Dual orexin receptor antagonist 12 inhibits expression of proteins in neurons and glia implicated in peripheral and central sensitization.

Sensitization and activation of trigeminal nociceptors is implicated in prevalent and debilitating orofacial pain conditions including temporomandibular joint (TMJ) disorders. Orexins are excitatory neuropeptides that function to regulate many physiological processes and are reported to modulate nociception. To determine the role of orexins in an inflammatory model of trigeminal activation, the effects of a dual orexin receptor antagonist (DORA-12) on levels of proteins that promote peripheral and central sensitization and changes in nocifensive responses were investigated. In adult male Sprague-Dawley rats, mRNA for orexin receptor 1 (OX1R) and receptor 2 (OX2R) were detected in trigeminal ganglia and spinal trigeminal nucleus (STN). OX1R immunoreactivity was localized primarily in neuronal cell bodies in the V3 region of the ganglion and in laminas I-II of the STN. Animals injected bilaterally with complete Freund's adjuvant (CFA) in the TMJ capsule exhibited increased expression of P-p38, P-ERK, and lba1 in trigeminal ganglia and P-ERK and lba1 in the STN at 2 days post injection. However, levels of each of these proteins in rats receiving daily oral DORA-12 were inhibited to near basal levels. Similarly, administration of DORA-12 on days 3 and 4 post CFA injection in the TMJ effectively inhibited the prolonged stimulated expression of protein kinase A, NFkB, and Iba1 in the STN on day 5 post injection. While injection of CFA mediated a nocifensive response to mechanical stimulation of the orofacial region at 2h and 3 and 5 days post injection, treatment with DORA-12 suppressed the nocifensive response on day 5. Somewhat surprisingly, nocifensive responses were again observed on day 10 post CFA stimulation in the absence of daily DORA-12 administration. Our results provide evidence that DORA-12 can inhibit CFA-induced stimulation of trigeminal sensory neurons by inhibiting expression of proteins associated with sensitization of peripheral and central neurons and nociception.

Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study.

BACKGROUND: We sought to assess a novel, noninvasive, portable vagal nerve stimulator (nVNS) for acute treatment of migraine. METHODS: Participants with migraine with or without aura were eligible for an open-label, single-arm, multiple-attack study. Up to four migraine attacks were treated with two 90-second doses, at 15-minute intervals delivered to the right cervical branch of the vagus nerve within a six-week time period. Subjects were asked to self-treat at moderate or severe pain, or after 20 minutes of mild pain. RESULTS: Of 30 enrolled patients (25 females, five males, median age 39), two treated no attacks, and one treated aura only, leaving a Full Analysis Set of 27 treating 80 attacks with pain. An adverse event was reported in 13 patients, notably: neck twitching (n = 1), raspy voice (n = 1) and redness at the device site (n = 1). No unanticipated, serious or severe adverse events were reported. The pain-free rate at two hours was four of 19 (21%) for the first treated attack with a moderate or severe headache at baseline. For all moderate or severe attacks at baseline, the pain-free rate was 12/54 (22%). CONCLUSIONS: nVNS may be an effective and well-tolerated acute treatment for migraine in certain patients.

A comparison of the environmental impact of Jersey compared with Holstein milk for cheese production.

The objective of this study was to compare the environmental impact of Jersey or Holstein milk production sufficient to yield 500,000 t of cheese (equivalent cheese yield) both with and without recombinant bovine somatotropin use. The deterministic model used 2009 DairyMetrics (Dairy Records Management Systems, Raleigh, NC) population data for milk yield and composition (Jersey: 20.9 kg/d, 4.8% fat, 3.7% protein; Holstein: 29.1 kg/d, 3.8% fat, 3.1% protein), age at first calving, calving interval, and culling rate. Each population contained lactating and dry cows, bulls, and herd replacements for which rations were formulated according to DairyPro (Agricultural Modeling and Training Systems, Cornell, Ithaca, NY) at breed-appropriate body weights (BW), with mature cows weighing 454 kg (Jersey) or 680 kg (Holstein). Resource inputs included feedstuffs, water, land, fertilizers, and fossil fuels. Waste outputs included manure and greenhouse gas emissions. Cheese yield (kg) was calculated according to the Van Slyke equation. A yield of 500,000 t of cheese required 4.94 billion kg of Holstein milk compared with 3.99 billion kg of Jersey milk-a direct consequence of differences in milk nutrient density (fat and protein contents) between the 2 populations. The reduced daily milk yield of Jersey cows increased the population size required to supply sufficient milk for the required cheese yield, but the differential in BW between the Jersey and Holstein breeds reduced the body mass of the Jersey population by 125×10(3) t. Consequently, the population energy requirement was reduced by 7,177×10(6) MJ, water use by 252×10(9) L, and cropland use by 97.5×10(3) ha per 500,000 t of cheese yield. Nitrogen and phosphorus excretion were reduced by 17,234 and 1,492 t, respectively, through the use of Jersey milk to yield 500,000 t of Cheddar cheese. The carbon footprint was reduced by 1,662×10(3) t of CO(2)-equivalents per 500,000 t of cheese in Jersey cows compared with Holsteins. Use of recombinant bovine somatotropin reduced resource use and waste output in supplemented populations, with decreases in carbon footprint equivalent to 10.0% (Jersey) and 7.5% (Holstein) compared with nonsupplemented populations. The interaction between milk nutrient density and BW demonstrated by the Jersey population overcame the reduced daily milk yield, thus reducing resource use and environmental impact. This reduction was achieved through 2 mechanisms: diluting population maintenance overhead through improved milk nutrient density and reducing maintenance overhead through a reduction in productive and nonproductive body mass within the population.

Effect of recombinant bovine somatotropin and a shortened or no dry period on the performance of lactating dairy cows.

The objective of this study was to determine the effects of altering dry period length in multiparous dairy cows (n = 341) on milk production for a full lactation (294 d). The study used 3 commercial herds in the western United States. Cows producing greater than 8,400 kg of mature-equivalent milk were assigned to treatments 60 d before their due dates. The 4 treatments were 1) 60-d dry period, label use of recombinant bovine somatotropin (rbST; 60d-L); 2) 32-d dry period, label use of rbST (32d-L); 3) 0-d dry period, label use of rbST (0d-L); and 4) 0-d dry period, continuous use of rbST (0d-C). Cows with shortened dry periods produced 625, 1,000, and 1,042 kg of milk during the prepartum period for treatments 2 to 4, respectively. During the postpartum period, cows on the 32d-L treatment produced similar amounts of milk compared with the 60d-L treatment (11,490 vs. 11,968 kg, respectively). However, cows on the 0d-L (10,316 kg) and 0d-C (10,195 kg) treatments produced significantly lower amounts of milk during the postpartum period compared with the 60d-L treatment. Total milk production from the prepartum and postpartum periods was not altered significantly and was 11,974, 12,112, 11,310, and 11,230 kg for treatments 1 to 4, respectively. The concentrations of beta-hydroxybutyrate and nonesterified fatty acids in serum after calving were decreased for cows on the 32d-L, 0d-L, and 0d-C treatments compared with cows on the 60d-L treatment, which may indicate improved metabolic status.

The environmental impact of dairy production: 1944 compared with 2007.

A common perception is that pasture-based, low-input dairy systems characteristic of the 1940s were more conducive to environmental stewardship than modern milk production systems. The objective of this study was to compare the environmental impact of modern (2007) US dairy production with historical production practices as exemplified by the US dairy system in 1944. A deterministic model based on the metabolism and nutrient requirements of the dairy herd was used to estimate resource inputs and waste outputs per billion kg of milk. Both the modern and historical production systems were modeled using characteristic management practices, herd population dynamics, and production data from US dairy farms. Modern dairy practices require considerably fewer resources than dairying in 1944 with 21% of animals, 23% of feedstuffs, 35% of the water, and only 10% of the land required to produce the same 1 billion kg of milk. Waste outputs were similarly reduced, with modern dairy systems producing 24% of the manure, 43% of CH(4), and 56% of N(2)O per billion kg of milk compared with equivalent milk from historical dairying. The carbon footprint per billion kilograms of milk produced in 2007 was 37% of equivalent milk production in 1944. To fulfill the increasing requirements of the US population for dairy products, it is essential to adopt management practices and technologies that improve productive efficiency, allowing milk production to be increased while reducing resource use and mitigating environmental impact.

Biodegradation of coumaphos, chlorferon, and diethylthiophosphate using bacteria immobilized in Ca-alginate gel beads.

Calcium-alginate immobilized cell systems were developed for the detoxification and biodegradation of coumaphos, an organophosphate insecticide, and its hydrolysis products, chlorferon and diethlythiophosphate (DETP). Optimum bead loadings for bioreactor operation were found to be 200 g-beads/L for chlorferon degradation and 300 g-beads/L for DETP degradation. Using waste cattle dip (UCD) solution as substrate, the degradation rate for an immobilized consortium of chlorferon-degrading bacteria was five times greater than that for freely suspended cells, and hydrolysis of coumaphos by immobilized OPH(+)Escherichia coli was 2.5 times greater. The enhanced degradation of immobilized cells was due primarily to protection of the cells from inhibitory substances present in the UCD solution. In addition, physiological changes of the cells caused by Ca-alginate immobilization may have contributed to increased reaction rates. Degradation rates for repeated operations increased for successive batches indicating that cells became better adapted to the reaction conditions over time.

Treatment satisfaction and efficacy of the rapid release formulation of sumatriptan 100 mg tablets utilising an early intervention paradigm in patients previously unsatisfied with sumatriptan.

AIMS: To evaluate treatment satisfaction, efficacy and functional ability of the rapid release formulation of sumatriptan 100 mg tablets (sumatriptan RT 100 mg) in an early intervention paradigm in patients who were dissatisfied with low-dose sumatriptan and not completely satisfied with their current migraine regimen. METHODS: Experienced migraineurs who reported a mild migraine pain phase, dissatisfaction with the previous sumatriptan treatment and some dissatisfaction with their current treatment regimen had no experience with sumatriptan at the 100 mg dose were enrolled in an open-label, single group study. Subjects were instructed to treat four migraine attacks within 30 min of the onset of mild pain. Treatment satisfaction was measured with the Patient Perception of Migraine Questionnaire Revised version (PPMQ-R) questionnaire. RESULTS: More than half of the subjects were either very satisfied or satisfied with the efficacy of early intervention sumatriptan RT 100 mg after each attack and at the follow-up study visit. The mean total PPMQ-R score was 75.2 out of 100. Between 63% and 73% of subjects were pain-free within 4 h of dosing. Between 79% and 90% of subjects reported an ability to function normally within 4 h of taking the study medication. CONCLUSION: Subjects who were previously unsatisfied with lower doses of sumatriptan and less than very satisfied with their current treatment regimen were more likely to be satisfied or very satisfied with sumatriptan RT 100 mg in an early intervention paradigm. Results were consistent across four migraine attacks and at a follow-up visit. The treatment satisfaction results corresponded with positive results on efficacy measures and a functional status measure.

Determination of diffusion coefficients and diffusion characteristics for chlorferon and diethylthiophosphate in Ca-alginate gel beads.

Diffusion characteristics of chlorferon and diethylthiophosphate (DETP) in Ca-alginate gel beads were studied to assist in designing and operating bioreactor systems. Diffusion coefficients for chlorferon and DETP in Ca-alginate gel beads determined at conditions suitable for biodegradation studies were 2.70 x 10(-11) m(2)/s and 4.28 x 10(-11) m(2)/s, respectively. Diffusivities of chlorferon and DETP were influenced by several factors, including viscosity of the bulk solution, agitation speed, and the concentrations of diffusing substrate and immobilized cells. Diffusion coefficients increased with increasing agitation speed, probably due to poor mixing at low speed and some attrition of beads at high speeds. Diffusion coefficients also increased with decreasing substrate concentration. Increased cell concentration in the gel beads caused lower diffusivity. Theoretical models to predict diffusivities as a function of cell weight fraction overestimated the effective diffusivities for both chlorferon and DETP, but linear relations between effective diffusivity and cell weight fraction were derived from experimental data. Calcium-alginate gel beads with radii of 1.65-1.70 mm used in this study were not subject to diffusional limitations: external mass transfer resistances were negligible based on Biot number calculations and effectiveness factors indicated that internal mass transfer resistance was negligible. Therefore, the degradation rates of chlorferon and DETP inside Ca-alginate gel beads were reaction-limited.

Symptoms of cutaneous sensitivity pre-treatment and post-treatment: results from the rizatriptan TAME studies.

The presence of cutaneous allodynia may predict response to triptans. Identical randomized double-blind studies were conducted comparing the efficacy of rizatriptan 10 mg or placebo administered within 1 h of headache onset, while pain was mild. The primary endpoint was freedom from pain at 2 h. Presence of symptoms suggesting cutaneous sensitivity (SCS) at baseline and at 2 h post-treatment was recorded. Before treatment, 29% of rizatriptan patients and 22% of placebo patients reported SCS. At 2 h, the percentage of patients with SCS was significantly decreased with rizatriptan. The presence of SCS pre-treatment was not predictive of response to rizatriptan. Most patients with SCS at 2 h were non-responders. Early treatment with rizatriptan significantly reduced the percentage of patients with SCS at 2 h. The presence of SCS at baseline did not predict pain-free response, but presence of SCS at 2 h correlated with lack of a 2-h pain-free response.

Biodegradation of chlorferon and diethylthiophosphate by consortia enriched from waste cattle dip solution.

Chlorferon and diethylthiophosphate (DETP) are the hydrolysis products of coumaphos, an organophosphate pesticide. In this research, two consortia of bacterial cultures, one responsible for degrading chlorferon and the other for degrading DETP, were selectively enriched from waste cattle dip solution. The enriched cultures were used as inocula to grow biomass for biodegradation studies. For chlorferon degradation, the optimum biomass concentration was found to be 80g/L, and pH 7.5 was selected as the optimal operating pH. Chlorferon degradation was characterized by substrate inhibition kinetics with parameter values estimated to be V(m)=0.062+/-0.011mg/(g-biomass)h, K(m)=21+/-7mg/L, and K(Si)=118+/-45mg/L. For DETP degradation, the optimum biomass concentration was found to be 60g/L, and the optimum pH was in the range of 7.5-8. DETP degradation was characterized by Michaelis-Menten kinetics with parameter values estimated to be V(m)=1.52+/-0.10mg/(g-biomass)h and K(m)=610+/-106mg/L.

Eletriptan in the early treatment of acute migraine: influence of pain intensity and time of dosing.

This double-blind, placebo-controlled study was designed to evaluate the efficacy and tolerability of early treatment of a single migraine attack, when headache pain was mild, with two doses (20 mg and 40 mg) of eletriptan. Patients (N = 613; female 79%; mean age 39 years) meeting International Headache Society criteria for migraine were encouraged, but not required, to utilize early treatment, thus providing an opportunity to assess the relative contribution to efficacy of pain severity and timing of dose. For the total patient sample (mild-to-severe headaches), 2-h pain-free rates were significantly higher than placebo (22%) on both eletriptan 20 mg (35%; P < 0.01) and eletriptan 40 mg (47%; P < 0.0001). For the cohort of patients who treated their headache when the pain intensity was mild, the 2-h pain-free rate on eletriptan 40 mg was 68% compared with 25% on placebo (P < 0.0001). Pain intensity at the time of taking eletriptan appeared to influence outcome more than the timing of the dose relative to headache onset. Eletriptan was well-tolerated, with adverse event rates similar to placebo when mild headaches were treated.

The responsiveness of headache impact scales scored using 'classical' and 'modern' psychometric methods: a re-analysis of three clinical trials.

BACKGROUND: While item response theory (IRT) offers many theoretical advantages over classical test theory in the construction and scoring of patient based measures of health few studies compare scales constructed from both methodologies head to head. OBJECTIVE: Compare the responsiveness to treatment of migraine specific scales scored using summated rating scale methods vs. IRT methods. METHODS: The data came from three clinical studies of migraine treatment that used the Migraine Specific Quality of Life Questionnaire (MSQ). Five methods of quantifying responsiveness were used to evaluate and compare changes from pre- to post-treatment in MSQ scales scored using Likert and IRT scaling methods. RESULTS: Changes in all MSQ scale scores from pre- to post-treatment were highly significant in all three studies. A single index scored from the MSQ using IRT methods was determined to be more responsive than any one of the MSQ subscales across the five methods used to quantify responsiveness. Across 13 of the 15 tests (5 responsiveness methods * 3 studies) conducted, the single index scored from the MSQ using IRT methods was the most responsive measure. CONCLUSIONS: IRT methods increased the responsiveness of the MSQ to the treatment of migraine. The results agree with the psychometric evidence that suggest that it is feasible to score a single index from the MSQ using IRT methods. This approach warrants further testing with other measures of migraine impact.

A study of the feasibility of Internet administration of a computerized health survey: the headache impact test (HIT).

BACKGROUND: Headache impact test (HIT) is a precise, practical tool that quantifies the impact of headache on respondents' lives. It is the first widely-available dynamic health assessment (DynHA). Applications of this brief, precise survey include population based screening for disabling headaches, tracking of individual patient scores over time, disease management programs and others. We use data from Internet HIT assessments during the fall of 2000 to (1) evaluate characteristics of respondents and assessments, (2) assess the utility of joint administration of HIT and the SF-8 Health Survey (SF-8) to screen for migraine and depression, and (3) explore associations between HIT scores and subsequent healthcare-related attitudes and behaviors. METHODS: We analyzed Internet HIT surveys completed between 9/1 and 11/30/2000 (n = 19,195). Subsamples include respondents who also completed (1) a 12-item Internet survey assessing severity, frequency, cause and management of headaches; (2) an e-mail survey measuring healthcare-related behaviors; (3) the SF-8; or (4) the website registration process, providing age and gender data. We used analysis of variance (ANOVA) to evaluate HIT score differences associated with age, gender, headache severity or frequency, and healthcare-related behaviors and attitudes and chi2 tests to assess the prevalence and comorbidity of migraine and depression. RESULTS: Three-quarters of respondents achieved a precise HIT score in < or = 5 items. Most had moderate/severe headaches; 65% had headaches at least monthly. HIT scores were directly related to headache severity and frequency. Most respondents were females, with significantly higher HIT scores than males. Most HIT respondents were between ages 25 and 54 (HIT scores were higher for younger respondents). Sixty four percent screened positive for migraine; 20% for depression. Both conditions were more prevalent among females than males. Comorbid migraine and depression was 50% more prevalent among females and increased with age until age 50. Patients with worse headache impact were more likely to seek care, discuss headaches with their providers and find HIT useful. CONCLUSIONS: It is feasible to use Internet-based dynamic assessments to measure health status. These data complement previous results showing that HIT differentiates respondents according to headache characteristics (severity and frequency). HIT plus SF-8 yields a practical screen for migraine and depression in headache patients and may lead to more effective treatment for patients with these conditions. Preliminary findings suggest that the experience of taking HIT on the Internet may motivate headache patients to seek care and discuss headaches with their providers.

A six-item short-form survey for measuring headache impact: the HIT-6.

BACKGROUND: Migraine and other severe headaches can cause suffering and reduce functioning and productivity. Patients are the best source of information about such impact. OBJECTIVE: To develop a new short form (HIT-6) for assessing the impact of headaches that has broad content coverage but is brief as well as reliable and valid enough to use in screening and monitoring patients in clinical research and practice. METHODS: HIT-6 items were selected from an existing item pool of 54 items and from 35 items suggested by clinicians. Items were selected and modified based on content validity, item response theory (IRT) information functions, item internal consistency, distributions of scores, clinical validity, and linguistic analyses. The HIT-6 was evaluated in an Internet-based survey of headache sufferers (n = 1103) who were members of America Online (AOL). After 14 days, 540 participated in a follow-up survey. RESULTS: HIT-6 covers six content categories represented in widely used surveys of headache impact. Internal consistency, alternate forms, and test-retest reliability estimates of HIT-6 were 0.89, 0.90, and 0.80, respectively. Individual patient score confidence intervals (95%) of app. +/-5 were observed for 88% of all respondents. In tests of validity in discriminating across diagnostic and headache severity groups, relative validity (RV) coefficients of 0.82 and 1.00 were observed for HIT-6, in comparison with the Total Score. Patient-level classifications based in HIT-6 were accurate 88.7% of the time at the recommended cut-off score for a probability of migraine diagnosis. HIT-6 was responsive to self-reported changes in headache impact. CONCLUSIONS: The IRT model estimated for a 'pool' of items from widely used measures of headache impact was useful in constructing an efficient, reliable, and valid 'static' short form (HIT-6) for use in screening and monitoring patient outcomes.

Establishing principles for migraine management in primary care.

Published guidelines for the management of migraine in primary care were evaluated by an international advisory board of headache specialists, to establish evidence-based principles of migraine management that could be recommended for international use. Twelve principles of migraine management were identified, covering screening, diagnosis, management and treatments: Almost all headaches are benign/primary and can be managed by all practising clinicians. Use questions/a questionnaire to assess the impact on daily living and everyday activities, for diagnostic screening and to aid management decisions. Share migraine management between the clinician and the patient. Provide individualised care for migraine and encourage patients to manage their migraine. Follow up patients, preferably with migraine calendars or diaries. Regularly re-evaluate the success of therapy using specific outcome measures and monitor the use of acute and prophylactic medications regularly. Adapt migraine management to changes that occur in the illness and its presentation over the years. Provide acute medication to all migraine patients and recommend it is taken at the appropriate time, during the attack. Provide rescue medication/symptomatic treatment for when the initial therapy fails. Offer to prescribe prophylactic medications, as well as lifestyle changes, to patients who have four or more migraine attacks per month or who are resistant to acute medications. Consider concurrent co-morbidities in the choice of appropriate prophylactic medication. Work with the patient to achieve comfort with mutually agreed upon treatment and ensure that it is practical for their lifestyle and headache presentation. Using these principles, practising clinicians can screen and diagnose their headache patients effectively and manage their migraine patients over the long-term natural history of the migraine process. In this way, the majority of migraine patients can be well treated in primary care, ensuring a structured and individualised approach to headache management, and conserving valuable healthcare resources.

Enhanced-rate biodegradation of organophosphate neurotoxins by immobilized nongrowing bacteria.

Pesticide wastes generated from livestock dipping operations containing the organophosphate (OP) insecticide coumaphos (CP) are well suited for disposal by biodegradation since they are highly concentrated (approximately 1 g/L), generally contained, and lack additional toxic components. In this study, a significantly enhanced efficiency of degrading CP in cattle dip waste (CDW) is reported using a dense, nongrowing cell population that functions without the addition of nutrients required for growing cell cultures. A recombinant strain of Escherichia coli containing the opd gene for organophosphate hydrolase (OPH), which is capable of active hydrolysis of OP neurotoxins including CP, was cultivated in a rich medium containing all essential nutrients. Cells were harvested and utilized in lab scale experiments in the form of either freely suspended cells or cells immobilized within a macroporous gel matrix, poly(vinyl alcohol) (PVA) cryogel. Significantly higher degradation rates were achieved with either suspended or immobilized OPH(+) cells compared to rates with the microbial consortium naturally present in CDW. Of the two nongrowing cell systems, the detoxification rate with immobilized cells was approximately twice that of freely suspended cells, and kinetic studies demonstrated that a higher maximum reaction rate was achieved with the immobilized cell system. A comparative study using both the CDW and pure CP substrates with free cells indicated that the CDW contained one or more factors that reduced the bioavailability of CP. The immobilized cells retained their activity over a 4-month period of use and storage, demonstrating both sustained catalytic activity and long-term mechanical stability.

Clinical efficacy of frovatriptan: placebo-controlled studies.

OBJECTIVE: To confirm the clinical efficacy of frovatriptan 2.5 mg. BACKGROUND: Frovatriptan is a new 5-hydroxytryptamine (5-HT)(1B/1D) receptor agonist being developed for the acute treatment of migraine with or without aura. Results from preclinical and clinical pharmacology studies showed frovatriptan to be a potent 5-HT(1B) receptor agonist with a long terminal elimination half-life (26 hours) and a broad therapeutic index. DESIGN: Three randomized, placebo-controlled, double-blind, parallel-group trials, in a total of 2676 patients, were performed to confirm the clinical efficacy of frovatriptan 2.5 mg for the acute treatment of migraine. RESULTS: In all three studies, headache response 2 hours after frovatriptan dosing was significantly greater than that seen with placebo (P < or = .001) with approximately a two-fold measure of effect over placebo for headache response at 2 and 4 hours postdosing. Time to headache response occurred within 1.5 hours in a substantial proportion of patients. The incidence of 24-hour headache recurrence with frovatriptan was low (10% to 25%). Frovatriptan therapy also was associated with a high degree of patient satisfaction. CONCLUSIONS: Frovatriptan represents a consistently effective acute treatment for migraine and accompanying symptoms.

Diagnostic lessons from the spectrum study.

Article abstract Migraine is a heterogeneous condition that causes symptoms that vary both among individuals and within individuals from attack to attack. We examined and reviewed several important lessons on the diagnosis of migraine learned from the distribution of headache types and patterns of treatment response in the Spectrum Study, including recruitment and diagnostic issues. The accuracy of an initial diagnosis, assigned by a clinician in the context of a clinical trial, was compared with the results of a final diagnosis, assigned by a neurologist, reviewing the initial evaluation as well as headache diaries for up to 10 attacks. Several lessons can be learned from the Spectrum Study. Recruitment difficulties teach us that disabling tension-type headache is difficult to find, suggesting that it is rare. Examination of the final diagnosis given after diary evaluations suggests that a diagnosis of migraine can usually be confirmed for patients with disabling headache. After reclassification of the final sample of 432 subjects, 24/75 (32%) patients initially clinically classified as having disabling episodic tension-type headache proved to have migraine or migrainous headache after a diary review. Among study participants, 90% of subjects with disabling headache (HIMQ score >250) had a migraine-related disorder. Treatment response suggests that, in migraineurs, tension-type headaches may have a pathophysiology similar to that of migraine. The diary data show that mild headaches in patients with disabling migraine often evolve into full-blown migraine. The Spectrum Study supports the view that, for patients with disabling episodic headache, migraine is often the correct diagnosis. In clinical practice, the suspicion of migraine should be high for patients experiencing episodic disabling headache. Assessment of headache-related disability may assist practitioners in making a diagnosis of migraine.