Methodology of drug trials in migraine: History and suggestions for the future.

There is a multitude of scientific papers and guideline papers on the methodology of drug trials in migraine. Here, we try to condense this into a single paper and to make proposals for future consideration. Literature known by the authors and from reference lists of relevant publications was used for the history.

The putative proton-coupled organic cation antiporter is involved in uptake of triptans into human brain capillary endothelial cells.

Background: Triptans are anti-migraine drugs with a potential central site of action. However, it is not known to what extent triptans cross the blood-brain barrier (BBB). The aim of this study was therefore to determine if triptans pass the brain capillary endothelium and investigate the possible underlying mechanisms with focus on the involvement of the putative proton-coupled organic cation (H/OC) antiporter.

Multi-omic analyses of triptan-treated migraine attacks gives insight into molecular mechanisms.

Migraine is a common, polygenic disorder that is characterized by moderate to severe headache attacks. Migraine attacks are commonly treated with triptans, i.e.

Doubtful use of placebo following placebo in recent controlled trials of lasmiditan and ubrogepant for the treatment of migraine attacks.

Purpose: In four large controlled trials with lasmiditan and ubrogepant placebo was administered in the first step to demonstrate an effect on migraine attack. In the same trials the investigators also asked the question: is a second dose of the drug effective in non-responders to the first dose? In this phase patients who received placebo in the first phase of the trial again after 2 hours received another dose of placebo.

Conclusion: To be ethical, clinical research requires balancing rigorous science with the protection of human subjects; and it is, in our view, questionable whether placebo was used with "scientific rigor" in the second step of these trials, and this design is not recommended.

Naratriptan is as effective as sumatriptan for the treatment of migraine attacks when used properly. A mini-review.

Background: Naratriptan, marketed in a low oral dose of 2.5 mg, is generally regarded as a less-effective triptan with a slower onset of action than most other triptans in the treatment of migraine attacks. In this review, naratriptan will be compared with sumatriptan, the standard triptan.

Can tendon reflexes be elicited by both stretch and vibration in man?

Aim Of Study: When the biceps tendon is tapped, a contraction is elicited in the biceps muscle. This also occurs with tapping of the radial bone, and it has been suggested that vibration is a stimulus for deep tendon reflexes. We investigated whether the normal stimulus for the deep tendon reflex is a sudden stretch, a phasic vibration, or both.

Erenumab prevents the occurrence of migraine attacks and not just migraine days: Post-hoc analyses of a phase III study.

Background: This post-hoc analysis was conducted to evaluate the effect of erenumab on monthly migraine days, monthly migraine attacks, and attack duration in patients with episodic migraine to investigate whether erenumab actually prevents the occurrence of migraine attacks and/or shortens them.

Methods: We conducted a post-hoc analysis of the data from the STRIVE study, in 955 patients with episodic migraine. Relative changes from baseline to mean over months 4, 5 and 6 of the double-blind treatment phase in monthly migraine days, monthly migraine attacks and mean migraine attack duration were assessed.

Prevention of migraine with monoclonal antibodies against CGRP or the CGRP receptor: Addition to the S1 guideline: Therapy of migraine attacks and prevention of migraine. Recommendations of the Germany Society of Neurology and the German Migraine and Headache Society.

Monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor (Erenumab) or against CGRP (Eptinezumab, Fremanezumab, Galcanezumab) are new substances for the preventive treatment of migraine. They represent an extension of the therapeutic options, which already exist in migraine prevention. In randomized, placebo-controlled studies, the efficacy and good tolerability of these specific substances have been demonstrated in patients with episodic and chronic migraine.

Pharmacological strategies to treat attacks of episodic migraine in adults.

Introduction: Migraine patients prioritize early complete relief of headache and associated symptoms, sustained freedom of pain, and good tolerability. One major obstacle for the successful use of drug treatment of migraine attack is that the speed of action of triptans, 5-HT receptor agonists, is delayed.

Areas Covered: In this review, the author discusses the following features of acute migraine drugs: pharmacology; pharmacokinetics, and absorption of drugs during migraine attacks.

Onset of action in placebo-controlled migraine attacks trials: A literature review and recommendation.

Background: Migraine patients want acute treatment to provide complete relief of the migraine attack within 30 minutes. Traditionally, "speed of onset of effect" is evaluated by estimating the time-point for first statistical separation of drug and placebo. The estimated onset of effect can be a few percent difference of patients being pain free in very large randomised, controlled trials.

Pain freedom after 2 hours should be the primary outcome in controlled trials treating migraine attacks.

Background: Pain freedom after 2 hours is the recommended primary endpoint by the International Headache Society in randomized trials investigating drug treatment of acute migraine attacks. In order to demonstrate an early effect of a drug, some drug companies, however, have promoted headache relief (improvement from severe or moderate pain to mild or no pain) at earlier time points than 2 hours as outcome parameter.

Methods And Results: We analyzed the relationship between pain freedom and headache relief in acute migraine trials and observed that persistent mild headache constituted 90% of headache relief after 0.

Problematic presentation and use of efficacy measures in current trials of CGRP monoclonal antibodies for episodic migraine prevention: A mini-review.

Background: In trials of monoclonal antibodies against calcitonin gene-related peptide or its receptor for prevention of episodic migraine, we observed two problematic aspects: a) The graphic presentations; b) the methods of calculating "response rates" (≥50% decrease of monthly migraine days from baseline).

Observations: Decrease in monthly migraine days is presented, over time, in figures on a downward (negative) scale from zero at baseline, with the ordinate stopped just beyond the maximum effect of the active drugs. In one trial, decreases in monthly migraine days were -1.

Why is the therapeutic effect of acute antimigraine drugs delayed? A review of controlled trials and hypotheses about the delay of effect.

In randomised controlled trials (RCTs) of oral drug treatment of migraine attacks, efficacy is evaluated after 2 hours. The effect of oral naratriptan 2.5 mg with a maximum blood concentration (T ) at 2 hours increases from 2 to 4 hours in RCTs.

Pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology.

The aim of this study was to evaluate the pharmacokinetic variability of beta-adrenergic blocking agents used in cardiology by reviewing single-dose and steady-state pharmacokinetic studies from the literature. PubMed was searched for pharmacokinetic studies of beta-adrenergic blocking agents, both single-dose and steady-state studies. The studies included reported maximum plasma concentration (C) and/or area under the concentration curve (AUC).

The nitric oxide synthase inhibitor and serotonin-receptor agonist NXN-188 during the aura phase of migraine with aura: A randomized, double-blind, placebo-controlled cross-over study.

Background and aims NXN-188 is a combined neuronal nitric oxide synthase (nNOS) inhibitor and 5HT-1B/1D receptor agonist which has previously shown efficacy in the acute treatment of migraine. Nitric oxide (NO) is involved in the pathogenesis of migraine pain and is formed after cortical spreading depression. Therefore NXN-188 could perhaps prevent the development of the headache phase in migraine with aura if taken during the aura.

Evaluating the reporting of adverse events in controlled clinical trials conducted in 2010-2015 on migraine drug treatments.

Background In 2008, the International Headache Society published guidelines on the "evaluation and registration of adverse events in clinical drug trials on migraine". They listed seven recommendations for reporting adverse events in randomized controlled trials on migraine. The present study aimed to evaluate adherence to these recommendations, and based on the results, to recommend improvements.

Pharmacokinetic Variability of Drugs Used for Prophylactic Treatment of Migraine.

In this review, we evaluate the variability in the pharmacokinetics of 11 drugs with established prophylactic effects in migraine to facilitate 'personalized medicine' with these drugs. PubMed was searched for 'single-dose' and 'steady-state' pharmacokinetic studies of these 11 drugs. The maximum plasma concentration was reported in 248 single-dose and 115 steady-state pharmacokinetic studies, and the area under the plasma concentration-time curve was reported in 299 single-dose studies and 112 steady-state pharmacokinetic studies.

Central Pontine Myelinolysis and Localized Fluorodeoxyglucose Uptake Seen on F-FDG PET/CT.

Case report describing the finding of central pontine myelinolysis (CPM) using combined fluorine-18 ( F)-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). The patient was a known alcoholic who, during admission was under treatment for hyponatremia, showed a significant decline in both motor and cognitive function. Combined F-FDG PET/CT showed localized FDG uptake in the pons, consistent with the finding of CPM observed on magnetic resonance imaging (MRI).

[Hourglass neurinoma resulted in symptoms of polyneuropathy].

Distal symmetric polyneuropathy (DSP) is a common condition where limited diagnostic evaluation is usually required. We present a case story of a 50-year-old male who had symptoms of DSP, but electrodiagnostic testing suggested a more proximal lesion, and magnetic resonance imaging showed a spinal nerve root schwannoma. The patient recovered completely after surgery.

Meralgia Paresthetica after Prone Positioning Ventilation in the Intensive Care Unit.

Meralgia paresthetica (MP) is a mononeuropathy of the lateral femoral cutaneous nerve (LFCN) caused by external compression of the nerve during its course close to the anterior superior iliac spine. We present a case of a patient with acute respiratory distress induced by pneumonia who was admitted to the intensive care unit (ICU) for mechanical ventilation. In the ICU, the patient received one session of prone position ventilation for 8.