Multimechanistic (sumatriptan-naproxen) early intervention for the acute treatment of migraine.

BACKGROUND: Research suggests treating a migraine at the first sign of pain increases the likelihood of the best clinical outcome. OBJECTIVE: To investigate the efficacy and tolerability of a fixed-dose, single-tablet formulation of sumatriptan 85 mg, formulated with RT Technology, and naproxen sodium 500 mg (sumatriptan/naproxen) as early intervention acute therapy for migraine. METHODS: Patients (aged 18 to 65 years) with International Headache Society-defined migraine with or without aura were enrolled in one of two identically designed, randomized, double-blind, parallel group, placebo-controlled studies. Patients treated a single migraine within 1 hour of onset of migraine head pain and while the pain was mild with either sumatriptan/naproxen or placebo. The primary efficacy measure was the percentage of patients who became pain-free 2 hours postdose. RESULTS: Intent-to-treat analyses consisted of 576 and 535 migraineurs. At 2 hours, 52% and 51% of sumatriptan/naproxen-treated patients were pain free, as compared to 17% and 15% of placebo-treated patients (p < 0.001). Significant pain-free responses in favor of sumatriptan/naproxen were demonstrated as early as 30 minutes, maintained at 1 hour, and sustained from 2 to 24 hours. At 2 and 4 hours, sumatriptan/naproxen provided significantly lower rates of traditional migraine-associated symptoms (nausea, photophobia, and phonophobia) and nontraditional migraine-associated symptoms (neck pain/discomfort and sinus pain/pressure). The most commonly reported adverse events were nausea (< or =4%) and dizziness (< or =2%). CONCLUSION: The fixed-dose single-tablet formulation of sumatriptan/naproxen was effective and well tolerated in an early intervention paradigm for the acute treatment of migraine, including traditional and nontraditional symptoms.

Medication overuse headache.

Medication overuse headache is a common feature underlying chronic headache, especially migraine. It also represents a major therapeutic challenge, especially in headache specialty clinics where it can represent the majority of patients. The syndrome remains under-diagnosed and the role of symptomatic medication overuse underestimated. Physicians should be properly educated in this area of pain, for prevention of this too often intractable syndrome could be improved. The basis of therapy is discontinuance of the abused medication. Additional treatment relies on a multifaceted approach that embraces management of psychiatric comorbidities and emphasizes patient education. Various pharmacological regimens, abortive and prophylactic, are available. Further scientific study is warranted to elucidate the ultimate mechanisms of this syndrome and define more effective treatments. This article gives detailed clinical description, tentative pathophysiologic explanation and therapeutic suggestions.

A study to determine the accuracy of a computerized algorithm for interpretation of EEGs.

The main use of computerized EEG has been in sleep studies. A comprehensive system of interpreting routine EEGs by computers has not yet been developed and is technically difficult. We have tried to incorporate computers in the analysis and interpretation of EEGs by using information obtained from visual analysis of EEG in the present work. The purpose of this study was to determine the accuracy of such an algorithm. An electroencephalographer visually analyzed routine EEGs and the data was entered into an EEG Worksheet. The electroencephalographer then interpreted the data and a report was dictated and transcribed. Data from the EEG Worksheet was entered into a computer for interpretation, clinical correlation, and report preparation. Results indicate that the algorithm used with the EEG Worksheet can correctly interpret and clinically correlate visually-analyzed EEG data entered into a computer and reduce time for EEG report generation.

Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine.

In this randomized, double-blind, placebo-controlled, parallel-group study, patients received a single 50-mg oral dose of a 5-HT(1D) agonist, PNU-142633 (n = 34), or matching placebo (n = 35) during an acute migraine attack. No statistically significant treatment effects were observed at 1 and 2 h after dosing, even after stratifying by baseline headache intensity. At 1 and 2 h post-dose, 8.8% and 29.4% of the PNU-142633 group, respectively, and 8.6% and 40.0% of the placebo group, respectively, experienced headache relief; 2.9% and 8.8% of the PNU-142633 group and 0% and 5.7% of the placebo group were free of headache pain. Adverse events associated with PNU-142633 treatment included chest pain (two patients) and QTc prolongation (three patients). Results from this study suggest that anti-migraine efficacy is not mediated solely through the 5-HT(1D) receptor subtype, although this receptor may contribute, at least in part, to the adverse cardiovascular effects observed with 5-HT agonist medications.

Chronic daily headache in the posttrauma syndrome: relation to extent of head injury.

OBJECTIVE: To evaluate the occurrence of continued intermittent headache and chronic daily headache in patients with head injury and the relationship between severity of the headache problem and intensity of the head injury. BACKGROUND: In the majority of patients with posttraumatic headache, the condition is self-limited, but a minority of patients may develop persistent headaches. The features of posttraumatic headache may vary, but the most distressing type is the chronic daily headache. This study evaluates occurrence of chronic daily headache in relation to the intensity of head injury. METHODS: All patients with head injury who were seen by the senior author (J.R.C.) in the Southern Illinois University Medical School (SIUMS) Neurology Clinic between 1980 and 1991 were identified from the SIUMS headache registry. Data on headache status before and after head injury was obtained, and patients with more than one headache per week before head injury were excluded. Each patient's headache status at the time of the clinic visit was classified as chronic daily headache (headache occurring at least 5 of 7 days for 6 months), intermittent migraine, or no headache. Head injury severity was graded by duration of loss of consciousness or amnesia as minimal (less than 5 minutes), mild (5 to 60 minutes), moderate (1 to 24 hours), or severe (more than 24 hours). RESULTS: There was an inverse relation between extent of head injury and occurrence of chronic daily headache. For minimal head injury (n = 54), 80% had chronic daily headache, and 11% had no headache, while for moderate/severe head injury (n = 23), only 27% had chronic daily headache, and 68% had no headache (P<.001, chi2). CONCLUSION: This study suggests that the risk of developing posttraumatic chronic daily headache is greater for less severe head injury compared with moderate/severe head injury. The reason for this relation is unclear.

Treatment of migraine with BMS180048: response at 2 hours. North American BMS180048 Study Group.

BMS180048 is a 5HT agonist that was well-tolerated in early phase II trials. This study utilized a double-blind, parallel-group dose ranging format, comparing BMS180048 in doses of 25, 50, or 75 mg to placebo in effectiveness of treatment of a single migraine headache. To assess tolerability of BMS180048, patients received a test dose of the medication they would receive for a headache in the clinic under observation. If no significant side effects occurred, patients were allowed to treat a headache. Headaches were moderate or severe in intensity before treatment, and response at 2 hours was tabulated. Reduction to mild or no headache was the criteria for successful response. Response rates at 2 hours were as follows: placebo--19 of 53 subjects (35.8%); 25 mg--21 of 53 subjects (40.3%); 50 mg--34 of 53 subjects (64.2%); 75 mg--35 of 55 subjects (63.6%) The improvement for subjects treated with 50 or 75 mg of BMS180048 when compared to placebo was highly significant (P < .01). Nausea, photophobia, and phonophobia improved 35% to 50% for BMS180048-treated subjects and 20% to 24% in the placebo group. The improvement in these symptoms in comparison to placebo was statistically significant only for nausea in those treated with 75 mg of BMS180048 (P = .02). Side effects were mild for the most part, and no serious adverse events occurred. The study suggests BMS180048 is effective in acute symptomatic therapy of migraine.

Onset of neurologic deficits after treatment with dihydroergotamine in a patient with sagittal sinus thrombosis.

A woman with a 7-year history of intermittent migraine had 3 months of gradually worsening headaches. Initial neurologic examination including fundus examination was normal, and initial head computerized tomographic (CT) scan and magnetic resonance imaging (MRI) were thought to be normal. The patient was given dihydroergotamine (DHE-45), 1.0 mg, intravenously for relief of headache. Five hours later, she complained of severe diffuse headache and nausea. Neurologic examination showed left arm weakness and sensory loss, blurring of the left optic disc, and bilateral Babinski signs. Cerebral arteriography demonstrated thrombosis of the sagittal sinus, which in retrospect was present on the initial contrast CT scan and MRI scan. The patient's deficits worsened, and she eventually died 20 days later as a result of cerebral infarctions and increased intracranial pressure, despite attempts at selective thrombolysis of the sagittal sinus. DHE has potent venoconstrictive effects. We suspect that DHE helped precipitate neurologic deterioration in this patient with sagittal sinus thrombosis.

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.

Antiplatelet therapy in the treatment of cerebrovascular disease.

Aspirin and the new agent ticlopidine have been the most thoroughly evaluated of the platelet-antiaggregating drugs used for the prevention of stroke and other vascular events. Numerous trials have shown aspirin to be effective in reducing the risk of myocardial infarction (MI), recurrent transient ischemic attacks, stroke, and vascular death in men at high risk for these events. Primary prevention trials have shown that aspirin reduces the risk of MI in healthy men over 50 years of age but does not reduce the risk of stroke. Two large, multicenter trials have shown that ticlopidine is effective in reducing the risk of fatal and nonfatal stroke in both men and women. Ticlopidine may also be effective in reducing the risk of recurrent stroke in patients who have had a completed thromboembolic stroke.

Headache to worry about.

The headache to worry about is one that is unique or different from headaches which the patient has suffered in the past. The association with the headache of meningismus or of focal neurologic symptoms of oculoparesis, other cranial nerve palsies, hemiparesis, or loss of consciousness are particularly worrisome, especially if onset is recent and acute. Headaches related to arteritis or vasculitis usually have a slower subacute course but may also produce focal neurologic deficits. For subjects over 50 years old, temporal arteritis is always a consideration and any new type of headache requires testing of the sedimentation rate to rule out this treatable but potentially devastating problem.

Headache as a risk factor in atherosclerosis-related diseases.

A group of 350 migraineurs (87 male, 263 female) and 300 controls without migraine (104 male, 196 female) were questioned about occurrence, in parents, of the atherosclerosis-related diseases (ASRD) of diabetes mellitus (DM), hypertension (HBP), myocardial infarction (MI), and stroke as well as about recurrent severe headache (RSHA). Occurrence of DM, HBP, MI and stroke was compared for mothers and fathers of migraine vs. those of control subjects and no significant differences were found. The mothers and fathers were pooled and resegregated by presence or absence of RSHA and then occurrence of DM, HBP, MI and stroke again compared. For mothers there was increased occurrence of stroke and DM in the RSHA group but the differences were not significant. For RSHA fathers there was increased incidence of MI (p less than .10) and HBP (p less than .01). Aggregate occurrence of all ASRD was evaluated for RSHA vs. no-RSHA parents. ASRD occurred more frequently in the RSHA than in the no-RSHA parents (p less than .05). Breakdown by age showed that this occurred at all ages in men (p less than .05) but in women the difference was significant only under age 60 (p less than .05). This study suggests that RSHA, which is primarily migraine, may be a risk factor or a marker for occurrence of ASRD.

Visualization of brain iron by mid-field MR.

Brain iron was visualized on a mid-field (0.5 T) scanner using a spin-echo pulse sequence. Methemoglobin was hyperintense on T1- and T2-weighted images. Deoxyhemoglobin, hemosiderin, and ferritin were seen as decreased intensity on T2-weighted images. The spin-echo pulse sequences were improved for identification of deoxyhemoglobin, hemosiderin, and ferritin by prolonging the TR to 3000 msec and the TE to 80-120 msec. Phase-encoding artifacts at the level of the sylvian fissures caused increased noise, obscuring the brain iron in the lentiform nuclei with the TE of 120 msec. This artifact was substantially reduced or eliminated by lowering the TE to 80 msec, changing the phase-encoding gradient to the Y axis, or using additional pulsing in the slice and read gradients. Use of either the improved spin-echo or gradient-echo pulse sequences on a mid-field MR scanner provides improved evaluation of brain iron.

Placebo effect and clinical trials in migraine therapy.

Migraine is a cyclical condition in which the cycles may occur or remit in an unpredictable fashion. The goal of prophylactic antimigraine therapy is to induce remission of an active cycle of migraine or to inhibit occurrence of individual headaches until the cycle remits for other reasons. The placebo effect probably takes advantage of these cycles. The placebo effect is significant and quite potent. The placebo effect may be divided into (1) the initial effect and (2) the continuing effect which is seen following a stabilization period. The initial placebo effect is dramatic with 62% of 188 subjects improving by 75% after 4 weeks of placebo. The continuing effect is demonstrated by occurrence of 75% further improvement in 28% of 282 subjects in 7 studies in which comparison of results after 4-12 weeks was made with a placebo stabilization period. The placebo effect is a very potent one and must be taken into account in designing and carrying out studies of migraine therapy.

Modulation of spinal synaptic transmission by beta-melanocyte stimulating hormone (beta-MSH).

Synaptic modulation refers to altered excitability of a synapse by a substance that does not produce a spike potential at the synapse. Available evidence points to the conclusion that beta-melanocyte stimulating hormone (beta-MSH) modulates synaptic transmission through monosynaptic pathways in the cat spinal cord. Earlier evidence is reviewed, and new data are presented. In the first experiments populations of cells contributing to a knee jerk were studied using the Lloyd preparation, and MSH was found to increase the monosynaptic reflex. With intracellular single unit recording techniques, beta-MSH was found to facilitate recovery from synaptic transmission. With extracellular single unit recording techniques and iontophoretic methods for drug application, beta-MSH has been found to increase the probability of generation of single spike potentials by alpha-motoneurons in response to orthodromic stimulation. Administration of beta-MSH did not cause spontaneous discharge of alpha-motoneurons. The physiological and pharmacological importance of synaptic modulation is discussed.

"Numb, clumsy hands" and high cervical spondylosis.

Thirteen patients with cervical spondylosis and high compressive myelopathy between C-3 and C-5 presented with a distinctive clinical syndrome of "numb, clumsy hands" and stereoanesthesia of the hands. Loss of position and vibration sense was much more severe in the hands than in the legs. Relative sparing of primary sensory modalities and motor and bladder functions were other features. Most patients were incorrectly diagnosed at first and cervical myelography was the critical diagnostic test. Pathology was confirmed surgically or at autopsy. Early recognition and treatment resulted in lessened disability. The syndrome is a distinctive and unusual manifestation of high cervical myelopathy, and it has seldom been reported associated with cervical spondylosis.