Acta Neurol Scand 2005: 112: 259–264 DOI: 10.1111/j.1600-0404.2005.00476.x
`
`Copyright Ó Blackwell Munksgaard 2005
`ACTA NEUROLOGICA
`SCANDINAVICA
`
`Hypertension in headache patients? A
`clinical study
`
`Pietrini U, De Luca M, De Santis G. Hypertension in headache patients?
`A clinical study.
`Acta Neurol Scand 2005: 112: 259–264. Ó Blackwell Munksgaard 2005.
`
`Objectives – The aim of the present study was to assess the prevalence
`of hypertension in patients with headache, coming to the observation
`of an Headache Center. Materials and methods – A total of 1486
`consecutive outpatients were examined, and blood pressure was
`determined in all patients. Results – Migraine without aura (MO) was
`the most common diagnosis, followed by migraine associated with
`tension-type headache, migraine with aura (MA), episodic tension-type
`headache (ETTH), chronic tension-type headache (CTTH), cluster
`headache (CH), and medication-overuse headache (MOH).
`Hypertension was present in 28% of the patients, and it was
`particularly common in MOH (60.6%), CTTH (55.3%), CH (35%),
`ETTH (31.4%), less common in MO (23%) and MA (16.9%). In all
`headache groups, the prevalence of hypertension was higher than in the
`general population, within all age groups. After adjustment for age and
`gender, hypertension was found to be more common in tension-type,
`and especially in CTTH, than in migraine. These findings could be
`affected by ÔBerkson’s biasÕ: and should not be extrapolated to the
`general population, but apply only to the subpopulation of patients
`who come to the observation of an Headache Center, and who may
`have more disabling symptoms. Conclusion – Hypertension could be
`one of the factors leading to exacerbation of the frequency and severity
`of attacks, both in migraine and tension-type headache. Hypertension
`has important therapeutic implications and should be actively sought
`in headache patients, and more thoroughly investigated, with ad-hoc
`surveys in the general population.
`
`U. Pietrini1, M. De Luca1,
`G. De Santis2
`1Headache Center, Department of Internal Medicine,
`University of Florence, Florence, Italy; 2Department of
`Economics and Statistics, University of Messina,
`Messina, Italy
`
`Key words: headache; migraine; tension-type
`headache; cluster headache; medication-overuse
`headache; comorbidity; hypertension; Berkson's bias
`
`Dr Umberto Pietrini, Centro Cefalee, Dipartimento di
`medicina Interna, Villa Monna Tessa – V.le Pieraccini,
`18 – 50139 Firenze, Italy
`e-mail: u.pietrini@libero.it
`
`Accepted for publication May 20, 2005
`
`Considerable controversy surrounds the associ-
`ation of headache with hypertension, as some
`studies suggest a link with migraine and tension-
`type headache (1–3), possibly limited to high
`diastolic blood pressure and migraine in women
`(4), while other studies deny such an association
`(5–7) or, on the contrary, suggest a link between
`headache and lower values of blood pressure (8). In
`a large series of patients, however, headache was
`found to be very common in hypertensive patients,
`and to ameliorate after antihypertensive treatment
`(9). This finding has been confirmed in more recent
`
`Abbreviations: CH, cluster headache; CTTH, chronic tension-type headache; ETTH,
`episodic tension-type headache; MA, migraine with aura; MO, migraine without
`aura; MOH, medication-overuse headache.
`
`studies (10, 11). Moreover, a number of studies
`have shown an association between chronic daily
`headache and hypertension (12–16). The aim of the
`present study was to assess the prevalence of
`hypertension in outpatients with migraine, tension-
`type headache, and other forms of primary head-
`aches, or medication-overuse headache (MOH),
`coming to the observation of an Headache Center.
`
`Materials and methods
`
`Consecutive outpatients coming for their first visit
`to the ambulatory of
`the Headache Center,
`Department of Internal Medicine, University of
`Florence, from January 2000 to December 2001
`were considered for this study. At their initial visit
`all patients underwent a thorough medical visit
`
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`IPR2018-01427
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`Pietrini et al.
`
`including their medical and headache history,
`general
`and
`neurological
`examination,
`and
`determination of blood pressure. In patients show-
`ing a systolic arterial blood pressure ‡140 mmHg
`or a diastolic blood pressure ‡90 mmHg two other
`blood pressure determinations in a month were
`taken for diagnosis, according to the methods
`exposed in the ÔSixth Report of the Joint National
`Committee on Prevention, Detection, Evaluation
`and Treatment of High Blood PressureÕ (17), and
`the average of the three determinations was used
`for statistical analysis.
`Patients were seated in a chair with their backs
`supported and their arms bared and supported at
`heart level. Measurements were taken after 5 min
`of rest with a mercury sphygmomanometer, and
`two readings separated by 2 min were averaged.
`The diagnosis of headache was made according to
`the IHS 1988 criteria (18), through a questionnaire
`followed by a structured interview. Eight sub-
`groups were used for the analysis: migraine with
`aura (MA), migraine without aura (MO), episodic
`tension-type headache (ETTH), chronic tension-
`Ômixed headacheÕ,
`type headache (CTTH),
`i.e.
`association of migraine with tension-type headache
`(mixed), cluster headache (CH), other forms of
`primary headaches,
`including all other
`forms
`(other), and medication-overuse headache (MOH).
`The two diagnostic classes of
`the 1988 IHS
`classification Ôergotamine-induced headacheÕ and
`Ôheadache induced by abuse of analgesicsÕ were
`merged together, and subsequently reclassified as
`MOH, according to the latest IHS classification
`(19). When more than one symptomatic drug was
`overused, the patient was classified according to
`the most frequently used drug in the last 3 months,
`based on self-reporting by patients.
`Patients with secondary headaches other than
`due to substance abuse were excluded from the
`study. Hypertension was defined as systolic blood
`pressure of 140 mmHg or higher, or diastolic
`blood pressure of 90 mmHg or higher, or current
`treatment with antihypertensive drugs. In order to
`test for the excessive prevalence of hypertension in
`(some of) the eight subgroups, we compared the
`actual to the theoretical frequencies of hypertensive
`patients in each of them. Theoretical frequencies
`were obtained with an indirect standardization, so
`as to keep into account the peculiar age and gender
`composition of each subgroup, and under the
`so-called ÔnullÕ hypothesis, i.e. assuming absence of
`influence of each diagnosis on the chances of being
`hypertensive (see the Appendix for the details). The
`significancy of the differences (actual vs theoret-
`ical) was determined using a chi-square test. As this
`proved significant (see below) for the eight-column
`
`260
`
`table, we further investigated specifically whether
`the association with hypertension differed between
`migraine (MA + MO) and tension-type headache
`(ETTH + CTTH), and as the answer was positive,
`we also compared MA to MO, and, separately,
`ETTH to CTTH, in all cases standardizing by age
`and gender, in order to obtain unbiased theoretical
`frequencies. The other headache subgroups were
`not considered in this restricted analysis, as in the
`mixed headache group migraine and tension-type
`headache coexisted, while the other groups inclu-
`ded too few patients.
`
`Results
`
`During the study period, 1486 patients (1008
`females and 478 males) were diagnosed with pri-
`mary headaches or MOH: MO was by far the most
`common diagnosis (718 patients),
`followed by
`Ômixed headacheÕ (342 patients), MA (124 patients),
`ETTH (105 patients), CTTH (94 patients), CH (60
`patients), and MOH (33 patients), while 10 patients
`presented rare forms of primary headaches. In all
`headache subgroups, women were more represented
`than men, with the exception of CH (m/f ratio ¼
`3.62) and ETTH (m/f ratio ¼ 1.1). In the MOH
`group, 28 of 33 patients overused non-steroidal anti-
`inflammatory agents (NSAIDs),
`three patients
`paracetamol, and two patients ergotamine (data
`not shown). Table 1 shows the frequency of the
`different headache subtypes in men and women.
`Hypertension was a common finding, as it was
`present in 28% of the patients, and it was partic-
`ularly common in MOH (60.6%),
`in CTTH
`(55.3%), CH (35%) and ETTH (31.4%), and less
`common in MO (22.9%) and in MA (16.9%). As
`could be expected, patients with Ômixed headacheÕ
`showed a frequency of hypertension intermediate
`between tension-type headache patients
`and
`migraine patients (Table 2).
`After adjustment for gender and age, the differ-
`ence in the prevalence of hypertension between the
`eight subgroups was less striking (Table 2, theor-
`etical prevalence), mainly because patients in the
`MOH and CTTH were older, and the prevalence of
`hypertension is known to increase with age. In the
`statistical analysis however the difference in the
`prevalence of hypertension proved highly signifi-
`cant, both considering all the eight subgroups
`(P < 0.001) or only the four main subgroups
`(P < 0.001).
`(MA, MO, ETTH and CTTH)
`Merging MA with MO and ETTH with CTTH, to
`obtain a Ômigraine groupÕ and a Ôtension-type
`headache groupÕ, the difference in the prevalence
`of hypertension was again significant (P < 0.001)
`with hypertension being more frequent in tension-
`
`2
`
`2
`
`

`

`Hypertension in headache patients
`
`Table 1 Demographic characteristics of the different headache subtypes in the patient sample
`
`MOH (n ¼ 33) CH (n ¼ 60) CTTH (n ¼ 94)
`
`ETTH (n ¼ 105) MA (n ¼ 124) MO (n ¼ 718) Mixed (n ¼ 342) Other (n ¼ 10)
`
`Total (n ¼ 1486)
`
`Females
`Males
`Mean age (SD)
`
`30
`3
`47.9 (14.5)
`
`13
`47
`40.1 (11.8)
`
`64
`30
`40.8 (18.1)
`
`50
`55
`36.2 (18.7)
`
`90
`34
`32.5 (14.2)
`
`493
`225
`35.1 (14.1)
`
`263
`79
`36 (14.4)
`
`5
`5
`43.6 (15.7)
`
`1008
`478
`36.1 (14.9)
`
`MOH, medication-overuse headache; CH, cluster headache; CTTH, chronic tension-type headache; ETTH, episodic tension-type headache; MA, migraine with aura; MO,
`migraine without aura; Mixed, mixed headache (see text); Other, all other forms.
`
`Table 2 Actual and theoretical* prevalence of hypertension in patients with different headache subtypes
`
`MOH (n ¼ 33)
`
`CH (n ¼ 60)
`
`CTTH (n ¼ 94)
`
`ETTH (n ¼ 105) MA (n ¼ 124) MO (n ¼ 718) Mixed (n ¼ 342) Other (n ¼ 10)
`
`Total (n ¼ 1486)
`
`Actual
`Theoretical*
`
`20 (60.6)
`14 (42.4)
`
`21 (35)
`23 (38.3)
`
`52 (55.3)
`33 (35.1)
`
`33 (31.4)
`33 (31.4)
`
`21 (16.9)
`29 (23.4)
`
`165 (23)
`190 (26.5)
`
`97 (28.4)
`90 (26.3)
`
`7 (70.0)
`4 (40.0)
`
`416 (28)
`416 (28)
`
`Values in parentheses are in percentage. MOH, medication-overuse headache; CH, cluster headache; CTTH, chronic tension-type headache; ETTH, episodic tension-type
`headache; MA, migraine with aura; MO, migraine without aura; Mixed, mixed headache (see text); Other, all other forms.
`*Assuming absence of influence of headache subtype on hypertension, and after adjustment for age and gender.
`
`type headache than in migraine. Conversely, the
`differences within subtypes, i.e. between MA and
`MO on the one hand, and between ETTH and
`CTTH on the other, did not pass the significant test,
`although in the latter case the difference was greater.
`
`Discussion
`
`Although tension-type headache is more prevalent
`than migraine in the general population (20), MO
`was the more common diagnosis in our patients, in
`line with a similar study conducted in an other
`Headache Center (2). This may be due to the fact
`that only patients suffering from severe tension-
`type headache seek medical advise in specialized
`clinics. The number of patients with MOH (33 of
`1486 patients) was very low, compared to what is
`reported in the literature (20, 21), as many patients
`with MOH were hospitalized at our clinic, and
`their clinical recordings were not included in this
`study, that was conducted in an outpatient setting.
`The link between headache and hypertension has
`been addressed in relatively few studies, and is a
`highly controversial subject. Both conditions are
`extremely common in the general population, and
`their coexistence in an individual patient could
`therefore be merely coincidental.
`Comorbidity, e.g. between hypertension and
`migraine, or hypertension and tension-type head-
`ache, could be postulated only if the association
`between hypertension and some form of primary
`headache was observed systematically in the general
`population. Comorbidity, if present, could be due
`to different factors, e.g. a common physiopatho-
`logy, or the association with a particular genotype,
`although a preliminary study on genotyping for the
`
`complement C3F has apparently ruled out an
`association between migraine and hypertension
`ÔheadacheÕ
`(22). To further confound matters,
`could simply be a generic symptom of hypertension
`(and therefore a secondary headache), and in fact as
`early as in 1913 headache was indicated as the most
`common complaint in hypertensive patients (23),
`and recently an association between hypertension
`and morning headaches was evidenced (24), but in
`neither of these two studies it was possible to
`distinguish true migraine, or true tension-type
`headache, or a secondary headache due to hyper-
`tension, from a generic complaint of ÔheadacheÕ.
`Other studies did not show a positive association
`between headache and hypertension (25, 26) or
`suggested that headache could be a side effect of
`antihypertensive
`treatment
`(27–29). Probably
`reflecting uncertainty about this matter,
`in the
`latest classification of headache disorders (19),
`under the heading Ôsecondary headachesÕ,
`it is
`stated that Ômild or moderate hypertension does
`not appear to cause headache, and whether mod-
`erate hypertension predisposes to headache remains
`controversialÕ. We found a high prevalence of
`hypertension in patients with primary headaches,
`particularly in CTTH, CH and ETTH, and even
`higher in patients wit MOH. The prevalence of
`hypertension in our study, for all headache and age
`subgroups (data not shown), was higher than that
`observed in the general population (30). After age-
`and gender-adjustment, hypertension was found to
`be more common in tension-type headache than in
`migraine,
`suggesting
`a possible
`comorbidity
`between tension-type headache and hypertension.
`To our knowledge, this is the first report of such
`a finding. In another study on a sample of patients
`
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`
`3
`
`3
`
`

`

`Pietrini et al.
`
`observed at an Headache Center, Cirillo et al. (2)
`found a prevalence of hypertension comparable to
`our results for MO and MA, but not for tension-
`type headache, where a lower prevalence of
`hypertension was found. Another study still, once
`again at an Headache Center but on a small sample
`of patients, gave results in line with our findings for
`the prevalence of hypertension both in migraine
`and tension-type headache (3).
`Other studies have questioned the association
`between headache and hypertension (5–7), or have
`shown a higher prevalence of headache in subjects
`with lower blood pressure values (8). Interestingly,
`however, in one of these negative studies (8), a link
`between high diastolic blood pressure values and
`headache in men and migraine in women was
`found in one of the analyses, rendering the results
`of the study less clear-cut. Moreover, one study
`giving negative results (5) was based on the
`behaviour of ambulatory blood pressure deter-
`minations surrounding episodes of headache in
`hypertensive patients, and addressed therefore a
`somehow different problem. We suspect that the
`discrepancies in the results of these studies could be
`due to the substantial difference in the observed
`populations: two of the remaining three studies
`showing negative results were conducted in the
`general population (6, 8), and headache character-
`istics is subjects sampled from the general popula-
`tion could be different from those of patients
`coming to the observation of Headache Centers,
`who normally have more disabling symptoms. In
`short, the results of our study could be limited to
`patients with more severe forms of headache, in
`whom hypertension could cause a higher frequency
`and a greater severity of attacks. The association
`between chronic daily headache and hypertension
`has already been reported (12–16). Only large and
`accurately planned studies conducted in the general
`population could help to assess the possible exist-
`ence of comorbidity between hypertension and
`some forms of primary headache, and the preval-
`ence of secondary headache, due to hypertension.
`Patients enrolled in clinic-based study form a
`sample subject to the so-called Berkson’s bias (31),
`as patients with both hypertension and headache
`are more likely to come to the observation of
`Headache Centers (or other hospital-based clinics)
`than patients with headache only, or hypertension
`only, giving rise to a spurious association. Indeed,
`we tend to think that this is in fact the point, and
`that hypertension causes an exacerbation in the
`frequency and severity of attacks, probably in
`tension-type headache more than in migraine,
`urging patients to seek medical help in Headache
`Centers.
`Interestingly, we found a very high
`
`262
`
`prevalence of hypertension in patients with abuse
`of analgesics, and this seems to be only partially due
`to the demographic characteristics of this subgroup
`(Tables 1 and 2) so that the pharmacological effects
`of NSAIDs could be involved for patients taking
`these drugs, as the administration of some NSAIDs
`has been associated with an increase in blood
`pressure values (32, 33). An alternative explanation
`could again invoke hypertension causing an
`increase in the frequency and intensity of attacks,
`leading to overuse of analgesics.
`In conclusion, we found a high prevalence of
`hypertension in MOH and in different forms of
`primary headaches, and in patients with tension-
`type headache more than in patients with migraine,
`although these findings could be limited to patients
`coming to the observation of Headache Centers.
`This is not without therapeutic implications: in our
`experience, a good control of hypertension (and
`particularly of diastolic blood pressure values) is
`essential in order to alleviate or resolve headache
`symptoms both in migraine and tension-type
`headache. Well designed population-based studies
`would be needed to estimate the true prevalence of
`hypertension in primary headaches
`such as
`migraine,
`tension-type headache and CH, and
`also the prevalence of secondary headache, due to
`hypertension.
`
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`
`Appendix
`
`The indirect standardization procedure with which we deter-
`mined the theoretical number of hypertensive patients by
`headache subtype is as follows. Table A1 gives the distribution
`by sex and age class of our patients in general and of those with
`hypertension. We can therefore calculate the proportions with
`hypertension in each cell.
`We now observe the sex and age distribution of patients
`with the various headache subtypes, and apply the proportions
`with hypertension obtained (column c in Table A1) to estimate
`the theoretical frequencies,
`i.e. the number of hypertensive
`patients we should expect in each case if age and sex had an
`
`Table A1 Demographic characteristics of the different headache subtypes in the
`patient sample
`
`(a) All patients
`
`(b) Hypertensive
`patients
`
`(c) % with
`hypertension
`
`Age class
`
`Females Males All
`
`Females Males All
`
`Females Males All
`
`0–17
`18–29
`30–39
`40–49
`50–59
`60–69
`70+
`All
`
`95
`256
`256
`187
`133
`63
`18
`1008
`
`80
`104
`133
`92
`38
`20
`11
`478
`
`175
`360
`389
`279
`171
`83
`29
`1486
`
`0
`27
`52
`53
`69
`45
`15
`261
`
`0
`24
`49
`37
`25
`10
`10
`155
`
`0
`51
`101
`90
`94
`55
`25
`416
`
`0.0
`10.5
`20.3
`28.3
`51.9
`71.4
`83.3
`25.9
`
`0.0
`23.1
`36.8
`40.2
`65.8
`50.0
`90.9
`32.4
`
`0.0
`14.2
`26.0
`32.3
`55.0
`66.3
`86.2
`28.0
`
`Table A2 Demographic characteristics of the different headache subtypes in the
`patient sample
`
`(a) Headache subtype: CTTH
`
`(b) Theoretical hypertensive
`
`Age class
`
`Females
`
`Males
`
`0–17
`18–29
`30–39
`40–49
`50–59
`60–69
`70+
`All
`
`5
`17
`9
`8
`10
`12
`3
`64
`
`4
`7
`6
`7
`2
`1
`3
`30
`
`All
`
`9
`24
`15
`15
`12
`13
`6
`94
`
`Females
`
`Males
`
`0
`1.8
`1.8
`2.3
`5.2
`8.6
`2.5
`22.1
`
`0
`1.6
`2.2
`2.8
`1.3
`0.5
`2.7
`11.2
`
`All
`
`0
`3.4
`4.0
`5.1
`6.5
`9.1
`5.2
`33.3
`
`263
`
`5
`
`5
`
`

`

`Pietrini et al.
`
`impact on hypertension, but the headache subtype under
`scrutiny had not. For instance, for the 94 patients with CTTH
`we find the data of Table A2, where the theoretical number of
`hypertensive patients of column (b) is obtained by multiplying
`the empirical frequencies of column (a) by the proportions of
`
`column (c) of Table A1. This gives about 33 expected
`hypertensive patients with CTTH and therefore about
`(94 ) 33¼) 61 non-hypertensive patients with CTTH. Repeat-
`ing the procedure by all headache subtypes gives the expected
`figures of Table 2 in the text.
`
`264
`
`6
`
`6
`
`

`

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