AIM:

To explore a possible differential effect of sumatriptan on extracerebral versus cerebral arteries, we examined the superficial temporal (STA), middle meningeal (MMA), extracranial internal carotid (ICAextra), intracranial internal carotid (ICAintra), middle cerebral (MCA) and basilar arteries (BA).

METHODS:

The arterial circumferences were recorded blindly using high-resolution magnetic resonance angiography before and after subcutaneous sumatriptan injection (6 mg) in 18 healthy volunteers.

RESULTS:

We found significant constrictions of MMA (16.5%), STA (16.4%) and ICAextra (15.2%) ( P  ≤ 0.001). Smaller, but statistically significant, constrictions were seen in MCA (5.5%) and BA (2.1%) ( P  ≤ 0.012). ICAintra change 1.8% was not significant ( P  = 0.179). The constriction of cerebral arteries was significantly smaller than the constriction of extracerebral arteries ( P  < 0.000001).

CONCLUSION:

Sumatriptan constricts extracerebral arteries more than cerebral arteries. We suggest that sumatriptan may exert its anti-migraine action outside of the blood-brain barrier.

INTRODUCTION:

If a drug has a slow dissociation from the receptor this can result in a long duration of effect and a slow effect. The long duration of the antimigraine effect of dihydroergotamine (DHE) has been reported previously whereas a possible slow onset of DHE's antimigraine effect, which is the subject of this review, has only rarely been mentioned.

METHODS:

Eight randomised, controlled trials (RCT) with DHE for acute treatment with migraine were selected from the literature. The speed of the effect of DHE in migraine was evaluated by plotting the effect up to four hours against time.

FINDINGS:

Subcutaneous DHE 1 mg was inferior to subcutaneous sumatriptan 6 mg for headache relief for the first two hours but equally effective after three hours. After intranasal DHE 2 mg the mean therapeutic gain increased slowly up to four hours. For orally inhaled DHE 0.5 mg there was a considerable time lag between therapeutic gain (maximum after two hours) and plasma concentrations of DHE (Tmax = 12 min).

CONCLUSION:

DHE has a slow dissociation from the receptor; and this basic attribute of the drug is the most likely cause of the general relatively slow anti-migraine effect of DHE.

Kainic acid (KA) is an excitatory and neurotoxic substance. The role of α-calcitonin gene-related peptide (α-CGRP) in the regulation of KA-induced hippocampal neuronal cell death was investigated in the present study. The intracerebroventricular (i.c.v.) administration with KA (0.07μg) increased hippocampal α-CGRP mRNA level in ICR mice. The α-CGRP mRNA level began to increase at 1h, reached at maximal level at 6 and 12h, and returned to the control level by 24h after i.c.v. administration with KA. In addition, KA-induced hippocampal CA3 neuronal death in C57BL6 (wild type) group was more pronounced compared to KA-induced hippocampal CA3 pyramidal cell death in α-CGRP knock-out (KO) group. Furthermore, sumatriptan, a CGRP releasing inhibitor, significantly protected the pyramidal cell death in CA3 hippocampal region induced by KA administered i.c.v. in ICR mice. Our results suggest that α-CGRP may play an important role in the regulation of KA-induced pyramidal cell death in CA3 region of the hippocampus.

AIMS:

The present study analyzed the potential antinociceptive effect of the antimigraine drugs sumatriptan, dihydroergotamine or methysergide in rats submitted to the formalin test. Moreover, by using selective antagonists, the role of 5-HT1B/1D serotonergic receptors was investigated in the antinociception induced by these antimigraine drugs. MAIN

METHODS:

The formalin test was used to assess the nociceptive activity. Overt pain-like behavior (flinching, 1h) and evoked nociception (long-lasting secondary mechanical allodynia and hyperalgesia, 6days) were determined in the same rat. KEY

FINDINGS:

Ipsilateral, but not contralateral, pre-treatment (in μg/paw) with sumatriptan (10-300), methysergide (1-30) or dihydroergotamine (1-30) significantly prevented flinching behavior (at 1h) as well as secondary allodynia and hyperalgesia (at day 6) induced by formalin. Interestingly, the antinociceptive (flinching), antiallodynic and antihyperalgesic effects of sumatriptan were completely prevented by peripheral pre-treatment with selective antagonists at the 5-HT1B (SB 224289; 100) or 5-HT1D (BRL 15572; 100) receptors. In contrast, the acute antinociceptive effects of methysergide and dihydroergotamine were partially prevented by SB 224289 and BRL 15572. The antiallodynic and antihyperalgesic effects of both drugs were completely prevented by BRL 15572 and partially prevented by SB 224289. Given alone, SB 224289 or BRL 15572 did not modify per se the long-lasting secondary allodynia and hyperalgesia.

SIGNIFICANCE:

The above findings suggest that: (i) the antimigraine drugs sumatriptan, methysergide and dihydroergotamine reduce the acute and chronic nociception induced by formalin; and (ii) this antinociceptive effect results from activation of peripheral 5-HT1B/1D serotonergic receptors.

Migraine is a common disease in children and adolescents. The incidence of migraine has increased alarmingly in the general population during recent decades. Migraine causes considerable individual suffering and impaired quality of life. Therefore, appropriate management is essential. In this article, the treatment of acute migraine in children and adolescents will be reviewed. Only a few randomized controlled studies have been published and high placebo rates are a major problem for proving superiority of active drugs. Generally, acetaminophen (paracetamol) and ibuprofen are accepted as drugs of first choice, even though the evidence is poor for the former and limited for latter. Among 14 studies on triptans in adolescents, 9 showed some superiority over placebo with respect to pain relief and pain freedom, and among 6 studies in children, 5 suggest some superiority over placebo. Sumatriptan nasal spray and zolmitriptan nasal spray have been approved for adolescents in Europe; almotriptan has been approved for adolescents in the USA, as has rizatriptan for patients aged 6-17 years. A recent study demonstrated the efficacy of a fixed combination of sumatriptan and naproxen in adolescents with migraine. In conclusion, evidence for the pharmacological treatment of acute migraine in children is very poor and evidence for adolescents is better but still limited.

Serotonin (5-HT) modulates pain and anxiety from within the midbrain periaqueductal grey (PAG). In the present study, the effects of 5-HT and 5-HT1/2 subtype selective ligands on rat PAG neurons were examined using whole-cell patch-clamp recordings in brain slices. In voltage clamp, 5-HT produced outward and inward currents in distinct subpopulations of neurons which varied throughout different subregions of the PAG. The 5-HT1A agonist R(+)-8-OH-DPAT (1 µM) produced outward currents in subpopulations of PAG neurons. By contrast, sumatriptan (1 µM) and other 5-HT1B,D and F subtype agonists had little, or no postsynaptic activity. The 5-HT2A/C agonists DOI (3 µM) and TCB-2 (1 µM) produced inward currents in subpopulations of PAG neurons, and DOI enhanced evoked IPSCs (inhibitory postsynaptic currents) via a presynaptic mechanism. In current clamp, both R(+)-8-OH-DPAT and sumatriptan produced an excitatory increase in evoked mixed PSPs (postsynaptic potentials). In addition, R(+)-8-OH-DPAT, but not sumatriptan directly hyperpolarised PAG neurons. By contrast, the 5-HT2 agonist DOI depolarised subpopulations of neurons and produced an inhibitory decrease in evoked mixed PSPs. These findings indicate that 5-HT1A and 5-HT1B/D ligands have partly overlapping inhibitory effects on membrane excitability and synaptic transmission within the PAG, which are functionally opposed by 5-HT2A/C actions in specific PAG subregions.

Abstract Many efficacy endpoints have been used in clinical trials of acute migraine pharmacotherapy. Headache response or headache relief (i.e., moderate/severe pain reduced to mild/no pain) at a single, specified time-point, traditionally the primary endpoint, and headache recurrence (i.e., return of pain after initial postdose relief) are inadequate. Headache relief does not provide information about pain-free response and counts a partial response as a treatment success. Headache recurrence can reflect sustained efficacy but is confounded by initial response to treatment, because ineffective drugs have low recurrence rates. The International Headache Society (IHS) guidelines state that 2 hour pain-free response and sustained pain-free response (i.e., freedom from pain with no recurrence or use of rescue or study medication 2-24 hours postdose) provide the most clinically relevant information about the efficacy of migraine pharmacotherapy. The pain-free criterion counts partial responses as failures and thus is a more rigorous test of therapeutic benefit than headache relief, and the two endpoints together incorporate the main treatment attributes that determine patient satisfaction. As an example, consider needle-free subcutaneous sumatriptan and oral triptan tablets. An open-label study of needle-free subcutaneous sumatriptan by Cady and colleagues found that 2 hour pain-free response and sustained pain-free response were 64% and 42% respectively. For oral triptan tablets, the 2001 metaanalysis by Ferrari and colleagues reported 2 hour pain-free response rates ranging from 23% to 38% and sustained pain-free response rates ranging from 11% to 26%. The measures of pain-free response 2 hours postdose and sustained pain-free response can differentiate among treatments and be used to guide therapeutic choices.

The application of the potentiometric multisensor system (electronic tongue, ET) for quantification of the bitter taste of structurally diverse active pharmaceutical ingredients (API) is reported. The measurements were performed using a set of bitter substances that had been assessed by a professional human sensory panel and the in vivo rat brief access taste aversion (BATA) model to produce bitterness intensity scores for each substance at different concentrations. The set consisted of eight substances, both inorganic and organic - azelastine, caffeine, chlorhexidine, potassium nitrate, naratriptan, paracetamol, quinine, and sumatriptan. With the aim of enhancing the response of the sensors to the studied APIs, measurements were carried out at different pH levels ranging from 2 to 10, thus promoting ionization of the compounds. This experiment yielded a 3 way data array (samples×sensors×pH levels) from which 3wayPLS regression models were constructed with both human panel and rat model reference data. These models revealed that artificial assessment of bitter taste with ET in the chosen set of API's is possible with average relative errors of 16% in terms of human panel bitterness score and 25% in terms of inhibition values from in vivo rat model data. Furthermore, these 3wayPLS models were applied for prediction of the bitterness in blind test samples of a further set of API's. The results of the prediction were compared with the inhibition values obtained from the in vivo rat model.

If you vomit with migraines, get full-blown migraines upon awakening, or want rapid relief without injections, consider a nasal spray. Options include triptans (zolmitriptan [Zomig] or sumatriptan [Imitrex]), DHE (Migranal), or an NSAID (Sprix).

To assess ictal adiponectin (ADP) levels before and after acute abortive treatment in women episodic migraineurs.Peripheral blood specimens were collected from women episodic migraineurs before and after acute abortive treatment with sumatriptan/naproxen sodium vs placebo. Univariate and multivariate models were utilized to examine the relationship between serum total ADP (T-ADP), ADP oligomers (high molecular weight [HMW], middle molecular weight, and low molecular weight [LMW]-ADP), and ADP ratio levels and pain severity. Paired t-tests and random intercept longitudinal models were utilized to assess the mean changes in T-ADP, ADP oligomers, and ratios over time in treatment responders and nonresponders.Twenty participants (11 responders, 9 nonresponders) have been studied to date. In all participants, increases in the HMW : LMW ADP ratio were associated with an increase in pain severity. For every 1 point increase in the HMW : LMW ratio, pain severity increased by 0.22 (Confidence Interval [CI]: 0.07, 0.37; P = .004). In contrast, for every 0.25 μg/mL increase in LMW-ADP, pain severity decreased by 0.20 (CI: -0.41, -0.002; P = .047). In treatment responders, T-ADP levels were reduced at 30 minutes (12.52 ± 3.4; P = .03), 60 minutes (12.32 ± 3.2; P = .017), and 120 minutes (12.65 ± 3.2; P = .016) after treatment as compared with onset (13.48 ± 3.8). Additionally, in responders, the HMW : LMW ratio level was greater at pain onset (3.70 ± 1.9 μg/mL) as compared with nonresponders (2.29 ± 0.71 μg/mL), P = .050. Responders also showed a decrease in the HMW : LMW ratio at 60 minutes (2.37 ± 1.1; P = .002) and 120 minutes (2.76 ± 1.4; P = .02) after treatment as compared with onset (3.70 ± 1.9). These changes in responders remained significant after adjusting for covariates, including measured body mass index (m-BMI). Although nonresponders showed no significant changes in unadjusted T-ADP or ADP oligomer or ratio levels, the HMW : LMW ratio was increased in nonresponders after adjustments (P = .025).In this pilot study of women episodic migraineurs, the HMW : LMW ADP ratio level was associated with migraine severity and predictive of acute treatment response. ADP and the HMW : LMW ratio of ADP represent potential novel biomarkers and drug targets for episodic migraine.