Ethical considerations in biomedical research: a personal view.

PREMISE: Ethical considerations are made when an experiment is planned and take a regulatory system of moral principles into account. DISCUSSION: Ethical considerations should first and foremost be made in order to protect the individual subject/animal from being exposed to any unethical and perhaps even illegal intervention and to ensure that the experimental conditions used are appropriate. SUMMARY: The main role of research ethics committees is to assess the scientific and ethical aspects of submitted protocols and follow up the trial until its closure.

Randomised trial on episodic cluster headache with an angiotensin II receptor blocker.

OBJECTIVES: The aim of this study was to evaluate the angiotensin II receptor antagonist candesartan as prophylactic medication in patients with episodic cluster headache. METHODS: This study comprised a prospective, placebo-controlled, double-blind, parallel-designed trial performed in seven centres in Scandinavia. Forty (40) patients with episodic cluster headache (ICHD-2) were recruited and randomised over a five-year period to placebo or 16 mg candesartan in the first week, and placebo or 32 mg candesartan in the second and third week. RESULTS: The number of cluster headache attacks (primary efficacy variable) during the three-week treatment period was reduced from 14.3 ± 9.2 attacks in week 1 to 5.6 ± 7.0 attacks in week 3 (-61%) in the candesartan group and from 16.8 ± 14.1 attacks in week 1 to 10.5 ± 11.3 attacks in week 3 (-38%) in the placebo group. The difference between the candesartan and placebo group was not significant with the pre-planned non-parametric ranking test, but a post-hoc exact Poisson test, which takes into account the temporal properties of the data, revealed a significant result ( P < 0.0001). CONCLUSIONS: This was a negative trial. Post-hoc statistics suitable to describe the temporal changes in cluster headache indicate that conduction of future larger studies may be justified.

Dihydroergotamine, ergotamine, methysergide and sumatriptan - basic science in relation to migraine treatment.

The 5-hydroxytryptamine (5-HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5-HT(1B) , 5-HT(1D) , and 5-HT(1F) receptors. Ergotamine, dihydroergotamine, and methysergide, as well as the "triptan" sumatriptan, are all agonists for these receptors. The receptor profile and degree of selectivity of these four drugs differ, which is reflected by their side effects that limit their use in the acute and prophylactic treatment of migraine. The acute antimigraine efficacy of these remedies is very much dependent on the formulation used where, in general, parenteral formulations are more effective in reliving the symptoms of a migraine attack.

Subjective well-being in patients with chronic tension-type headache: effect of acupuncture, physical training, and relaxation training.

BACKGROUND: Episodic tension-type headache is a common problem affecting approximately 2 of 3 of the population. The origin of tension-type headache is multifactorial, but the pathogenesis is still unclear. In some individuals episodic tension-type headache transforms into chronic tension-type headache (CTTH). Subjective symptoms related to the central nervous system might affect patients subjective well-being and quality of life. OBJECTIVE: This study compared 3 nonpharmacologic treatments; acupuncture, relaxation training, and physical training on subjective well-being in patients with CTTH. METHODS: Ninety consecutive patients with CTTH were randomly allocated to acupuncture, relaxation training, or physical training. At baseline 88 age-matched and sex-matched healthy controls were compared with the patients with CTTH. Subjective, central nervous system-related symptoms that might affect patients' subjective well-being and quality of life were assessed with the Minor Symptom Evaluation Profile, which contains 24 self-administered standardized items with visual analog scale responses. Fifteen items are categorized into 3 dimensions: contentment, vitality, and sleep. Assessments were made before treatment, immediately after, and 3 and 6 months after the last treatment. RESULTS: Baseline values of the total score of the 24 items and the 3 dimensions were generally lower in patients with tension-type headache compared with the reference group. No significant differences were found among the 3 treatment groups during the baseline period. All treatments proportionally improved the subjective, central nervous system-related symptoms in patients with CTTH. The 3-month follow-up, the total score of the Minor Symptom Evaluation Profile was significantly improved in the physical training group compared with the acupuncture group (P=0.036). Total mean over period was also highest in the physical training group compared with the acupuncture group (P=0.025). The vitality and sleep dimension was significantly improved at the 6-month follow-up in the relaxation training group compared with the acupuncture group (P=0.04). CONCLUSIONS: Physical training and relaxation training seem to be preferable nonpharmacologic treatments for improvement of central nervous system-related symptoms and subjective well-being for patients with CTTH.

BI 44370 TA, an oral CGRP antagonist for the treatment of acute migraine attacks: results from a phase II study.

METHODS: Four hundred and sixty-one adult subjects with migraine were randomised to one of five treatments, the oral antagonist at the calcitonin gene-related peptide (CGRP) receptor BI 44370 TA (50 mg, 200 mg, 400 mg), active comparator eletriptan 40 mg or placebo. The analysis included 341 subjects who took study medication. RESULTS: The primary endpoint, pain-free after two hours, was reached by significantly more subjects in the BI 44370 TA 400 mg (20/73 = 27.4%) and eletriptan 40 mg (24/69 = 34.8%) groups compared to placebo (6/70 = 8.6%, p = .0016), but not by subjects in the BI 44370 TA 200 mg group (14/65 = 21.5%). The effect of 50 mg BI 44370 TA (5/64 = 7.8%) was similar to that of placebo. Analysis of secondary endpoints supported the conclusion from the primary analysis. The frequency of adverse events was low in all groups. CONCLUSION: Efficacy of BI 44370 TA was shown in a dose-dependent manner in the treatment of acute migraine attacks.

Randomized, controlled trial of telcagepant over four migraine attacks.

METHODS: This study evaluated the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant (tablet formulation) for treatment of a migraine attack and across four attacks. Adults with migraine were randomized, double-blind, to telcagepant 140 mg, telcagepant 280 mg, or control treatment sequences to treat four moderate-to-severe migraine attacks. Control patients received placebo for three attacks and telcagepant 140 mg for one attack. Efficacy for the first attack (Attack 1) and consistency of efficacy over multiple attacks were assessed. For an individual patient, consistent efficacy was defined as ≥ 3 successes, and lack of consistent efficacy was defined as ≥ 2 failures, in treatment response. A total of 1677 patients treated ≥ 1 attack and 1263 treated all four attacks. RESULTS: Based on Attack 1 data, telcagepant 140 mg and 280 mg were significantly (p < .001) more effective than placebo for 2-hour pain freedom, 2-hour pain relief, 2-hour absence of migraine-associated symptoms (phonophobia, photophobia, nausea), and 2-24 hours sustained pain freedom. The percentage of patients with 2-hour pain freedom consistency and 2-hour pain relief consistency was significantly (p < .001) higher for both telcagepant treatment sequences versus control. Adverse events within 48 hours for telcagepant with an incidence ≥ 2% and twice that of placebo were somnolence (placebo = 2.3%, 140 mg = 5.9%, 280 mg = 5.7%) and vomiting (placebo = 1.4%, 140 mg = 1.0%, 280 mg = 2.9%). CONCLUSION: Telcagepant 140 mg and 280 mg were effective for treatment of a migraine attack and were more consistently effective than control for intermittent treatment of up to four migraine attacks. Telcagepant was generally well tolerated. (Clinicaltrials.gov; NCT00483704).

The course of frequent episodic migraine in a large headache clinic population: a 12-year retrospective follow-up study.

BACKGROUND: Despite its high prevalence, little is known about the clinical course of migraine. Presented here are the findings of a 12-year follow-up study involving patients diagnosed at baseline with frequent episodic migraine. OBJECTIVE: The main objectives were to determine the long-term outcome of patients with frequent episodic migraine and to identify factors predictive of a favorable vs less favorable prognosis. METHODS: A total of 374 subjects (200 women, 174 men) were selected randomly from a total population of 2812 patients initially diagnosed before December 31, 1996, with episodic migraine and at baseline experiencing 1 to 6 attacks per month. Their subsequent migraine course was evaluated via telephone interviews conducted between 2005 and 2006. RESULTS: Migraine attacks had ceased in 110 (29%) of the 374 patients (57 women and 53 men). The remaining 264 subjects continued to experience migraine attacks at follow-up, and a change in attack frequency was reported by 80% (of whom 80% reported fewer attacks). Sixty-six percent reported a change in pain intensity over time, and of these 83% reported milder pain. Only 6 subjects (6/374 = 1.6%) had developed chronic migraine. CONCLUSION: These data from a headache clinic population suggest that migraine has a favorable prognosis in most patients. Whether the findings reflect the natural history of the disorder or interval improvements in headache management remains conjectural.

The impact of migraine prevention on daily activities: a longitudinal and responder analysis from three topiramate placebo-controlled clinical trials.

BACKGROUND: Topiramate is approved for the prophylaxis (prevention) of migraine headache in adults. The most common adverse events in the three pivotal, randomized, double-blind, placebo-controlled trials were paresthesia, fatigue, cognitive impairment, anorexia, nausea, and taste alteration. In these trials, topiramate 100 mg/d significantly improved Migraine-Specific Questionnaire (MSQ) scores versus placebo (p < 0.001). The MSQ measures how much migraine limits/interrupts daily performance. Pooled analyses of pivotal trial data were conducted to further assess how topiramate 100 mg/d affects daily activities and patient functioning. METHODS: Mean MSQ and Medical Outcome Study Short Form 36 (SF-36) change scores (baseline to each double-blind assessment point) were calculated for pooled intent-to-treat (ITT) patients. Additionally, pooled ITT patients receiving topiramate 100 mg/d or placebo were combined and divided into two responder groups according to percent reduction in monthly migraine frequency: < 50% responders or >or= 50% responders. Between-group differences were assessed using analysis of covariance. RESULTS: Of 756 patients (mean age 39.8 years, 86% female), 384 received topiramate 100 mg/d and 372 placebo. Topiramate significantly improved all three MSQ domains throughout the double-blind phase versus placebo (p = 0.024 [week 8], p < 0.001 [weeks 16 and 26] for role prevention; p < 0.001 for role restriction and emotional function [all time points]). Topiramate 100 mg/d significantly improved SF-36 physical component scores (PCS) throughout the double-blind phase versus placebo (p < 0.001, all time points) and significantly improved mental component scores (MCS) at week 26 (p = 0.043). The greatest topiramate-associated improvements on SF-36 subscales were seen for bodily pain and general health perceptions (p < 0.05; weeks 8, 16, and 26), and physical functioning, vitality, role-physical, and social functioning (p < 0.05; weeks 16 and 26). Significantly greater improvements in all three MSQ domains, as well as the PCS and MCS of SF-36, were observed for >or= 50% responders versus < 50% responders (p < 0.001). Significantly greater percentages of topiramate-treated patients were >or= 50% responders versus placebo (46% versus 23%; p < 0.001). CONCLUSION: Topiramate 100 mg/d significantly improved daily activities and patient functioning at all time points throughout the double-blind phase. Daily function and health status significantly improved for those achieving a >or= 50% migraine frequency reduction.

Satisfaction with current migraine therapy: experience from 3 centers in US and Sweden.

OBJECTIVE: To assess the level of satisfaction and determinants of satisfaction or dissatisfaction of patients presenting in tertiary care, in regard to their usual care (UC) for the acute treatment of migraine. DESIGN/METHODS: Patients seen in 3 headache centers were assessed by means of 21 attributes related to their UC. Questions covered satisfaction with efficacy (including onset of relief, degree of relief, consistency of action, ease of use), tolerability (lack of side effects overall, CNS side effects, other side effects), and willingness to continue using the same medication and to change to another medication. All questions were answered on a 5-point scale (where 1 was strongly agree, 2 was agree, 3 was neutral, 4 was disagree, and 5 was strongly disagree). RESULTS: We assessed 183 subjects (74.8% women, mean age = 39.3 years). UC consisted, as a single drug or combination, of: triptan conventional tablets--62%; triptan disintegrating tablets--8%; sumatriptan nasal spray 9%; sumatriptan injection, 9%; nontriptans--19.6%. Most (54%) had no benefit within the first hour of treatment. The maximum benefit took more than 1 hour to be reached in 69%, and more than 2 hours in 36%. After the maximum benefit had been reached, pain worsened in 61%. Although 58% were satisfied with the degree of relief, 37% were dissatisfied with the speed of effect, 50% with the recurrence of pain, and 42% with the need for a second dose. Most were satisfied with the tolerability (56%). Finally, most (79.7%) said they were willing to try another acute medication. CONCLUSIONS: An important subset of patients, including a large subgroup of patients using triptans, is dissatisfied with their UC. Clinical trials assessing patients' preference should be conducted to complement the information from clinical trials.

Rofecoxib in the acute treatment of migraine: a randomized controlled clinical trial.

OBJECTIVE: To investigate the efficacy, tolerability, and safety of rofecoxib and ibuprofen for acute migraine treatment. BACKGROUND: Rofecoxib was effective and well tolerated in a previous study of treatment of a single migraine attack. We sought to replicate these findings for a single attack and also study the clinical profile of rofecoxib in the acute treatment of multiple migraine attacks. Ibuprofen was included as a reference nonselective NSAID. METHODS: Adult migraineurs (n = 783) treated one migraine attack with either rofecoxib (25 or 50 mg), ibuprofen 400 mg, or placebo in a randomized, double-blind study. Patients could elect to enroll in a 3-month double-blind extension phase. RESULTS: In the single-attack phase, headache relief at 2 hours postdose was reported by 59.4%, 62.2%, and 57.7% of patients who took rofecoxib 25 mg, rofecoxib 50 mg, and ibuprofen 400 mg, respectively, versus 30.5% for placebo (all P < .001 vs placebo). The active drugs were statistically superior to placebo on a variety of additional measures. In the extension phase, the mean percentage of patients' attacks with headache relief at 2 hours postdose was 61.8% for rofecoxib 25 mg, 65.4% for rofecoxib 50 mg, and 59.3% for ibuprofen 400 mg. The mean percentage of patients' attacks with 24-hour sustained headache relief was greater for rofecoxib 50 mg (52.0%) than for rofecoxib 25 mg (47.8%, P < .050) or ibuprofen (39.0%, P < .010). In the single-attack phase, the adverse event rate was higher for rofecoxib 50 mg (37.8%) than placebo (27.8%, P < .050); rates were similar to placebo for rofecoxib 25 mg (32.0%, n.s.) and ibuprofen 400 mg (28.1%, n.s.). In the extension phase, treatment groups had similar adverse event rates. CONCLUSIONS: Rofecoxib 25 and 50 mg and ibuprofen 400 mg were effective and generally well tolerated in the acute treatment of migraine.

Cutaneous allodynia and migraine: another view.

The paradigm of early treatment of the migraine attack at mild pain intensity has become one alternative to circumventing the problem of compromised oral absorption of symptomatic drugs due to migraine-induced gastrointestinal dysmotility. Early treatment also has been proposed to be advantageous because most migraineurs could be less responsive to delayed treatment, owing to the development of central sensitization of the trigeminal pain transmission. Ranking the underlying principles, it seems that the improved response to an oral triptan formulation at mild migraine symptom intensity has more to do with less impaired gastrointestinal absorption in the early stage of the attack than decreasing the time and preventing chances for central sensitization and development of cutaneous allodynia. Furthermore, parenteral administration of a triptan is always more likely to provide relief of symptoms than conventional tablets, even when it is used later in the course of the migraine attack. Individually tailored use of the available triptan formulations will increase, without any doubt, the within-migraineur consistency of response. It also will reduce the overall proportion of migraine attacks or migraineurs not responding to triptan treatment. Notwithstanding, the recommendation of early treatment during the migraine attack when the pain is mild remains valid.

Patients' preference for triptans and other medications as a tool for assessing the efficacy of acute treatments for migraine.

Oral triptans are effective and well tolerated acute treatments for migraine, but clinical differences between them are small and difficult to measure in conventional clinical trials. Patient preference assesses a global measure of efficacy and tolerability, and may be a more sensitive means of distinguishing between these drugs. In a series of studies, patients consistently expressed a clear preference for triptans over their usual non-triptan acute medications, e.g., analgesics and ergotamine. Direct comparator studies of patient preference with oral triptans showed that patients could distinguish between different triptans, and between different formulations of the same triptan. Patients could even distinguish between the three oral doses of sumatriptan. The most frequently provided reasons for preference were speed of response and overall effectiveness. Patient preference is a sensitive clinical trial endpoint and physicians should consider using it when reviewing the efficacy of acute migraine medications.

Topiramate improves health-related quality of life when used to prevent migraine.

OBJECTIVE: To assess changes in health-related quality of life (HRQoL) measures among patients receiving topiramate (TPM) 100 mg/d in two divided doses for migraine prevention in three randomized, double-blind, placebo-controlled, 26-week trials with similar protocols and study populations. BACKGROUND: Migraine substantially impairs HRQoL and work productivity before, during, and after attacks. Approximately 50% of patients with migraine could be recommended for preventive therapies, yet only 3% to 5% of patients receive them. TPM is an effective and generally well-tolerated migraine prophylactic (preventive) therapy for adults, as demonstrated in several randomized, double-blind, placebo-controlled trials. The most common adverse events in double-blind, placebo-controlled studies of TPM in migraine prevention are paresthesia, fatigue, anorexia, nausea, taste alteration, and diarrhea. DESIGN AND METHODS: The Migraine-Specific Questionnaire (MSQ, version 2.1) was used to assess the effect of TPM 100 mg/d on the functionality and HRQoL of randomized intent-to-treat (ITT) and study-completer populations pooled from three randomized, double-blind, placebo-controlled trials. MSQ scores (0 to 100, higher score indicates better functioning) were assessed for the following three domains: role restriction (examines the degree to which performance of daily activities is limited by migraine), role prevention (examines the degree to which performance of daily activities is interrupted by migraine), and emotional function (examines feelings of frustration and helplessness due to migraine). Between-group differences from baseline in mean MSQ domain scores for TPM 100 mg/d and placebo were compared using a mixed-effects model with piecewise linear regression. Effect sizes were calculated to estimate the magnitude of change in HRQoL that can be associated with TPM therapy. RESULTS: TPM 100 mg/d significantly improved all three MSQ domains compared with placebo for both the ITT (TPM, n = 372; placebo, n = 362) and study-completer (TPM, n = 220; placebo, n = 216) populations (P < .001 for all three domains, both populations). Effect sizes for TPM 100 mg/d varied from 0.40 to 0.78, indicating that the changes in MSQ scores for TPM 100 mg/d were moderate and may be clinically significant. CONCLUSION: TPM 100 mg/d has been shown to be effective in the prevention of migraine headache in adults. As the MSQ results from the three randomized, placebo-controlled trials indicate, HRQoL is significantly improved for up to 6 months following initiation of treatment.

Two replicate randomized, double-blind, placebo-controlled trials of the time to onset of pain relief in the acute treatment of migraine with a fast-disintegrating/rapid-release formulation of sumatriptan tablets.

BACKGROUND: The gastric stasis that commonly accompanies migraine headache may impair absorption of conventional oral tablets in the stomach. A fast-disintegrating/rapid-release formulation of sumatriptan has been developed to enhance tablet disintegration and drug dispersion and potentially improve absorption. OBJECTIVE: Two studies were conducted comparing the time to onset of relief from moderate or severe migraine pain with the fast-disintegrating/rapid-release formulation of sumatriptan tablets 50 and 100 mg and placebo. METHODS: These were 2 identically designed randomized, double-blind, parallel-group studies. Sumatriptan 50 or 100 mg or placebo was taken on an outpatient basis to treat a single moderate or severe migraine attack. Using a personal digital assistant, patients recorded the time of dosing and the time at which pain severity reached none or mild (ie, pain relief) or none (ie, pain free) in real time so that the time to onset of relief could be measured as a continuous variable. Onset of relief was defined as the earliest time point at which a statistically significant difference in pain relief compared with placebo was achieved and maintained through 2 hours after dosing. Before dosing and at pre-determined time points after dosing, patients also provided an assessment of migraine pain as none, mild, moderate, or severe. At a clinic visit within 1 week after treatment of the migraine attack, patients were queried about adverse events. For each adverse event, investigators recorded whether study medication was considered the cause. Data analyses were undertaken for each study individually and, in post hoc analyses of the primary and key secondary end points, on pooled data from both studies. RESULTS: The 2 studies comprised 2696 patients: 902 received sumatriptan 50 mg, 902 received sumatriptan 100 mg, and 892 received placebo. Patients' mean age ranged from 40.2 to 40.8 years across treatment groups, and most patients were female (83%-87%) and white (92%-93%). In the analysis of pooled data, sumatriptan tablets provided significantly more effective pain relief compared with placebo as early as 20 minutes after dosing with the 100-mg dose and as early as 30 minutes after dosing with the 50-mg dose (P < or = 0.05). Similar results were observed for the individual studies: in study 1, sumatriptan tablets were significantly more effective than placebo at 25 minutes with the 100-mg dose and at 50 minutes with the 50-mg dose; in study 2, sumatriptan tablets were significantly more effective than placebo at 17 minutes for the 100-mg dose and at 30 minutes for the 50-mg dose (P < or = 0.05). In the pooled data, the cumulative percentages of patients with pain relief by 2 hours after dosing were 72% for the 100-mg dose and 67% for the 50-mg dose, compared with 42% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). The cumulative percentages of patients with a pain-free response by 2 hours were 47% for the 100-mg dose, 40% for the 50-mg dose, and 15% for placebo (P < or = 0.001, both sumatriptan doses vs placebo). In the individual studies, significantly more patients receiving either sumatriptan dose were migraine free 2 hours after dosing and had sustained pain relief and a sustained pain-free response over 24 hours compared with placebo (P < or = 0.001, both sumatriptan doses vs placebo). The only drug-related adverse events reported in >2% of patients in any treatment group in either study were nausea (both studies: 3% sumatriptan 100 mg, 2% sumatriptan 50 mg, 1% placebo) and paresthesia (study 1: <1% sumatriptan 100 mg, <1% sumatriptan 50 mg, 0% placebo; study 2: 3% sumatriptan 100 mg, 1% sumatriptan 50 mg, <1% placebo). CONCLUSIONS: In these studies, sumatriptan tablets in a fast-disintegrating/rapid-release formulation were effective for the acute treatment of moderate to severe migraine pain, were generally well tolerated, and achieved an onset of pain relief as early as 20 minutes for 100 mg and as early as 30 minutes for 50 mg.

Non-oral formulations of triptans and their use in acute migraine.

The introduction of triptans (5-HT (1B/1D) agonists) into clinical practice has expanded the therapeutic options for doctors treating migraine sufferers. The triptans are available in several different formulations such as conventional oral tablets, orally disintegrating wafers, subcutaneous injections, nasal sprays, and suppositories, which provide an excellent opportunity to tailor therapy to individual patients' needs. Although the oral formulations are the most popular with patients, they are not the most appropriate route of administration for drug delivery during the migraine attack. Due to gastrointestinal dysmotility, the intestinal absorption of any triptan administered orally may be impaired and treatment effects become inconsistent. For this reason, triptans preferably should be prescribed in a non-oral formulation (injection, nasal spray, or suppository). Parenteral administration of a triptan is more likely to provide relief of symptoms, even when it is used later in the course of the migraine attack.