Rapid resolution of migraine symptoms after initiating the preventive treatment eptinezumab during a migraine attack: results from the randomized RELIEF trial.

BACKGROUND: Eptinezumab is an anti-calcitonin gene-related peptide (CGRP) monoclonal antibody approved for the preventive treatment of migraine. In the phase 3 RELIEF study, eptinezumab resulted in shorter time to headache pain freedom and time to absence of most bothersome symptom (MBS; including nausea, photophobia, or phonophobia) compared with placebo when administered during a migraine attack. The objective of this exploratory analysis was to examine the earliest time points that eptinezumab separated from placebo (P < .05) on headache- and migraine-associated symptoms when administered during a migraine attack. METHODS: RELIEF, a multicenter, parallel-group, double-blind trial, occurred from November 7, 2019, through July 8, 2020. Adults considered candidates for preventive treatment were randomized to eptinezumab 100 mg (N = 238) or placebo (N = 242) administered intravenously over 30 min within 1-6 h of migraine onset. Outcome measures included headache pain freedom/relief and absence of MBS, patient's choice of photophobia, phonophobia, or nausea, at regular intervals from 0.5 to 48 h after infusion start. Censoring was applied at time of acute rescue medication use. RESULTS: At hour 1, more eptinezumab-treated patients achieved headache pain freedom (9.7%), headache pain relief (38.7%), and absence of MBS (33.2%) versus placebo (4.1%, 26.9%, and 22.1%, respectively; P < .05 all), with separation from placebo (P < .05) through hour 48. Eptinezumab separated from placebo (P < .05) at hour 1 in absence-of-photophobia (29.4% vs 17.0%) and absence-of-phonophobia (41.2% vs 27.2%) and through hour 48. Initial separation from placebo (P < .05) in absence-of-nausea occurred at end-of-infusion (0.5 h; 36.7% vs 25.4%, respectively). CONCLUSION: Preventive treatment with eptinezumab initiated during a migraine attack resulted in more patients achieving headache pain freedom/relief and absence of MBS, with separation from placebo (P < .05) as early as 0.5-1 h following the start of infusion. Rapid resolution of headache- and migraine-associated symptoms by a peripherally acting, intravenously administered antibody suggest a peripheral site of pharmacological action for CGRP blockade. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04152083 .

ß-Blockers for the Treatment of Misophonia and Misokinesia.

ABSTRACT: Misophonia is an adverse physical and emotional reaction to certain repetitive trigger sounds, usually generated by other people. Misokinesia refers to visual triggers that are sometimes (but not always) related to trigger sounds. Despite how common and disabling these conditions can be, medication treatment of misophonia and misokinesia is largely unexplored. We present the first case of using a ß-blocker (propranolol) to successfully treat a patient experiencing misophonia and misokinesia. A moderate dose (60 mg) of propranolol completely eliminated multiple auditory and visual trigger symptoms related to other people eating. His trigger response symptoms included overwhelming negative emotions and prominent sympathetic overactivity (fight-or-flight response). These symptoms were so severe that he had avoided most meals with friends and family for the past several years. Propranolol eliminated the emotional and physiological effects of both the auditory and visual triggers, with an Amsterdam Misophonia Scale score reduction from 15 to 2. This enabled him to resume eating meals with family and friends with no distress. The medication was well tolerated. In summary, we report the novel finding that ß-blockers were markedly effective at treating the physical and emotional symptoms of a patient with misophonia and misokinesia. This suggests a novel treatment approach for these conditions.

A randomized study of IV prochlorperazine plus diphenhydramine versus IV hydromorphone for migraine-associated symptoms: A post hoc analysis.

OBJECTIVE: We conducted a randomized trial among emergency department patients with migraine to determine the relative impact on migraine-associated symptoms of hydromorphone, an opioid, versus prochlorperazine, an antidopaminergic antiemetic. METHODS: This was a post hoc analysis of data from a double-blind study registered at http://clinicaltrials.gov (NCT02389829). Patients who met International Classification of Headache Disorders, 3rd edition criteria for migraine without aura or for probable migraine without aura were eligible for participation. Participants received either hydromorphone 1 mg IV or prochlorperazine 10 mg IV plus diphenhydramine 25 mg IV and could receive a second dose of the same medication 1 h later if needed. The outcomes were sustained relief of nausea, photophobia, and phonophobia. RESULTS: A total of 127 patients were enrolled, of whom 63 received prochlorperazine and 64 received hydromorphone. Of 49 patients in the prochlorperazine arm who reported nausea at baseline, 34 (69.4%) reported complete resolution without relapse versus 15/49 (30.6%) in the hydromorphone arm (absolute risk reduction [ARR] = 38.8%, 95% CI: 20.5%-57.0%, p < 0.001). Of 55 patients in the prochlorperazine arm who reported photophobia at baseline, 23 (41.8%) reported complete resolution without relapse versus 13/62 (20.9%) patients treated with hydromorphone (ARR = 20.8%, 95% CI: 4.3%-37.3%, p = 0.014). Of 56 patients in the prochlorperazine arm who reported phonophobia at baseline, 25 (44.6%) reported complete resolution without relapse versus 16/59 (27.1%) in the hydromorphone arm (ARR = 17.5%, 95% CI: 0.3%-34.8%, p = 0.049). For adverse events, three patients in the prochlorperazine arm reported anxiety or restlessness, and nine patients in the hydromorphone arm reported dizziness or weakness. CONCLUSIONS: Prochlorperazine plus diphenhydramine is more efficacious than hydromorphone for the treatment of migraine-associated symptoms.

IM ketorolac vs diclofenac potassium powder for oral solution for the acute treatment of severe migraine: a randomized controlled trial.

BACKGROUND: Diclofenac potassium for oral solution (CAMBIA®) may be an alternative for patients who would otherwise need to be seen in a healthcare setting for parenteral ketorolac. CAMBIA® is FDA-approved for the abortive treatment of migraine and has demonstrated superiority over generic diclofenac tablets with rapid migraine reduction. This study assessed for efficacy of CAMBIA® as an alternative outpatient treatment for refractory migraine to parenteral ketorolac. METHODS: We performed an exploratory, single-center, double-blind, double-dummy randomized controlled trial comparing CAMBIA® with IM ketorolac. Participants were randomized to receive either ketorolac 60 mg IM with dummy oral solution or CAMBIA® 50 mg, together with IM injection of normal saline. The primary endpoint was headache severity, self-rated on a scale 0-3. Secondary endpoints included self-rated nausea, disability, and photo- or phonophobia, as well as presence of side effects and need for additional rescue therapy. RESULTS: A total of 23 patients were enrolled. Ten patients received the study drug and 13 patients received IM ketorolac as the control. There were no major differences observed with respect to the primary outcome of mean headache severity at successive time points over a 24-h follow-up period. No major differences were found with respect to average disability, nausea, and photo- or phonophobia ratings. No major adverse events were reported. CONCLUSION: In treatment of refractory migraine headache, CAMBIA® may provide similar benefits as IM ketorolac without increasing the risk of treatment failure, major bleeding, or cardiovascular events. However, larger studies are needed to confirm this finding. TRIAL REGISTRATION: Clinicaltrials.gov: NCT # 02664116, Titled "IM Ketorolac vs Diclofenac Potassium Powder for Oral Solution (CAMBIA®) for the Acute Treatment of Severe Migraine". Registered 26 January 2016, https://clinicaltrials.gov/ct2/show/NCT02664116?term=02664116&rank=1.

Ubrogepant for the Treatment of Migraine.

BACKGROUND: Ubrogepant is an oral, small-molecule calcitonin gene-related peptide receptor antagonist for acute migraine treatment. METHODS: We conducted a randomized trial to evaluate the efficacy, safety, and side-effect profile of ubrogepant. We assigned adults with migraine, with or without aura, in a 1:1:1 ratio to receive an initial dose of placebo, ubrogepant at a dose of 50 mg, or ubrogepant at a dose of 100 mg for treatment of a single migraine attack, with the option to take a second dose. The coprimary efficacy end points were freedom from pain at 2 hours after the initial dose and absence of the most bothersome migraine-associated symptom at 2 hours. Secondary end points included pain relief (at 2 hours), sustained pain relief (from 2 to 24 hours), sustained freedom from pain (from 2 to 24 hours), and absence of symptoms associated with migraine (photophobia, phonophobia, and nausea) at 2 hours. RESULTS: A total of 1672 participants were enrolled; 559 were assigned to receive placebo, 556 to receive 50 mg of ubrogepant, and 557 to receive 100 mg of ubrogepant. The percentage of participants who had freedom from pain at 2 hours was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P = 0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<0.001). The percentage of participants who had freedom from the most bothersome symptom at 2 hours was 27.8% in the placebo group, 38.6% in the 50-mg ubrogepant group (P = 0.002), and 37.7% in the 100-mg ubrogepant group (P = 0.002). Adverse events within 48 hours after the initial or optional second dose were reported in 12.8% of participants in the placebo group, in 9.4% in the 50-mg ubrogepant group, and in 16.3% in the 100-mg ubrogepant group. The most common adverse events were nausea, somnolence, and dry mouth (reported in 0.4 to 4.1%); these events were more frequent in the 100-mg ubrogepant group (reported in 2.1 to 4.1%). Serious adverse events reported within 30 days in the ubrogepant groups included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none of the events occurred within 48 hours after the dose. CONCLUSIONS: A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine. (Funded by Allergan; ClinicalTrials.gov number, NCT02828020.).

Synergistic Transcriptional Changes in AMPA and GABAA Receptor Genes Support Compensatory Plasticity Following Unilateral Hearing Loss.

Debilitating perceptual disorders including tinnitus, hyperacusis, phantom limb pain and visual release hallucinations may reflect aberrant patterns of neural activity in central sensory pathways following a loss of peripheral sensory input. Here, we explore short- and long-term changes in gene expression that may contribute to hyperexcitability following a sudden, profound loss of auditory input from one ear. We used fluorescence in situ hybridization to quantify mRNA levels for genes encoding AMPA and GABAA receptor subunits (Gria2 and Gabra1, respectively) in single neurons from the inferior colliculus (IC) and auditory cortex (ACtx). Thirty days after unilateral hearing loss, Gria2 levels were significantly increased while Gabra1 levels were significantly decreased. Transcriptional rebalancing was more pronounced in ACtx than IC and bore no obvious relationship to the degree of hearing loss. By contrast to the opposing, synergistic shifts in Gria2 and Gabra1 observed 30 days after hearing loss, we found that transcription levels for both genes were equivalently reduced after 5 days of hearing loss, producing no net change in the excitatory/inhibitory transcriptional balance. Opposing transcriptional shifts in AMPA and GABA receptor genes that emerge several weeks after a peripheral insult could promote both sensitization and disinhibition to support a homeostatic recovery of neural activity following auditory deprivation. Imprecise transcriptional changes could also drive the system toward perceptual hypersensitivity, degraded temporal processing and the irrepressible perception of non-existent environmental stimuli, a trio of perceptual impairments that often accompany chronic sensory deprivation.

Efficacy and safety of DFN-11 (sumatriptan injection, 3 mg) in adults with episodic migraine: an 8-week open-label extension study.

BACKGROUND: DFN-11, a 3 mg sumatriptan subcutaneous (SC) autoinjector for acute treatment of migraine, has not been assessed previously in multiple attacks. The objective of this study was to evaluate the efficacy, tolerability, and safety of DFN-11 in the acute treatment of multiple migraine attacks. METHODS: This was an 8-week open-label extension of multicenter, randomized, double-blind, placebo-controlled US study. Subjects averaging 2 to 6 episodic migraine attacks per month were randomized to DFN-11 or placebo to treat a single attack of moderate-to-severe intensity and then entered the extension study to assess the efficacy, tolerability, and safety of DFN-11 in multiple attacks of any pain intensity. RESULTS: Overall, 234 subjects enrolled in the open-label period, and 29 (12.4%) discontinued early. A total of 848 migraine episodes were treated with 1042 doses of open-label DFN-11 and subjects treated a mean (SD) of 3.9 (2.3) attacks. At 2 h postdose in attacks 1 (N = 216), 2 (N = 186), 3 (N = 142) and 4 (N = 110), respectively, pain freedom rates were 57.6%, 64.6%, 61.6%, and 66.3%; pain relief rates were 83.4%, 88.4%, 84.1%, and 81.7%; most bothersome symptom (MBS)-free rates were 69.0%, 76.5%, 77.7%, and 74.7%; nausea-free rates were 78.1%, 84.6%, 86.5%, and 85.7%; photophobia-free rates were 75.3%, 76.4%, 72.3%, and 77.5%; and phonophobia-free rates were 75.2%, 77.5%, 73.6%, and 76.0%. Overall, 40.6% (89/219) of subjects reported treatment-emergent adverse events (TEAE), the most common of which were associated with the injection site: swelling (12.8%), pain (11.4%), irritation (6.4%), and bruising (6.4%). Most subjects (65.2%, 58/89) had mild TEAEs; severe TEAEs were reported by 1 subject (treatment-related jaw tightness). Five subjects (2.1%) discontinued due to adverse events, which included mild throat tightness (n = 2), moderate hernia pain (n = 1), moderate hypersensitivity (n = 1), and 1 subject with mild nausea and moderate injection site swelling. There were no serious TEAEs and no new or unexpected safety findings. CONCLUSION: DFN-11 was effective, tolerable, and safe in the acute treatment of 4 migraine attacks over 8 weeks, with consistent responses on pain and associated symptoms. Most TEAEs were mild, with a very low incidence of triptan-related TEAEs. DFN-11 is potentially an effective and safe alternative for the acute treatment of migraine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02569853 . Registered 07 October 2015.

An item response theory based integrated model of headache, nausea, photophobia, and phonophobia in migraine patients.

This study developed an integrated model of severity scores of migraine headache and the incidence of nausea, photophobia, and phonophobia to predict the natural time course of migraine symptoms, which are likely to occur by a common disease progression mechanism. Data were acquired from two phase 3 clinical trials conducted during the development of eletriptan. Only the placebo arm was used for analysis. A conventional proportional odds model was compared with an item response theory (IRT) based approach. Results suggested that the IRT based approach led to a better model fit, successfully revealing the difference in relief rates among different symptoms, which was the fastest in phonophobia and the slowest in headache. Simulation with the developed model suggested that using headache scores at 4 h post-dose attained greatest statistical power, yielding sample size of 100 per arm given drug effect of 40%, as compared to that of 200 per arm when 2 h post-dose scores were used as in the original eletriptan protocol. This work demonstrated the usefulness of an IRT based model as applied to analyzing multidimensional migraine symptoms and designing clinical trials. Our model can be similarly applied to analyzing other multiple endpoints sharing a common underlying mechanism.

Use of Most Bothersome Symptom as a Coprimary Endpoint in Migraine Clinical Trials: A Post-Hoc Analysis of the Pivotal ZOTRIP Randomized, Controlled Trial.

OBJECTIVE: To better understand the utility of using pain freedom and most bothersome headache-associated symptom (MBS) freedom as co-primary endpoints in clinical trials of acute migraine interventions. BACKGROUND: Adhesive dermally applied microarray (ADAM) is an investigational system for intracutaneous drug administration. The recently completed pivotal Phase 2b/3 study (ZOTRIP), evaluating ADAM zolmitriptan for the treatment of acute moderate to severe migraine, was one of the first large studies to incorporate MBS freedom and pain freedom as co-primary endpoints per recently issued guidance by the US Food and Drug Administration. In this trial, the proportion of patients treated with ADAM zolmitriptan 3.8 mg, who were pain-free and MBS-free at 2 hours post-dose, was significantly higher than for placebo. METHODS: We undertook a post-hoc analysis of data from the ZOTRIP trial to examine how the outcomes from this trial compare to what might have been achieved using the conventional co-primary endpoints of pain relief, nausea, photophobia, and phonophobia. RESULTS: Of the 159 patients treated with ADAM zolmitriptan 3.8 mg or placebo, prospectively designated MBS were photophobia (n = 79), phonophobia (n = 43), and nausea (n = 37). Two-hour pain free rates in those with photophobia as the MBS were 36% for ADAM zolmitriptan 3.8 mg and 14% for placebo (P = .02). Corresponding rates for those with phonophobia as the MBS were 14% and 41% (P = .05). For those whose MBS was nausea, corresponding values were 56% and 16%, respectively (P = .01). Two-hour freedom from the MBS for active drug vs placebo were 67% vs 35% (P < .01) for photophobia, 55% vs 43% (P = .45) for phonophobia, and 89% vs 58% for nausea (P = .04). MBS freedom but not pain freedom was achieved in 28%. Only 1 patient (1%) achieved pain freedom, but not MBS freedom. The proportion with both pain and MBS freedom was highest (56%) among those whose MBS was nausea. CONCLUSION: In this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co-primary endpoints.

Survey on the Effectiveness of Dietary Supplements to Treat Tinnitus.

PURPOSE: We surveyed the benefit of dietary supplements to treat tinnitus and reported adverse effects. METHOD: A website was created for people with tinnitus to complete a variety of questions. RESULTS: The 1,788 subjects who responded to questionnaires came from 53 different countries; 413 (23.1%) reported taking supplements. No effect on tinnitus was reported in 70.7%, improvement in 19.0%, and worsening in 10.3%. Adverse effects were reported in 6% (n = 36), including bleeding, diarrhea, headache, and others. Supplements were reported to be helpful for sleep: melatonin (effect size, d = 1.228) and lipoflavonoid (d = 0.5244); emotional reactions: melatonin (d = 0.6138) and lipoflavonoid (d = 0.457); hearing: Ginkgo biloba (d = 0.3758); and concentration Ginkgo biloba (d = 0.3611). The positive, subjective reports should be interpreted cautiously; many might have reported a positive effect because they were committed to treatment and expected a benefit. Users of supplements were more likely to have loudness hyperacusis and to have a louder tinnitus. CONCLUSIONS: The use of dietary supplements to treat tinnitus is common, particularly with Ginkgo biloba, lipoflavonoids, magnesium, melatonin, vitamin B12, and zinc. It is likely that some supplements will help with sleep for some patients. However, they are generally not effective, and many produced adverse effects. We concluded that dietary supplements should not be recommended to treat tinnitus but could have a positive outcome on tinnitus reactions in some people.

Loudness perception affected by early age hearing loss.

Tinnitus and hyperacusis, commonly seen in adults, are also reported in children. Although clinical studies found children with tinnitus and hyperacusis often suffered from recurrent otitis media, there is no direct study on how temporary hearing loss in the early age affects the sound loudness perception. In this study, sound loudness changes in rats affected by perforation of the tympanic membranes (TM) have been studied using an operant conditioning based behavioral task. We detected significant increases of sound loudness and susceptibility to audiogenic seizures (AGS) in rats with bilateral TM damage at postnatal 16 days. As increase to sound sensitivity is commonly seen in hyperacusis and tinnitus patients, these results suggest that early age hearing loss is a high risk factor to induce tinnitus and hyperacusis in children. In the TM damaged rats, we also detected a reduced expression of GABA receptor δ and α6 subunits in the inferior colliculus (IC) compared to the controls. Treatment of vigabatrin (60 mg/kg/day, 7-14 days), an anti-seizure drug that inhibits the catabolism of GABA, not only blocked AGS, but also significantly attenuated the loudness response. Administration of vigabatrin following the early age TM damage could even prevent rats from developing AGS. These results suggest that TM damage at an early age may cause a permanent reduction of GABA tonic inhibition which is critical towards the maintenance of normal loudness processing of the IC. Increasing GABA concentration during the critical period may alleviate the impairment in the brain induced by early age hearing loss.

Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults.

BACKGROUND: This is an updated version of the original Cochrane review published in Issue 11, 2010 (Derry 2010). Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting, which are commonly associated with migraine. OBJECTIVES: To determine the efficacy and tolerability of paracetamol (acetaminophen), alone or in combination with an antiemetic, compared with placebo and other active interventions in the treatment of acute migraine in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 4 October 2010 for the original review, and to 13 February 2013 for the update. Two clinical trials registers (ClinicalTrials.gov and gsk-clinicalstudyregister.com) were also searched on both occasions. SELECTION CRITERIA: We included randomised, double-blind, placebo- or active-controlled studies using self-administered paracetamol to treat a migraine headache episode, with at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared with placebo or other active treatment. MAIN RESULTS: Searches for the update identified one additional study for inclusion. Eleven studies (2942 participants, 5109 attacks) compared paracetamol 1000 mg, alone or in combination with an antiemetic, with placebo or other active comparators, mainly sumatriptan 100 mg. For all efficacy outcomes paracetamol was superior to placebo, with NNTs of 12 (19% response with paracetamol, 10% with placebo), 5.0 (56% response with paracetamol, 36% with placebo) and 5.2 (39% response with paracetamol, 20% with placebo) for 2-hour pain-free and 2- and 1-hour headache relief, respectively, when medication was taken for moderate to severe pain.Paracetamol 1000 mg plus metoclopramide 10 mg was not significantly different from oral sumatriptan 100 mg for 2-hour headache relief; there were no 2-hour pain-free data.Adverse event rates were similar between paracetamol and placebo, and between paracetamol plus metoclopramide and sumatriptan. No serious adverse events occurred with paracetamol alone, but more serious and/or severe adverse events occurred with sumatriptan than with the combination therapy (NNH 32). AUTHORS' CONCLUSIONS: Paracetamol 1000 mg alone is statistically superior to placebo in the treatment of acute migraine, but the NNT of 12 for pain-free response at two hours is inferior to at of other commonly used analgesics. Given the low cost and wide availability of paracetamol, it may be a useful first choice drug for acute migraine in those with contraindications to, or who cannot tolerate, non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin. The addition of 10 mg metoclopramide gives short-term efficacy equivalent to oral sumatriptan 100 mg. Adverse events with paracetamol did not differ from placebo; serious and/or severe adverse events were slightly more common with sumatriptan than with paracetamol plus metoclopramide.

Diclofenac with or without an antiemetic for acute migraine headaches in adults.

BACKGROUND: Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter (OTC) analgesics. Diclofenac is an established analgesic, and new formulations using the potassium or epolamine salts, which can be dissolved in water, have been developed for rapid absorption, which may be beneficial in acute migraine. Co-therapy with an antiemetic should help to reduce the nausea and vomiting commonly associated with migraine. OBJECTIVES: To determine the efficacy and tolerability of diclofenac, alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine headaches in adults. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Relief Database, ClinicalTrials.gov, and reference lists for studies through 27 September 2011. SELECTION CRITERIA: We included randomised, double-blind, placebo- and/or active-controlled studies using self administered diclofenac to treat a migraine headache episode, with at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We used numbers of participants achieving each outcome to calculate relative risk (or 'risk ratio') and numbers needed to treat to benefit (NNT) or harm (NNH) compared to placebo or a different active treatment. MAIN RESULTS: Five studies (1356 participants) compared oral diclofenac with placebo, and one also compared it with sumatriptan; none combined diclofenac with a self administered antiemetic. Four studies treated attacks with single doses of medication, and two allowed an optional second dose for inadequate response. Only two studies, with three active treatment arms, provided data for pooled analysis of primary outcomes. For single doses of diclofenac potassium 50 mg versus placebo (two studies), the NNTs were 6.2, 8.9, and 9.5 for pain-free at two hours, headache relief at two hours, and pain-free responses at 24 hours, respectively.Associated symptoms of nausea, photophobia and phonophobia, and functional disability were reduced within two hours, and similar numbers of participants experienced adverse events, which were mostly mild and transient.There were insufficient data to evaluate other doses of oral diclofenac, or to compare different formulations or different dosing regimens; only one study compared oral diclofenac with an active comparator (oral sumatriptan 100 mg). AUTHORS' CONCLUSIONS: Oral diclofenac potassium 50 mg is an effective treatment for acute migraine, providing relief from pain and associated symptoms, although only a minority of patients experience pain-free responses. Adverse events are mostly mild and transient and occur at the same rate as with placebo.

Cochlear hearing loss in patients with Laron syndrome.

The aim of this prospective clinical study was to test auditory function in patients with Laron syndrome, either untreated or treated with insulin-like growth factor I (IGF-I). The study group consisted of 11 patients with Laron syndrome: 5 untreated adults, 5 children and young adults treated with replacement IGF-I starting at bone age <2 years, and 1 adolescent who started replacement therapy at bone age 4.6 years. The auditory evaluation included pure tone and speech audiometry, tympanometry and acoustic reflexes, otoacoustic emissions, loudness dynamics, auditory brain stem responses and a hyperacusis questionnaire. All untreated patients and the patient who started treatment late had various degrees of sensorineural hearing loss and auditory hypersensitivity; acoustic middle ear reflexes were absent in most of them. All treated children had normal hearing and no auditory hypersensitivity; most had recordable middle ear acoustic reflexes. In conclusion, auditory defects seem to be associated with Laron syndrome and may be prevented by starting treatment with IGF-I at an early developmental age.

Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults.

BACKGROUND: Migraine is a common, disabling condition and a burden for the individual, health services and society. Many sufferers choose not to, or are unable to, seek professional help and rely on over-the-counter analgesics. Co-therapy with an antiemetic should help to reduce nausea and vomiting commonly associated with migraine. OBJECTIVES: To determine the efficacy and tolerability of paracetamol (acetaminophen), alone or in combination with an antiemetic, compared to placebo and other active interventions in the treatment of acute migraine in adults. SEARCH STRATEGY: We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies through 4 October 2010. SELECTION CRITERIA: We included randomised, double-blind, placebo- or active-controlled studies using self-administered paracetamol to treat a migraine headache episode, with at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Numbers of participants achieving each outcome were used to calculate relative risk and numbers needed to treat (NNT) or harm (NNH) compared to placebo or other active treatment. MAIN RESULTS: Ten studies (2769 participants, 4062 attacks) compared paracetamol 1000 mg, alone or in combination with an antiemetic, with placebo or other active comparators, mainly sumatriptan 100 mg. For all efficacy outcomes paracetamol was superior to placebo, with NNTs of 12, 5.2 and 5.0 for 2-hour pain-free and 1- and 2-hour headache relief, respectively, when medication was taken for moderate to severe pain. Nausea, photophobia and phonophobia were reduced more with paracetamol than with placebo at 2 hours (NNTs of 7 to 11); more individuals were free of any functional disability at 2 hours with paracetamol (NNT 10); and fewer participants needed rescue medication over 6 hours (NNT 6).Paracetamol 1000 mg plus metoclopramide 10 mg was not significantly different from oral sumatriptan 100 mg for 2-hour headache relief; there were no 2-hour pain-free data. There was no significant difference between the paracetamol plus metoclopramide combination and sumatriptan for relief of "light/noise sensitivity" at 2 hours, but slightly more individuals needed rescue medication over 24 hours with the combination therapy (NNT 17).Adverse event rates were similar between paracetamol and placebo, and between paracetamol plus metoclopramide and sumatriptan. No serious adverse events occurred with paracetamol alone, but more "major" adverse events occurred with sumatriptan than with the combination therapy (NNH 32). AUTHORS' CONCLUSIONS: Paracetamol 1000 mg alone is an effective treatment for acute migraine headaches, and the addition of 10 mg metoclopramide gives short-term efficacy equivalent to oral sumatriptan 100 mg. Adverse events with paracetamol did not differ from placebo; "major" adverse events were slightly more common with sumatriptan than with paracetamol plus metoclopramide.

Randomized, controlled trial of telcagepant for the acute treatment of migraine.

BACKGROUND: The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. In this large phase 3 clinical trial, we sought to confirm the efficacy of telcagepant, the first orally bioavailable CGRP receptor antagonist. METHODS: Adults with migraine with or without aura (International Headache Society criteria) treated a moderate or severe attack with oral telcagepant 50 mg (n = 177), 150 mg (n = 381), 300 mg (n = 371), or placebo (n = 365) in a randomized, double-blind trial. The 5 co-primary endpoints were pain freedom, pain relief, and absence of photophobia, absence of phonophobia, and absence of nausea, all at 2 hours postdose. The key secondary endpoint was 2-24 hour sustained pain freedom. The prespecified primary efficacy analyses evaluated the 150 mg and 300 mg groups; the 50-mg group was included on an exploratory basis to further characterize the dose response but was not prespecified for analysis. Tolerability was assessed by adverse experience reports. RESULTS: Telcagepant 300 mg was more effective (p

Does risperidone improve hyperacusia in children with autism?

INTRODUCTION: Many of children with autism have hyperacusia, an increased sensation to sound. It can lead to their avoidance from some sounds or they may cover their ears. There was not found any published report about possible effect of any medication for improving hyperacusia in children with autism. CASE REPORT: The patient is a 5 and half year old girl with autism and hyperacusia. According to her mother's report, severity of hyperacusia was improved after taking risperidone. CONCLUSION: Hyperacusia was improved after initiation of risperidone and disappeared after discontinuation of risperidone. It re-happened in the re-challenge test. This supports the possible role of risperidone. To the author's knowledge, this is the first report of possible risperidone effect on hyperacusia in the literature.

Identification of negative predictors of pain-free response to triptans: analysis of the eletriptan database.

Thirty to forty percent of migraineurs do not respond to any given triptan treatment. We identified clinical variables that significantly predict therapeutic non-response and evaluated the efficacy of eletriptan (20, 40 and 80 mg) and sumatriptan (100 mg) vs. placebo in a subgroup of patients with all predictor variables. First-attack data were pooled from 10 randomized, double-blind, placebo-controlled migraine trials (n = 8473). Multivariate regression analyses identified three significant baseline predictors of failure to achieve 2-h pain-free response: severe headache pain, presence of photophobia/phonophobia and presence of nausea. Time of dosing following headache onset did not influence 2-h pain-free response. Among patients with all three risk factors (n = 2010; 24% of total sample), 2-h pain-free response was significantly higher in patients receiving all three doses of eletriptan or sumatriptan vs. placebo (all P < 0.01). Thus, eletriptan and sumatriptan are efficacious in difficult-to-treat patients at high risk for non-response to triptans.

A meta-analysis of the placebo response in acute migraine and how this response may be influenced by some of the characteristics of clinical trials.

Migraine is the most common cause of vascular headache and a highly prevalent illness. In the last 20 years, the discovery of new agents has increased clinical research on migraine. In most of clinical trials that have been conducted, the efficacy was established using a placebo as a control treatment. The objective of the study reported here was to analyse the response rate in patients who received a placebo as well as to determine how a number of the methodological factors may affect the effect of the placebo in clinical trials of acute migraine. Computer-based information searches were conducted on the Medline database. Data analysis included the outcomes 'pain relief', 'pain-free', 'associated symptoms', 'recurrence', 'patients' opinion' about pain relief and 'adverse events'. Administration route, study design and country in which the study was carried out were the methodological factors that were analyzed. Meta-analysis was computed using Mantel-Haenszel, and a total of 98 papers were considered in the final analysis. After 2 h, 28.6% of the patients of the placebo group improved and 8.8% were pain-free. The percentage of pain-free patients was the highest in the placebo and active drug groups in which the placebo or drug had been administered subcutaneously, in parallel design studies (vs. cross-over trials) and in studies performed in Europe (vs. North America). Adverse events in the placebo group were significantly higher in studies performed in North America. These data reinforce the need for knowing the magnitude of the placebo response in each specific situation during the planning of clinical trials on acute migraine.