Effects of Subcutaneous Sumatriptan on Plasma Growth Hormone Concentrations in Migraine Patients

Abstract

The purpose of this study was to assess the sensitivity of 5-HT_1D receptors in migraine using sumatriptan as a pharmacological probe. The drug stimulates the release of growth hormone (GH) and this effect may be used to explore the function of cerebral serotonergic systems in vivo. We administered sumatriptan and placebo to 15 migraineurs and to 10 controls. Blood samples were collected -15, 0, 15, 30, 45, 60 and 90 min after injection. Placebo had no effect on hormone concentrations. Sumatriptan induced a significant (P < 0.01) increase in GH concentrations both in migraine patients and healthy controls. The GH increase was not significantly different in the two groups. Our results suggest that cerebral serotonergic functions mediated by 5-HT_1D receptors are not altered in migraine. Sumatriptan overuse could lead to adverse effects mediated by its neuroendocrine activity.

Introduction

Serotonin(5-HT) is thought to play an important role in the pathogenesis of migraine. Several clinical studies have shown changes in circulating levels of serotonin and its metabolites during migraine attacks (1, 2). Serotonergic agents may induce migraine-like symptoms (3, 4) while pharmacological agents that modulate 5-HT receptors are effective both in attacks and in migraine prophylaxis (5, 6). However, despite several clinical and experimental investigations, the precise mechanism of serotonin involvement in migraine has not been fully established (7).

Sumatriptan is a 5HT_1B/1D receptor agonist effective in the treatment of acute migraine attacks. Several studies in healthy volunteers (8–10) have shown that the subcutaneous administration of the drug induces a significant increase in growth hormone (GH) plasmatic concentrations. The secretion of GH from pituitary is controlled by several neurohormones and neurotransmitters. Studies in humans and experimental animals have shown that the increase of GH concentrations after sumatriptan administration is mediated through the specific activation of 5-HT_1D receptors, located both pre- and postsynaptically (8, 11). This effect has been used as a neuropharmacological tool in several psychiatric and neurological diseases, like major depression and Parkinson's disease, in order to explore cerebral serotonergic functions in vivo (12–15). At present, despite the frequent use of the drug, no data in migraine patients are available.

The main purpose of this study was to assess the sensitivity of 5HT_1D receptors in migraine patients using subcutaneous sumatriptan as a pharmacological challenge test. Several authors postulated that migraine is related to a 5-HT receptors hypersensitivity (16) but available experimental data are scarce (17, 18).

We studied a group of migraine patients (with and without aura) and healthy controls to verify the hypothesis of an abnormal sensitivity of 5-HT_1D receptors in the disease.

Methods

Subjects

Fifteen migraine patients (10 females, five males; mean age ± SD = 28.4 ± 7.6 years) were recruited from the out-patient population at the Headache Centre of the University of Torino. The diagnosis of migraine was made according to the International Headache Society criteria (IHS) (19). Six patients (four females, two males) fulfilled IHS criteria for migraine with aura and nine patients (seven females and two males) for migraine without aura. Mean duration (± SD) of the disease was 13.5 ± 8.4 years. Mean frequency of the crises (± SD) was 48 ± 25.5 days with headache per year. All patients were in the headache-free period and did not take prophylactic anti-migraine treatment for at least 2 weeks prior to testing. Patients with mood or anxiety disorders were excluded (State-Trait Anxiety Inventory-X1, -X2 and Beck Depression Inventory).

Ten healthy volunteers (six females, four males; mean age ± SD = 28.3 ± 3.7 years), matched for age, sex and phase of the menstrual cycle, served as controls. All subjects gave their informed consent to the study.

Procedures

The study was conducted at the Headache Centre of the University of Torino (Italy) according to a standardized protocol. Each subject underwent two tests, one with subcutaneous sumatriptan (6 mg) and the other with placebo (2 ml subcutaneous saline), in a double blind fashion. In each subject the tests were separated by 3–6 days. Testing began at 09.00 after overnight fasting. All subjects were confined to bed and were not allowed to eat or to sleep. An indwelling intravenous catheter was inserted in a forearm vein and kept patent with a slow infusion of 0.9% NaCl. A 45−min period was allowed for relaxation. Two baseline blood samples (−15 and 0 min) were taken. Subsequent blood samples were taken at + 15, + 30, + 45, + 60 and + 90 min after injection.

Assays

Blood samples were collected into sterile tubes. Tubes were immediately centrifuged at 4°C and the plasma was stored at −80°C until assayed. Plasma GH concentrations were measured using a commercially available IRMA kit (HGH-CTK, Sorin, Saluggia, Italy). The sensitivity of GH assay was 0.15 µg/l. The intra-assay and inter-assay coefficients of variation (± SD) were 5.1–7.5% and 2.6–5.4%. All samples from each subject were analysed in the same assay. One control subject had a raised baseline level of GH (6.9 µ/l) and the results of this test were discarded from the GH analysis.

Statistics

The statistical evaluation was performed using GBSTAT – version 6.5. anova for repeated measures and Student's t-test were used, comparing both mean hormone peak values and area under the secretory curve (AUC). AUC was calculated by a trapezoidal method. Data are reported as mean ± SEM. The level of statistical significance was taken at P < 0.05.

Results

After sumatriptan injection both healthy subjects and migraine patients reported mild and transients side-effects, like feelings of heaviness, pressure on the chest, warmth and dizziness.

Basal GH concentrations were not significantly different in healthy controls and migraine patients both in the placebo and in the drug test (controls: 0.30 ± 0.14 and 1.23 ± 0.64 µ/L; migraine patients: 0.44 ± 0.13 and 0.35 ± 0.05 µ/l at time 0; values are mean ± SEM).

Figure 1 shows the effects of placebo and sumatriptan administration on GH concentrations in healthy controls and migraine patients. Total GH secretion after sumatriptan and placebo, expressed as AUC, is illustrated in Fig. 2.

Figure 1

Mean ±SEM GH secretion after placebo (▴–▵) (2 ml saline, s.c., at 0 min) and after sumatriptan (•–○) (6 mg, s.c., at 0 min) in healthy controls and migraine patients. Vertical bars indicate SEM.∗P < 0.05, ∗∗P < 0.01 in comparison with values at time 0.

Figure 2

GH secretion, expressed as AUC, after placebo and after sumatriptan in healthy controls and in migraine patients. Vertical bars indicate SEM. (P = n.s.).

The administration of sumatriptan induced a significant increase (P < 0.05 at times 30 and 90 min; P < 0.01 at 45 and 60 min in comparison with values at time 0) of GH concentrations both in controls and migraine patients (Fig. 1). No significant difference in sumatriptan-induced GH release was found in the two groups (Fig. 1 and Fig. 2). Placebo had no significant effect on plasma GH concentrations.

Twenty per cent of migraine patients and 11.1% of controls showed no increase of GH plasmatic concentrations after drug administration (no single point value higher than value at time 0).

The comparison of GH response to sumatriptan in migraine patients with and without aura showed no significant difference (AUC: 248.5 ± 77.5 in patients affected by migraine with aura, 306 ± 119.6 in patients with migraine without aura).

In migraine patients no correlation was found between duration of the disease and sumatriptan-induced GH release, expressed as AUC.

Discussion

The results of our study suggest that in migraine patients during the headache-free period there is no alteration in 5-HT_1D receptors sensitivity. The GH response to sumatriptan challenge was the same in the group of migraine patients and in healthy controls. Furthermore, no significant difference between migraine with aura and migraine without aura patients was found.

The neuroendocrine challenge paradigm is considered a powerful research tool in headache research (20). However, since this is the first study to measure 5-HT_1D receptor responsivity in migraine patients using sumatriptan as a pharmacological probe, the findings of this study must be considered preliminary.

5-HT receptor function in migraine patients has been scarcely investigated. Using positron emission tomography and 18F-fluorosetoperone, a 5-HT₂ specific radioligand, Chabriat et al. (21) showed that cortical 5-HT₂ receptors are unaltered in migraine sufferers between attacks. Neuroendocrine studies have been performed using fenfluramine and m-chlorophenylpiperazine (mCPP), the principal metabolite of trazodone, and evaluating the effects of these drugs on pituitary secretion. In the headache-free period, the prolactin response to fenfluramine was higher in migraine patients than in controls (22), suggesting a central5-HT hypersensitivity. After mCPP administration, Gordon et al. (23) found no statistically significant differences in neuroendocrine responses between the migraine subjects and the normal subjects, while Leone et al. (18) demonstrated a significantly higher increase of prolactin release in migraine without aura patients than in controls and suggested that cerebral 5-HT_1A receptors are hypersensitive in the disease. However, mCPP is characterized by a large variability in the pharmacokinetic and pharmacodynamic parameters and it is doubtful whether it is a useful compound for challenge tests (24). Additional studies on the functional status of 5-HT receptors in migraine are needed.

Several studies showed that approximately 20% of migraine patients do not respond to oral or subcutaneous sumatriptan (so-called sumatriptan non-responders) (25, 26). At present, no clear risk factor for the absence of a clinical response to the drug has been identified (27) and the mechanisms underlying this phenomenon are still to be clarified.

In our study, we observed that a similar percentage of healthy controls and migraine patients showed no GH increase over basal concentrations after sumatriptan injection. The phenomenon was observed in a similar percentage of healthy volunteers involved in other studies (14, 28). The failure of GH response to all known CNS-mediated stimuli in humans commonly occurs in 15–20% of subjects (29) and this fact probably depends on a physiological phase of somatostatin hyperactivity at the moment of the application of the stimuli. Additional factors cannot be ruled out.

Additional studies in migraine patients are necessary to evaluate the possibility of a relationship between the absence of the clinical response to the drug and the neuroendocrine response.

Recently, population-based studies showed that a percentage of migraineurs use sumatriptan too often (sumatriptan ‘overuse’ or ‘misuse’) (30, 31). A small group of patients (4%) take the drug daily or more than 10 times each week while approximately 20% of migraine patients use sumatriptan more than 10 times each month (30). At present, no clinical symptom related to sumatriptan overuse has been described and the long-term health effects of sumatriptan overuse are not known. The results of our study suggest it is necessary to investigate patients with sumatriptan overuse for symptoms related to altered GH secretion.