Anodal transcranial direct current stimulation in chronic migraine and medication overuse headache: A pilot double-blind randomized sham-controlled trial.

OBJECTIVES: Little evidence is available on the role of transcranial direct current stimulation (tDCS) in patients affected by chronic migraine (CM) and medication overuse headache (MOH). We aim to investigate the effects of tDCS in patients with CM and MOH as well as its role on brain activity. METHODS: Twenty patients with CM and MOH were hospitalized for a 7-day detoxification treatment. Upon admission, patients were randomly assigned to anodal tDCS or sham stimulation delivered over the primary motor cortex contralateral to the prevalent migraine pain side every day for 5 days. Clinical data were recorded at baseline (T0), after 1 month (T2) and 6 months (T3). EEG recording was performed at T0, at the end of the tDCS/Sham treatment, and at T2. RESULTS: At T2 and T3, we found a significant reduction in monthly migraine days (p = 0.001), which were more pronounced in the tDCS group when compared to the sham group (p = 0.016). At T2, we found a significant increase of alpha rhythm in occipital leads, which was significantly higher in tDCS group when compared to sham group. CONCLUSIONS: tDCS showed adjuvant effects to detoxification in the management of patients with CM and MOH. The EEG recording showed a significant potentiation of alpha rhythm, which may represent a correlate of the underlying changes in cortico-thalamic connections. SIGNIFICANCE: This study suggests a possible role for tDCS in the treatment of CM and MOH. The observed clinical improvement is coupled with a potentiation of EEG alpha rhythm.

Poor patient awareness and frequent misdiagnosis of migraine: findings from a large transcontinental cohort.

BACKGROUND AND PURPOSE: Although migraine is the second most disabling condition worldwide, there is poor awareness of it. The objective was to assess the awareness of migraine and previous diagnostic and therapeutic consultations and treatments in a large international population of migraineurs. METHODS: This was a multicentre study conducted in 12 headache centres in seven countries. Each centre recruited up to 100 patients referred for a first visit and diagnosed with migraine. Subjects were given a structured clinical questionnaire-based interview about the perceptions of the type of headache they suffered from, its cause, previous diagnoses, investigations and treatments. RESULTS: In all, 1161 patients completed the study. Twenty-eight per cent of participants were aware that they suffered from migraine. Sixty-four per cent called their migraine 'headache'; less commonly they used terms such as 'cervical pain' (4%), tension headache (3%) and sinusitis (1%). Eight per cent of general practitioners and 35% of specialists (of whom 51% were neurologists and/or headache specialists) consulted for migraine formulated the correct diagnosis. Before participating in the study, 50% of patients had undergone X-ray, computed tomography and/or magnetic resonance imaging of the cervical spine and 76% underwent brain and/or cervical spine imaging for migraine. Twenty-eight per cent of patients had received symptomatic migraine-specific medications and 29% at least one migraine preventive medication. CONCLUSIONS: Although migraine is a very common disease, poor awareness of it amongst patients and physicians is still an issue in several countries. This highlights the importance of the promotion of migraine awareness to reduce its burden and limit direct and indirect costs and the risk of exposure to useless investigations.

Psychological factors associated with failure of detoxification treatment in chronic headache associated with medication overuse.

AIM: The aim of this study was to evaluate the psychological factors associated with a negative outcome following detoxification in a 2-month follow-up in medication-overuse headache. METHODS: All consecutive patients entering the detoxification program were analysed in a prospective, non-randomised fashion. Psychiatric conditions and personality characteristics were assessed using the Structured Clinical Interview for DSM-IV Disorders (SCID-I) and the Minnesota Multiphasic Personality Inventory (MMPI)-2. χ2 tests, one-way analyses of variance, and odds ratios (ORs) were used. RESULTS: A total of 248 patients completed the follow-up: 156 stopped overuse and their headaches reverted to an episodic pattern (Group A); 23 kept overusing without any benefit on headache frequency (Group B); and 51 stopped overuse without any benefit on headache frequency (Group C). The prognostic factors for the outcome of Group B were higher scores on the correction (OR 1.128; p = 0.036), depression (OR 1.071; p = 0.05), hysteria (OR 1.106; p = 0.023), and overcontrolled hostility (OR 1.182; p = 0.04) MMPI-2 scales, whereas those for Group C were psychiatric comorbidities (OR 1.502; p = 0.021) and higher scores on the hysteria scale (OR 1.125; p = 0.004). CONCLUSIONS: The outcome of detoxification is influenced by psychological factors that should be considered when considering treatment strategies.

Variability of the characteristics of a migraine attack within patients.

BACKGROUND: Migraine attacks may present different features in different patients and also within the same patient. The percentage of patients reporting stereotyped attacks and those reporting attacks with different phenotypes has not been the object of specific investigations. OBJECTIVE: The objective of this article is to evaluate the percentage of migraine patients reporting the same characteristics, in terms of phenotype and response to symptomatic medications on three consecutive migraine attacks. METHODS: Thirty patients with migraine without aura prospectively recorded the features of three consecutive attacks in a headache diary. Characteristics recorded were: pain intensity, presence of nausea, vomiting, photophobia, phonophophia, osmophobia, allodynia, cranial autonomic symptoms (at least one), and premonitory symptoms. Patients were allowed to take frovatriptan as symptomatic medication, whose efficacy was evaluated as the two hours pain-free status. RESULTS: None of the patients presented identical characteristics on the three studied attacks. This was still the case if we reduced the number of variables evaluated from 11 to seven of the eight core features indicated by the ICHD. Considering just six variables: unilaterality and quality of pain, presence/absence of nausea, vomiting, photophobia and phonophobia, only two patients (6%) had identical features on three consecutive attacks.With respect to the response to frovatriptan, 39% of patients had the same response, either positive (i.e. pain free after two hours) or negative (i.e. not pain free after two hours) on three consecutive attacks. CONCLUSION: Migraine attacks show a high variability not just among patients, but also within the same patient. Our data indicate that stereotypy of attacks is uncommon, and reinforces the underlying logic of the current operational classification system.

Impact of headache disorders in Italy and the public-health and policy implications: a population-based study within the Eurolight Project.

BACKGROUND: Migraine, tension-type headache (TTH) and medication-overuse headache (MOH) are disabling lifelong illnesses. The Eurolight project, a partnership activity within the Global Campaign against Headache, assessed the impact of headache disorders in ten countries in Europe using a structured questionnaire coupled with various sampling methods. Here we present the findings from the Italian population. METHODS: Questionnaires were distributed to a stratified sample (N = 3500) of the adult (18-65 years) inhabitants of Pavia province (1.05 % of the general population), randomly selected in cooperation with the local health service. Questions included demographic and diagnostic enquries, and assessment of various aspects of impact and health-care utilisation. RESULTS: Altogether 500 questionnaires were returned of which 487 were adequately completed for analysis (58 % female, 42 % male). Among these, gender-adjusted lifetime prevalence of headache was 82.5 %, higher in females than in males (91.2 % vs 72.4 %; p < 0.0001). Gender-adjusted 1-year prevalence was 74.2 % (females 87.7 %, males 61.1 %; p < 0.0001). The most prevalent headache type was migraine (gender-adjusted 1-year prevalence 42.9 %; females 54.6 %, males 32.5 %; p < 0.0001), followed by TTH (28.6 %; no gender-related difference); all causes of headache on ≥15 days/month were reported by 7.0 % of participants (females 10.6 %, males 2.0 %; p = 0.0002), of whom 2.1 %,, all female (p = 0.0064) concomitantly overused acute medications (therefore probable MOH). Only 16.6 % of responders reporting headache had received a diagnosis from a doctor, and very few (2.4 %) were taking preventative medications. Headache had negative impacts on different aspects of life: education, career and earnings, family and social life. Each person with headache had lost, on average, 2.3 days from paid work and 2.4 days from household work, and missed social occasions on 1.2 days, in the preceding 3 months. An increasing gradient for impact was observed from episodic to chronic forms of headache. CONCLUSIONS: Our study reveals that in Italy, as in other countries, migraine, TTH and MOH are highly prevalent and are associated with significant personal impact. These findings have important implications for health policy in Italy.

Cost of Chronic and Episodic Migraine. A pilot study from a tertiary headache centre in northern Italy.

BACKGROUND: Chronic migraine (CM) has a high impact on functional performance and quality of life (QoL). CM also has a relevant burden on the National Health Service (NHS), however precise figures are lacking. In this pilot study we compared the impact in terms of costs of CM and episodic migraine (EM) on the individual and on the National Health System (NHS). Furthermore, we comparatively evaluated the impact of CM and EM on functional capability and on QoL of sufferers. METHODS: We enrolled 92 consecutive patients attending the Pavia headache centre: 51 subjects with CM and 41 with episodic migraine (EM). Patients were tested with disability scales (MIDAS, HIT-6, SF-36) and with an ad hoc semi-structured questionnaire. RESULTS: The direct mean annual cost (in euro) per patient suffering from CM was €2250.0 ± 1796.1, against €523.6 ± 825.8 per patient with EM. The cost loaded on NHS was €2110.4 ± 1756.9 for CM, €468.3 ± 801.8 for EM. The total economic load and the different sub-items were significantly different between groups (CM vs. EM p = 0.001 for each value). CM subjects had higher scores than EM for MIDAS (98.4 ± 72,3 vs 15.5 ± 17.7, p = 0.001) and for HIT-6 (66.1 ± 8.4 vs 58.7 ± 10.1, p = 0.001). The SF-36 score was 39.9 ± 14,74 for CM and 66.2 ± 18.2 for EM (p = 0.001). CONCLUSIONS: CM is a disabling condition with a huge impact on the QoL of sufferers and a significant economic impact on the NHS. The adequate management of CM, reverting it back to EM, will provide a dual benefit: on the individual and on the society.

Functional polymorphisms in COMT and SLC6A4 genes influence the prognosis of patients with medication overuse headache after withdrawal therapy.

BACKGROUND AND PURPOSE: It is currently unknown if common genetic variants influence the prognosis of patients with medication overuse headache (MOH). Here the role of two common single nucleotide polymorphisms in the COMT gene (rs4680 and rs6269), as well as the STin2 variable number tandem repeat (VNTR) polymorphism in the SLC6A4 gene, were evaluated as predictors for long-term outcomes of MOH patients after withdrawal therapy. METHODS: Genotyping was conducted by polymerase chain reaction (PCR), PCR restriction fragment length polymorphism analysis or real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood. Gene variants association was evaluated by logistic regression analysis adjusted for clinical confounding factors, and the threshold of statistical significance for multiple testing was set at P < 0.012. RESULTS: Sixty-five MOH patients with unsuccessful detoxification and 83 MOH patients with effective drug withdrawal therapy were available for the analysis. rs4680G allele carriers or the COMT rs6269G-rs4680G haplotype were found to be associated with a lower risk of relapse within the first year after successful detoxification therapy, in comparison with homozygous rs4680A allele carriers [odds ratio (OR) 0.17, 95% confidence interval (CI) 0.05-0.61, P = 0.007] or with the COMT rs6269A-rs4680A haplotype (OR 0.19, 95% CI 0.06-0.54, P = 0.003), respectively. In addition, carriers of the STin2 VNTR short allele were found at higher odds for the composite poor outcome including unsuccessful withdrawal therapy and relapse within 12 months of follow-up after successful detoxification (OR 2.81, 95%CI 1.26-6.25, P = 0.009). CONCLUSIONS: Our results indicate that genotyping for COMT rs4680 and SLC6A4 STin2 VNTR could be useful for the identification of MOH patients at higher risk of poor prognosis after drug withdrawal.

A consensus protocol for the management of medication-overuse headache: Evaluation in a multicentric, multinational study.

INTRODUCTION: The management of medication-overuse headache (MOH) is often difficult and no specific guidelines are available as regards the most practical and effective approaches. In this study we defined and tested a consensus protocol for the management of MOH on a large population of patients distributed in different countries. SUBJECTS AND METHODS: The protocol was based on evidence from the literature and on consolidated expertise of the members of the consensus group. The study was conducted according to a multicentric interventional design with the enrolment of 376 MOH subjects in four centres from Europe and two centres in Latin America. The majority of patients were treated according to an outpatient detoxification programme. The post-detoxification follow-up lasted six months. RESULTS: At the final evaluation, two-thirds of the subjects were no longer overusers and in 46.5% of subjects headache had reverted back to an episodic pattern of headache. When comparing the subjects who underwent out-patient detoxification vs those treated with in-patient detoxification, both regimens proved effective, although the drop-out rate was higher in the out-patient approach. CONCLUSIONS: The present findings support the effectiveness and usability of the proposed consensus protocol in different countries with different health care modalities.

Association of haplotype combination of serotonin transporter gene polymorphisms with monthly headache days in MOH patients.

OBJECTIVES: To evaluate the role of 5-HTTLPR, STin2 VNTR, and rs1042173T>G polymorphisms of the serotonin transporter gene (SLC6A4) as susceptibility factors for medication overuse headache (MOH) and to assess their value as predictors of the number of headache days per month, a potential marker of disease severity. METHODS: Genotyping was performed by PCR and PCR-RFLP on genomic DNA extracted from peripheral blood of 227 MOH patients and 312 control subjects. Logistic regression analysis was used to evaluate the association between the SL6A4 gene polymorphisms and MOH risk. The association between polymorphic variants and monthly headache days was evaluated by linear regression analysis. RESULTS: Logistic regression analysis, adjusted for age and gender, revealed a nominal association between rs1042173T>G and MOH risk (TT vs. TG + GG, OR: 1.58 95% CI: 1.05-2.37, P = 0.028). In the linear regression analysis adjusted for age, gender, primary headache diagnosis, acute drug overused and monthly drug number, STin2 VNTR was found nominally associated with monthly headache days (12/12 vs. others, difference: 1.55 days, 95% CI: 0.01-3.08, P = 0.050). When STin2 VNTR and rs1042173T>G were analyzed in haplotypic combination, a global haplotype association emerged with monthly headache days which remained significant after Bonferroni correction for multiple comparisons (global haplotype association P = 0.0056). CONCLUSION: Although a minor contribution of SLC6A4 variants in the genetic liability of MOH cannot be excluded, haplotype-based analysis of STin2 VNTR and rs1042173T>G polymorphisms allowed to identify a subgroup of MOH patients with a higher number of monthly headache and, possibly, with a more severe disease.

SUNCT syndrome with paroxysmal mydriasis: Clinical and pupillometric findings.

SUNCT syndrome (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) is a primary headache characterised by a high frequency of attacks associated with marked autonomic periocular signs and symptoms. Activation of the hypothalamus via the superior salivary nucleus is probably responsible for some of the autonomic involvement observed during SUNCT attacks. We describe a case of SUNCT with unusual autonomic features (e.g., mydriasis) and early onset. Pupillometric studies were performed both in a basal condition (without anisocoria) and after instillation of phenylephrine (a drug with direct sympathomimetic activity) and pilocarpine (a parasympathetic agonist). The findings in this patient seem to indicate involvement of the ocular sympathetic supply in SUNCT, responsible for the mydriasis, and seem to strengthen the possibility that the autonomic phenomena in this syndrome vary with different levels of pain severity.

Risk factors in medication-overuse headache: a 1-year follow-up study (care II protocol).

To investigate factors influencing prognosis in medication-overuse headache (MOH), we conducted a 12-month follow-up of patients with probable MOH. We recruited 215 patients consecutively admitted to our headache centre for an inpatient detoxification treatment. We analysed likely predictor factors for headache resolution (sex, age, primary headache, psychiatric comorbidity, type and timing of overuse). Mann-Whitney U-test and chi-squared test were used. One year after withdrawal, we had complete data on 172 patients (80%): 38 of these patients (22%) had relapsed into overuse and 134 (78%) had not. The negative prognostic factors for relapse were: intake of more than 30 doses/month (P = 0.004), smoking (P = 0.012), alcohol consumption (P = 0.037), non-confirmation of MOH diagnosis 2 months after detoxification (P = 0.000), and return to overused drug(s) (P = 0.000). The 1-year relapse rate was 22%. The existence of sub-groups of MOH patients with such risk factors could influence treatment strategies.

Sensitisation of spinal cord pain processing in medication overuse headache involves supraspinal pain control.

Medication overuse could interfere with the activity of critical brain regions involved in the supraspinal control of pain signals at the trigeminal and spinal level, leading to a sensitisation phenomenon responsible for chronic pain. We hypothesised that medication-overuse headache (MOH) patients might display abnormal processing of pain stimuli at the spinal level and defective functioning of the diffuse noxious inhibitory controls. We tested 31 MOH patients before (bWT) and after (aWT) standard inpatient withdrawal treatment, 28 episodic migraine (EM) patients and 23 healthy control subjects. We measured the threshold, the area and the temporal summation threshold (TST) of the nociceptive withdrawal reflex before, during and after activation of the diffuse noxious inhibitory controls by means of the cold pressor test. A significantly lower TST was found in both the MOH (bWT and aWT) and the EM patients compared with the controls, and in the MOH patients bWT compared with both the MOH patients aWT and the EM patients. In the MOH bWT patients the cold pressor test induced a TST increase significantly lower than that found in the MOH aWT, EM and control groups. Abnormal spinal cord pain processing and a decrease of the antinociceptive activity of the supraspinal structures in MOH patients can be hypothesised. These abnormalities could, in part, be related to the medication overuse, given that the withdrawal treatment was related to an improvement in the neurophysiological findings.

Medication overuse headache and applicability of the ICHD-II diagnostic criteria: 1-year follow-up study (CARE I protocol).

Medication overuse headache (MOH) is a growing problem worldwide and a challenge for clinicians and investigators. This study aims to contribute to the ongoing debate surrounding the classification of MOH. Applying the revised diagnostic criteria for MOH contained in the updated International Classification of Headache Disorders (ICHD-II), we enrolled 140 probable MOH (p-MOH) patients. They were submitted to an in-patient detoxification protocol and re-examined 2, 6 and 12 months later to confirm, or otherwise, the diagnosis of MOH and to observe the evolution of their headache. MOH diagnosis was confirmed 2 months after detoxification in 71% of patients, who reverted to an episodic headache pattern and stopped their drug overuse The overall clinical situation at 2 months closely reflected the 1-year trend. The 2-month period after drug withdrawal should be retained as a diagnostic criterion in the ICHD-II because it is useful not only as a diagnostic parameter, but also as predictor of a good outcome of 1-year drug withdrawal. In addition, the present findings point to the need for a more objective criterion to quantify headache frequency after drug withdrawal.

The usefulness and applicability of a basic headache diary before first consultation: results of a pilot study conducted in two centres.

We tested the usefulness and applicability of a simplified headache diary in the diagnosis of migraine (M), tension-type headache (TTH) and medication overuse headache (MOH). The diary was given to headache patients before their first consultation at the headache centre. Seventy-six naive headache patients completed the study. Their understanding of the diary proved highly satisfactory. The patients' level of compliance was also good, with 71% returning the diary completely filled in. The data entered in the diary were deemed complete for the diagnostic purpose in 93% of cases. The level of agreement between headache information gathered through clinical interview and the headache diary was satisfactory. When comparing the diary with the clinical interview, sensitivity was 92% for M, 75% for TTH and MOH. Specificity was 58% for M and TTH, 87% for MOH. Combined use of a diagnostic diary and clinical interview is recommended from the first consultation for headache.

The wolframin His611Arg polymorphism influences medication overuse headache.

Homozygosis for wolframin (WFS1) mutations determines Wolfram syndrome (WS), and common polymorphisms of WFS1 are associated with psychiatric illnesses and dependence behaviour. To test the influence of WFS1 polymorphisms on medication overuse headache (MOH), a chronic headache condition related to symptomatic drugs overuse, we analyzed 82 MOH patients for the WFS1 His611Arg polymorphism, and performed a comparison between clinical features of Arg/Arg (R/R) and non-R/R individuals. Individuals harbouring the R/R genotype showed significantly higher monthly drug consumption (t=-3.504; p=0.00075) and more severe depressive symptoms on the BDI questionnaire (t=-3.048; p=0.003) than non-R/R. WFS1 polymorphism emerged as the only significant predictor of drug consumption, at the multivariate regression analysis (F=12.277; d.f.=1,80; p=0.00075, adjusted R2=0.122). These results implicate WFS1 in the clinical picture of MOH, may be through an influence on need for drugs as in other conditions of abuse behaviour.

Headache attributed to infection: observations on the IHS classification (ICHD-II).

The aim of this study was to revise some topics in the chapter "Headache attributed to infections" in the last International Headache Society (IHS) classification. The authors searched for original studies and reviews about headache associated with infections. A checklist was submitted to 15 neurologists to quantify the relevance, comprehensibility and coherence between definitions, criteria and comments for each paragraph. The following paragraphs were fully discussed: (1) headache attributed to lymphocytic meningitis. This topic, being rather heterogeneous, should be divided into different subgroups; (2) headache attributed to HIV/AIDS. Distinctive features are not specified and diagnostic criteria are rather confusing; and (3) chronic post-infection headache. Diagnostic criteria should be reconsidered as the symptom "pain" is not the main diagnostic criterion. The authors propose the revision of three paragraphs of the new IHS classification to better define the most likely headache profile in specific CNS infections. The authors also underline the need to plan further ad hoc prospective studies.

Diaries and calendars for migraine. A review.

Headache is one of the most common types of pain and, in the absence of biological markers, headache diagnosis depends only on information obtained from clinical interviews and physical and neurological examinations. Headache diaries make it possible to record prospectively the characteristics of every attack and the use of headache calendars is indicated for evaluating the time pattern of headache, identifying aggravating factors and evaluating the efficacy of preventive treatment. This may reduce the recall bias and increase accuracy in the description. The use of diagnostic headache diaries does have some limitations because the patient's general acceptance is still limited and some subjects are not able to fill in a diary. In this review, we considered diaries and calendars especially designed for migraine and, in particular, we aimed at: (i) determining what instruments are available in clinical practice for diagnosis and follow-up of treatments; and (ii) describing the tools that have been developed for research and their main applications in the headache field. In addition to the literature review, we added two paragraphs concerning the authors' experience of the use of diaries and calendars in headache centres and their proposals for future areas of research.

Peripheral levels of BDNF and NGF in primary headaches.

Neurotrophins, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF), have been implicated in the generation and modulation of pain. To investigate whether alterations in neurotrophin levels can be detected in subjects suffering from nociceptive disorders, such as primary headaches, we determined the peripheral (platelet and plasma) levels of BDNF and NGF in patients suffering from migraine, with or without aura, or cluster headache (CH), in the interictal phase, and in healthy volunteers. All primary headaches patients studied showed significantly decreased platelet levels of BDNF (migraine vs. controls P<0.001; CH vs. controls P<0.01), while a selective reduction of platelet NGF was observed in migraine sufferers and not in CH patients compared with control subjects (migraine vs. controls P<0.001). These changes were not accompanied by significant modifications of neurotrophin plasma levels. Our findings show for the first time that changes in peripheral levels of neurotrophines (BDNF and NGF) occur in patients suffering from different types of primary headaches, suggesting a potential involvement of BDNF and NGF in the pathophysiology of these disorders, and raising the possibility that differences in peripheral neurotrophins may help to distinguish migraine biologically from CH.

Familial basilar migraine associated with a new mutation in the ATP1A2 gene.

Basilar migraine (BM), familial hemiplegic migraine (FHM), and sporadic hemiplegic migraine (SHM) are phenotypically similar subtypes of migraine with aura, differentiated only by motor symptoms, which are absent in BM. Mutations in CACNA1A and ATP1A2 have been found in FHM. The authors detected a novel mutation in the ATP1A2 gene (R548H) in members of a family with BM, suggesting that BM and FHM may be allelic disorders.

Estradiol supplementation modulates neuroendocrine response to M-chlorophenylpiperazine in menstrual status migrainosus triggered by oral contraception-free interval.

BACKGROUND: Migraine triggered by oral contraception (OC)-free interval is very common and may be extremely severe, long-lasting and poorly responsive to analgesics (status migrainosus). The serotoninergic (5-HT) system is crucially involved in pain threshold and it is sensitive to estradiol (E2). Therefore, we aimed to assess neuroendocrine correlates of OC status migrainosus in response to the direct central 5-HT agonist meta-chlorophenylpiperazine (m-CPP) and to test the effect of transdermal E2 supplementation of the OC-free interval. METHODS: Clinical investigative protocol, single-blinded placebo-controlled treatment. Oral m-CPP (0.5 mg/kg body weight) challenge test was performed in 10 patients with status migrainosus occurring within 48 h of the discontinuation of a monophasic pill (30 microg of ethinyl estradiol and 150 microg of desogestrel) and in six healthy women assuming the same OC as controls. In a consecutive menstrual cycle, patients with OC status migrainosus underwent to the same test after they were blindly treated with 2.0 g of percutaneous E2 gel or placebo daily during the pill-free interval. Plasma prolactin and cortisol levels and clinical characteristics of migraine attacks were evaluated. RESULTS: Women with OC-status migrainosus showed a derangement of prolactin release (F = 4.8; P < 0.01) and a lack of cortisol response (F = 5.8; P < 0.001) after m-CPP in comparison with controls. Transdermal E2 during the pill-free interval significantly restored prolactin (F = 2.8; P < 0.01) and cortisol responses (F = 18.9; P < 0.001) against placebo and positively affected the duration (P < 0.001), the number of hours in which pain intensity prohibits daily activity (P < 0.001), the episodes of vomiting (P < 0.001) and the consumption of analgesics (P < 0.001). CONCLUSIONS: Status migrainosus triggered by OC-free interval is associated with impaired prolactin and cortisol responses following m-CPP challenge. Transdermal E2 supplementation is able to restore neuroendocrine response to this specific 5-HT agent, exerting a positive clinical effect on the course of menstrually related migraine.