Self-administered subcutaneous diclofenac sodium in acute migraine attack: A randomized, double-blind, placebo-controlled dose-finding pilot study.

BACKGROUND: A novel formulation of diclofenac, complexed with hydroxypropyl-ß-cyclodextrin (HPßCD) as a solubility enhancer, in a prefilled syringe for self-administered subcutaneous injection may overcome the limitations of acute migraine treatments administered by oral, rectal, intramuscular, or intravenous routes. METHODS: This multicentre, phase 2, double-blind, randomized, placebo-controlled, dose-finding pilot study evaluated the efficacy, safety and tolerability of three different doses (25/50/75 mg/1 mL) of subcutaneous diclofenac sodium in the treatment of an acute migraine attack in 122 subjects. The primary efficacy endpoint was the percentage of patients pain-free at 2 hours after the study drug injection. RESULTS: A significantly higher percentage of patients in the 50 mg diclofenac group 14 (46.7%) were pain-free at 2 hours when compared with placebo: 9 (29.0%) (p = 0.01). The 50 mg dose proved superior to placebo also in the majority of the secondary endpoints. The overall global impression favoured diclofenac vs placebo. There were no adverse events leading to study withdrawal. The majority of treatment-emergent adverse events were mild. CONCLUSIONS: The 50 mg dose of this novel formulation of diclofenac represents a valuable self-administered option for the acute treatment of migraine attacks.Trial registration: EudraCT Registration No. 2017-004828-29.

A prospective study on osmophobia in migraine versus tension-type headache in a large series of attacks.

BACKGROUND: In literature, osmophobia is reported as a specific migrainous symptom with a prevalence of up to 95%. Despite the International Classification of Headache Disorders 2nd edition proposal of including osmophobia among accompanying symptoms, it was no longer mentioned in the ICHD 3rd edition. METHODS: We conducted a prospective study on 193 patients suffering from migraine without aura, migraine with aura, episodic tension-type headache or a combination of these. After a retrospective interview, each patient was asked to describe in detail osmophobia, when present, in the following four headache attacks. RESULTS: In all, 45.7% of migraine without aura attacks were associated with osmophobia, 67.2% of migraineurs reported osmophobia in at least a quarter of the attacks. No episodic tension-type headache attack was associated with osmophobia. It was associated with photophobia or phonophobia in 4.3% of migraine without aura attacks, and it was the only accompanying symptom in 4.7% of migraine without aura attacks. The inclusion of osmophobia in the ICHD-3 diagnostic criteria would enable a 9.0% increased diagnostic sensitivity. CONCLUSION: Osmophobia is a specific clinical marker of migraine, easy to ascertain and able to disentangle the sometimes challenging differential diagnosis between migraine without aura and episodic tension-type headache. We recommend its inclusion among the diagnostic criteria for migraine as it increases sensitivity, showing absolute specificity.

First Attack and Clinical Presentation of Hemiplegic Migraine in Pediatric Age: A Multicenter Retrospective Study and Literature Review.

Background: Data on clinical presentation of Hemiplegic Migraine (HM) are quite limited in the literature, particularly in the pediatric age. The aim of the present study is to describe in detail the phenotypic features at onset and during the first years of disease of sporadic (SHM) and familial (FHM) pediatric hemiplegic migraine and to review the pertinent literature. Results: Retrospective study of a cohort of children and adolescents diagnosed with hemiplegic migraine, recruited from 11 Italian specialized Juvenile Headache Centers. Forty-six cases (24 females) were collected and divided in two subgroups: 32 SHM (16 females), 14 FHM (8 females). Mean age at onset was 10.5 ± 3.8 y (range: 2-16 y). Mean duration of motor aura was 3.5 h (range: 5 min-48 h). SHM cases experienced more prolonged attacks than FHM cases, with significantly longer duration of both motor aura and of total HM attack. Sensory (65%) and basilar-type auras (63%) were frequently associated to the motor aura, without significant differences between SHM and FHM. At follow-up (mean duration 4.4 years) the mean frequency of attacks was 2.2 per year in the first year after disease onset, higher in FHM than in SHM cases (3.9 vs. 1.5 per year, respectively). A literature review retrieved seven studies, all but one were based on mixed adults and children cohorts. Conclusions: This study represents the first Italian pediatric series of HM ever reported, including both FHM and SHM patients. Our cohort highlights that in the pediatric HM has an heterogeneous clinical onset. Children present fewer non-motor auras as compared to adults and in some cases the first attack is preceded by transient neurological signs and symptoms in early childhood. In SHM cases, attacks were less frequent but more severe and prolonged, while FHM patients had less intense but more frequent attacks and a longer phase of active disease. Differently from previous studies, the majority of our cases, even with early onset and severe attacks, had a favorable clinical evolution.

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.

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).

Diagnosis and management of headache attributed to airplane travel.

The headache attributed to airplane travel, also named "airplane headache", is characterized by the sudden onset of a severe head pain exclusively in relation to airplane flights, mainly during the landing phase. Secondary causes, such as upper respiratory tract infections or acute sinusitis, must be ruled out. Although its cause is not thoroughly understood, sinus barotrauma should be reasonably involved in the pathophysiological mechanisms. Furthermore, in the current International Classification of Headache Disorders, rapid descent from high altitude is not considered as a possible cause of headache, although the onset of such pain in airplane travellers or aviators has been well known since the beginning of the aviation era. On the basis of a survey we conducted with the courteous cooperation of people who had experienced this type of headache, we proposed diagnostic criteria to be added to the forthcoming revision of the International Classification of Headache Disorders. Their formal validation would favour further studies aimed at improving knowledge of the pathophysiological mechanisms involved and at implementing preventative measures.

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.

Focus on therapy of the Chapter IV headaches provoked by exertional factors: primary cough headache, primary exertional headache and primary headache associated with sexual activity.

Primary cough headache, primary exertional headache and primary headache associated with sexual activity are distinct entities, even though they share several features: acute onset, the absence of structural brain disease and exertional factors as precipitating events. In this short review, we illustrate the possible treatment strategies on the basis of information collected from a systematic analysis of the international literature.

Focus on therapy of hypnic headache.

Hypnic headache (HH) is a primary headache disorder, which occurs exclusively during sleep and usually begins after 50 years of age. There are no controlled trials for the treatment of HH. We reviewed all the available papers, including 119 cases published in literature up to date, reporting the efficacy of the medications used to treat HH. Acute treatment is not recommended, since no drug proved to be clearly effective and also because the intensity and the duration of the attacks do not require the intake of a medication in most cases. As for prevention, a wide variety of medications were reported to be of benefit in HH. The drugs that were found to be effective in at least five cases are: lithium, indomethacin, caffeine and flunarizine. Lithium was the most extensively studied compound and demonstrated to be an efficacious treatment in 32 cases. Unfortunately, despite its efficacy, significant adverse effects and poor tolerability are not rare, mainly in elderly patients. Many patients reported a good response to indomethacin, but some could not tolerate it. Caffeine and melatonin treatments did not yield robust evidence to recommend their use as single preventive agents. Nevertheless, their association with lithium or indomethacin seems to produce an additional therapeutic efficacy. A course of lithium should be tried first, followed 3-4 months later by tapering. If headache recurs during tapering, a longer duration of therapy may be needed. If lithium treatment does not provide a significant response, indomethacin can be commenced as second-line approach. If these treatments prove to be ineffective or poorly tolerated, other agents, such as caffeine and melatonin, can be administered.

Focus on therapy of primary stabbing headache.

Primary stabbing headache (PSH) is a short-lasting but troublesome headache disorder, which has been known for several decades. The head pain occurs as a single stab or as a series of stabs generally involving the area supplied by the first division of trigeminal nerve. Stabs last for approximately a few seconds, occurring and recurring from once to multiple times per day in an irregular pattern. For the diagnosis of PSH, it is mandatory that any other underlying disorder is ruled out. Indomethacin represents the principal option in the treatment of PSH, despite therapeutic failure in up to 35% of the cases. Recent reports showed that cyclooxygenase-2 (COX-2) inhibitors, gabapentin, nifedipine, paracetamol and melatonin may also be effective. In this report, we focus on the therapy of PSH summarizing the information collected from a systematic analysis of the international literature over the period 1980-2009.