Headache

2010 the Authors

Journal compilation 2010 American Headache Society

ISSN 0017-8748
doi: 10.1111/j.1526-4610.2010.01657.x
Published by Wiley Periodicals, Inc.

Brief Communications
Changes in Salivary Prostaglandin Levels During Menstrual
Migraine With Associated Dysmenorrhea
head_1657

844..851

Paul L. Durham, PhD; Carrie V. Vause, MS; Frederick Derosier, DO; Susan McDonald, MA;
Roger Cady, MD; Vincent Martin, MD

Objective.To measure prostaglandin levels in the saliva of individuals during menstrual migraine associated with
dysmenorrhea (MMaD) and in response to treatment with a single tablet combination of sumatriptan succinate and naproxen
sodium.
Background.Prostaglandins are thought to play a role in MMaD as elevated serum prostaglandin levels have been
reported during attacks of menstrual migraine and are increased in the menstrual fluid of women with dysmenorrhea. While
triptans are the primary line of migraine treatment, nonsteriodal anti-inflammatory drugs are the most commonly prescribed
therapy for dysmenorrhea symptoms. Data from recent clinical studies have provided evidence that treatment with a single
tablet combination of sumatriptan and naproxen sodium is an effective abortive therapy for attacks of MMaD.
Methods.Women diagnosed with MMaD were treated with a sumatriptan succinate and naproxen sodium single tablet
combination or placebo at time of migraine attack. Saliva samples were collected at time of attack as well as 2 and 4 hours after
treatment. PGD2, PGE2, PGF2, PGI2, and TXA2 levels were determined by enzyme-linked immunosorbent assay.
Results.Elevated levels of PGD2, PGF2, and TXA2 at 2 and 4 hours and PGE2 at 4 hours were found in saliva obtained
from placebo subjects when compared with onset of attack levels. However, in subjects treated with a single tablet combination
of sumatriptan and naproxen sodium, the levels of PGD2, PGF2, and PGE2 were not elevated at either time point while TXA2
levels were still elevated at 4 hours.
Conclusions.Data from this pilot study provide evidence that saliva levels of several prostaglandins increase during
attacks of MMaD and that treatment with a single tablet combination of sumatriptan and naproxen sodium prevents elevation
of prostaglandin levels.
Key words: dysmenorrhea, migraine, prostaglandins, saliva
Abbreviations: MMaD menstrual migraine associated with dysmenorrhea, NSAIDs nonsteroidal anti-inflammatory drugs,
PGs prostaglandins, SumaRT/Nap sumatriptan succinate and naproxen sodium single tablet combination
(Headache 2010;50:844-851)

From the Center for Biomedical & Life Sciences, Missouri State University, Springfield, MO, USA (P.L. Durham and C.V. Vause);
GlaxoSmithKline, RTP, NC, USA (F. Derosier and S. McDonald); Banyan Group, Inc., Springfield, MO, USA (R. Cady); Department of Internal Medicine, University of Cincinnati, Cincinnati, OH, USA (V. Martin).
NIH Registration Numbers: NCT00329459 and NCT00329355, ClinicalTrials.gov
Financial support: Supported by GlaxoSmithKline, Inc. (Substudies TRX105850/TRX105852) and sponsored by POZEN, Inc.
Address all correspondence to P.L. Durham, Center for Biomedical & Life Sciences, Missouri State University, Springfield, MO
65806, USA.
Accepted for publication January 24, 2010.
Conflict of Interest: Frederick Derosier, DO, and Susan McDonald, MA, are employed by GlaxoSmithKline. Paul Durham, PhD,
Roger Cady, MD, and Vince Martin, MD, receive support from GlaxoSmithKline. Carrie Vause, MS, has no conflict of interest.

844

Headache
Menstrual migraine has been defined by the
International Headache Society (IHS) as a predictable migraine attack during perimenstrual time
periods, confirmed in 2 out of 3 menstrual cycles.1
Menstrual migraine has a prevalence of 3% in the
general female population but can occur in 42-61% of
female migraineurs.2,3 Dysmenorrhea may be encountered by 40-50% of all women4 and is characterized
by intense pain and uterine cramps during menstruation.5 Furthermore, it has recently been suggested
that menstrual migraine and dysmenorrhea may
share a common pathogenesis.6
Prostaglandins (PGs) may provide the link to
explain the possible shared pathogenesis between
these 2 menstrually related disorders. Elevated serum
PG levels are found during attacks of menstrual
migraine,7 and PG inhibitors abort and prevent menstrual migraine.8 Serum and salivary PG levels are
also increased during headache-free time periods
within migraineurs.9 Likewise, levels of PGs are
increased in the menstrual fluid of those with dysmenorrhea and PG inhibitors are effective abortive therapies for dysmenorrhea.10 Therefore, PGs may play an
important role in the pathogeneses of menstrual
migraine and dysmenorrhea.
While triptans are the primary line of migraine
treatment for most physicians, nonsteroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed therapy for dysmenorrhea
symptoms. It was hypothesized that attacks of menstrual migraine associated with dysmenorrhea
(MMaD) might represent a subgroup of attacks that
were prostaglandin-mediated and thus more
responsive to a triptan/NSAID combination therapy.
Toward this end, 2 replicate studies were conducted
to determine if a sumatriptan succinate and naproxen
sodium single tablet combination (SumaRT/Nap) was
an effective abortive therapy for attacks of
MMaD.11,12 These studies demonstrated significantly
higher 2-hour pain-free rates in patients receiving the
SumaRT/Nap therapy than in those receiving
placebo. There was also a reduction in dysmenorrhea
symptoms in the SumaRT/Nap group when data were
pooled from both studies.11
Although previous studies have shown that
PGE2, PGI2, and TXA2 were present in human saliva

845
during migraine,13,14 the levels of these and other PGs
during the attack phase and in response to treatment
of MMaD have not been investigated. Previous
studies involving analysis of human saliva proteins
and other molecules has provided evidence that
levels of certain salivary molecules correlated with
pathological condition and therapeutic response.15-17
The goal of this substudy was to evaluate PG levels in
saliva obtained from individuals during MMaD as
well as determine the effects of SumaRT/Nap treatment on salivary PG levels.

METHODS
Patients and Treatment.The subjects for this
substudy were selected from 2 large clinical trials
(NCT00329459 and NCT00329355) involving randomized, multicenter, double-blind, parallel group,
replicate studies to investigate the efficacy of
SumaRT/Nap for the treatment of menstrual
migraine. Subjects were female migraneurs meeting
IHS criteria for migraine 1.1 or 1.2 who typically
experience symptoms of primary dysmenorrhea at
the onset of MMaD. Subjects could not be pregnant
and had to agree to practice approved methods of
contraception during the study or otherwise be physiologically incapable of becoming pregnant. Exclusion
criteria included a history of inflammatory bowel
disease or other conditions that required daily
NSAID medications. Protocols for this study were
approved and conducted in accordance with ethical
standards of Human Subjects Institutional Review
Boards at all study sites.
Women with MMaD were randomly assigned 1:1
to receive a single tablet of sumatriptan succinate,
85 mg, and naproxen sodium, 500 mg (SumaRT/Nap)
or placebo. Subjects were instructed to treat within
the first hour of MMaD attack onset while pain was
mild. Rescue medication was allowed 2 hours after
the initial dose of SumaRT/Nap or placebo as prescribed by a physician. A second dose of SumaRT/
Nap was allowed as a rescue medication.
Saliva Collection.Subjects collected saliva
samples according to a previously published protocol.16 Briefly, all subjects prepared the mouth by
rinsing with tap water and expectorating. The mouth
was stimulated to release saliva by an application of

846
sterile 2% citric acid (Sigma, St. Louis, MO, USA) to
the tip and sides of the tongue with a cotton-tipped
applicator. The first 2 minutes of saliva was discarded
to prevent mixing of stimulated and unstimulated
saliva. Citric acid was continually applied every 30
seconds for an additional 5 minutes or until 5 mL of
saliva was collected. Subjects collected saliva by
expectorating into a cold 50 mL polypropylene
conical tube (MidSci, St. Louis, MO, USA). After collection, all samples were kept at -20C until preparation for analysis. Samples were taken at 3 time points:
MMaD baseline (pretreatment during an attack), 2
hours after treatment, and 4 hours after treatment.
PG Analysis.Saliva samples were thawed slowly
at room temperature and placed on ice. The volume
of each sample was recorded. Samples were centrifuged at 3000 rpm at 4C and the resultant supernatant utilized for PG and total protein analysis. PGD2,
PGE2, 8-isoprostane PGF2a (PGF2), 6-keto PGF1a, a
stable metabolite of the prostacyclin PGI2, and
thromboxane B2, the stable metabolite of thromboxane A2, were analyzed by ELISA (Cayman Chemical,
Ann Arbor, MI, USA) according to manufacturers
instructions. The amount of PG was normalized to the
volume of saliva collected and amount of total
protein, which was determined using a standard
protein assay (Bio-Rad Laboratories, Hercules, CA,
USA).
Statistical
Analysis.Intra-subject
statistical
analysis was performed with the nonparametric Wilcoxon matched pairs signed-rank test, while betweengroup statistical analysis utilized the nonparametric
MannWhitney U-test. All statistical tests were performed using Minitab15 statistical software. Results
of statistical analyses were considered significant at
P < .05. All values are reported relative to baseline
levels (set to 1) + SEM. Subjects who rescued with an
additional dose of SumaRT/Nap or another rescue
medication were not included in any statistical
analysis.

RESULTS
The 15 subjects selected for this study included
white women age ranged from 23 years to 48 years.
Subjects reported an average of 3.46 0.4 migraines
per month with a total average of 6.13 0.8 headache

May 2010
days per month. All subjects reported having additional migraines other than MMaD.
PGD2 levels were increased over attack onset
levels at 2 and 4 hours after treatment with placebo
(P < .05) but were not significantly increased in subjects treated with SumaRT/Nap (Fig. 1A). Mean
PGD2 levels at attack were 355.37 88.6 nmol/mg
total protein for placebo-treated subjects and
214.18 36.3 nmol/mg total protein for SumaRT/

Fig 1.Effect of SumaRT/Nap treatment on salivary levels of

PGD2, PGF2, and TXA2 during a migraine attack. Placebotreated subjects are represented by black boxes (n = 6) while
SumaRT/Nap-treated subjects are represented by light grey
boxes (n = 9). Mean SEM are shown. Values for the placebo
and SumaRT/Nap, whose means were made equal to 1, were
normalized to their respective levels during at attack. *P < .05
relative subjects at attack, #P < .05 relative to placebo-treated
subjects 2 or 4 hours post treatment. PG = prostaglandins;
SumaRT/Nap = sumatriptan succinate and naproxen sodium
single tablet combination.

Headache
Nap-treated subjects. Similarly, PGF2 levels, which
were increased over attack onset levels at 2 and 4
hours (P < .05) in the placebo group, were not
increased following treatment with SumaRT/Nap at 2
and 4 hours (Fig. 1B). The mean attack onset levels
for PGF2 were 4.51 0.74 nmol/mg total protein for
placebo and 2.14 0.45 nmol/mg total protein for
SumaRT/Nap treatment. TXA2 levels, measured as
the metabolite TXB2, were similar to PGD2 and PGF2
trends and were increased at 2 and 4 hours (P < .05)
in placebo-treated subjects (Fig. 1C). However, while
TXA2 levels were not increased in SumaRT/Naptreated patients at 2 hours, TXA2 levels were not significantly different from attack levels at the 4-hour
time point in response to SumaRT/Nap. Attack onset
levels were 53.46 14.0 nmol/mg total protein for
placebo and 39.06 7.12 nmol/mg total protein for
SumaRT/Nap treatment for TXA2. In summary, there
were significant differences between placebo and
SumaRT/Nap treatment at 2 and 4 hours for PGD2
and PGF2, as well as a significant difference in TXA2
levels at 2 hours.
PGE2 and PGI2 levels did not follow the same
trend as seen with the other PGs. For example, levels
of PGE2 were only increased at the 4-hour time point
in placebo-treated subjects (P < .05) (Fig. 2A). In
addition, while PGE2 levels were significantly below
placebo-treated and attack levels 2 hours after treatment with SumaRT/Nap (P < .05), PGE2 levels were
similar to attack levels 4 hours post treatment
(Fig. 2A). The PGE2 levels during an attack were
4.87 1.64 nmol/mg total protein for placebo subjects and 3.88 2.27 nmol/mg total protein for the
SumaRT/Nap-treated subjects. PGI2 levels, measured
as the metabolite 6-keto PG F1a, were not significantly
different from attack onset in either group or time
point (Fig. 2B). The PGI2 levels during an attack were
17.5 5.34 nmol/mg total protein for placebo subjects and 14.94 5.91 nmol/mg total protein for the
SumaRT/Nap-treated subjects.

DISCUSSION
Based on pharmacological studies, it is known
that triptans and NSAIDs target different mechanisms of migraine pathology,18,19 and both have been
suggested as acute and short-term prophylactic treat-

847

Fig 2.Effect of SumaRT/Nap treatment on salivary levels of

PGE2 and PGI2 during a migraine attack. Placebo-treated subjects are represented by black boxes (n = 6) while SumaRT/
Nap-treated subjects are represented by light grey boxes
(n = 9). Mean SEM are shown. Values for the placebo and
SumaRT/Nap, whose means were made equal to 1, were normalized to their respective levels during at attack. *P < .05
relative subjects at attack, #P < .05 relative to placebo-treated
subjects 2 or 4 hours post treatment. PG = prostaglandins;
SumaRT/Nap = sumatriptan succinate and naproxen sodium
single tablet combination.

ments for menstrual migraine.20,21 Results from

recently published studies provide evidence that a
single tablet of SumaRT/Nap may be more effective
in treating migraine headache than either compound
alone.11,12,22 It is thought that the addition of naproxen
sodium, which is known to inhibit PG synthesis, may
contribute to improved drug efficacy as PGs are
implicated in the pathology of MMaD.7,10 A novel
finding of our study was that while salivary levels of
PGD2 and PGF2 increased significantly after migraine
onset in placebo-treated MMaD subjects, the levels of
these PGs were not elevated in subjects treated with
SumaRT/Nap. Although TXA2 showed a similar
trend with elevated levels 2 and 4 hours after onset of
attack in placebo-treated subjects, the levels of TXA2

848
were elevated after SumaRT/Nap at the 4-hour time
point. Interestingly, PGE2 levels were significantly
below attack levels in response to SumaRT/Nap at 2
hours but not significantly different from placebotreated controls at 4 hours. We found that PGI2 levels
did not increase in saliva in placebo or SumaRT/Naptreated subjects at either time point. Data from our
study provide the first evidence, to our knowledge,
that levels of several PG decrease with SumaRT/Nap
treatment, a finding that correlates with pain-free
outcome.
Our results with respect to levels of PGE2, TXA2
during MMaD, PGI2 are similar to previously
reported findings for these PGs during a migraine
attack when compared with interictal time periods.
We found that while salivary levels of PGD2 and
PGF2 reached peak amounts by 2 hours after the
onset of the attack, TXA2 and PGE2 levels reached
peak amounts by 4 hours. In agreement, other investigators have reported elevated levels of PGE2 during
migraine attacks. For example, Nattero et al7 demonstrated that plasma concentrations of PGE2 were
increased during attacks of pure menstrual migraine
when compared with other days of the menstrual
cycle. Similarly, in a study by Sarchielli et al,23 the
plasma levels of PGE2 were reported to increase
during a migraine attack and reached peak levels by
2-4 hours after onset. In addition, Vardi et al24 demonstrated that salivary PGE2 was increased during a
migraine attack when compared with an interictal
time period. Furthermore, Tuca et al25 showed that
salivary levels of PGE2 and thromboxane B2 (eg,
metabolite of TXA2) were increased during7 a
migraine attack compared with an interictal time
period. We also found elevated levels of TXB2 during
an attack, a finding in contrast to the study by Nattero
et al7 in which TXB2 levels were not increased during
attack. Our finding that 6-keto-PGF1a (eg, metabolite
of PGI2) levels were not elevated during an attack are
in agreement with results from a previous study.7
Although data from our study have shown that
the levels of several PGs are elevated during attack,
we can only speculate on the role of the PGs in
MMaD pathology at this time. PGs are found
throughout the nervous system and are known to play
an important role in homeostatic as well as pathologic

May 2010
states.26 It is known that PGs are generated during
perimenstrual time periods as a result of hormone
withdrawal. Declining serum levels of progesterone
up-regulate cyclooxygenase-2 enzymes within epithelial cells of the uterus.27 The subsequent synthesis of
PGs by the uterus and their release into the circulation could theoretically trigger and/or modulate
attacks of MMaD as well as symptoms of dysmenorrhea. It is also possible that declining progesterone
levels might up-regulate PG synthesis within the
trigeminovascular system and cause sensitization of
sensory trigeminal afferents and, thus, lower their
threshold of activation. In support of this notion,
increased levels of PGs have been found to modulate
neurotransmission within sensory neurons of the
trigeminovascular system. Direct application of PGD2
and PGE2 to adult rat trigeminal neurons was
reported to cause increased release of CGRP.28 In
addition, PGD2, which can be released from mast
cells, is known to modulate nociception,29,30 and is also
involved in cellcell communication and neuronal
sensitization through neurohormonal functioning.31,32 Similarly, PGE2 has been shown to enhance
the excitability state of small diameter trigeminal
ganglion cells.33 Importantly, PGF2 is thought to play
an important role in dysmenorrhea, but is also
involved in hyperalgesia and allodynia.34 Taken
together, it is unlikely that the actions of PGs on the
trigeminovascular system are mediated through the
effects of 1 PG subtype alone. Thus, the net effect of
PGs in MMaD is likely mediated by the cumulative
action of several PGs. Furthermore, PGs, which are
secreted by endometrial tissue and immune cells, may
act to sensitize trigeminal nerves, and thus facilitate a
migraine attack by lowering their threshold of activation to other inflammatory molecules.
Multiple studies have detailed the advantages of
using saliva as a readily available, noninvasive means
of detecting biomarkers for orofacial and other systemic disorders.16,35-37 For example, results from recent
studies have demonstrated the diagnostic potential of
using salivary biomarkers for studying the progression and treatment of a variety of diseases, including
type II diabetes, breast cancer, and oral cancer as well
as determining human immunodeficiency virus (HIV)
load and the onset of preterm labor.36,38 In addition,

Headache
we have recently found that salivary levels of CGRP
correlate with therapeutic response to triptan treatment.16,17 Importantly, in the study by Cady et al,17 it
was shown that CGRP levels were elevated over
interictal levels during the premonitory period as well
as the mild and moderate headache phases of
migraine in subjects responsive to rizatriptan. In contrast, saliva CGRP levels were not elevated over
baseline at any phase of a migraine attack in subjects
who did not respond to rizatriptan.17 Thus, successful
response to rizatriptan was found to correlate with
return of CGRP levels to interictal levels. It will be of
clinical importance to determine whether changes in
the level of PGs shown to be elevated in this pilot
study will be reliable and specific indicators of
MMaD pathology and predictive of responsiveness
to SumaRT/Nap as well as other new migraine
therapies.
In conclusion, data from this substudy provide
evidence to support that changes in salivary levels of
the PGs, PGD2 and PGF2, and possibly PGE2 and
TXA2, correlate with headache pain associated with
MMaD attacks and may be predictive of the effectiveness of SumaRT/Nap to treat this type of
migraine. Additional larger studies are required to
further clarify the role of PGs in MMaD, as well as
identify and validate the use of saliva PG levels as
diagnostic and therapeutic indexes for MMaD and
other types of headaches.
Unlabeled Use of Products Disclosure: Treximet
has been approved for use in adults for the acute
treatment of migraine with or without aura.
Acknowledgments: The authors would like to
acknowledge Dr. Lisa Mannix and Dr. Merle Diamond
for their contributions to study design and data collection
for the sub-study.

STATEMENT OF AUTHORSHIP
Category 1
(a) Conception and Design
Paul L. Durham; Carrie V. Vause; Roger Cady;
Vincent Martin
(b) Acquisition of Data
Paul L. Durham; Carrie V. Vause; Roger Cady;
Vincent Martin

849
(c) Analysis and Interpretation of Data
Paul L. Durham; Carrie V. Vause; Frederick
Derosier; Susan McDonald; Roger Cady; Vincent
Martin
Category 2
(a) Drafting the Article
Paul L. Durham; Carrie V. Vause; Roger Cady;
Vincent Martin
(b) Revising It for Intellectual Content
Paul L. Durham; Carrie V. Vause; Frederick
Derosier; Susan McDonald; Roger Cady; Vincent
Martin
Category 3
(a) Final Approval of the Completed Article
Paul L. Durham; Carrie V. Vause; Frederick
Derosier; Susan McDonald; Roger Cady; Vincent
Martin

REFERENCES
1. International Headache Society. The international
classification of headache disorders: 2nd edition.
Cephalalgia. 2004;24(Suppl. 1):1-160.
2. Martin VT, Behbehani M. Ovarian hormones and
migraine headache: Understanding mechanisms
and pathogenesisPart 2. Headache. 2006;46:365386.
3. Martin VT, Wernke S, Mandell K, et al. Symptoms
of premenstrual syndrome and their association
with migraine headache. Headache. 2006;46:125137.
4. Ylikorkala O, Dawood MY. New concepts in dysmenorrhea. Am J Obstet Gynecol. 1978;130:833-847.
5. Baker FC, Driver HS, Rogers GG, Paiker J, Mitchell
D. High nocturnal body temperatures and disturbed
sleep in women with primary dysmenorrhea. Am J
Physiol. 1999;277:E1013-E1021.
6. Mannix LK. Menstrual-related pain conditions:
Dysmenorrhea and migraine. J Womens Health.
2008;17:879-891.
7. Nattero G, Allais G, De Lorenzo C, et al. Relevance
of prostaglandins in true menstrual migraine. Headache. 1989;29:233-238.
8. Al-Waili NS. Treatment of menstrual migraine with
prostaglandin synthesis inhibitor mefenamic acid:
Double-blind study with placebo. Eur J Med Res.
2000;5:176-182.

850
9. Mohammadian P, Hummel T, Arora C, Carpenter T.
Peripheral levels of inflammatry mediators in
migraineurs druing headache-free periods. Headache. 2001;41:867-872.
10. Milsom I, Minic M, Dawood MY, et al. Comparison
of the efficacy and safety of nonprescription doses of
naproxen and naproxen sodium with ibuprofen,
acetaminophen, and placebo in the treatment of
primary dysmenorrhea: a pooled analysis of five
studies. Clin Ther. 2002;24:1384-1400.
11. Martin V, Mannix L, Ballard J, Derosier F, Lener S,
McDonald S. Relief of menstrual symptoms and
migraine after early treatment with a fixed
single-tablet formulation of sumatriptan with RT
technology and naproxen sodium (SumaRT/Nap).
Neurology. 2008;70:A355.
12. Mannix LK, Martin VT, Cady RK, et al. Combination treatment for menstrual migraine and dysmenorrhea using sumatriptan-naproxen: Two randomized controlled trials. Obstet Gynecol.
2009;114:106-113.
13. Mohammadian P, Hummel T, Arora C, Carpenter T.
Peripheral levels of inflammatory mediators in
migraineurs during headache-free periods. Headache. 2001;41:867-872.
14. Puig-Parellada P, Planas JM, Gimenez J, et al.
Plasma and saliva levels of PGI2 and TXA2 in the
headache-free period of classical migraine patients.
The effects of nicardipine. Headache. 1991;31:156158.
15. Nicolodi M, Del Bianco E. Sensory neuropeptides
(substance P, calcitonin gene-related peptide) and
vasoactive intestinal polypeptide in human saliva:
Their pattern in migraine and cluster headache.
Cephalalgia. 1990;10:39-50.
16. Bellamy J, Cady R, Durham P. Salivary levels of
CGRP and VIP in rhinosinusitis and migraine
patients. Headache. 2006;46:24-33.
17. Cady R, Vause C, Ho T, Bigal M, Durham P.
Elevated saliva calcitonin gene-related peptide
levels during acute migraine predict therapeutic
response to rizatriptan. Headache. 2009;49:12581266.
18. Brandes JL, Smith T, Diamond M, Ames MH. Openlabel, long-term tolerability of naratriptan for shortterm prevention of menstrually related migraine.
Headache. 2007;47:886-894.
19. Durham P, Russo A. Stimulation of the calcitonin
gene-related peptide enhancer by mitogen-activated
protein kinases and repression by an antimigraine

May 2010

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.
32.

drug in trigeminal ganglia neurons. J Neurosci.

2003;23:807-815.
Allais G, Bussone G, De Lorenzo C, et al. Naproxen
sodium in short-term prophylaxis of pure menstrual
migraine: Pathophysiological and clinical considerations. Neurol Sci. 2007;28(Suppl. 2):S225-S228.
Evers S, Afra J, Frese A, et al. EFNS guideline on
the drug treatment of migraineRevised report of
an EFNS task force. Eur J Neurol. 2009;16:968-981.
Brandes JL, Kudrow D, Stark SR, et al. Sumatriptannaproxen for acute treatment of migraine: A randomized trial. JAMA. 2007;297:1443-1454.
Sarchielli P, Alberti A, Codini M, Floridi A, Gallai
V. Nitric oxide metabolites, prostaglandins and
trigeminal vasoactive peptides in internal jugular
vein blood during spontaneous migraine attacks.
Cephalalgia. 2000;20:907-918.
Vardi J, Flechter S, Alguati A, Regev I, Ayalon D.
ProstaglandinE2 levels in the saliva of common
migrainous women. Headache. 1983;23:59-61.
Tuca JO, Planas JM, Parellada PP. Increase in PGE2
and TXA2 in the saliva of common migraine
patients. Action of calcium channel blockers. Headache. 1989;29:498-501.
Simmons DL, Botting RM, Hla T. Cyclooxygenase
isozymes: The biology of prostaglandin synthesis
and inhibition. Pharmacol Rev. 2004;56:387-437.
Critchley HO, Jones RL, Lea RG, et al. Role of
inflammatory mediators in human endometrium
during progesterone withdrawal and early pregnancy. J Clin Endocrinol Metab. 1999;84:240-248.
Jenkins DW, Feniuk W, Humphrey PP. Characterization of the prostanoid receptor types involved in
mediating calcitonin gene-related peptide release
from cultured rat trigeminal neurones. Br J Pharmacol. 2001;134:1296-1302.
Abdel-Halim MS, Hamberg M, Sjoquist B, Anggard
E. Identification of prostaglandin D2 as a major
prostaglandin in homogenates of rat brain. Prostaglandins. 1977;14:633-643.
Liang X, Wu L, Hand T, Andreasson K. Prostaglandin D2 mediates neuronal protection via the DP1
receptor. J Neurochem. 2005;92:477-486.
Urade Y, Hayaishi O. Prostaglandin D synthase:
Structure and function. Vitam Horm. 2000;58:89-120.
Vesin MF, Barakat-Walter I, Droz B. Preferential
synthesis of prostaglandin D2 by neurons and prostaglandin E2 by fibroblasts and nonneuronal cells in
chick dorsal root ganglia. J Neurochem. 1991;57:167174.

Headache
33. Kadoi J, Takeda M, Matsumoto S. Prostaglandin E2
potentiates the excitability of small diameter
trigeminal root ganglion neurons projecting onto
the superficial layer of the cervical dorsal horn in
rats. Exp Brain Res. 2007;176:227-236.
34. Jabbour HN, Sales KJ. Prostaglandin receptor signalling and function in human endometrial pathology. Trends Endocrinol Metab. 2004;15:398-404.
35. Kaufman E, Lamster IB. The diagnostic applications
of salivaA review. Crit Rev Oral Biol Med. 2002;
13:197-212.
36. Lawrence HP. Salivary markers of systemic disease:
Noninvasive diagnosis of disease and monitoring of
general health. J Can Dent Assoc. 2002;68:170-174.
37. Li Y, Denny P, Ho CM, et al. The Oral Fluid MEMS/
NEMS Chip (OFMNC): Diagnostic and translational applications. Adv Dent Res. 2005;18:3-5.

851
38. Segal A, Wong DT. Salivary diagnostics: Enhancing
disease detection and making medicine better. Eur J
Dent Educ. 2008;12(Suppl. 1):22-29.

SUPPORTING INFORMATION
Additional Supporting Information may be found in the
online version of this article:
Appendix S1.Headache
Checklist.

Basic

Science

Article

Please note: Wiley-Blackwell is not responsible for the

content or functionality of any supporting materials supplied by the authors. Any queries (other than missing
material) should be directed to the corresponding
author for the article.

Copyright of Headache: The Journal of Head & Face Pain is the property of Wiley-Blackwell and its content
may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express
written permission. However, users may print, download, or email articles for individual use.