Letters to the Editor

Headache Medicine – A Comment

Headache medicine is an integral part of neurology.Given the fact that there are no¨ surgical, invasive, or com-plex diagnostic procedures involved in headache medicine,and since headache medicine is mainstream neurology, theneurological community should seriously question (1) the re-quirement for a separate headache certification in the fieldof neurology and (2) the reason why ALL neurologists arenot mandated to be experts in headache medicine by theAmerican Board of Psychiatry and Neurology.

Dr. Finkel points out that the 105 neurologists whohave been certified by the United Council for Neuro-logic Subspecialties–Headache Medicine (this author in-cluded), were certified under the practice track.1 The bright-est headache researchers and clinicians in the world are partof this group. None of us completed a headache fellowship.We read, attend conferences, teach, and apply the basic sci-ence of headache medicine to manage our patients. If aneurological subspecialty requires in-depth training of in-vasive, surgical, or diagnostic procedures, or contains a bodyof knowledge that is outside the scope of mainstream neurol-ogy, then a 1-year fellowship with special certification shouldbe required. For example, in pain management it is impor-tant to master all the invasive procedures and be compe-tent in the medical and invasive aspects of this field so as tocompetently practice pain medicine without causing harm topatients. However, for neurologists not to be able to compre-hensively master headache medicine during residency withcontinuity of expertise into clinical practice is very disturb-ing and sends the wrong message to the public. The publicexpects that a neurologist is most competent with the author-itative final word on headache disorders. Now we are tellingthe public that we have 2 neurologists, a neurologist that isboard certified in neurology who is expected to be proficientin managing headache patients, and another type of neurolo-gist who is more competent in managing headaches. Imaginethe ludicrous analogy of certification in chest pain medicinein cardiology, and certification in abdominal pain medicinein gastroenterology.

The medical community should be indebted and veryrespectful of the important headache medicine contribu-

tions made by neurologists who limit their work to headachein academic settings as teachers, researchers, and clinicians.All neurologists have the duty to stay abreast and be ex-perts in all neurological disorders. Regardless of the scopeof practice, a good neurologist has strong foundations in gen-eral medicine and especially in all neurological disorders asheadache patients almost always have co-existing/co-morbidissues. Headache medicine can be easily assimilated into3-year residency programs and into patient practice.Headache pathophysiology, treatment, differential diag-noses, does not require specialty training or specialtycertification. Subspecialty training and certification is cer-tainly essential in many areas of medicine and surgery. How-ever, fellowship training and certification for neurologistsfor headache is absurd and resonates elitism. One wonderswhat it will mean to be a neurologist when other groups suchas movement disorders and multiple sclerosis start formingtheir own certification/fellowship clubs.

James A. Charles, MD, FAANNew Jersey Medical School – Department

of NeurosciencesNewark, New Jersey

REFERENCE

1. Finkel AG. Headache medicine. Headache: J Head and FacePain. 2007;47:473-474.

Headache Medicine: Academic Teachingin Europe. The Sapienza UniversityMaster’s Degree

The cultural movement, which conduced in the last5-years headache disorders outside of an excellent but lim-ited world of experts, is finally giving ripe fruits. The “flywheel” of this trend based on the increase of awarenessfor headache disorders has evolved towards an indispens-able capillarization of specialist education, in order to pre-pare the medical profession to a health problem of globaldimensions.

1224

Headache 1225

The demand of specialties or hyperspecialties suchas Headache Medicine has become evident since severalyears, however without significant accomplishments. Boththe American Headache Society (AHS) and, across theocean, Lifting the Burden (LTB) and European HeadacheFederation (EHF), served the same purpose with dif-ferent methods by training a new class of experts inthis particular field. On one hand, the AHS, institutedin 2006 provides a Headache Medicine Diploma accred-ited by the United Council for Neurological Subspecialties(UCNS).

Furthermore, AHS does offer a voluntary course to helppotential examinees prepare for the certification multiplechoice exam.1 In the near future all applicants also will needto have completed a certified headache fellowship.2

In the meantime, a purely academic approach hasbeen consolidated in Europe into the Master’s degree inHeadache Medicine.3 This Master’s degree each year enrollsphysicians from different geographical areas and is based ona series of theoretical lectures held by a yearly renewed in-ternational faculty.4 Clinical activity takes places at a cen-ter of excellence and completes the course.Teaching activityis implemented by the Blackboard Academic Suite learn-ing platform (http://bb.uniroma1.it), which offers access toslides and videos of the lectures, as well as online evaluationtests.5 Teaching sessions often produce tutorials available inthe online library of the Masters web site, for the use of stu-dents.6 The annual course concludes with a traditional finalexam and a thesis discussion.

The cultural chain train the trainers in HeadacheMedicine already allowed to activate within LTB the sec-ond teaching step at national level towards primary carephysicians, through the regional involvement as trainersof doctors who achieved the Academic Master’s Degreein previous editions. At this level there are particularlyuseful diagnostic and therapeutic aids for primary careshaped by LTB in conjunction with EHF as supplement ofThe Journal of Headache and Pain, which can be down-loaded free-of-charge from the Springer web site of thejournal.7

The European educational pathway in HeadacheMedicine is progressively increasing its significance8 and theacademic year 2007–2008 will see the accomplishment of the5 degree years of excellence in Headache Medicine educa-tion. The auspice is in abidance with the necessary holisticeducation of the Medicine student, this tendency could findhospitality in pre-lauream education9 as sensitization meanstowards headache disorders and not in almost complete sco-tomy, as it often happens.

Paolo Martelletti, MDSapienza University of Rome

2nd School of MedicineDepartment of Medical Sciences

Sant’Andrea Hospital, Rome, Italy

REFERENCES

1. Headache Medicine Diplomates. Headache. 2007;47:349-350.2. Accreditation of Headache Medicine Fellowships. Headache.

2007;47:644.3. Master in Headache Medicine. Rome Sapienza University.

Available at: http://w3.uniroma1.it/headache (Accessed onMay 7, 2007).

4. Martelletti P, Haimanot RT, Lainez MJ, et al. The GlobalCampaign (GC) to reduce the burden of headache worldwide.The international team for specialist education. J HeadachePain. 2005;6:261-263.

5. Martelletti P. The distance learning on headache disordersand pain. J Headache Pain. 2002;3:159.

6. Martelletti P. Starting tutorials in headache medicine educa-tion. J Headache Pain. 2006;7:55-56.

7. Steiner TJ, Paemeleire K, Jensen R, et al. European principlesof management of common headache disorders in primarycare. J Headache Pain. 2007;8:S1-S28.

8. Martelletti P. Academic specialist education in headachemedicine. Next move for the headache community. JHeadache Pain. 2005;6:103-104.

9. Young WB, Rosen N, Sheftel F. Square one: Headache edu-cation for medical student. Headache. 2007;47:351-354.

Headache Medicine–A Response

Before responding to this contrapuntal duet of impor-tant letters, 2 facts must be stated: (i) It is the policy of theJournal that reviewers are not provided with the names ofauthors, including letters removing the incentive for invec-tive or personal vendettas; (i) I am a volunteer member ofthe marketing team of the United Council of NeurologicSubspecialties (UCNS), all the rest of whom are paid staffof UCNS.

These 2 letters offer a great opportunity to learn andeducate. The first extols the existence and virtues of a Eu-ropean initiative, lift the burden, whose stated goal is to im-prove the care of patients with headache by offering addi-tional training to practitioners interested in that care. I amnot involved with this initiative, but applaud the effort torecognize those individuals willing to give their time to im-proving their professional skills. We should all take a look

1226 September 2007

at their program and see what it might offer us in America.The second tolls a false warning based upon inaccuracies andopinion.

First, and greatest importance to the AHS, the creden-tialing of individuals in headache medicine is not only forneurologists. Many of those who recently received certifi-cates are not neurologists, including an internist who prac-tices with us within the department of neurology. This ac-complished one of the core missions of the UCNS: to rec-ognize expertise in Neurologic Subspecialty Areas (NSA)where multidisciplinary backgrounds enhance the teachingand practice of that area. The letter makes it appear thatonly neurologists practice headache medicine and perhapsthe writer would have been better to take this fight to theAAN since his argument is elitist by default.

The writer then states: “For example, in pain manage-ment it is important to master all the invasive proceduresand be competent in the medical and invasive aspects ofthis field so as to competently practice pain medicine with-out causing harm to patients.” In fact, no procedural train-ing is mandated. Neurologists, psychiatrists, and physiatristswho complete ACGME accredited pain medicine fellow-ships are not uniformly responsible for performing thoseprocedures. Extensive knowledge of their performance andutility is required. The expert therefore becomes a responsi-ble source of information for those patients with questionsabout procedures and alternatives to procedures.1 It mustalso be stated that privileges to perform procedures aregranted by hospitals not by the ABMS or other certifyingagencies.

The writer claims that we are no different from generalneurologists who must know the ways of headache medicineas they must know the ways of MS and movement disor-ders. The UCNS has approved other subspecialty areas towhich neurologists in training are exposed including be-havioral neurology and neuropsychiatry, clinical neuromus-cular pathology, neuroimaging, neurocritical care, neuro-oncology, and newly approved applications geriatric neurol-ogy and autonomic disorders. Both the multiple sclerosis andmovement disorders sections of the AAN of neurology haveexpressed interest in the UCNS process. The point is: inter-est groups initiated these applications. In all medicine thereis an inevitable extension of knowledge and with it the prac-tical and intellectual desire to use that knowledge to focuspractice and improve patient care.

In deference to individuals who gained expertise priorto accredited training programs, a practice track has alwaysbeen standard for all new certifications. Pain medicine closedthat track after an allotted time to allow many of us, myself

included, to sit for the examination. All historical special-ties went through this process. The readers must thereforebe aware that after the next 4 examinations, credentialingin headache medicine will be available only to those whocomplete an accredited fellowship.

Last of all, the writer cites abdominal pain and chestpain as examples where expertise requires additional pro-cedural training. On both counts he or she is wrong. Gas-troenterology has recognized a need for additional training,2 Pelvic pain has fellowships and a specialist in cardiovascu-lar diseases is not required to perform invasive proceduressuch as catheterizations.3 In point of fact there are 94 subspe-cialties recognized by the ABMS4 including 4 sleep medicineboards. The writer is correct in assuming that training breedsexpertise. The need for so many boards is a different topicof discussion, but a fact nonetheless.

Certification is not equal to competence. But certifi-cation does allow us to train others in programs arduouslydesigned and implemented according to the highest possi-ble standards established by society via organizations suchas the ACGME and UCNS. By offering a time limited prac-tice track, society recognizes those who have dedicated theirpractice to patients whose burden of disease requires knowl-edge not routinely gained in residency training. This addi-tional training eventually allows experts to reap greater re-wards for the additional time required when seeing thesesicker patients especially in areas where the lack of pro-cedures cap income. State boards recognize this, as dopayers.

Headache medicine in America is in its adolescence andefforts to improve reimbursement are underway. Certifica-tion allows this initiative to move forward. The writers fromEurope recognize the need to lift the burden, tolling a bellto bring us to attention. My colleague from neurology, andI presume from America, makes the unfortunate mistake offilling the air with errors of fact and clanging a false alarmto shift the focus away from the “big tent” which housesheadache medicine. I thank the Journal for giving me thisopportunity to respond to both.

Additional thanks to Benson Munger, PhD AssociateDirector, Arizona Emergency Medicine Research Center(AEMRC), University of Arizona School of Medicine andconsultant for subspecialty issues for the UCNS who re-viewed this letter for factual content.

Alan Finkel, MDNeurology,

University of North Carolina at Chapel Hill,Chapel Hill, NC

Headache 1227

REFERENCES

1. http://www.acgme.org/acWebsite/downloads/RRC progReq/181pr600.pdf. Accessed August 6, 2007.

2. Kirsch M. GI fellowship training – the missing piece. Am JGastroenterol. 2005;100:1912-1913.

3. http://www.acgme.org/adspublic/ Accessed August 6, 2007.4. http://www.abms.org/Publications˙and˙Resources/ Accessed

August 6, 2007.

Efficacy of Frovatriptan

We appreciate Dr. Tfelt-Hansen’s enquiry about theefficacy data from the comparative, double-blind, ran-domized clinical trial between frovatriptan and sumatrip-tan.1 In keeping with company policy to publish trialdata, the efficacy data from the trial comparing frova-triptan 2.5 mg and sumatriptan 100 mg have been ac-cepted for presentation at the European Federation ofNeurological Sciences meeting in Brussels, August 25–28,2007.

John Hutchison, PhD, FRCPDevelopment Director

Vernalis plc.

REFERENCE

1. Tfelt-Hansen P. Efficacy of frovatriptan. Headache. 2007;47:934-934.

Endothelial Nitric Oxide SynthasePolymorphisms as Risk Factorsfor Migraine

Borroni and colleagues investigated the relationship be-tween migraine and a single nucleotide polymorphism (SNP)in exon 7 of the endothelial nitric oxide synthase (eNOS)gene.1 However, there is no evidence for a functional sig-nificance for this SNP,2 and it is highly probable that theincreased risk attributed to this SNP is due to another asso-ciated SNP in the promoter region of eNOS, or to the com-bined effect of both.3,4 In fact, the analysis of haplotypesinvolving combinations of genetic markers usually leads tomore interesting conclusions regarding the possible involve-ment of a specific gene in a clinical condition, as it has beenrecently shown to be the case of hypertensive patients.5-7 Ofnote, eNOS haplotypes associated with hypertension did notdepend on race,5 which is a factor that significantly changes

the distribution of eNOS gene alleles.8 Borroni and col-leagues argue that their study is a pilot study.1 It would prob-ably be interesting to examine more definite genetic markers(haplotypes) in a further investigation.

William Fergusson, MDPrivate practice

Congressional Lane, 345Rockville, MD

REFERENCES

1. Borroni B, Rao R, Liberini P, et al. Endothelial nitric ox-ide synthase (Glu298Asp) polymorphism is an independentrisk factor for migraine with aura. Headache. 2006;46:1575-1579.

2. Metzger IF, Souza-Costa DC, Marroni AS, et al. Endothelialnitric oxide synthase gene haplotypes associated with circu-lating concentrations of nitric oxide products in healthy men.Pharmacogenet Genomics. 2005;15:565-570.

3. Tanus-Santos JE, Desai M, Deak LR, et al. Effects of endothe-lial nitric oxide synthase gene polymorphisms on plateletfunction, nitric oxide release, and interactions with estradiol.Pharmacogenetics. 2002;12:407-413.

4. Tanus-Santos JE, Desai M, Flockhart DA. Effects of eth-nicity on the distribution of clinically relevant endothe-lial nitric oxide variants. Pharmacogenetics. 2001;11:719-725.

5. Sandrim VC, Coelho EB, Nobre F, et al. Susceptible andprotective eNOS haplotypes in hypertensive black and whitesubjects. Atherosclerosis. 2006;186:428-432.

6. Sandrim VC, de Syllos RWC, Lisboa HRK, et al. Endothe-lial nitric oxide synthase haplotypes affect the susceptibil-ity to hypertension in patients with type 2 diabetes mellitus.Atherosclerosis. 2006;189:241-246.

7. Sandrim VC, Yugar-Toledo JC, Desta Z, et al. Endothelialnitric oxide synthase haplotypes are related to blood pres-sure elevation, but not to resistance to antihypertensive drugtherapy. J Hypertens. 2006;24:2393-2397.

8. Marroni AS, Metzger IF, Souza-Costa DC, et al. Consistentinterethnic differences in the distribution of clinically rele-vant endothelial nitric oxide synthase (eNOS) genetic poly-morphisms. Nitric Oxide. 2005;12:177-182.

Endothelial Nitric Oxide SynthasePolymorphisms as Risk Factorsfor Migraine: A Response

In our work, we chose the Asp298 common variant ofthe endothelial nitric oxide synthase (eNOS) gene because

1228 September 2007

several associations have been described between this poly-morphism and eNOS activity or endothelial function.1 Amechanism by which eNOS Glu298Asp might reduce nitricoxide (NO) bioavailability has also been reported.2,3 TheeNOS Asp298 protein has an enhanced susceptibility to in-tracellular proteolytic cleavage compared with the eNOSGlu298, which could lead to reduced vascular NO genera-tion, because the cleaved fragments would be expected tolack NO synthase activity.3-5 Accordingly, the Asp298 allelehas been associated with enhanced vascular responsivenessto phenylephrine,6 and with differences in endothelial re-sponses to smoking and ω-3 fatty acid levels.7

We do not exclude that other polymorphisms withineNOS gene might contribute to the observed effect. We com-pletely agree with the author’s point of view, and we thinkthat the studies of different haplotypes are warranted forfurther highlighting stronger associations and confirm theseresults.

Barbara Borroni, MDAlessandro Padovani, MD

Department of Medical SciencesNeurological Clinic

University of BresciaBrescia, Italy

REFERENCES

1. Borroni B, Rao R, Liberini P, et al. Endothelial nitric oxidesynthase (Glu298Asp) polymorphism is an independent riskfactor for migraine with aura. Headache. 2006;46:1575-1579.

2. Veldman BA, Spiering W, Doevendans PA, et al. TheGlu298Asp polymorphism of the NOS 3 gene as a determi-nant of the baseline production of nitric oxide. J Hypertens.2002;20:2023-2027.

3. Tesauro M, Thompson WC, Rogliani P, et al. Intracellularprocessing of endothelial nitric oxide synthase isoforms as-sociated with differences in severity of cardiopulmonary dis-eases: Cleavage of proteins with aspartate vs. glutamate atposition 298. Proc Natl Acad Sci USA. 2000;97:2832-2835.

4. Fairchild TA, Fulton D, Fontana JT, et al. Acidic hydrolysisas a mechanism for the cleavage of the Glu(298)–>Asp vari-ant of human endothelial nitric-oxide synthase. J Biol Chem.2001;276:26674-26679.

5. Wang XL, Mahaney MC, Sim AS, et al. Genetic contribu-tion of the endothelial constitutive nitric oxide synthase geneto plasma nitric oxide levels. Arterioscler Thromb Vasc Biol.1997;17:3147-3153.

6. Philip I, Plantefeve G, Vuillaumier-Barrot S, et al. G894Tpolymorphism in the endothelial nitric oxide synthase geneis associated with an enhanced vascular responsiveness tophenylephrine. Circulation. 1999;99:3096-3098.

7. Leeson CP, Hingorani AD, Mullen MJ, et al. Glu298Asp en-dothelial nitric oxide synthase gene polymorphism interactswith environmental and dietary factors to influence endothe-lial function. Circ Res. 2002;90:1153-1158.

A Clinical Study of Migraine Evolution

The interesting and unique paper by Pryse-Phillips et al1

underscores the need to take the natural history of acute mi-graine into consideration in the acute treatment plan of themigraineur. They described “the time to moderate/severepain” in 253 migraine patients to be 1 hour or less in 64.4%of migraineurs, more likely to be earlier in aura patients thannon-aura patients. I found that 48.1% of 647 migraineurs de-scribed the “time to peak” of their headache in 60 minutesor less,2 also with more aura patients experiencing faster on-set to the peak intensity of headache than patients withoutaura.

These 2 times are not the same. “Time to peak” ofheadache may be a more definable measurement than “timeto moderate/severe pain” but both need further study andshould be incorporated into studies of acute migraine treat-ment.

I found that headache woke patients from sleep orpatients awoke from sleep with migraine in 35.4% of pa-tients occasionally, 23.9% frequently, and in 11.7% very fre-quently.2 The general assumption is that patients waking orbeing woken from sleep have an attack that is more advancedat a time when she/he is able to treat it. Adding to these rapidonset migraine and sleep related migraine patients, are thosewith early nausea and vomiting interfering with oral ther-apy, further increasing the number of migraineurs requiringa modification of “standard” treatment in at least some oftheir headaches.

A caveat worth commenting on. While the data ofPryse-Phillips (questionnaire) and mine (direct questioningby headache clinician) were collected prospectively and arequite similar, both studies relied on the memory of the pa-tients. With widespread use of triptans prospective untreatedmigraine attack studies are difficult to achieve. However, thishas been achieved recently and Linde et al3 are to be com-mended for a truly prospective study (albeit with small num-bers) of the natural history of the evolution of the untreatedacute migraine attack.

Leslie Kelman, MDHeadache Center of Atlanta, 5671 Peachtree

Dunwoody Road, Suite 620, Atlanta, GA

Headache 1229

REFERENCES

1. Pryse-Phillips W, Aube M, Bailey P, et al. A clinical study ofmigraine evolution. Headache. 2006;46:1480-1486.

2. Kelman L. Pain characteristics of the acute migraine attack.Headache. 2006;46:942-953.

3. Linde M, Mellberg A, Dahlof C. The natural course of mi-graine attacks. A prospective analysis of untreated attackscompared with attacks treated with a triptan. Cephalalgia.2006;26:712-721.

A Clinical Study of Migraine Evolution

“We appreciate Dr. Kelman’s interest in, and valu-able comments upon, our paper. While “Time to peak” ofheadache might possibly be a more definable end-point than“time to moderate/severe pain,” even that measure has onemajor disadvantage; in order to define it, the patient has toexperience noticeable relief and then to think back to de-termine when the pain was actually at its peak. It is thus aretrospective assessment made under stress. We chose ourmeasure because it follows standard clinical guidelines andis in general use.

“The figures from Dr. Kelman’s study and from oursshow fair correlation, especially since they were derived fromdifferent populations, and encourage us to believe that ourconclusions were appropriate.”

William Pryse-Phillips, MDNeurology, Memorial University

7 Monkstown RoadSt. Johns’s, Newfoundland, A1C-3T1

Canada

“The Mystery of Figure 2”—A Casefor Ovulatory Migraine?

I read with great interest the important article by Dr. Su-lak et al on the impact of eliminating the placebo week in oralcontraceptives.1 Having treated hundreds of women withmenstrual related migraine with this approach (and otherhormonal strategies), I found 2 items of particular interest.

First, I was surprised that the authors reported adifference in placebo-week headaches in users of 19-nortestosterone (19-NorT) oral contraceptives when com-pared to those on pills containing drospirenone (DRSP).Keeping in mind that this was an open-label trial, the firstassumption must be that difference could be attributed to

subjects’ expectation of improvement on an investigationalregimen, particularly in the absence of investigator blinding.With blinding and placebo control, fair comparisons couldbe made, but in their absence, this conclusion is not war-ranted. Furthermore, the ethinyl estradiol (EE) content(s)of the assorted 19-NorT therapies was not characterized.The active treatment is a proprietary formulation contain-ing 30 mcg EE; it is certainly plausible that the differencesin estrogen-withdrawal migraines might be attributable torelatively higher or lower estrogen formulations and not tothe “unique progestin.”

More importantly, I would like to draw attention to themystery in Figure 2—which presents mean daily headachescores for 102 women, comparing “the 28 days of the last 21/7cycle of DRSP/EE, which included a 7-day placebo intervaland the first 28 days of the extended regimen of DRSP/EEwithout a 7-day placebo interval.” The authors report thatheadache scores on the first 24 days of the cycles do notdiffer, but scores on days 25 through 28 differ significantly.

Keep in mind that Figure 2 portrays eight consecu-tive weeks of treatment that differ only in the last 7 days—

days 22 though 28 of the second cycle. A quick glance atthe figure shows a corresponding separation in headachescores almost immediately (from days 23 through 28). How-ever, there is also distinct separation earlier in the cycle—from days 13 through 17—before there has been any dif-

ference in the treatment regimen. Am I correct in surmisingthat the reason comparison was limited to days 25 through28—rather than the full 7 days—was that the mysteriousmid-cycle separation rendered the more logical comparisoninsignificant?

How do the authors explain the separation on days 13through 17? These are mean scores from a relatively largepopulation. Days 4 through 12 are absolutely identical, yetdays 13 through 17 show significant separation before anychange in treatment.

Ordinarily, when I see this predictable mid-cycleheadache pattern in my patients on oral contraceptives, Isuspect the patient is ovulating. Dr. Birtch recently reportedin Contraception that break-through ovulation is not un-common on low-dose pills, and is seen more often withconventionally administered oral contraceptives than withextended dosing regimens. The placebo week allows forresidual ovarian activity with follicle development—and oc-casionally, ovulation. As we know, contraceptive efficacy isnot compromised, due to progestin’s multiple mechanisms.Did the extended-regimen pills come from commerciallyavailable 21/7 packages or were they supplied separately?Is a post-hoc analysis of those pills planned?

1230 September 2007

Finally, I would like to offer an alternative interpre-tation to one of the study’s findings. The authors expresssurprise that extended therapy with DRSP/EE benefitednot only estrogen-withdrawal headaches, but headachesthroughout the treatment period. It may be that the realimportance of Figure 2 is that it makes a clear case for the ex-istence of another estrogen-withdrawal headache—the post-ovulatory migraine—an entity many of our patients clinicallyendorse, but one that has remained elusive in previous at-tempts to identify and characterize.

Anne H. Calhoun, MDDepartment of Neurology

University of North CarolinaChapel Hill, NC

REFERENCE

1. Sulak P, Willis S, Kuehl T, Coffee A, Clark J. Headaches andoral contraceptives: Impact of eliminating the standard 7-dayplacebo interval. Headache. 2007;47:27-37.

The Mystery of Figure 2—A Case forOvulatory Migraine? A Response

We appreciate the comments by Dr. Calhoun and an op-portunity to provide our understanding of the 2 issues raised.In regard to the comparison of 19-nortestosterone oral con-traceptive pills in 54 patients switching to the study medica-tion, an oral contraceptive pill with drospirenone, this obser-vation was provided knowing the limitations mentioned byDr. Calhoun. However, as mentioned in the discussion sec-tion of our manuscript, although the current study was nota randomized or blinded trial, the findings of improvementdeserve to be confirmed in a study of appropriate designand powered to detect the effects noted. While subjects useda variety of 19-nortestosterone containing pills, the ethinylestradiol doses were between 30 and 35 mcg and thereforesimilar to the 30 mcg content of the study pill.

In regard to Figure 2, as Dr. Calhoun suggests, the in-significant deviation of headache scores for the 2 groups ofobservations between days 13 and 17 hints at more than apotential random variation. The statistical method utilizedto compare these daily observations within subjects involvedanalysis of variance with Duncan’s post-hoc testing and onlydemonstrated significant (P < .05) differences between the 2sets of observations for days 25 through 28. However, as sug-gested by Sullivan et al1 and us previously,2 hormone with-

drawal symptoms, including headaches, in subjects using oralcontraceptive pills in the 21/7 format begin to increase beforethe onset of the 7-day pill-free interval and are related to thedemise of follicle recruitment initiated during the previouspill-free interval. While some follicles stimulated during thisrecruitment may ovulate, Sullivan’s observations supportsthe concept that these follicles lose pituitary support andundergo atresia, thereby withdrawing their contribution ofestradiol in the interval of the third week of active pills (days14–21). This timing coincides with the “bumps” seen in bothintervals of data, beginning at day 13 in the 21/7 cycle andday 18 of the extended cycle. Because the 102 patients fol-lowed in the current study included many without headacheas one of their hormone-withdrawal symptoms, the poten-tial to detect significant differences in timing of such pointsfrom cycle to cycle is reduced. Finally, the pills used for theextended regimen were derived from the same commerciallyavailable 21/7 packages as those used for the 21/7 portion ofthe study.

We hope that these additions shed more light on theissues presented by Dr. Calhoun. As we would all agree, al-tering patterns of administration of a commonly used medi-cation by women has the potential to improve their qualityof life. At the very least, this should stimulate additionalresearch.

Patricia Sulak, MDSherilyn Willis, MD

Thomas Kuehl, PhDAndrea Coffee, MD

Jeffrey Clark, DOScott and White Memorial

Hospital—Obstetrics and GynecologyTemple, TX

REFERENCES

1. Sullivan H, Furniss H, Spona J, Elstein M. Effect of 21-day and24-day oral ontraceptives decreases follicular development.Fertil Steril. 1999;72:115-20.

2. Sulak PJ, Scow RD, Preece C, Riggs MW, Kuehl TJ. Hormonewithdrawal symptoms in oral contraceptive users. Obstet Gy-necol. 2000;95:261-6.

Harry Potter Writes

First of all, please can I offer my thanks to ProfessorSheftell, Dr. Steiner, and Ms. Thomas for their interest inand analysis of my headaches.1

Headache 1231

But with all due respect, they did not address an im-portant question. It is all very well to give my headaches aMuggle International Headache Society (MIHS) classifica-tion, but what then should be the best treatment?

To me, it seems impossible that the weak magic of fre-quentist statistics, so highly valued by the members of theMIHS, could help tailor the right potion for my headaches.But perhaps this weak magic is at least better than non-magical meta-analyses.

Furthermore, if frequentist statistics are the gold stan-dard, then there is automatically another question: Shouldherbal-based remedies be scrutinized in the same way asthe potions of Muggle pharmaceutical companies by Mug-gle regulatory authorities? Although both teach the use ofpotions, Professor Slughorn can be trusted, while ProfessorSnape is quite another matter. And, as we all know only be-cause we have studied it, you can’t take chances with man-drake (Mandragora officinarum).

Harry PotterGryffindor HouseHogwart’s SchoolUnited Kingdom

(Recommend AIR MAIL, ie, by owl)

With thanks to

Anthony FoxEBD Group-Research2032 Cortedel Nogal, CarlsbadCalifornia 92011T: (760) 930-0500 F: (760) 930-0520Email: cranham@aol.com

REFERENCE

1. Sheftell F, Steiner TJ, Thomas H. Harry Potter and the curseof headache. Headache. 2007;47:911-916.