Polymorphisms of the Proinflammatory Cytokine Genes Modulate the Response to NSAIDs but Not to Triptans in Migraine Attacks.

Migraine is a common neurovascular disorder characterized by recurrent episodes of headache and associated neurological symptoms. At present, a significant portion of patients do not obtain a satisfactory response to acute pain-relieving therapies, including NSAIDs and triptans. In this context, pharmacogenetics plays a key role in the understanding of such a diverse response. In order to investigate whether functional polymorphisms in proinflammatory cytokine genes (IL-1α, IL-1ß, IL-1RN; IL-6 and TNF-α) may influence the response to acute treatment, 313 consecutive patients with episodic migraine without aura were enrolled. Pain relief by administration of NSAIDs or triptans for three consecutive migraine attacks was evaluated. We found a significant association between A allele of the TNF-α promoter (−308 A/G) and a lack of efficacy after NSAID administration (p < 0.01, OR 2.51, 95% CI: 1.33 < OR < 4.75 compared to the G allele). Remaining polymorphisms had no significant effect on pain relief. Our study showed that a functional polymorphism in the TNF-α gene significantly modulates the clinical response to NSAID administration in acute attacks. Patients with higher production of the active cytokine during stress showed a significantly lower anti-migraine effect. Our results further support a role for TNF-α in the pathophysiological mechanisms of migraine attack.

Comparison of the Effect of Tanacethum Parthenium, 5-Hydroxy Tryptophan, and Magnesium (Aurastop) versus Magnesium Alone on Aura Phenomenon and Its Evolution.

None of the clinical trials on migraine conducted thus far have focused on the possibility to modulate the phenomenon of aura. Furthermore, whether proper management of aura results in a better control of the headache phase has been poorly investigated. In the setting of a single-center, pilot, clinical trial, we aimed at comparing the effects of Aurastop (a combination of tanacetum parthenium (150 mg extracted at 0.8% = 1.2 mg di of active parthenolide), griffonia simplicifoila (20 mg of 5-hydroxy tryptophan), and magnesium (185 mg of magnesium pidolatum)) with those of magnesium alone (2.25 grams/tablet, corresponding to 184 mg of Mg++) in the treatment of acute attacks of migraine with aura. Between June 2017 and June 2018, 50 consecutive patients (27/23 male/female; mean age, 31 [18-57] years) with at least 3 episodes of aura per year were included (t 0). Participants were instructed to keep track of the following 4 episodes of migraine with aura (t 1) and invited to assume (1) a tablet of Aurastop at the beginning of the following 2 episodes of aura and (2) a magnesium tablet alone at the occurrence of the third and fourth aura attacks. Forty-eight patients (96.0%) had >50% reduction in aura duration when treated with Aurastop vs. 7 patients (14.0%) when treated with magnesium alone (p < 0.001); 48 patients (96.0%) had >50% reduction of aura-related disability when receiving Aurastop vs. 5 patients (10.0%) when treated with magnesium alone (p < 0.001); however, patients receiving Aurastop did not need to take pain killers in 35% of aura attacks vs. 3% when assuming magnesium (p < 0.001). These results support the hypothesis that Aurastop might be effective in interfering with the phenomenon of aura and provide evidence that the clinical benefit attributable to this combination of molecules might be greater than that obtained with single compounds of proven effect on the biology of migraine.

Prevalence of headache attributed to aeroplane travel in headache outpatient populations: An Italian multicentric survey.

BACKGROUND: To assess the prevalence of headache attributed to aeroplane travel (AH) in patients referred to Italian Headache Centres. MATERIAL AND METHOD: 869 consecutive patients visiting six Italian headache centres during a 6 month-period (October 2013 to March 2014) were enrolled in the survey. Among them, 136 (15.6%) had never flown and therefore were excluded from the study. The remaining 733 patients (f = 586, m = 147; age 39.1 ± 17.3) were asked about the occurrence of headache attacks during flight; those who answered the question positively filled in a detailed questionnaire that allowed the features of the attacks to be defined. RESULTS: Headache attacks during the flight was reported by 34/733 subjects; four presented attacks fulfilling ICHD-3 beta (1) criteria for migraine without aura and therefore were not further considered. The features of the remaining 30 (4.0%; m = 18, f = 12, age 36.4 ± 7.3) completely fulfilled the ICHD-3 beta criteria for AH. In more detail, the pain was unilateral (fronto-orbital: n = 23; fronto-parietal: n = 7; without side-shift: n = 25, with side-shift: n = 5), lasting up to 30 min in 29 subjects. All the patients reported the pain as very severe or unbearable and landing as the phase of travel in which the attack appeared. In four cases, a postictal, milder, dull headache could last up to 24 hours. Accompanying symptoms were present in eight cases (restlessness: n = 5; conjunctival injection and tearing: n = 2; restlessness + ipsilateral conjunctival injection and tearing: n = 1). The fear of experiencing further attacks negatively affected the propensity for future flights in 90.0% of subjects (n = 27). In all the patients, AH onset did not coincide with the first flight experience. Concomitant migraine without aura was diagnosed in 24, tension-type headache in four, migraine without aura + tension-type headache in two cases; none suffered from cluster headache. Five subjects reported AH on each flight, 20 in > 50% of flights, five occasionally. Despite the severe intensity of the pain, only one third of this sample spontaneously reverted to a pharmacological treatment; the most useful strategy combines a decongestant nasal spray plus the intake of a simple analgesic 30 min before the estimated attack. Spontaneous manoeuvres were applied by 18 patients (Valsalva-like: n = 12; compression: n = 2; both manoeuvres: n = 4), more often without significant improvement. These data confirm our previous finding on the clinical features of AH. CONCLUSION: AH was found in 4.0% of a multicentre, large sample of patients with flight experiences. Although limited to a sample of patients followed in six Italian headache centres, to the best of our knowledge these are the first epidemiological data on AH gathered by direct interview. If properly investigated, AH seems to be a not infrequent condition, which, when diagnosed, could probably be prevented in many cases.

Efficacy of frovatriptan as compared to other triptans in migraine with aura.

BACKGROUND: The treatment of migraine attacks with aura by triptans is difficult since triptans most probably are not efficacious when taken during the aura phase. Moreover, there are insufficient data from randomised studies whether triptans are efficacious in migraine attacks with aura when taken during the headache phase. In this metaanalysis, we aimed to compare the efficacy of frovatriptan versus rizatriptan, zolmitriptan, and almotriptan. METHODS: Five double-blind, randomized, controlled crossover trials were pooled. All trials had an identical design. Patients were asked to treat three consecutive migraine attacks with frovatriptan 2.5 mg and three consecutive migraine attacks with a comparative triptan (rizatriptan 10 mg; zomitriptan 2.5 mg; almotriptan 12.5 mg). RESULTS: In this analysis, 117 migraine attacks with aura could be included (intention-to-treat population). The mean headache intensity after 2 hours was 1.2 +/- 1.0 for frovatriptan and 1.6 +/- 1.0 for the other triptans (p<0.05); all triptans showed significant improvement of headache. Frovatriptan resulted in significantly lower relapse rates at 24 hours and 48 hours when taken in migraine attacks with aura. CONCLUSIONS: Our data suggest that frovatriptan is efficacious and even superior in some endpoints also when taken during the headache phase in migraine attacks with aura. This is of particular importance for those many patients who have migraine attacks both without and with aura.

KCNK18 (TRESK) genetic variants in Italian patients with migraine.

OBJECTIVES: To evaluate the prevalence of KCNK18 gene mutations in a dataset of Italian migraineurs, with and without aura, and in healthy controls, and to investigate in silico the functional effects of the mutations. BACKGROUND: A role for the KCNK18 gene encoding for TRESK, a member of the family of potassium channel, has been recently suggested in migraine with aura. METHODS: We sequenced the KCNK18 gene in 425 migraineurs (255 with aura and 170 without aura) and 247 healthy controls. RESULTS: Five genetic variants (R10G, C110R, Y163Y, S231P, and F372L) were found in 13 (5.1%) out of 255 migraine with aura patients, and 6 variants (R10G, D46D, C110R, Y163Y, S178T, and S231P) were identified in 12 (7.1%) out of 170 migraine without aura patients. In 2.8% of controls, the R10G and L20V substitutions were found. In silico analysis suggested that C110R, S178T, S231P, and F372L mutations may have potential damaging effect on channel function, whereas the remaining mutations may have low damaging effect. CONCLUSIONS: Our study shows the presence of several KCNK18 gene mutations in both migraine with aura and migraine without aura. However, the precise role of this gene in migraine predisposition deserves further studies.

Efficacy and pharmacokinetic activity of frovatriptan compared to rizatriptan in patients with moderate-to-severe migraine.

BACKGROUND: Migraine is a painful neurological disorder that affects over 10% of the general population. Frovatriptan and rizatriptan are antimigraine agents belonging to the triptan class. Although previous studies have independently compared the efficacy of these agents, contemporaneous data examining both pharmacokinetic (PK) properties and efficacy in parallel have not previously been available. MATERIALS AND METHODS: In this single-center double-blind study, 18 subjects (ten female) were treated for a single migraine attack with frovatriptan 2.5 mg or rizatriptan 10 mg. Plasma concentrations were measured predose and at 2, 4, 6, 12, 24, 48, and 72 hours after drug administration. The primary end point of this study was to evaluate the association between PK parameters and efficacy measures and recurrence rate. Secondary end points were pain-free and pain-relief episodes at 2 and 4 hours, recurrent episodes within 48 hours, and cumulative hazard of recurrence within 72 hours. RESULTS: At baseline, approximately 17% of patients had mild migraine, while 83% had moderate-severe migraine. Although the time to maximum concentration was similar for both drugs (2.7 versus 2.3 hours), the terminal half-life for frovatriptan was longer than rizatriptan (29.3 versus 3.2 hours, P<0.0001). The proportion of patients who were pain-free at 4 hours without rescue medication was higher in the frovatriptan-treated group, (38.9 versus 5.6%, P=0.045). The cumulative hazard of recurrence over 72 h was reduced by frovatriptan compared to rizatriptan-treated patients (log-rank test, P=0.04). Pain-free and pain-relief episodes for the study period were positively correlated with the concentration:maximum concentration (Cmax) ratio for frovatriptan (r=0.52, P=0.028), but not rizatriptan. Recurrence rate was negatively correlated with the concentration:Cmax ratio for both frovatriptan (r=-0.96, P=0.0024) and rizatriptan (r=-0.98, P=0.0004). Fewer adverse events were observed for frovatriptan compared to rizatriptan (one versus eight, P=0.021). CONCLUSION: This pilot study indicates that a similar extent of initial pain relief is afforded by both triptans in migraine treatment. The longer duration of action of frovatriptan parallels and correlates with its PK profile.

Frovatriptan and rizatriptan economic EVAluation: the FREEVA study.

BACKGROUND: The present pharmacoeconomic study compared the direct and indirect costs of using frovatriptan versus rizatriptan in the acute treatment of migraine. METHODS: Data on the cost-efficacy of the two triptans were derived from a recently published Italian, multicenter, randomized, double-blind, cross-over patient preference study, comparing frovatriptan versus rizatriptan. The direct costs were obtained by calculating the drug consumption, both of triptans and rescue medications. Prices of currently marketed drugs were obtained from Italian Drug Agency price list. The indirect costs were those related to absenteeism from the workplace due to migraine. RESULTS: 129 of the 148 patients with a current history of migraine randomized to the two study drugs and completing the study were analyzed. The number of attacks treated with only 1 dose of study drug was higher with frovatriptan (157 vs. 147), whereas the number of attacks treated with ≥2 doses of study medication was higher with rizatriptan (122 vs. 110 and 74 vs. 67, respectively). However, more patients treated with frovatriptan took a rescue medication (71 vs. 59). The total direct cost per attack (including study drug rescue medication) was 9.12 € for frovatriptan and 13.54 € for rizatriptan (p < 0.05 between-treatments). As for indirect costs, in the group of patients treated with frovatriptan the mean number of lost working hours was significantly (p < 0.05) lower (1.5 h) compared to the subjects who used rizatriptan (2.8 h). Based on the earned income per unit of work, indirect costs per attack resulted to be 24.55 € for frovatriptan and 45.84 € for rizatriptan. Overall, the total costs, including direct and indirect costs, were evaluated to be 33.67 € for frovatriptan and 59.38 € for rizatriptan, respectively. CONCLUSIONS: Within the limitations of this model analysis, frovatriptan was found to be significantly more cost-effective than rizatriptan. This outcome can be explained by the lower acquisition cost of frovatriptan, the need for fewer doses, and the loss of fewer working hours. This finding could drive selection of the most appropriate oral treatment for acute migraine attacks based on both individual patient's needs and the cost-effectiveness of the available drugs. TRIAL REGISTRATION: 2006-002572-17 (EudraCT).

Is Helicobacter pylori the infectious trigger for headache?: A review.

The interest that surrounds the bacterium Helicobacter pylori (H. pylori) is due not only to its causal role in several gastroduodenal diseases, but also to its supposed involvement in the pathogenesis of extra-gastric manifestations. This review provides a literature update on the hypothetic correlation between H. pylori and headache. To identify all publications on this issue, a MEDLINE search of all studies published in English from 1965 to 2013 was conducted. The authors examined three aspects of this potential association: epidemiology, intervention trials and pathogenesis. While in the former, the results are contradictory, in the intervention studies, it has been documented that at 6 and 12 months, bacterial eradication is associated to disappearance of symptoms in 23% and 28% of cases, and to a significant decrease of intensity, frequency and duration of acute attacks in the remaining patients. Under a pathogenetic aspect, if H. pylori has a role, it does not act through oxidative stress. In conclusion, the eradication of H. pylori seems efficient at least in a subgroup of patients suffering from migraine. Further investigations should focalize on particular subgroups of patients and, encouraged from data produced by intervention studies, evaluate the long-term benefit of eradication.

Italian guidelines for primary headaches: 2012 revised version.

The first edition of the Italian diagnostic and therapeutic guidelines for primary headaches in adults was published in J Headache Pain 2(Suppl. 1):105-190 (2001). Ten years later, the guideline committee of the Italian Society for the Study of Headaches (SISC) decided it was time to update therapeutic guidelines. A literature search was carried out on Medline database, and all articles on primary headache treatments in English, German, French and Italian published from February 2001 to December 2011 were taken into account. Only randomized controlled trials (RCT) and meta-analyses were analysed for each drug. If RCT were lacking, open studies and case series were also examined. According to the previous edition, four levels of recommendation were defined on the basis of levels of evidence, scientific strength of evidence and clinical effectiveness. Recommendations for symptomatic and prophylactic treatment of migraine and cluster headache were therefore revised with respect to previous 2001 guidelines and a section was dedicated to non-pharmacological treatment. This article reports a summary of the revised version published in extenso in an Italian version.

Frovatriptan versus almotriptan for acute treatment of menstrual migraine: analysis of a double-blind, randomized, cross-over, multicenter, Italian, comparative study.

The objective of the study was to compare the efficacy and safety of frovatriptan and almotriptan in women with menstrually related migraine (IHS Classification of Headache disorders) enrolled in a multicenter, randomized, double-blind, cross-over study. Patients received frovatriptan 2.5 mg or almotriptan 12.5 mg in a randomized sequence: after treating 3 episodes of migraine in no more than 3 months with the first treatment, the patient was switched to the other treatment. 67 of the 96 female patients of the intention-to-treat population of the main study had regular menstrual cycles and were thus included in this subgroup analysis. 77 migraine attacks classified as related to menses were treated with frovatriptan and 78 with almotriptan. Rate of pain relief at 2 and 4 h was 36 and 53 % for frovatriptan and 41 and 50 % for almotriptan (p = NS between treatments). Rate of pain free at 2 and 4 h was 19 and 47 % with frovatriptan and 29 and 54 % for almotriptan (p = NS). At 24 h, 62 % of frovatriptan-treated and 67 % of almotriptan-treated patients had pain relief, while 60 versus 67 % were pain free (p = NS). Recurrence at 24 h was significantly (p < 0.05) lower with frovatriptan (8 vs. 21 % almotriptan). This was the case also at 48 h (9 vs. 24 %, p < 0.05). Frovatriptan was as effective as almotriptan in the immediate treatment of menstrually related migraine attacks. However, it showed a more favorable sustained effect, as shown by a lower rate of migraine recurrence.

Efficacy of frovatriptan in the acute treatment of menstrually related migraine: analysis of a double-blind, randomized, cross-over, multicenter, Italian, comparative study versus rizatriptan.

The objectives of this study are to assess the efficacy and safety of frovatriptan, and rizatriptan in the subgroup of women with menstrually related migraine of a multicenter, randomized, double blind, cross-over study. Each patient received frovatriptan 2.5 mg or rizatriptan 10 mg in a randomized sequence: after treating 3 episodes of migraine in not more than 3 months with the first treatment, the patient had to switch to the other treatment. Menstrually related migraine was defined according to the criteria listed in the Appendix of the last IHS Classification of Headache disorders. 99 out of the 125 patients included in the intention-to-treat analysis of the main study were of a female gender: 93 had regular menstrual cycles and were, thus, included in this analysis. A total of 49 attacks classified as menstrually related migraine were treated with frovatriptan and 59 with rizatriptan. Rate of pain relief at 2 h was 58% for frovatriptan and 64% for rizatriptan (p = NS), while rate of pain free at 2 h was 31 and 34% (p = NS), respectively. At 24 h, 67 and 81% of frovatriptan-treated, and 61 and 74% of rizatriptan-treated patients were pain free and had pain relief, respectively (p = NS). Recurrence at 24 h was significantly (p < 0.01) lower with frovatriptan (10 vs. 32% rizatriptan). Frovatriptan was as effective as rizatriptan in the immediate treatment of menstrually related migraine attacks while showing a favorable sustained effect with a lower rate of migraine recurrence. These results need to be confirmed by randomized, double-blind, prospective, large clinical trials.

A double-blind, randomized, multicenter, Italian study of frovatriptan versus almotriptan for the acute treatment of migraine.

The objective of this study was to evaluate patients' satisfaction with acute treatment of migraine with frovatriptan or almotriptan by preference questionnaire. One hundred and thirty three subjects with a history of migraine with or without aura (IHS 2004 criteria), with at least one migraine attack in the preceding 6 months, were enrolled and randomized to frovatriptan 2.5 mg or almotriptan 12.5 mg, treating 1-3 attacks. The study had a multicenter, randomized, double blind, cross-over design, with treatment periods lasting <3 months. At study end patients assigned preference to one of the treatments using a questionnaire with a score from 0 to 5 (primary endpoint). Secondary endpoints were pain free and pain relief episodes at 2 and 4 h, and recurrent and sustained pain free episodes within 48 h. Of the 133 patients (86%, intention-to-treat population) 114 of them expressed a preference for a triptan. The average preference score was not significantly different between frovatriptan (3.1 ± 1.3) and almotriptan (3.4 ± 1.3). The rates of pain free (30% frovatriptan vs. 32% almotriptan) and pain relief (54% vs. 56%) episodes at 2 h did not significantly differ between treatments. This was the case also at 4 h (pain free: 56% vs. 59%; pain relief: 75% vs. 72%). Recurrent episodes were significantly (P < 0.05) less frequent under frovatriptan (30% vs. 44%), also for the attacks treated within 30 min. No significant differences were observed in sustained pain free episodes (21% vs. 18%). The tolerability profile was similar between the two drugs. In conclusion, our study suggests that frovatriptan has a similar efficacy of almotriptan in the short-term, while some advantages are observed during long-term treatment.

A double-blind, randomized, multicenter, Italian study of frovatriptan versus rizatriptan for the acute treatment of migraine.

The objective of this study was to assess patient satisfaction with acute treatment of migraine with frovatriptan or rizatriptan by preference questionnaire. 148 subjects with a history of migraine with or without aura (IHS 2004 criteria), with at least one migraine attack per month in the preceding 6 months, were enrolled and randomized to frovatriptan 2.5 mg or rizatriptan 10 mg treating 1-3 attacks. The study had a multicenter, randomized, double-blind, cross-over design, with treatment periods lasting <3 months. At the end of the study, patients assigned preference to one of the treatments using a questionnaire with a score from 0 to 5 (primary endpoint). Secondary endpoints were pain-free and pain relief episodes at 2 h, and recurrent and sustained pain-free episodes within 48 h. 104 of the 125 patients (83%, intention-to-treat population) expressed a preference for a triptan. The average preference score was not significantly different between frovatriptan (2.9±1.3) and rizatriptan (3.2±1.1). The rates of pain-free (33% frovatriptan vs. 39% rizatriptan) and pain relief (55 vs. 62%) episodes at 2 h were not significantly different between the two treatments. The rate of recurrent episodes was significantly (p<0.001) lower under frovatriptan (21 vs. 43% rizatriptan). No significant differences were observed in sustained pain-free episodes (26% frovatriptan vs. 22% rizatriptan). The number of patients with adverse events was not significantly different between rizatriptan (34) and frovatriptan (25, p=NS). The results suggest that frovatriptan has a similar efficacy to rizatriptan, but a more prolonged duration of action.

Cluster headache is associated with the alcohol dehydrogenase 4 (ADH4) gene.

BACKGROUND/OBJECTIVES: Alcohol is a well-known trigger factor for cluster headache attacks during the active phases of the disease. The alcohol dehydrogenase (ADH) pathway, which converts alcohol to the toxic substance acetaldehyde, is responsible for most of the alcohol breakdown in the liver. Humans have 7 ADH genes, tightly clustered on chromosome 4q21-q25, that encode different ADH isoforms. The ADH4 gene encodes the class II ADH4 pi subunit, which contributes, in addition to alcohol, to the metabolization of a wide variety of substrates, including retinol, other aliphatic alcohols, hydroxysteroids, and biogenic amines. The purpose of this study was to investigate the association of genetic variants within the ADH4 gene with cluster headache susceptibility and phenotype. METHODS: A total of 110 consecutive unrelated cluster headache patients and 203 age- and sex-matched healthy controls of Caucasian origin were involved in the study. Patients and controls were genotyped for 2 bi-allelic single nucleotide polymorphisms (SNPs) of the ADH4 gene: SNP1 - rs1800759 and SNP2 - rs1126671. Allele, genotype, and haplotype frequencies of the examined polymorphisms were compared between cases and controls. RESULTS: Genotype frequencies of the rs1126671 polymorphism resulted significantly different between cluster headache patients and controls (chi(2) = 10.269, P = .006). The carriage of the AA genotype, in comparison with remaining genotypes, was associated with a significantly increased disease risk (OR = 2.33, 95% CI: 1.25-4.37). Haplotype analysis confirmed the association between the ADH4 gene and the disease. No association between different clinical characteristics of cluster headache and the examined polymorphisms was found. CONCLUSION: Our data suggest that cluster headache is associated with the ADH4 gene or a linked locus. Additional studies are warranted to elucidate the role of this gene in the etiopathogenesis of the disease.

Tolerability and efficacy of a combination of paracetamol and caffeine in the treatment of tension-type headache: a randomised, double-blind, double-dummy, cross-over study versus placebo and naproxen sodium.

The main aim of this study was to confirm in an Italian population affected by tension-type headache (TTH) the good profile of safety and tolerability of the combination paracetamol 1,000 mg-caffeine 130 mg (PCF) observed in previous studies, by a comparison with naproxen sodium 550 mg (NAP) and placebo (PLA). A secondary objective was to assess the efficacy of PCF in the acute treatment of TTH. This was a multicentre, randomised, double-blind, double-dummy, crossover, placebo-controlled trial. Tolerability was assessed by recording adverse events by the patient in the 4-h post-dose treatment. To assess the efficacy, the sum of pain intensity differences (SPID) and the total pain relief (TOTPAR) were calculated. Comparing PCF and NAP and PCF and PLA for tolerability, the difference was nonsignificant but the result regarding noninferiority was inconclusive, whilst NAP was noninferior to PLA. As regards SPID and TOTPAR, both PCF and NAP were better than placebo (P < 0.05), but not significantly different from each other. In conclusion, PCF was well-tolerated and effective in the treatment of acute TTH.

HLA-DRB1 genotyping in Italian migraine patients.

We examined the distribution of HLA-DRB1 alleles in a cohort 255 Italian migraine patients and in a control group of 325 healthy subjects. 214 patients fulfilled the ICHD-II criteria for migraine without aura and 41 patients the criteria for migraine with aura. The frequency of DRB1*16 allele was found to be significantly increased in migraine without aura patients (p=0.02; OR 1.97, 95% CI: 1.10-3.54) than in healthy controls. The frequencies of HLA-DRB1 alleles were not significantly different between migraine with aura patients and controls. We did not detect any effect of DRB1 alleles on age at onset, duration of the disease, frequency and duration of migraine attacks. Our data suggest the presence of a genetic susceptibility factor for migraine without aura within the HLA region.

Association between migraine and HLA-DRB1 gene polymorphisms.

We examined the distribution of HLA-DRB1 alleles in a cohort of 255 Italian migraine patients and in a control group of 325 healthy subjects. The frequency of DRB1*12 allele was found to be significantly reduced (p=0.02) in patients with migraine while the DRB1*16 allele was significantly increased (p=0.04) in comparison with controls. When the patients were divided into disease subgroups (migraine with and without aura), HLA-DRB1**16 allele was significantly increased (p<0.05) only in migraine without aura patients. We conclude that, in Italian patients, migraine is associated with different alleles of the HLA-DRB1 locus. Our data suggest the presence of a genetic susceptibility factor for migraine within the HLA region.

Attachment styles and headache.

The internal working model on attachment dimensions changes with significant emotional experiences. The purpose of this study was to evaluate if and how the internal working models correlate with primary headaches. Attachment dimensions of subjects suffering from primary headaches were studied. One hundred and fourteen subjects [68 with migraine, 23 with tension-type headache (according to ICHD-I criteria), 23 with chronic daily headache (according to Silberstein's criteria)], were studied and compared with a control group of 57 subjects (matched in sex, age and social level) not suffering from any primary headache. Attachment dimensions were investigated using the Adult Attachment Questionnaire (AAQ) and the Attachment Style Questionnaire (ASQ). Headache sufferers seem to be characterised by attachment styles of the "insecure" type. In particular they seem to feel extremely ill at ease if there is an expectation of reduction of interpersonal distance.