377

Sumatriptan Nasal Spray and Cognitive FunctionDuring Migraine: Results of an Open-Label Study

Kathleen Farmer, PsyD; Roger Cady, MD; Joseph Bleiberg, PhD; Dennis Reeves, PhD; Gayla Putnam, MA; Stephen O’Quinn, PharmD; Alice Batenhorst, PharmD

Objective.—To examine measures of cognitive function during acute migraine, before and after treatmentwith sumatriptan nasal spray, 20 mg.

Background.—Migraineurs frequently report symptoms of cognitive impairment during migraine. The effi-cacy of sumatriptan for treatment of migraine-related cognitive impairment is undocumented.

Methods.—This open-label, single-attack study of 28 subjects used the Headache Care Center-Automated Neu-ropsychological Assessment Metrics, a computerized neuropsychological assessment battery, to measure cognitivefunction under three patient conditions: migraine-free, untreated migraine, and following sumatriptan (primary out-come). Headache response and pain-free response, percent effectiveness, and clinical disability were measured.

Results.—Cognitive function (simple reaction time, sustained attention/concentration, working memory, vi-sual-spatial processing) and alertness/fatigue were adversely affected during migraine compared with migraine-free performance (

P

,

.05), and rapidly restored following sumatriptan nasal spray, 20 mg (

P

,

.05). Headache andpain-free response were 86% and 68%, respectively, at 135 minutes postdose. Changes in migraine pain severity,clinical disability, and percent effectiveness following treatment with sumatriptan nasal spray, 20 mg, were signifi-cantly correlated with cognitive function measures across all subtests (

P

,

.001).

Conclusions.—Sumatriptan nasal spray, 20 mg, restored migraine-related cognitive function and clinical disability.

Key words: sumatriptan, cognitive function, migraine, disability

Abbreviations: ANAM Automated Neuropsychological Assessment Metrics, HCC-ANAM Health Care Center-Automated Neuropsychological Assessment Metrics, NS nasal spray, SRT simple reaction time,CPT continuous performance test, MTS matching to sample, MP mathematic processing, SSSStanford Sleepiness Scale

(

Headache

2001;41:377-384)

The deleterious effects of migraine on patientwell-being, social functioning, work productivity, anddisability are well documented.

1-3

Complex neuropsy-

chological symptoms (language, visual, and cognitive-dysmnesic dysfunction) have also been described duringmigraine.

4

However, the scientific association be-tween migraine-related disability and neuropsycho-logic (ie, cognitive) impairment has been limited topatient-rated assessments of effectiveness. Traditionaldefinitions of patient disability do not account for thedecline in effectiveness frequently reported while pa-tients continue activities during untreated migraine.Reduced effectiveness has been identified as the great-est contributor to workplace productivity loss,

3

andmay be the result of migraine-related cognitive impair-ment. Objective measures that clarify the relationshipbetween patient disability and cognitive impairmentwould greatly enhance our understanding of migraine

From the Headache Care Center, Springfield, Mo (Drs.Farmer and Cady); National Rehabilitation Hospital, Wash-ington, DC (Dr. Bleiberg); Naval Hospital, Guam (Dr.Reeves); Glaxo Wellcome Inc, Research Triangle Park, NC(Ms. Putnam and Drs. O’Quinn and Batenhorst).

Presented in part at the 42nd Annual Scientific Meeting of theAmerican Headache Society, Montreal, Quebec, Canada,June 23-25, 2000.

Address all correspondence to Dr. Kathleen Farmer, Head-ache Care Center, 1230 East Kingsley, Springfield, MO 65804.

Accepted for publication December 7, 2000.

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as a serious disorder with significant health outcomes,and may result in more effective medical care forthose with migraine.

Previous studies of migraine-related cognitive im-pairment have produced inconclusive or conflictingresults.

5-8

One study conducted during the interictaland postictal periods found that patients with mi-graine with aura experienced delays on tasks that re-quire selective attention and concentration.

9

How-ever, in a study conducted during acute migraine,significant differences in reaction time, memory, andlanguage were identified.

10

Anecdotally, patients fre-quently report difficulty thinking and remembering,as well as feelings of mental slowness and fatigue, dur-ing migraine. The varied study designs and neuropsy-chological batteries used in these studies failed to re-liably identify and quantify the cognitive impairmentdescribed by patients during migraine, some lackedmeasurement sensitivity, and some were poorly suitedfor serial testing paradigms.

We report an investigation of migraine-relatedcognitive function using a computerized cognitive as-sessment battery that is highly sensitive to centralnervous system integrity and specifically designed forrepeated-measures paradigms. The Automated Neu-ropsychological Assessment Metrics (ANAM), Ver-sion 1.0, is a battery of standardized, computerizedtests designed for precise measurement of sustainedconcentration and attention, mental flexibility, spatialand cognitive processing, short- and long-term mem-ory, and working memory.

11,12

Portions of this batteryhave been used successfully to monitor cognitive im-pairment in studies of histamine-receptor antago-nists.

13

The Headache Care Center-Automated Neu-ropsychological Assessment Metrics (HCC-ANAM)was assembled using selected ANAM subtests thatsupport the hierarchical cognitive levels of the Reitan-Wolfson conceptual model.

14

An earlier pilot study ofmigraineurs demonstrated HCC-ANAM sensitivity toacute migraine and recovery from migraine followingtreatment with sumatriptan injection, 6 mg.

15

Sumatriptan nasal spray (NS), 20 mg, has beenshown to be effective for the treatment of acute mi-graine and its associated symptoms.

16-19

However, nostudies have examined the effect of sumatriptan oncognitive function during acute migraine. We con-

ducted a small open-label study using the HCC-ANAMto evaluate the effect of acute migraine on cognitivefunction, as well as the efficacy of sumatriptan NS,20 mg, in the recovery of functional cognitive pro-cessing, using the HCC-ANAM.

METHODS

Subjects.—

Men and women aged 18 to 65 yearswith a diagnosis of migraine with or without aura us-ing the International Headache Society (IHS) criteria(1.1 and 1.2)

20

were eligible for study participation.Subjects were required to have at least a 1-year his-tory of migraine with onset prior to aged 50 years,and to have experienced one to six moderate or se-vere migraines within each of the 2 months prior toscreening. Patients whose usual daily activities wereaffected by migraine in the 2 months prior to studyenrollment and who had successfully treated one mi-graine with sumatriptan prior to screening partici-pated in the study.

Subjects were not eligible for study participationif they had confirmed or suspected ischemic heart dis-ease; Prinzmetal angina; history or evidence of ischemicabdominal syndromes, peripheral vascular disease orRaynaud syndrome; cardiac arrhythmias requiring medi-cation or clinically significant electrocardiogram abnor-mality; history of cerebrovascular pathology includingstroke, congenital heart disease, cardiovascular or cere-brovascular disease; or uncontrolled hypertension. Sub-jects could not have basilar or hemiplegic migraine, im-paired hepatic or renal function, evidence of alcohol ordrug abuse within the previous year, recent head trauma,history of epilepsy, active sinus disease, or a contraindi-cation to the use of sumatriptan.

Subjects could not have a history of ergotamineabuse in the 3 months prior to screening, and couldnot use ergotamine-containing medication 24 hoursbefore or after study drug administration. Subjectscould not use monoamine oxidase inhibitors within 2weeks prior to screening, or have a change in prophy-lactic medication from screening HCC-ANAM test-ing. Subjects were required to have 15 or fewer daysof tension headache per month in either of the 2months prior to screening. Women were excluded ifthey were pregnant, breast-feeding, or sexually activeand not using adequate contraceptive measures.

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Procedures.—

A midwestern US clinic receivedinstitutional board approval to conduct the study, andall subjects completed written informed consent priorto study enrollment. Participants were screened in theclinic while migraine-free and provided medical andmigraine histories as well as concurrent medicationuse. Each received a complete physical examinationincluding assessment of vital signs, serum pregnancytests (women of childbearing potential), and an elec-trocardiogram if clinically indicated (visit 1). Subjectscompleted the HCC-ANAM cognitive function testthree times (T1, T2, and T3) and were instructed toreturn to the clinic for treatment of their next moder-ate-to-severe migraine.

Subjects returned to the clinic during an acutemigraine (visit 2) and updated their medical historyand concurrent medication usage. Vital signs and aurine pregnancy test (women) were performed. Eachparticipant completed efficacy, clinical disability, andpercent effectiveness measures (T4) and cognitive func-tion tests (T5) before and 15 (T6), 45 (T7), 75 (T8),105 (T9), and 135 minutes (T10) after treatment withsumatriptan NS, 20 mg.

Cognitive Function.—

Cognitive function was as-sessed using the HCC-ANAM and included simplereaction time (SRT), continuous performance test(CPT), matching to sample (MTS), and mathematicalprocessing (MP). All HCC-ANAM tests were admin-istered by IBM-compatible computer using a keyboardor mouse as the response device. The Stanford Sleepi-ness Scale (SSS) was used to measure alertness and/orfatigue. The primary efficacy end point was cognitivefunction postdose sumatriptan NS, 20 mg (T6-T10).

Simple Reaction Time.—

Simple reaction time is aclassic visual-motor response time test that measuresthe speed and the ability to detect a stimulus. A sim-ple stimulus (image of a snowflake) is presented onthe computer screen, and the subject must press amouse button as quickly as possible each time thestimulus appears.

21

Continuous Performance Test.—

The CPT is a let-ter comparison test that assesses a subject’s ability tosustain high levels of concentration with rapidly shift-ing mental sets; it is an index of lapses in attentionand working memory. Uppercase letters, A throughZ, are presented individually in a randomized sequence

in the center of the computer screen. The subject mustcontinuously monitor the letters and identify the let-ters that match the immediately preceding letter bypressing a specific mouse button.

Matching to Sample.—

Matching to sample is de-rived from operant conditioning studies, conductedby B.F. Skinner in the early 1950s, as a measure of vi-sual-spatial skills and short-term memory.

21

Duringthis test, a checkerboard matrix is presented on thecomputer screen, followed by two matrices presentedside by side. The subject must determine which of thetwo sets matches the initial matrix and press a specificmouse button to indicate the choice.

Mathematical Processing.—

Mathematical process-ing is a measure of efficiency in performing simple arith-metic. During this test, subjects are required to solvearithmetic equations that include addition and sub-traction, eg, 5

1

2

2

3

5

?.

22

The subject must then in-dicate, as quickly as possible, whether the answer isgreater or less than 5 by clicking a mouse button.

Stanford Sleepiness Scale.—

The SSS consists ofstatements that describe individual perceptions ofalertness and fatigue.

23

Subjects read seven statementsand choose the one that best describes how they feelat the time of the test. Statements range from “feel-ing wide awake, alert, and energetic” to “sleep onsetsoon, losing struggle to remain awake.”

Efficacy.—

Head pain was subject-rated using a4-point pain scale (0

5

no pain, 1

5

mild pain,2

5

moderate pain, 3

5

severe pain) and recorded pre-dose and 15, 45, 75, 105, and 135 minutes after the ad-ministration of sumatriptan NS, 20 mg. Headache re-sponse was defined as a reduction in predose headpain severity from moderate or severe to mild or nopain postdose. Pain-free response was defined as areduction in predose head pain severity from moder-ate or severe to no pain postdose.

Clinical Disability.—

Clinical disability was subject-rated using a 4-point scale (0

5

ability to work/functionnormally, 1

5

ability to function mildly impaired, 2

5

ability to function moderately impaired, 3

5

ability tofunction severely impaired) and recorded predose and15, 45, 75, 105, and 135 minutes after the administrationof sumatriptan NS, 20 mg.

Percent Effectiveness.—

Subjects estimated theireffectiveness at performing a daily activity or work-

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ing using a 0% to 100% scale (0%

5

not effective and100%

5

fully effective) predose, 15, 45, 75, 105, and135 minutes postdose.

Associated Symptoms.—

The presence or absenceof nausea, vomiting, phonophobia, and photophobiawas reported predose and 15, 45, 75, 105, and 135 min-utes postdose.

Safety.—

This study was not designed to evaluatesafety, as subjects had used sumatriptan previously.Safety was assessed through the reporting of seriousadverse events using a MedWatch Form 3500A within24 hours of occurrence.

Statistical Analyses.—

Cognitive function and ef-ficacy analyses were performed on the intent-to-treatpopulation. Descriptive statistics are presented fordemographics, headache response, pain-free response,and safety. Simple reaction time was scored for reac-tion time in milliseconds. Three HCC-ANAM subtests(CPT, MTS, MP) were scored for throughput, definedas the number of correct responses per minute, a mea-sure of efficiency that combined both speed and accu-racy in a single score. Group means were calculatedfrom individual subject means for each HCC-ANAMsubtest and the SSS across the three migraine condi-tions: migraine-free, migraine, and recovery. EachHCC-ANAM subtest was analyzed using a repeated-measures 1

3

3 (migraine-free, untreated migraine,and recovery) analysis of variance (ANOVA), andeach ANOVA was followed by three post hoc

t

tests(migraine-free versus untreated migraine, migraine-free versus recovery, and untreated migraine versusrecovery) to identify statistical significance betweenmigraine conditions, with

P

,

.05 considered statisti-cally significant. Spearman’s correlation coefficient (

r

)was used to examine the relationship between efficacyand disability measures and cognitive function dimen-sions to determine if the scores were systematically re-lated.

RESULTS

Subjects.—

Twenty-eight women with a mean ageof 43.7 years (range, 26 to 64 years) were enrolledand completed the study. No subjects had a historyof prior head trauma or brain injury. Most partici-pants were married (23 [82%] of 28) and employedoutside the home (19 [68%] of 28). When reporting to

the clinic for visit 2, 79% (22 of 28) of the subjects re-ported moderate head pain, and 21% (6 of 28) re-ported severe head pain. On average, subjects ratedtheir percent effectiveness at performing daily activi-ties or work during untreated migraine (predose) as48%. Eleven percent (3 of 28) of the subjects re-ported mild clinical disability as a result of their mi-graine pain, 82% (23 of 28) were moderately impaired,and 7% (2 of 28) were severely impaired. Eighty-ninepercent (25 of 28) of subjects reported phonophobiaand photophobia, 71% (20 of 28) reported nausea,and 7% (2 of 28) reported vomiting predose.

Cognitive Function.—

The 1

3

3 analyses of vari-ance for each individual measure of cognitive func-tion were significantly different beyond the

P

5

.001level. Post hoc

t

tests revealed that cognitive functionwas significantly impaired during untreated migrainecompared to baseline (migraine-free) (Figures 1through 5). This cognitive impairment was restoredduring the recovery phase following administrationof sumatriptan NS, 20 mg, compared with untreatedmigraine (Figures 1 through 5). Simple reaction timeand alertness (SSS) did not fully return to migraine-free levels during recovery, but were statistically dif-ferent for the decrements observed during untreatedmigraine (Figures 1 and 5). Mathematical processingscores during the recovery phase were elevated abovethose reported during the migraine-free phase (Fig-ure 4).

Fig 1.—Mean simple reaction time at three subject conditions(migraine-free, untreated migraine, and recovery). Two-tailedt test comparing migraine-free versus untreated migraine (P,.01)and untreated migraine versus recovery with sumatriptan NS,20 mg (P,.01). P,.05 is considered significant.

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Efficacy.—

Nearly half of the subjects reportedheadache response as early as 15 minutes postdosesumatriptan NS, 20 mg. The proportion of subjectsreporting headache response and pain-free responseincreased progressively across the study period (Ta-ble 1), with 86% (24 of 28) of subjects reporting head-ache response and 68% (19 of 28) reporting pain-freeresponses 135 minutes postdose.

Clinical Disability.—

More than half of the sub-jects reported being only mildly impaired as early as15 minutes postdose. The proportion of subjects withclinical disability progressively declined throughoutthe study period (Table 1).

Effectiveness.—

Effectiveness in performing dailyactivities or work increased to 62% within 15 minutespostdose and continued to increase throughout thestudy period (Table 1).

Associated Symptoms.—

The proportion of sub-jects who reported vomiting predose was low and de-creased to zero 15 minutes postdose. The proportionreporting nausea decreased to 32% (9 of 28) within 15minutes postdose, declined further to 14% (4 of 28) 45minutes postdose, and remained at that level through-out the study. The incidence of phonophobia and pho-tophobia decreased to 29% (phonophobia, 8 of 28) and46% (photophobia, 13 of 28) 135 minutes postdose.

Fig 2.—Mean throughput (number of correct responses perminute) on the continuous performance test at three subjectconditions (migraine-free, untreated migraine, and recovery).Two-tailed t test comparing migraine-free versus untreated mi-graine (P,.01), and untreated migraine versus recovery withsumatriptan NS, 20 mg (P,.01). P,.05 is considered significant.

Fig 3.—Mean throughput (number of correct responses perminute) on matching to sample at three subject conditions(migraine-free, untreated migraine, and recovery). Two-tailedt test comparing migraine-free versus untreated migraine(P,.05), and untreated migraine versus recovery with suma-triptan NS, 20 mg (P,.01). P,.05 is considered significant.

Fig 4.—Mean throughput (number of correct responses perminute) on mathematical processing at three subject condi-tions (migraine-free, untreated migraine, and recovery). Two-tailed t test comparing migraine-free versus untreated migraine(P,.01), and untreated migraine versus recovery with suma-triptan NS, 20 mg (P,.01). P,.05 is considered significant.

Fig 5.—Subject-perceived alertness at three subject conditions(migraine-free, untreated migraine, and recovery). Percep-tions ranged from most alert (15feeling wide awake, alert,and energetic) to least alert (75sleep onset soon, losing strug-gle to remain awake). Two-tailed t test comparing migraine-free versus untreated migraine (P,.01), and untreated mi-graine versus recovery with sumatriptan NS, 20 mg (P,.01).P,.05 is considered significant.

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Safety.—

No serious adverse events were reported.

Relationship Between Efficacy, Disability, Effec-tiveness, and Cognitive Function.—

Changes in mi-graine pain severity, clinical disability, and subject-perceived effectiveness following treatment withsumatriptan NS, 20 mg, were significantly correlatedwith cognitive function measures across all subtests(Table 2).

COMMENTS

All measures of cognitive function and alertness/fatigue were significantly impaired during the un-treated migraine phase of the study. Subjects per-formed more slowly (SRT), their ability to process in-formation efficiently was impaired (MTS, CPT, MP),and they generally felt tired (SSS). Overall, the sub-jects’ ability to pay attention, concentrate, reason log-ically, and formulate concepts nonverbally were ad-versely affected which generally made the monitoringand retention of information more difficult. Theseobjective measures of cognitive impairment were sup-ported by declines in more traditional patient-ratedmeasures of clinical disability and percent effectiveness.

Sumatriptan NS, 20 mg, significantly restored allmeasures of cognitive function in the present study.Visual-motor response, energy levels, logical reason-ing, and the ability to concentrate were all signifi-cantly improved following treatment with sumatrip-

tan. However, some residual migraine effects remainedpostdose in SRT and alertness (SSS), and the clinicalimpact of these observations is unknown. Importantly,treatment with sumatriptan fully restored subjects’ability to accurately and quickly process informationacross multiple tasks and returned subjects to normallevels of performance. Treatment response was rapidwith sumatriptan, with nearly half of all patients re-porting headache response and reductions in clinicaldisability as early as 15 minutes following treatment,trends that were progressively enhanced across thefull study period. In addition, associated symptomsdeclined further demonstrating the clinical effective-ness of sumatriptan.

The cognitive impairment observed during theuntreated migraine phase of the present study scien-tifically links migraine-related disability with specificcognitive changes, findings that are supported by anearlier cognitive function study.

10

Patients in that studydemonstrated declines in reaction time, memory, andlanguage skills during migraine, as well as elevatedlevels of perceived cognitive impairment during se-vere migraine. The subjects in the present study re-ported similar declines in cognitive function duringacute migraine and demonstrate a systematic relation-ship between cognitive function, clinical disability, andpercent effectiveness following treatment with sumatrip-tan (Spearman correlations), supporting our hypothesis

Table 1.—Headache Response, Pain-Free Response, and Clinical Disability Predose and Postdose Sumatriptan NS, 20 mg, in a Study of Cognitive Function*

Post Sumatriptan NS 20 mg, min

Untreated Migraine 15 45 75 105 135

Headache response 13 (46) 21 (75) 23 (82) 24 (86) 24 (86)Pain-free response 0 6 (21) 10 (36) 15 (54) 19 (68)Clinical disability

Normal 0 0 8 (29) 10 (36) 17 (61) 18 (64)Mildly impaired 3 (11) 15 (54) 14 (50) 13 (46) 7 (25) 6 (21)Moderately impaired 23 (82) 9 (32) 4 (14) 3 (11) 2 (7) 2 (7)Severely impaired 2 (7) 4 (14) 2 (7) 2 (7) 2 (7) 2 (7)

Overall percent effectiveness 48 62 71 77 81 83

*Values are number (percentage) unless otherwise indicated.

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that sumatriptan NS, 20 mg, restores migraine-relatedcognitive impairment.

The ANAM has been used extensively by the USmilitary for precise measurement of mental fatigueand cognitive function, primarily in pilots duringflight.

11,12

Those with migraine have anecdotally de-scribed difficulty thinking and remembering, as wellas feelings of mental slowness and fatigue duringacute migraine. Within that context, we offer the firstquantitative, objective evidence of cognitive disabil-ity using the HCC-ANAM that is systematicallylinked to patient-reported declines in effectiveness.Studies of migraine in the workplace have identifiedreduced effectiveness as the largest contributor toproductivity loss

3

; these declines may be the result ofimpaired cognitive function. The documented returnof cognitive function following treatment with sumatrip-tan is encouraging and the implications for real-lifepursuits (occupational and/or daily activities), as wellas the clinical and socioeconomic impacts to employ-ers and patients, warrant further investigation.

Our results should be interpreted within the con-text of the present study. This was a small open-labelstudy that preselected subjects with migraine with a

documented response to sumatriptan. Cognitive perfor-mance of nonmigraineurs or placebo subjects was notevaluated. Interpretation of HCC-ANAM was basedupon a repeated-measures analysis that evaluates multi-ple comparisons within the same subject, a methodol-ogy widely accepted in the field of neuropsychology.The implications for administration and interpretationof the HCC-ANAM in general medical practice re-quires further investigation. Additionally, numericalprocessing (MP) was enhanced following treatmentwith sumatriptan, raising questions regarding possiblelong-term cognitive impairment in migraineurs, a find-ing that also requires further investigation.

In conclusion, we present evidence of significantcognitive impairment during untreated migraine thatis significantly restored following administration ofsumatriptan NS, 20 mg. Subjects responded slowlyand were less accurate at recall, short-term memory,visual-spatial skills, and logical analysis during acutemigraine, effects that were reversed following admin-istration of sumatriptan. This study provides quantifi-able evidence of the cognitive impairment subjec-tively described by individuals with migraine. Furtherinvestigation is needed to identify the clinical andtherapeutic usefulness of migraine-related cognitivefunction measures in clinical practice.

Acknowledgments: This study was supported by an

unrestricted grant from Glaxo Wellcome Inc, Research

Triangle Park, NC. Appreciation is expressed to Barbara

Wilson for her writing and editorial assistance.

REFERENCES

1. Stewart WF, Lipton RB, Celentano DD, Reed ML.Prevalence of migraine headache in the UnitedStates. Relation to age, income, race, and other so-ciodemographic factors.

JAMA.

1992;267:64-69.2. Cortelli P, Dahlof C, Bouchard J, et al. A multina-

tional investigation of the impact of subcutaneoussumatriptan. III: Workplace productivity and non-workplace activity.

Pharmacoeconomics.

1997;11(suppl 1):35-42.

3. Cady RK, Ryan R, Jhingran P, O’Quinn S, Pait DG.Sumatriptan injection reduces productivity loss dur-ing a migraine attack: results of a double-blind, pla-cebo-controlled trial.

Arch Intern Med.

1998;158:1013-1018.

Table 2.—Spearman Correlation Coefficients Between Traditional Efficacy (Pain Scores), Clinical Disability, and Percent Effectiveness Scores Following Treatment With

Sumatriptan NS, 20 mg

Cognitive Function Measure Correlation*

Simple reaction time Pain 0.59022Clinical disability 0.57091% Effectiveness

2

0.51411Continuousperformance test Pain

2

0.68197Clinical disability

2

0.68065% Effectiveness 0.65521

Matching to sample Pain

2

0.41671Clinical disability

2

0.37514% Effectiveness 0.37178

Mathematical processing Pain 20.44685Clinical disability 20.42177% Effectiveness 0.44953

Stanford Sleepiness Scale Pain 0.77967Clinical disability 0.77655% Effectiveness 20.76052

*P,.001.

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4. Ardila A, Sanchez E. Neuropsychologic symptomsin the migraine syndrome. Cephalalgia. 1988;8:67-70.

5. Palmer JE, Chronicle EP. Cognitive processing inmigraine: a failure to find facilitation in patients withaura. Cephalalgia. 1998;18:125-132.

6. Wang W, Schoenen J, Timsit-Berthier M. Cognitivefunctions in migraine without aura between attacks:a psychophysiological approach using the “oddball”paradigm. Neurophysiol Clin. 1995;25:3-11.

7. Wray SH, Mijovic-Prelec D, Kosslyn SM. Visualprocessing in migraineurs. Brain. 1995;118(pt 1):25-35.

8. Hooker WD, Raskin NH. Neuropsychologic alter-ations in classic and common migraine. Arch Neurol.1986;43:709-712.

9. Mulder EJ, Linssen WH, Passchier J, Orlebeke JF,de Geus EJ. Interictal and postictal cognitive changesin migraine. Cephalalgia. 1999;19:557-565.

10. Zeitlin C, Oddy M. Cognitive impairment in patientswith severe migraine. Br J Clin Psychol. 1984;23(pt 1):27-35.

11. Reeves D, Kane R, Winter K, Raynsford K, PancellaT. Automated Neuropsychological Assessment Met-rics (ANAM): Test Administrators Guide Version1.0. San Diego: National Cognition Recovery Foun-dation; 1994.

12. Levinson D, Reeves DL. Automated Neuropsycho-logical Assessment Metrics (ANAM): ANAM V1.0Normative Data. San Diego, Calif: National Cogni-tive Recovery Foundation; 1994.

13. Kay GG, Berman B, Mockoviak SH, et al. Initialand steady-state effects of diphenhydramine and lor-atadine on sedation, cognition, mood, and psycho-motor performance. Arch Intern Med. 1997;157:2350-2356.

14. Halstead-Reitan Neuropsychological Battery. Tucson,Ariz: Neuropsychology Press; 1985.

15. Farmer K, Cady RK, Reeves D, Bleiberg J. Cogni-tive efficiency during migraine [abstract]. Neurology.1999;52:A469-A470.

16. Ryan R, Elkind A, Baker CC, Mullican W, DeBus-sey S, Asgharnejad M. Sumatriptan nasal spray forthe acute treatment of migraine. Results of two clini-cal studies. Neurology. 1997;49:1225-1230.

17. Diamond S, Elkind A, Jackson RT, Ryan R, DeBus-sey S, Asgharnejad M. Multiple-attack efficacy andtolerability of sumatriptan nasal spray in the treat-ment of migraine. Arch Fam Med. 1998;7:234-240.

18. Dahlof CG, Boes-Hansen S, Cederberg CG, Hard-ebo JE, Henriksson A. How does sumatriptan nasalspray perform in clinical practice? Cephalalgia. 1998;18:278-282.

19. Peikert A, Becker WJ, Ashford EA, Dahlof C, Has-sani H, Salonen RJ. Sumatriptan nasal spray: a dose-ranging study in the acute treatment of migraine.Eur J Neurol. 1999;6:43-49.

20. Headache Classification Committee of the Interna-tional Headache Society. Classification and diagnos-tic criteria for headache disorders, cranial neuralgiasand facial pain. Cephalalgia. 1988;8(suppl 7):1-98.

21. Sternberg S. The discovery of processing stages: ex-tension of Donder’s method. Acta Psychol. 1969;30:276-313.

22. Shingledecker CA. A Task Battery for Applied Hu-man Performance Assessment Research. Dayton,Ohio: Wright-Patterson Airforce Base, AerospaceMedical Research Laboratory; 1984.

23. Hoddes E, Zarcone V, Smythe H, Phillips R, De-ment WC. Quantification of sleepiness: a new ap-proach. Psychophysiology. 1973;10:431-436.