain side-effect that frequently occurs during the use of AMT and flunarizine that were selected for the preventive treatment of patients with migraine and that causes the discontinuation of treatment, particularly in the female population, and the serum levels of leptin, insulin and C-peptide.

Materials and method

The protocol of this study was approved by the Local Ethics Committee. Each patient was informed about the study and consent forms were obtained.

A randomized open, prospective study was planned for patients between the ages of 16 and 50 who admitted to the Firat Medical Centre Neurology out-patient clinic over a planned period of 12 weeks and who were diagnosed as having migraine according to the criteria of the Headache Classification Committee of the International Headache Society (IHS) (16). Patients with migraine experiencing three or more attacks of severe headaches which lead to prominent functional loss in a month were included in the study. The patients were either newly diagnosed as being migraine sufferers or have not used any drugs for migraine prophylaxis in the previous 6 weeks. Exclusion criteria were as follows: presence of any concurrent psychiatric disease, any form of preventive treatment for migraine headaches during the previous 6 weeks, regular drug use including oral contraceptives, suffer from other causes of primary headaches, presence of chronic diseases (endocrinological, rheumatological, haematological, acute or chronic infectious and/or inflammatory), liver or kidney dysfunction, substance and alcohol abuse and BMI > 25. Neurological examinations and the cerebral radiological examinations of computerized tomography (CT) or magnetic resonance imaging (MRI) were performed in all patients. Baseline laboratory investigations (white blood cell count, differential counts, red blood cell count, creatinine, electrolytes, GOT, GPT, AP, γGT, Quick, partial thromboplastin time, serum electrophoresis, blood sedimentation rate, C-reactive protein, serum iron, transferrin, glucose) and thyroid function tests were also performed, and follicle stimulating hormone (FSH), luteinizing hormone (LH), prolactin, testosterone, growth hormone (GH), ACTH and cortisol serum levels were assessed and pelvic ultrasonography was performed to exclude polycystic ovary disease in women.

Each patient had a complete physical and neurological examination prior to being enrolled to the study. Prior to the commencement of preventive treatment, fasting blood samples were taken from the antecubital veins of patients at 9 a.m. in order to assess serum leptin, glucose, insulin and C-peptide levels and the performance of liver and kidney function tests. The blood samples were immediately centrifuged and plasma glucose levels measured with automatic glucose analyser (Beckman, Fullerton, CA, USA). Insulin (Serono Diagnostics, Freiburg, FRG), C-peptide (CIS Bio International, Cedex, France) and leptin (Human Leptin RIA kit, Linco Research, Inc., St. Charles, MO, USA) were determined in duplicate by commercially available radioimmunoassay kits with an interassay coefficient of variation of less than 5% for insulin and C-peptide. The interassay coefficient of variation for the leptin RIA was 5.5%. Patient height, weight, waist circumference and hip circumference were measured as well.

Twenty-five of the patients diagnosed as having migraines with or without aura, according to IHS criteria, requiring preventive treatment and recruited appropriate for age and sex were started on AMT 25 mg/day while another group of 24 patients with the same characteristics were started on flunarizine 10 mg/day. Acute treatment was administered when necessary. Height, weight, waist circumference and hip circumference measurements and serum level assays of leptin, glucose, insulin and C-peptide were performed in all patients prior to treatment and at the 4th and 12th weeks.

The statistical evaluation of data was performed using the SPSS 10.1 programme on a computer. In the assessment of repeating measurements of groups, test of variance analysis was used in repeated measurements (Two-way anova). Mann–Whitney U-test was used or the comparison of intergroup parameters while Spearman correlation test was used for the correlation analysis.

Results

Of the 49 patients included in the study, 39 patients completed the study. Five patients did not attend the regular follow-up. Three patients in the AMT group and one patient in the flunarizine group were excluded from the study because of intolerable side-effects due to the drugs (hypersomnia and orthostatic hypotension in the AMT group; fatigue and somnolence in the flunarizine group). One patient was excluded from the study because of surgical treatment applied after trauma. The demographic characteristics of the patients are shown in Table 1.

Table 1

Demographic characteristics of preventive treatment receiving groups

	Amitryptiline (n = 19)	Flunarizine (n = 20)
Age	33.36 ± 10.06	31.55 ± 10.23
Gender
Male	2 (10 .52%)	5 (25%)
Female	17 (89.48%)	15 (75%)
Migraine
With aura	5 (26.31%)	7 (35%)
Without aura	14 (73.69%)	13 (63%)

Upon comparison of BMI and serum levels of leptin, C-peptide, insulin and glucose between AMT and flunarizine groups, no statistical significance was detected between AMT and flunarizine groups (P > 0.05, Mann–Whitney U-test). When BMI, serum leptin, C-peptide and insulin values of patients in the AMT group were examined there was significant increase in all values of measures at 4th week and 12th week compared to their respective basal values (P < 0.01, Two-Way anova). At the same time, a positive correlation was determined between BMI and serum levels of leptin, C-peptide and insulin in AMT group (r = 0.590; r = 0.499; r = 0.485, respectively, P < 0.05, Spearman Correlation test).

In flunarizine group, there were statistically significant increase in BMI, serum leptin and C-peptide values at both 4th and 12th weeks compared to the values at baseline (P < 0.01, Two-Way anova). However, no significant correlation was detected between BMI and serum leptin and C-peptide levels in this group (r = 0.292; r = 0.257; r = 0.246, respectively, P > 0.05, Spearman Correlation test). Values among both groups were shown in Table 2.

Table 2

BMI, serum leptin, C-peptide and insulin levels of preventive treatment receiving groups

	Amitryptiline (n = 19)	Flunarizine (n = 20)
BMI
Baseline (kg/m²)	24.10 ± 0.89§ †	24.0 ± 0.87∗
4 week	25.22 ± 0.83	24.48 ± 0.84
12 week	25.55 ± 0.88	25.66 ± 0.95
Weight gain (kg)	3.2 ± 0.27	3.3 ± 0.67
C peptide (ng/ml)
Baseline	1.99 ± 0.12§ †	2.08 ± 0.10∗
4 week	2.78 ± 0.33	2.90 ± 0.16
12 week	3.60 ± 0.37	3.65 ± 0.33
Insulin (µU/ml)
Baseline	14.3 ± 6.4§ †	14.5 ± 6.7∗
4 week	15.4 ± 7.1	14.9 ± 6.5
12 week	16.3 ± 6.8	15.2 ± 7.3
Glucose (fasting mg/dl)
Baseline	88.0 ± 9	85.0 ± 7
4 week	91.0 ± 11	87.0 ± 10
12 week	93.0 ± 12	89.0 ± 8
Leptin (ng/ml)
Baseline	7.15 ± 1.13§ †	6.60 ± 1.36∗
4 week	12.31 ± 1.90	10.30 ± 2.87
12 week	16.85 ± 2.38	13.12 ± 2.17

Values are mean ± SEM.

P < 0.01, comparison between baseline and 12th week values of BMI, C-peptide, insulin and leptin in AMT group (two-way anova).

†

P < 0.05, positive correlation between BMI and C-peptide, insulin and leptin levels in AMT group (Spearman Correlation test).

∗

P < 0.01, comparison between BMI, C-peptide, insulin, leptin baseline and 12th week values in flunarizine group (two-way anova).

Discussion

Our study is the first study investigating the relationship between the weight gain side-effect of flunarizine and serum levels of leptin, insulin and C-peptide used when it's used in the preventive treatment of migraine. In both groups using flunarizine or AMT, a significant increase were detected in the BMI and serum leptin, C-peptide and insulin values at 12 weeks of treatment compared with pretreatment values (P < 0.01, Two-Way anova). Furthermore, a positive correlation was detected between the BMI and serum leptin, C-peptide and insulin levels in only the group receiving AMT (r = 0.590; r = 0.499; r = 0.485, respectively, P < 0.05, Spearman Correlation test). This is the first study reporting that AMT specifically increases serum leptin levels in migraine patients.

The aim of migraine preventive treatment is to reduce the frequency, duration and severity of headaches (1, 3, 17). When initiation of preventive treatment is needed, one of the first-line category drugs-namely the antidepressants, beta-adrenergic blockers, calcium channel antagonists, anticonvulsants and serotonin antagonists should be selected (1, 3, 17).

It has been reported that the tricyclic antidepressant amitriptyline is effective in migraine preventive treatment, as it reduces the frequency, duration and severity of headaches (3, 17, 18). It is still not fully evident through which mechanism AMT is effective in alleviating migraine headache. However, it inhibits re-uptake of both norepinephrine and 5-HT and acts as a 5-HT₂ receptor antagonist (19, 20). In addition, AMT have at least three other actions: blockade of muscarinic receptors, blockade of H1 histamine receptors, and blockade of alpha 1 adrenergic receptors (21). It has been reported that AMT also leads to dry mouth, constipation and sedation by anticholinergic action at muscarinic cholinergic receptors and cause weight gain by blockage of H1 histamine receptors (21). One of the side-effects of AMT treatment is weight gain (1, 3, 14, 18, 21, 22). Despite the lack of any conclusive evidence, it has been suggested that the weight gain effect of AMT may be due to high consumption of high energy beverages and increased desire for sweet foods as it leads to dry mouth (22, 23). In a study investigating the effect of psychotropic agents on body weight, it was found that AMP was inducing weight gain without increasing circulating levels of leptin (14). Whereas, in our study, a statistically significant increase was detected in BMI and serum levels of leptin, C-peptide and insulin in the group receiving AMT at both 4th and 12th weeks of therapy compared to the their respective values at baseline (P < 0.01, two-way anova). At the same time, a positive correlation was detected between BMI and serum levels of leptin, C-peptide and insulin in this group (r = 0.590; r = 0.499; r = 0.485, respectively, P < 0.05, Spearman Correlation test). The side-effect of AMT treatment that feeling of dry mouth increase desire and consumption to high energy containing beverages (22, 23). Thus, causes increased secretion of insulin which in turn leads to the elevation in serum levels of leptin (24). Experimental and clinical studies has demonstrated that insulin indirectly increases the leptin production in adipocytes by stimulating the oxidative glucose metabolism and utilization of glucose (25, 26). Insulin receptors which involved in eating behaviour have been shown to be present in several parts of brain including the arcuate nucleus (27). At the same time, intake of energy-producing substances has been reported to result in an increased acute leptin secretion (13). It is known that histaminergic neurons originating from the tuberomamillary nucleus of posterior thalamus send wide projections to the brain regions that involved in the energy regulation of the body (28). Histaminergic neurons are involved in the hypothalamic regulation of appetite and they suppresses the leptin induced food intake and levels of leptin (29). It has been demonstrated that neuronal appetite regulatory action of histamine involves postsynaptic H1-receptors in hypothalamus (30). In AMT group, intake of high energy beverages cause increase in serum levels of leptin and insulin, and increase in insulin secretion might also have secondary increasing affect on leptin levels. This hypothesis is consistent with the current literature. But, the controversial finding of increase of serum leptin levels was associated with the increase in BMI in AMT group, which is also a case in obese individuals, is likely be due to the yet not clarified fact that is also called leptin resistance (31). It has been suggested that leptin enters the brain by a saturable transport system and the capacity of leptin transport is lower in obese individuals, and this may provide a mechanism for leptin resistance (32). In another study, it has been reported that agents active at the alpha 1 adrenergic receptors are potent stimulators of leptin transporter located at the blood-brain barier (33). It is also possible that the alpha 1 adrenergic receptor blocking action of AMT may contribute to the leptin resistance by reducing leptin transport in blood brain barrier (BBB). The above mentioned mechanisms may underline, individually or in combination, our finding that there was an increase in serum leptin levels in parallel with the increase in BMI in patients treatment with AMT.

It is known that flunarizine, which is a calcium channel blocker, is widely used in the preventive treatment of migraine and that it reduces the frequency of attacks (3, 4, 34, 35). The mechanisms of action for the calcium channel blockers prevention of migraine are not fully understood. They are assumed to exert their beneficial effects in migraine treatment through the prevention of the hypoxia of cerebral neurons and the prevention of the contraction of vascular smooth muscles, and by inhibiting Ca²⁺ bound enzymes containing prostaglandin formation (3, 4, 17). Their most frequently seen side-effects are weight gain and drowsiness, followed by less frequently seen extrapyramidal (especially in elderly patients) and depressive symptoms (4, 36). It is still not known through which mechanisms flunarizine exerts its weight gain inducing effect. In our study, when BMI, serum leptin, C-peptide and insulin levels were statistically evaluated at baseline and at the 4th and 12th weeks of flunarizine treatment, a statistically significant increase was detected in the levels at 4th and 12th weeks compared with baseline measurements (P < 0.01, two-way anova). Leptin receptors are also present in the hypothalamus and they exert their effects on appetite and metabolic activity (13, 37). Moreover, acute leptin release has been reported to be calcium dependent (13). The peptide hormones ghrelin and neuropeptide-Y (NPY) are also having well known regulatory roles in food intake (38). It has been suggested that stimulatory effects of ghrelin and orexin are controlled by increase in cytosolic Ca²⁺ levels of NPY neurons in arcuate nucleus and this calcium increase may also play important role(s) in inhibition of leptin effects (38). The calcium channel blocking effect of flunarizine may mediate its actions on these systems. It is assumed that it can easily pass through the BBB due to the highly lipophilic property of the molecule and that it is probably associated with dopaminergic and serotoninergic neurotransmitter systems by acting on calcium channels on neuronal cell membranes in many places (34, 39). There is study reporting involvement of the protein nature transporters present in the BBB in the control of transport and the exchange of nutrients and lipophilic antimitotic and psychotropic drugs between the blood and brain (40). The weight gain despite the elevated serum leptin levels in flunarizine group is thought to be related to the leptin resistance. Due to its high lipophilic nature, flunarizine might interact with leptin transport system in the BBB and this may also contribute to the flunarizine induced leptin resistance. However, the calcium channel antagonist action of flunarizine in the central nervous system and its association with dopaminergic and serotoninergic neurotransmitter systems suggests that it may be related to the control of serum leptin levels (41).

In conclusion, by investigating the effects of AMT and flunarizine on serum leptin levels and BMI in migraine preventive treatment for the first time, we have found that the weight gain due to treatment with these agents was associated with significant increase in leptin levels. Thus suggesting leptin resistance, in addition to their effects on hypothalamic appetite centre, may mediate their weight gain inducing effect that often compromise their use in migraine treatment.

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Comparison of the Effects of Amitriptyline and Flunarizine on Weight Gain and Serum Leptin,C Peptide and Insulin Levels when used as Migraine Preventive Treatment

Abstract

Keywords

Introduction

Materials and method

Results

Discussion

References