Tonabersat, a gap-junction modulator: efficacy and safety in two randomized, placebo-controlled, dose-ranging studies of acute migraine.

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.

The use of outreach clinics for teaching undergraduate restorative dentistry.

AIM: To examine the experience of being an outreach teacher of undergraduate restorative dentistry; to describe the desirable characteristics of such teachers; and to consider the management of outreach teaching. DESIGN: A three year pilot of an outreach course in fourth year restorative dentistry began in 2001. Students spent one day per week treating adults in NHS community dental clinics, run by Primary Care Trusts (PCTs). Action research involved monitoring meetings with students, clinic staff (dental teachers and nurses), and PCT clinical service managers. These data are supplemented by an independent evaluation involving interviews with dental school academic staff, and an account by an outreach teacher. RESULTS: Outreach is a different and more demanding context for teaching restorative dentistry than the dental hospital, characterised by isolation, management responsibility, pressure, a steep learning curve, and stress. The desirable characteristics of outreach teachers are those which enable them to cope in this environment, together with a student-centred teaching style, and the appropriate knowledge. Management of teaching passed to the PCTs and this created an additional workload for them in relation to staffing, risk, and service-based issues. Four teaching surgeries were the maximum for a satisfactory level of patient care and student supervision. A key issue for the dental school is quality. The changes to teaching and the teaching environment introduced during and after the pilot to address problems identified are described. CONCLUSION: In developing facilities to enable students to benefit from the advantages of outreach, dental schools should recognise that the characteristics of the outreach environment need to be taken into account during planning, that staff selection is a critical success factor, and that an ongoing proactive approach to organisational arrangements and to the support of teaching staff is necessary.

Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study.

We studied the safety and efficacy of 0 U, 50 U, 100 U, 150 U (five sites), 86 Usub and 100 Usub (three sites) botulinum toxin type A (BoNTA; BOTOX); Allergan, Inc., Irvine, CA, USA) for the prophylaxis of chronic tension-type headache (CTTH). Three hundred patients (62.3% female; mean age 42.6 years) enrolled. For the primary endpoint, the mean change from baseline in the number of TTH-free days per month, there was no statistically significant difference between placebo and four BoNTA groups, but a significant difference favouring placebo vs. BoNTA 150 was observed (4.5 vs. 2.8 tension headache-free days/month; P = 0.007). All treatment groups improved at day 60. Although efficacy was not demonstrated for the primary endpoint, at day 90, more patients in three BoNTA groups had >or=50% decrease in tension headache days than did placebo (P

Patients treated by dental students in outreach: the first year of a pilot project.

This paper describes the patients treated by 4th year undergraduate students during the first year of a pilot outreach course to teach Restorative Dentistry in community clinics in 2001-02. Data were collected from 908 summaries of patient treatment completed by the students, and from 139 patient questionnaires. Some 75% of patients were aged between 16 and 64, 58% were female, and 16% had dental phobia or anxiety. Most lived locally to the clinic and 41% made their initial contact as an emergency or drop-in. Some 37% made only a single visit (including children treated as emergencies) but 22% made six or more visits. Did not attend (DNA) was a problem and 18% of patients DNA to complete their treatment. Students undertook the full range of restorative procedures, with the emphasis on direct restorations, preventive treatment and advice, scaling, extractions and emergency treatment. Patients' main reasons for attending the clinic were lay recommendation, the need for treatment, convenience, free treatment, or the lack of access to a dentist. Some 30% said they did not have or did not know of an alternative source of dental care, and half had not seen a dentist for at least 2 years. The study demonstrates that despite difficulties related to attendance, a suitable patient base can be established offering students the opportunity to provide comprehensive care for adults in a primary care setting.

Developing dental education in primary care: the student perspective.

A pilot outreach course in restorative dentistry based in community clinics began in 2001. As part of the evaluation, 48 fourth year students completed a questionnaire about their opinions of the new course, and about restorative dentistry clinics in the dental hospital. Time management was the most frequently mentioned gain from outreach. In relation to the dental school, students most often saw the specialised teaching staff as a gain. Outreach was equally or more important for students' confidence in clinical diagnosis of dental caries, treatment planning, direct restorations, communicating with patients, and managing patients, time, and resources. The dental hospital was equally or more important for their confidence in the diagnosis of periodontal disease, root planing, crowns, bridges, dentures, and communicating effectively with laboratory staff. Patients in outreach were seen as different from those at the dental hospital because they were unselected, and had different treatment needs. Meeting course requirements was the most frequent concern about outreach. In relation to the dental hospital, students were most often concerned about the quality of teaching and support available. Outreach and the dental hospital provided complementary experiences and the new course met its educational objectives.

Outreach teaching: is this the future for dental education?

Increasingly clinical teaching for all health professionals is moving out of teaching hospitals and into community settings. A recent workshop reviewed the place of outreach teaching in undergraduate dental education. This paper defines outreach teaching in terms of its main components; identifies its benefits for different stakeholders; sets out what is required to make it work; and looks at current trends offering opportunities for expansion.

Comparative study of a combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the treatment of migraine.

OBJECTIVE: To compare the safety and efficacy of isometheptene mucate, dichloralphenazone with acetaminophen to sumatriptan succinate for the treatment of mild-to-moderate migraine, with or without aura, when taken at the first sign of an attack. BACKGROUND: The Food and Drug Administration approved sumatriptan succinate and the combination of isometheptene mucate, dichloralphenazone with acetaminophen for the treatment of migraine. As part of the stratified treatment of migraine, those patients whose headaches are mild or moderate may benefit from nontriptan medications. Additionally, early treatment of acute migraine before the headache has become moderate or severe may improve response to treatment. METHODS: This was a multicenter, double-blind, randomized, parallel-group study to assess the safety and efficacy of the combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the early stages of a single migraine attack. Patients diagnosed with migraine, with or without aura, as defined by the International Headache Society diagnostic criteria were enrolled. RESULTS: One hundred thirty-seven patients were enrolled in the study. Data for efficacy were available for 126 patients; safety data were available for 128 patients. No statistically significant difference between the two active agents in the patient's response to treatment was demonstrated. Headache recurrence was not significantly different over the 24-hour evaluation period for those patients responding in the first 4 hours. In those with headache recurrence, it was statistically significantly more severe in those patients treated with sumatriptan succinate. Improvement in functional disability was, in general, better among those treated with isometheptene mucate, dichloralphenazone with acetaminophen. Global analysis of efficacy was similar in the two active groups. Patients treated with sumatriptan succinate were somewhat more likely to have adverse effects than the isometheptene mucate, dichloralphenazone with acetaminophen group. CONCLUSIONS: Both isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate are safe and effective when used early in the treatment of an acute migraine. Several parameters suggest that isometheptene mucate, dichloralphenazone with acetaminophen may have a slight advantage compared with sumatriptan succinate in the early treatment of mild-to-moderate migraine.

A long-term study to maximise migraine relief with zolmitriptan.

Part 1 of this international study was a randomised, double-blind, placebo-controlled study of 2.5 mg and 5 mg zolmitriptan (Zomig) in the treatment of persistent migraine headache, two hours after an initial dose of 2.5 mg zolmitriptan. Part 2 was a non-comparative evaluation of long-term, unrestricted zolmitriptan use for treatment of initial, persistent and recurrent migraine headaches. In Part 1, following the treatment of moderate or severe persistent headache, two-hour headache response rates with 5 mg zolmitriptan (51.6%, n = 322), 2.5 mg zolmitriptan (49.7%, n = 324) and placebo (51.6%, n = 343) were not significantly different. However, the pain-free response rate following the treatment of persistent migraine headache of any intensity was significantly higher with 5 mg zolmitriptan than with placebo (36.0% vs. 25.5%; p < 0.001). This was predominantly due to effects in the subgroup of patients with mild headache. Thus, migraine relief in patients whose initial headache shows a partial response to 2.5 mg zolmitriptan may be maximised by a second 5 mg dose. In Part 2 (involving 2499 evaluable patients), 65.8% of attacks were treated with a single dose of zolmitriptan (2.5 mg or 5 mg). Of those migraine attacks initially treated with 2.5 mg zolmitriptan, 70.3% required no further dose, similarly 62.7% of migraine attacks treated initially with 5 mg zolmitriptan only required a single dose. Over the whole attack (i.e. initial and any persistent headache), headache response rates to one or two zolmitriptan doses were greater than 88.8%. 'Level of pain' was the primary factor influencing the choice of dose. Zolmitriptan provided consistent migraine headache relief in the majority of patients and was well tolerated.

Multiple-attack efficacy and tolerability of sumatriptan nasal spray in the treatment of migraine.

OBJECTIVE: Sumatriptan hemisulfate nasal spray may provide a useful therapeutic option for patients with migraine who find injectable medications inconvenient or uncomfortable and for patients whose migraine-associated nausea and vomiting preclude the use of oral medication. This study was the first US trial to evaluate the effects of sumatriptan nasal spray administered for multiple migraine attacks. DESIGN/INTERVENTIONS: Sumatriptan nasal spray (5, 10, or 20 mg) was administered via a 1-shot nasal applicator into either nostril for up to 3 migraine attacks occurring over 6 months in a randomized, double-blind, parallel-group, placebo-controlled study. SETTING: Fifty-six outpatient clinical centers in the United States. PATIENTS: A total of 1086 men and women diagnosed with migraine with or without aura per International Headache Society criteria. MAIN OUTCOME MEASURES: Percentage of patients with headache relief (moderate or severe predose pain reduced to mild or none); percentage of patients with no or mild (vs moderate or severe) clinical disability; percentage of patients with nausea, vomiting, photophobia, or phonophobia; adverse events; clinical laboratory test results. RESULTS: Across attacks, headache relief in the 20-, 10-, and 5-mg drug and placebo groups was experienced 120 minutes postdose by 60%, 54%, 44%, and 32% of patients, respectively (P<.05 for each sumatriptan nasal spray group vs placebo, for the 10-mg vs 5-mg drug group, and for the 20-mg vs 5-mg drug group). Two thirds of the 20-mg patients treating 3 attacks experienced relief at 2 hours postdose for at least 2 of 3 attacks. Clinical disability scores at 120 minutes in the 20-, 10-, and 5-mg drug and placebo groups reflected no or mild impairment in 70%, 67%, 57%, and 50% of patients, respectively (P<.05 for the 10- or 20-mg drug group vs placebo group, and for the 20-mg vs 5- mg drug group). Similar efficacy rates were observed for nausea, photophobia, and phonophobia. For all parameters, individual-attack efficacy rates did not differ from across-attack rates. The incidence of adverse events was not dose related. The most frequently reported adverse event in the active treatment groups was taste disturbance (bad, bitter, or unpleasant). CONCLUSIONS: Sumatriptan hemisulfate nasal spray (5, 10, or 20 mg) is effective and well tolerated in the treatment of multiple migraine attacks. The 20-mg dose was associated with the highest efficacy rates across the greatest number of parameters.

Using metaphor to read the organisation of the NHS. National Health Service.

The paper is concerned with the complexity of the British National Health Service (NHS) as an organisation and with different ways of seeing this. Morgan proposes that explanations of organisational life are based on metaphors which highlight particular interpretations (Morgan, G., 1986, Images of Organisation. London, Sage). The ability to "read" a complex phenomenon depends on being able to see how these different aspects co-exist. The study applies metaphoric thinking to the organisation of the NHS. Utilising documentary data sources, a diagnostic reading is made examining different metaphors to highlight key aspects of the situation. The metaphors of machine and organism are drawn from Morgan's conceptual scheme, those of religion and marketplace are proposed as of particular relevance to the NHS. In the religious metaphor the focus is on the mission of the NHS in terms of its founding principles of universality, comprehensiveness, equality and collectivism. Perceived as a machine the NHS is characterised as an organisation originally based on technocratic rationality and its subsequent history interpreted as moving towards increasingly centralised control. An alternative perspective on the same events is considered in terms of the organic metaphor. In this view the NHS is examined as an open system, which is devolved, decentralised, participative and responsive to its environment. The image of the marketplace focuses on the impact on the organisation of the introduction of competition and incentives in the post-reform period. Other images are sketched briefly. In the critical evaluation the insights generated by the different images are assessed and the different interpretations linked together. It is concluded that metaphoric thinking enables us to appreciate and interpret the ambiguities and paradoxes in NHS organisational life.

Optimizing the dose of zolmitriptan (Zomig, 311C90) for the acute treatment of migraine. A multicenter, double-blind, placebo-controlled, dose range-finding study. The 017 Clinical Trial Study Group.

This study investigated the efficacy of zolmitriptan (Zomig, formerly 311C90) in acute migraine therapy. Patients with a history of migraine were randomized in a double-blind, multicenter, placebo-controlled, dose range-finding study of oral zolmitriptan 1, 2.5, 5, or 10 mg versus placebo for the treatment of a severe or moderate migraine headache. Patients with persistent or recurrent headache 4 to 24 hours after the initial dose, who did not take escape medication, were eligible to receive a second blinded dose of either zolmitriptan or placebo. Of 1,144 patients treated, 999 evaluable patients completed the study. The headache response rates with zolmitriptan doses > or = 2.5 mg were 44 to 51% at 1 hour, 65 to 67% at 2 hours, and 75 to 78% at 4 hours (all significantly superior to placebo). Also, zolmitriptan effectively relieved migraine-associated symptoms such as nausea, photophobia and phonophobia, and reduced activity impairment. Rates of headache recurrence, headache persistence, and use of escape medication were lower with zolmitriptan doses > or = 2.5 mg than with placebo. In patients with persistent or recurrent headache, a second zolmitriptan dose effectively treated both headache and nonheadache symptoms. Zolmitriptan was well tolerated, with a lower incidence of adverse events being reported with doses < or = 2.5 mg than with those > or = 5 mg. Zolmitriptan is a well tolerated and effective acute migraine therapy providing rapid relief of migraine headache within 1 hour. A clear dose-response relationship between efficacy and tolerability suggests that 2.5 mg is the optimal initial dose for the acute treatment of a migraine attack.

Sumatriptan nasal spray for the acute treatment of migraine. Results of two clinical studies.

BACKGROUND: Sumatriptan nasal spray may be particularly useful for patients whose nausea and vomiting preclude them from using oral migraine medication or for patients who prefer not to use an injectable migraine medication. The objective of this study was to evaluate in two clinical studies the efficacy and tolerability of the intranasal form of sumatriptan in the acute treatment of a single migraine attack. International Headache Society-diagnosed adult migraineurs in two randomized, double-blind, parallel-group, multicenter studies (n = 409 and 436) used sumatriptan nasal spray 20 mg, 10 mg, or placebo (2:1:1) for the acute treatment of a single migraine attack at home. Predose and at predetermined postdose intervals, patients recorded headache severity (none, mild, moderate, severe); time to meaningful relief; clinical disability (none, mildly impaired, severely impaired, bed rest required); presence/absence of nausea, photophobia, and phonophobia; and the occurrence of adverse events. Two hours postdose in the two studies, moderate or severe baseline pain was reduced to mild or none in 62 to 63% of patients treated with sumatriptan 20 mg, 43 to 54% of patients treated with sumatriptan 10 mg, and 29 to 35% of placebo-treated patients (p < 0.05 20 mg versus placebo for both studies and 10 mg versus placebo for study 1). Onset of relief relative to placebo began as early as 15 minutes postdose (sumatriptan 20 mg, study 2). Clinical disability at 2 hours postdose was reported as mildly impaired or normal in 72 to 74% of patients treated with sumatriptan 20 mg, 56 to 68% of patients treated with sumatriptan 10 mg, and 47 to 58% of placebo-treated patients (p < 0.05 20 mg versus placebo for both studies). Similar efficacy rates were observed for nausea, photophobia, and phonophobia. The most common adverse event in the active treatment groups was disturbance of taste (bad, bitter, or unpleasant taste). Aside from this event, the pattern and incidence of adverse events did not differ among treatment groups. From these results we determined that sumatriptan nasal spray is a rapidly effective, well-tolerated migraine treatment. The 20-mg dose was effective in treating the entire migraine symptom complex, and the 10-mg dose was less consistently effective.

Twenty-four-hour effectiveness of BMS 180048 in the acute treatment of migraine headaches.

The efficacy of BMS 180048, a 5-HT1 agonist in the acute treatment of a migraine headache, was evaluated in 216 patients. Three doses of the study drug were compared to placebo. Patients received a single test dose in the physician's office while being evaluated with a Holter monitor during a headache-free day. They then treated a migraines headache with a single dose of the study drug as an outpatient. The 150 mg- and 200-mg doses of BMS were significantly superior to placebo on change in pain intensity at 2 hours. Patients treated with BMS 180048 had a longer duration of response than placebo-treated patients. At the 24-hour point, only 24% of the 150-mg group and 25% of the 200-mg group had relapsed, compared to placebo which had a 42% relapse rate. It is concluded that BMS 180048 is an effective compound for the treatment of migraine headaches with a prolonged duration of response.

Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled, parallel-group study. Naratriptan S2WA3001 Study Group.

OBJECTIVE: To evaluate the efficacy and tolerability of naratriptan, a novel 5-HT1 agonist, in the acute treatment of migraine. DESIGN/METHODS: Six hundred thirteen migraineurs, diagnosed according to International Headache Society criteria, treated a single migraine attack with naratriptan tablets (2.5 mg, 1 mg, 0.25 mg, or 0.1 mg) or placebo in a randomized, double-blind, placebo-controlled, parallel-group study conducted at 54 United States centers. At dosing and at predetermined intervals beginning 30 minutes postdose, patients recorded migraine pain severity, clinical disability, and presence of associated migraine symptoms. Safety measures included adverse events, physical examinations, vital signs, ECGs, and clinical laboratory tests. RESULTS: Headache relief (moderate or severe pain at dosing reduced to mild or no pain) 4 hours postdose was reported in 60% of patients receiving naratriptan 2.5 mg compared with 50%, 35%, 32%, and 34% of patients receiving naratriptan 1 mg, 0.25 mg, 0.1 mg, and placebo, respectively (P < 0.05 naratriptan 2.5 mg and 1 mg versus placebo, 1 mg versus 0.1 mg, and 2.5 mg versus 0.1 mg and 0.25 mg). Clinical disability 4 hours postdose was reported as mild or none for 70% of patients receiving naratriptan 2.5 mg compared with 63%, 47%, 48%, and 48% of patients receiving naratriptan 1 mg, 0.25 mg, 0.1 mg, or placebo, respectively (P < 0.05 naratriptan 2.5 mg and 1 mg versus placebo, 1 mg versus 0.1 mg, and 2.5 mg versus 0.1 mg and 0.25 mg). Four-hour efficacy for absence of nausea, photophobia, and phonophobia was similar to efficacy for headache relief at each dose. The adverse event profile of each dose of naratriptan was similar to that of placebo. No clinically relevant change in any safety measure was reported. CONCLUSIONS: Naratriptan is effective and well tolerated for the acute treatment of migraine. The 2.5-mg dose appears to offer the optimum ratio of efficacy to tolerability.

Investigation of fatigue failure of S-65-HL "Super Tygon" roller pump tubing.

A failure analysis was performed on Norton S-65-HL Tygon tubing. Fatigue testing was performed on four sizes of this tubing, and essentially showed how the tubing wears out. A dynamic "life hours to failure" test, which was performed on the 3/8" internal diameter (ID) size, quantified when the tubing ruptured. Based on results of laboratory testing and the institution's clinical extracorporeal membrane oxygenation (ECMO) experience, a reasonable life expectancy for the 3/8" S-65-HL Tygon size was determined for use in this institution's neonatal ECMO system. An understanding of the expected performance of roller pump tubing-an integral component of the ECMO system-is imperative to providing safe, effective extracorporeal life support.

Transnasal butorphanol in the treatment of acute migraine.

We studied transnasal butorphanol (Stadol NS) for pain relief during acute migraine in a multicenter, randomized, double-blind, placebo controlled trial using ambulatory patients at 10 geographically diverse headache centers. Patients were volunteer adults diagnosed with migraine with or without aura by International Headache Society criteria. One hundred fifty-seven patients completed the study. We treated the pain of one headache in each patient with either transnasal butorphanol (n = 107) or transnasal placebo (n = 50). Pain relief, pain intensity, nausea, vomiting, and effect on function were measured periodically. Adverse experiences were documented. Global assessments were made at follow-up. With butorphanol, migraine pain was reduced from moderate, severe, or incapacitating to slight or absent for 35 patients (33%) within 30 minutes, for 50 patients (47%) within 1 hour, and for 76 (71%) within 6 hours, compared to 2 (4%), 8 (16%) and 15 (30%) respectively for placebo. Side effects were prominent, though confounded by the migraine. The most common side effects, compared to placebo, were dizziness (58% vs 4%), nausea and/or vomiting (38% vs 18%), and drowsiness (29% vs 0%). We conclude that transnasal butorphanol is a useful analgesic for the pain of acute migraine. Its prominent side effects and low self reinforcement rate may limit its usefulness in some patients, while increasing its appropriateness for others.

Drug abuse and headache.

Substance abuse has been reported frequently in chronic headache patients. The problem exists in most Western countries. Abuse of various compounds frequently leads to a state of dependency. Prescription as well as over-the-counter agents are often abused. Aspirin, acetaminophen, and caffeine are the most frequently abused compounds. Butalbital, ergot alkaloids, NSAIDS, and narcotic and oral or intranasal sympathomimetics are often abused. Patients with chronic daily headache complain of symptoms that may suggest a mixed-type headache. Features of migraine and muscle contraction headache often coexist in these individuals. It has been suggested that the most frequent cause for the transformation of a periodic headache into a daily headache is substance abuse. Substance abuse and drug dependency have multiple causes, and the etiology will reside with the compounds that are used to excess. The problem may arise as a result of poor instructions from the physician, improper diagnosis with gradual escalation in amounts of drug consumed, or a reinforcement mechanism and a brain stimulation-reward effect. The brain reward system has been studied with narcotics and psychomotor stimulants. It may be activated to a lesser degree with ergotamine, barbiturates, and other abused substances. The long-term effects of substance abuse are contingent on the compounds that are used. They may result in organ damage, medical complications, vascular injury, and a refractory state with chronic headache that eludes successful management of the headache disorder. Patients exhibit a less-than-satisfactory quality of life and are often depressed. Treatment includes outpatient care in cooperative, less dependent patients. Often patients will require inpatient management in order to discontinue use of the abused agents. Pharmacologic agents, behavior modification, psychotherapy, dietary intervention, and acupuncture may be necessary to treat the patient. Each patient must be treated by an interested physician, and the patient will require one or more of the preceding measures for a successful outcome. Often abused compounds must be discontinued in order to obtain a satisfactory response in an individual with chronic headache.