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Clinical Expert Series

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Primary Dysmenorrhea
Advances in Pathogenesis and Management
M. Yusoff Dawood,

MD

Primary dysmenorrhea is painful menstrual cramps without any evident pathology to account for
them, and it occurs in up to 50% of menstruating females and causes significant disruption in
quality of life and absenteeism. Current understanding implicates an excessive or imbalanced
amount of prostanoids and possibly eicosanoids released from the endometrium during
menstruation. The uterus is induced to contract frequently and dysrhythmically, with increased
basal tone and increased active pressure. Uterine hypercontractility, reduced uterine blood flow,
and increased peripheral nerve hypersensitivity induce pain. Diagnosis rests on a good history
with negative pelvic evaluation findings.
Evidence-based data support the efficacy of cyclooxygenase inhibitors, such as ibuprofen,
naproxen sodium, and ketoprofen, and estrogen-progestin oral contraceptive pills (OCPs).
Cyclooxygenase inhibitors reduce the amount of menstrual prostanoids released, with concomitant reduction in uterine hypercontractility, while OCPs inhibit endometrial development and
decrease menstrual prostanoids. An algorithm is provided for a simple approach to the
management of primary dysmenorrhea.
(Obstet Gynecol 2006;108:42841)

rimary dysmenorrhea is defined as painful menstrual cramps without any evident pathology to
account for them. It refers to any degree of perceived
cramping pain during menstruation.

PREVALENCE
A widely prevalent and common complaint among
young women, primary dysmenorrhea is estimated
to be present in 40 50% of them,1 with severe
forms giving rise to work or school absenteeism in
15% and the mild forms requiring no medication or
occasional over-the-counter (OTC) analgesics in
about 30%. In spite of advances in the treatment of
From the Departments of Obstetrics and Gynecology and Physiology, West
Virginia University School of Medicine, Morgantown, West Virginia.
Corresponding author: M. Yusoff Dawood, MD, Department of Obstetrics and
Gynecology, West Virginia University School of Medicine, PO Box 9186,
Morgantown, WV 265086-9186; e-mail: ydawood@hsc.wvu.edu.
2006 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/06

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VOL. 108, NO. 2, AUGUST 2006

primary dysmenorrhea, a recent study of 1,546


menstruating Canadian women found that 60%
were having the disorder.2 Sixty percent of the
dysmenorrheic women were having severe or moderate pain. Fifty-one percent reported limitation of
activities, and 17% reported absenteeism. Thus,
there appears to be underuse of currently available
OTC and prescription medications, or there is
insufficient dissemination of information about primary dysmenorrhea to targeted young populations.
The prevalence of primary dysmenorrhea decreases with increasing age: prevalence is highest in
the 20- to 24-year-old age group and decreases
progressively thereafter.3 There appears to be no
relationship with parity when age is factored in.
Dysmenorrhea is increased with smoking.2 Primary
dysmenorrhea occurs only during ovulatory cycles.4 Limited studies have suggested a decline in
dysmenorrhea with physical exercises, but critical
analysis and other studies do not support any
evidence-based relationship between exercise and
primary dysmenorrhea.5

OBSTETRICS & GYNECOLOGY

CLINICAL FEATURES
Primary dysmenorrhea presents with or shortly after
menarche. It may start within 6 months after menarche because it occurs only during ovulatory cycles,
which may not always be evident at menarche. Although it may occur as late as a year after menarche,
it is less likely to do so later when it should raise
suspicion of secondary dysmenorrhea.
Characterized by fluctuating, spasmodic menstrual cramps, sometimes referred to as labor-like
pains that begin only a few hours before or with the
onset of menstrual flow, the symptoms of primary
dysmenorrhea lasts only 23 days. The pains are most
intense on the first or second day of the menstrual
flow, or more precisely the first 24 36 hours, consistent with the time of maximal prostaglandin release
into the menstrual fluid (vide infra). The pains are
suprapubic in location with radiation into the inner
aspects of the thighs. The cramps are frequently
accompanied by backache, nausea, vomiting, and
diarrhea in a high percentage of cases.1 With severe
pains, the sufferers may be absent from school or
work for a day or two. In the severe forms, the pain
may present as an intense acute abdominal episode
and may mimic the presentation of an acute ectopic
pregnancy. General and pelvic examinations are essentially normal.
The typical history and absence of any positive
findings in the physical examination are key diagnostic features. The diagnostic history includes the proximities of the onset of primary dysmenorrhea with
menarche, the onset of symptoms with the onset of
menstrual flow, and the duration of menstrual cramping and its characteristic description. Thus, primary
dysmenorrhea should be diagnosed as a specific
entity, but there is no laboratory test for it.

primary dysmenorrhea compared with eumenorrheic


women, and 3) many clinical trials demonstrating the
efficacy of cyclooxygenase (COX) inhibitors in relieving the pain of primary dysmenorrhea through prostaglandin suppression and quantitative decrease of
menstrual fluid prostaglandins.

Prostanoids
In primary dysmenorrhea, there is increased abnormal uterine contractility, similar to uterine contractility induced with prostaglandins or their analogues for
labor or abortion. Symptoms such as nausea, vomiting,
and diarrhea occur in 60% or more of patients and are
similar to the adverse effects of prostaglandins.
Pickles and his colleagues6,7 postulated that menstrual stimulant or prostaglandins were elevated in
menstrual extracts of women with primary dysmenorrhea compared with eumenorrheic women.8 With
availability of radioimmunoassay and specific antiserum, several laboratories, including ours, were able
to measure small quantities of prostanoids in endometrium and menstrual fluid with greater precision.9 15 In most but not all women with primary
dysmenorrhea, there is increased endometrial secretion of menstrual prostaglandin F2 (PGF2) during the
menstrual phase.10,11 The release of prostaglandins
into the menstrual fluid is a continuous discontinuous
process,4 that is, the amount of menstrual fluid and
prostaglandins varies throughout any window of time.
The intensity of the menstrual cramps and associated
symptoms of dysmenorrhea are directly proportional
to the amount of PGF2 released4,13 (Fig. 1).

PATHOPHYSIOLOGY
Advances in the last three decades and current understanding suggest that in primary dysmenorrhea
there is abnormal and increased prostanoid and possibly eicosanoid secretion, which in turn induces
abnormal uterine contractions. The contractions reduce uterine blood flow, leading to uterine hypoxia.
That increased vasoactive prostanoid secretion is
responsible for the etiology of primary dysmenorrhea
is supported by 1) the striking similarity between the
clinical symptoms of primary dysmenorrhea and the
uterine contractions and adverse effects observed in
prostaglandin-induced abortion and labor, 2) substantial evidence demonstrating and correlating the
amount of menstrual prostanoids in women with

VOL. 108, NO. 2, AUGUST 2006

Fig. 1. Correlation between the amounts of prostaglandins


in prostaglandin F2 equivalents released per hour during
menstruation and the severity of the dysmenorrhea as
reflected by the dysmenorrhea score in a woman with
primary dysmenorrhea. Reproduced with permission from
Dawood MY. Hormones, prostaglandins and dysmenorrhea. In: Dawood MY, editor. Dysmenorrhea. Baltimore
(MD): Williams and Wilkins; 1982. p. 21. Copyright 1982,
Lippincott Williams & Wilkins.
Dawood. Advances in Primary Dysmenorrhea. Obstet Gynecol
2006.

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Advances in Primary Dysmenorrhea

429

When a nonsteroidal anti-inflammatory drug


(NSAID) such as ibuprofen is taken during menstruation, the menstrual fluid prostaglandins are significantly inhibited to levels similar to or lower than
those found in eumenorrheic women,1120 and clinical
relief is obtained. Similarly, when the patient is on a
combined oral contraceptive (estrogen and progestin), her menstrual fluid prostaglandins are significantly suppressed, with an accompanying reduction
in menstrual fluid volume/bleeding and concomitant
relief of pain compared with cycles given placebo or
no medication.3,12,16,19,21
Despite advances with prostaglandins in the
etiology of primary dysmenorrhea, there are patients with normal laparoscopic finding and severe
dysmenorrhea who do not have elevated menstrual
PGF2 to account for the severe cramping.11 The
prevalence of such patients is currently not known.
The role of prostanoids such as thromboxane A2,
prostacyclin, and leukotrienes in the pathogenesis
of primary dysmenorrhea is neither fully understood nor adequately explored. Prostacyclin, a potent vasodilator and uterine relaxant, appears to be
reduced in primary dysmenorrhea.22 This heightens
the uterine activity and vasoconstriction because
the uteronic and vasoconstrictive effects of the
other prostaglandins are less impeded. Increased
leukotriene produced by the 5-lipoxygenase enzyme pathway rather than the COX pathway may
account for some forms of primary dysmenorrhea
that are not responsive to NSAIDs.23 The 5-lipoxygenase pathway for the biosynthesis of leukotrienes
is outlined in Figure 2. Human endometrium and
myometrium can synthesize leukotrienes,23 thus
confirming the functional activity of the 5-lipoxygenase pathway and that leukotrienes are involved
in myometrial contractions.24 In women with primary dysmenorrhea, there are significantly higher
concentrations of menstrual leukotrienes,25,26 especially leukotriene C4 and leukotriene D4, than in
women without dysmenorrhea.27 Because specific
binding sites for leukotriene C4 are demonstrable
in myometrial cells,28 it is likely that leukotrienes
contribute to the uterine hypercontractility seen in
primary dysmenorrhea.
Prostaglandins and prostanoids are biosynthesized from arachidonic acid through the COX
pathway after production of arachidonic acid from
hydrolysis of phospholipids by phospholipase
(Fig. 3). When pregnancy does not occur, progesterone levels decline during the late luteal phase.
This causes labilization of lysosomes and release of
their phospholipase enzyme, which then hydro-

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Advances in Primary Dysmenorrhea

Fig. 2. The lipoxygenase (5-lipoxygenase and 12-lipoxygenase) pathways for biosynthesis of hydroxyperoxyeicosatetraenoic (HPETE) acid. Leukotrienes A, B, and C are eventually produced through the 5-lipoxygenase pathway. The
enzymes involved are shown in italics. Thus, blockade with
cyclo-oxygenase inhibitors, as happens with nonsteroidal
anti-inflammatory drugs (NSAIDs), have no effect on the
lipoxygenase pathway and biosynthesis of leukotrienes,
which may account for some cases of primary dysmenorrhea not responding to NSAID therapy.
Dawood. Advances in Primary Dysmenorrhea. Obstet Gynecol
2006.

lyzes the cell membrane phospholipids to generate


arachidonic acid as well as icosatetraenoic acid.
These compounds then serve as the precursors for
the COX and lipoxygenase pathways.

Vasopressin
Involvement of vasopressin in the pathogenesis of
primary dysmenorrhea is still controversial.29,30 Increased levels of circulating vasopressin during menstruation reported in women with primary dysmenorrhea31 can produce dysrhythmic uterine contractions
that reduce uterine blood flow and cause uterine
hypoxia. In limited studies, vasopressin antagonists
were able to neutralize the effect of endogenous

OBSTETRICS & GYNECOLOGY

Fig. 3. The arachidonic acid


cascade showing the cyclooxygenase (COX) pathway, the
biosynthesis of cyclic endoperoxides PGG and PGH, and the
final products: prostacyclin,
prostaglandins F (PGF) and E
(PGE), and thromboxane A2
(TxA2). The enzymes are shown
in italics. Thus, COX inhibitors
block early in the COX pathway. Prostaglandin F, PGE, and
TxA induce smooth muscle
contractions (uterine contractility, vasoconstriction) and hypersensitization of pain nerve
fibers.
Dawood. Advances in Primary
Dysmenorrhea. Obstet Gynecol
2006.

vasopressin and relieve dysmenorrhea.31,32 Other investigators could not confirm elevated plasma vasopressin in women with primary dysmenorrhea and
found that the vasopressin antagonist atosiban had no
effect on menstrual pain, intrauterine pressure, or
uterine artery pulsatility index in dysmenorrheic
women.30

Uterine Contractions
In normal eumenorrheic women, the uterus has welldefined contraction patterns that are influenced by
sex steroids, prostaglandins, and other uterotonic
substances throughout the menstrual cycle. Details of
the pattern have been well described.16,18 20,31,3335 Of
particular interest and relevance to the pathogenesis
of primary dysmenorrhea is the uterine contraction
pattern during menstruation when the symptoms of
dysmenorrhea occur. During menstruation in normal
women, the uterine basal tone is minimal (less than 10
mm Hg), there are 3 4 contractions during each
10-minute interval with active pressures at the peak of
a contraction reaching up to 120 mmHg (comparable
to the intrauterine pressure during the second stage of

VOL. 108, NO. 2, AUGUST 2006

labor with pushing), and the contractions are synchronous and rhythmical. In patients with primary dysmenorrhea, four contraction abnormalities alone or in
combination have been reported. They include elevated basal tone (more than 10 mmHg), which is
frequently seen,36 elevated active pressures (more
than 120 mmHg, often more than 150 180 mmHg),
increased number of contractions per 10 minutes
(more than 4 or 5), and nonrhythmic or incoordinate
uterine contractions. These abnormalities lead to poor
uterine reperfusion and oxygenation, thus giving rise
to pain. If more than one contraction abnormality is
present, they synergize with each other so that the
pain threshold is exceeded with much smaller
changes in each parameter than if only one anomaly
were present.

Uterine Blood Flow


Studies to determine uterine blood flow in women
have been difficult because of the highly invasive
methods and technically challenging requirements
involving hydrogen clearance, nitrous oxide, electromagnetic flowmeters, and the microsphere methods.

Dawood

Advances in Primary Dysmenorrhea

431

Thermoelectric blood flow recordings based on thermodilution have been used for assessing changes in
uterine pressure and variations in blood flow.37 41 In
eumenorrheic women the uterine contractions do not
affect uterine blood flow. By contrast, the strong and
abnormal uterine contractions in dysmenorrheic
women reduce uterine blood flow and cause myometrial ischemia, resulting in pain. Such changes can be
produced with pharmacologically induced uterine
contractions which, if excessive, will reduce blood
flow and produce cramplike pains. Administration of
an uterolytic, such as a calcium channel blocker or
NSAID, abrogates the hypercontractility and restores
blood flow to normal.
These earlier studies are now supported by
Doppler flow studies.42 The pulsatility index and
resistance index of both uterine arteries and the
arcuate artery were significantly higher on the first
day of menstruation in women with primary dysmenorrhea, suggesting increased blood flow impedance
and indicating uterine vasoconstriction as a cause of
the pain.

MANAGEMENT
There are three approaches to the management of
primary dysmenorrhea: pharmacological, nonpharmacological, and surgical. By far, the pharmacological approach has been better documented for efficacy,
whereas the other approaches have more variable
evidence.
In evaluating treatment efficacy, it is critically
important to consider not only the relief of pain but
also the powerful placebo effect in up to 35 40% of
dysmenorrheic subjects, the primary outcome index
(is it pain or something else) being evaluated, the time
to relief of pain (rapidity of onset) and onset of peak
pain relief, the duration of pain relief, and secondary
outcome indices (such as relief of associated symptoms, functionality as measured by reduction in absenteeism ,and qualitative improvement in performance).43 These have been discussed by us elsewhere
in detail.43 Only patients with primary dysmenorrhea
should be included, and the criteria for such a diagnosis should be adhered to, but laparoscopy is not
essential. Patients using an intrauterine device or oral
contraceptives should be excluded, although a few
trials have included them.
In primary dysmenorrhea, all trials should be
prospective, double-blind, and placebo-controlled, involving several cycles, with each treatment given for
23 cycles. After ibuprofen was shown to be effective,
it is now the gold standard against which new drugs or
treatment modalities are evaluated. Because of intra-

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individual cycle-to-cycle variability of dysmenorrhea


symptoms, it is preferable to use a parallel rather than
a crossover study design for trials using only a limited
number of cycles (23 cycles).43 There is little or no
crossover effect because primary dysmenorrhea is
confined to only 3 days or less, over which time the
pathophysiology (vide supra) occurs and clears off. A
crossover (blinded and random) from one treatment
or placebo to another is the optimum study design
because patients can act as their own controls or
treatment comparisons and the menstrual fluid prostaglandins can be reliably compared.

Pharmacological Agents
Nonsteroidal Anti-Inflammatory Drugs
(NSAIDs)
In women with dysmenorrhoea, NSAIDs are significantly more effective for pain relief than placebo
(odds ratio [OR] 7.91, 95% confidence interval [CI]
5.6511.09).44 Overall adverse effects were also significantly more common (OR 1.52, 95% CI 1.09 2.12).
There was insufficient power to detect differences
between different NSAIDs because most individual
comparisons were based on a few small trials unsuitable for meta-analysis. Thus there is insufficient evidence to determine which (if any) individual NSAID
is the most safe and effective for treatment of dysmenorrhoea. My personal preference is to select an
NSAID that has been around for a long time, is
currently available as a generic and therefore is
relatively inexpensive, and has many randomized
double-blinded clinical trials with data on time to
onset of relief with the first dose, in addition to overall
efficacy. Such NSAIDs are ibuprofen, sodium
naproxen, or ketoprofen. Thus far, trials have shown
ibuprofen, naproxen, ketoprofen, mefenamic acid,
and nimesulide to be significantly better than placebo
or comparably as effective as ibuprofen or naproxen
sodium. In our study, naproxen 400 mg provides
greater pain relief than placebo and acetaminophen
within 30 minutes and is maintained at 6 hours after
administration.45 Ketoprofen (100 mg) was reported
more effective at 45 minutes, continuing for up to 2
hours, than 500 mg naproxen, using visual analog
scale scores to assess pain.46 In a multicenter, randomized, double-blind, crossover study, we found 12.5
and 25 mg ketoprofen and 200 mg ibuprofen were
significantly better than placebo, with a similar sum of
the pain intensity differences and total pain relief
scores at 4 hours for the two NSAIDs.47 This does not
mean that other NSAIDs, including the COX-II
specific inhibitors, should not be considered. Never-

OBSTETRICS & GYNECOLOGY

theless, cost considerations, lack of superiority, and


concerns about the adverse effects of COX-II inhibitors do not support them as a first-line NSAID for
treatment of primary dysmenorrhea. Several NSAIDs
have been approved and are available as OTC medications, including ibuprofen, naproxen sodium,45 and
ketoprofen.47,48
Nonsteroidal anti-inflammatory drugs relieve primary dysmenorrhea by inhibiting endometrial prostaglandin production4 but also have direct analgesic
properties at the central nervous system level. Nonsteroidal anti-inflammatory drugs do not appear to
affect the development of the endometrium when
given during the menstrual phase for primary dysmenorrhea but directly inhibit COX activity and
therefore suppress endometrial prostaglandin biosynthesis and release. Thus, menstrual fluid volumes are
not affected, but menstrual fluid prostaglandin levels
are significantly reduced to or even below levels
found in normal pain-free cycles.4,1214,16,18,19 Accompanying the decrease in menstrual fluid prostaglandins is a return of the uterine activity to a pattern
similar to normal pain-free menstruation and relief of
the pain.4,16,18,37,40,41
Adverse effects of NSAIDs include gastrointestinal symptoms, central nervous system symptoms,
nephrotoxic and hepatotoxic effects, hematologic abnormalities, bronchospasm, fluid retention, and
edema, but with a 3-day regimen used in primary
dysmenorrheics who are usually young and healthy,
adverse effects are infrequent, well tolerated, and
usually confined to gastrointestinal symptoms such as
nausea, indigestion, heart burn, and vomiting. Interestingly, in most of the clinical trials, there are reported adverse effects of 711% with placebo-treated
cycles and a slightly higher incidence of 1516% with
the medications.
Cyclooxygenase II Inhibitors
The conversion of arachidonic acid into cyclic endoperoxides involves catalytic conversion by the enzyme cyclooxygenase (COX). There are two forms of
COX: I and II. Cyclooxygenase I is secreted basally
whereas COX II is secreted in response to a variety of
stimuli. Nonsteroidal anti-inflammatory drugs inhibit
both COX I and COX II. Because COX II responds
to stimuli, the COX II inhibitors are deemed more
specific and, therefore, unlikely to induce gastroduodenal ulcers. More specific COX II inhibitors are now
available, but concerns about their adverse effects
have recently attracted attention. Rofecoxib,49 valdecoxib,50,51 and lumiracoxib52 are effective for treating
primary dysmenorrhea. Thus far, COX II inhibitors

VOL. 108, NO. 2, AUGUST 2006

are equally effective but not better than naproxen


sodium.49,50,52 Given the above considerations, concerns about safety of COX II inhibitors, the short
duration of therapy for relieving primary dysmenorrhea, and the low costs of OTC NSAIDs such as
ibuprofen and naproxen, it is prudent to recommend
established NSAIDs with track records of long-term
safety as the preferred pharmacologic agent.
A Cochrane analysis found two trials on NSAID
for endometriosis but analyzed only one involving 24
patients53. There is no evidence that NSAIDs are
effective for pain in endometriosis.53 Earlier smaller
studies gave conflicting conclusions.54,55
Oral Contraceptive
A Cochrane analysis in 2001 concluded from four
randomized controlled trials that combined oral contraceptive pills (OCPs) with medium-dose estrogen
and first-/second-generation progestogens are more
effective than placebo for relief of primary dysmenorrhea.56 We have shown that such OCPs (estrogen
and progestin) reduce menstrual fluid volume and
prostaglandins to within, or even below, normal
range,4,12,13 with concomitant clinical relief during that
cycle. The relief and the reduction in prostaglandins
are confined only to that particular cycle, with no
carry-over effect after stopping the OCP.4,12,13 Oral
contraceptive pills may also lower the elevated
plasma vasopressin levels found in dysmenorrheic
women and lead to attenuation of the excessive
uterine activity.57 Monophasic and triphasic OCPs are
equally effective because there is no significant difference in the prevalence rate of dysmenorrhea between
users of these preparations,58 but the observations are
indirect. A recent randomized, double-blind, placebocontrolled trial of adolescents confirmed that lowdose (20 g ethinyl estradiol) OCP is also clinically
effective in relieving primary dysmenorrhea,59 albeit
the Moos Menstrual Distress Questionnaire, which
does not assess pain, was used. Analyses of extendeduse OCP found that few studies reported on menstrual pain, but the regimen fared slightly better than
cyclic use.60 There is insufficient information about
long-acting progestational contraceptives and primary dysmenorrhea.
Glyceryl Trinitrate
Diminished levels of nitric oxide induce myometrial
contractions while nitric oxide causes uterine relaxation. Thus glyceryl trinitrate as a source of nitric
oxide can be expected to relax the exaggerated
myometrial contractions in primary dysmenorrhea. A
recent review concluded that nitroglycerin signifi-

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Advances in Primary Dysmenorrhea

433

cantly reduces the pain in primary dysmenorrhea.61 A


pilot uncontrolled study found that satisfactory-toexcellent relief was obtained in 90% of patients with
primary dysmenorrhea.62 In a multinational, doubleblind, placebo-controlled, randomized crossover
study, transdermal glyceryl trinitrate 0.1 mg/h was
found to be significantly more effective during the
first 6 hours of treatment and demonstrated greater
overall efficacy than placebo.63 A comparison of
transdermal glyceryl trinitrate with diclofenac sodium
in an open, randomized, crossover trial found both
treatments to be effective during the first 2 hours after
medication but with slightly, but not significantly,
reduced efficacy for glyceryl trinitrate.64 In all the
studies, there is low tolerability for glyceryl trinitrate
because of headache occurring in 20 26% of patients.
The doses of glyceryl trinitrate patches used were
from 0.1 to 0.2 mg/h.
Magnesium
A Cochrane data analysis in 2001 found three small
trials comparing magnesium with placebo for relief of
primary dysmenorrhea.65 Magnesium was more effective, but the dose and regime were widely variable.
Magnesium has been given as magnesium pidolate.66
In one study, magnesium reduced menstrual fluid
PGF2 to 45% of its pretreatment levels,67 which
provides a mechanistic rationale for this therapy.
Currently, it is not clear what dose, preparation, and
regime to use for magnesium in treating primary
dysmenorrhea. Further studies are needed.
Calcium Antagonists
Nifedipine, a calcium channel blocker, inhibits
myometrial contractility, thereby relieving primary
dysmenorrhea.68 70 By blocking calcium entry into
smooth muscle cell, intracellular free calcium is
reduced, the muscle relaxes, contractions are reduced, vasodilatation is promoted, and ionic stimulation of prostanoids release is decreased. Adverse
effects reported from the studies include transient
facial flush, increased pulse rate, palpitations, and
headache.

Vitamin E
Treatment of primary dysmenorrhea with vitamin E
was reported in 1995,71 but evidence for its efficacy is
limited. In a recent randomized, double-blind, placebo-controlled trial, 500 international units vitamin E
and placebo were effective with more marked effects
for vitamin E, suggesting a potentially large placebo
effect.72 Recently, the same investigators found 100
mg vitamin E given for 5 days around menstruation
significantly reduced the severity and duration of
menstrual pain and blood loss than placebo.73 More
definitive trials are needed.
Vitamin E relieves primary dysmenorrhea, probably through prostaglandin biosynthesis, but there is
no data on menstrual fluid PGF2a and uterine contractility. In vitro and in vivo studies in mice suggest that
prostaglandin production is affected. Vitamin E increases the production of vasodilator prostacyclin and
prostaglandin E2 (PGE2), as well as a dose-dependent
upregulation of phospholipase A2 and arachidonic
acid release, but inhibits COX posttranslational activity74. In macrophages, vitamin E abrogates peroxynitrite induction of COX75 and significantly suppresses
arachidonic acid metabolism and prostaglandin production through inhibition of PLA2 and COX.76 78 In
short, vitamin E and its analogues suppress phospholipase A2 and COX activities to inhibit prostaglandin
production but promote vasodilator and uterine muscle
relaxing prostanoids such as prostacyclin.
Herbs
Adolescents who drank rose tea (n70) perceived less
menstrual pain and distress at 1, 3, and 6 months,
compared with controls (n60).79 Other herbs, such
as extracts of sweet fennel seeds (Foeniculum vulgare),
are less potent than naproxen for relief of primary
dysmenorrhea.80 A Cochrane analysis concluded that
a small trial showed fish oil (mega-3 fatty acids) to be
more effective than placebo.65 Krill oil significantly
reduces the number of analgesics used for dysmenorrhea.81 Currently there is insufficient evidence to
recommend the use of herbal and dietary therapies
for dysmenorrhea.

Nonpharmacologic Approaches
Vitamin B
One small trial found vitamin B6 was more effective
at reducing menstrual pain than placebo or a combination of magnesium and vitamin B6.65 A combination of magnesium and vitamin B6 was no different
from placebo. One large trial found that100 mg
vitamin B1 daily was more effective than placebo.

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Transcutaneous Electrical Nerve Stimulation


(TENS)
A recent Cochrane review analyzed seven randomized controlled trials of transcutaneous electrical
nerve stimulation (TENS) compared with placebo or
no treatment.82 Overall, high-frequency TENS is
more effective for pain relief in primary dysmenor-

OBSTETRICS & GYNECOLOGY

rhea than placebo TENS8390. Low-frequency TENS is


no more effective than placebo TENS. Our own
double-blind, randomized, placebo-controlled studies
using high frequency TENS found it to be significantly better than placebo TENS.83 Thirty percent of
severe dysmenorrheic cycles can be effectively relieved by TENS without need for pain medication.
The amount of back-up NSAID required in the
remaining 70% of cycles was significantly less than
without TENS. Transcutaneous electrical nerve stimulation is a noninvasive and effective method for
relief of primary dysmenorrhea and empowers the
woman to control her treatment because she can
regulate the intensity and duration of TENS applied.
Transcutaneous electrical nerve stimulation confers relief of pain through two potential mechanisms.
By sending a volley of afferent impulses through the
large diameter A sensory fibers of the same nerve
root, TENS raises the threshold for pain signals by
lowering the gate, thus blocking signal reception
along the same root from the uterine hypoxia and
hypercontractility.91,92 Thus, the uterine signals are
less perceived or appreciated. Transcutaneous electrical nerve stimulation also stimulates release of endorphins from the peripheral nerves and the spinal cord,
thus providing another avenue of partial pain attenuation. The opiate antagonist naloxone can neutralize
this effect.86
Acupuncture and Acupressure
Both acupuncture and acupressure have been tried
for relief of primary dysmenorrhea. However, the
limited trials and variable techniques and designs
used render systematic analysis difficult.9395 A Cochrane analysis and review82 found one small trial
showing acupuncture to be significantly more effective for pain relief than placebo acupuncture and two
no-treatment control groups. Given weekly for three
menstrual cycles, acupuncture reduced analgesic
medication by 41% compared with placebo acupuncture in women with primary dysmenorrhea.93 In a
recent study, acupuncture was successful in primary
dysmenorrhea (defined as no recurrence of symptoms
for 2 years or more and no need for medication) in
93% of patients, compared with only 3.7% in the
placebo group.94 In an uncontrolled international
pilot study, acupuncture point injection with vitamin
K alleviated primary dysmenorrhea with extension of
relief into nontreatment follow-up cycles.95 Thus,
there is some suggestive evidence that acupuncture
may play a role in the nonpharmacologic relief of
primary dysmenorrhea. However, well-designed,

VOL. 108, NO. 2, AUGUST 2006

controlled, larger, and more definitive trials are


needed.
The therapeutic efficacy of acupressure was considered similar to that of ibuprofen in relief of dysmenorrhea.96 Acupressure (both administered and
self-applied) at Sanyinjiao significantly reduced menstrual pain.97 Acupressure is a relatively effective,
cost-free method of self-care if the patient is not
interested in taking medications.
Other Nonmedication Self-Help Therapy
Continuous, low-level, heat-wrap therapy applied to
the suprapubic region is significantly superior to
acetaminophen throughout the first 8 hours of application for relief of primary dysmenorrhea.98 This can
be used by patients or as an adjunct to other better
evidence-based therapies. A randomized, placebocontrolled study found significant relief of primary
dysmenorrhea pain with magnet (2,500 gauss) compared with placebo magnettreated cycles.99

Surgical or Manipulative Approaches


Nerve Ablation
Observational studies support the use of uterosacral
nerve ablation and presacral neurectomy for primary
dysmenorrhoea. Both surgical procedures interrupt
the cervical sensory pain fibers in the pelvic area. A
Cochrane meta-analysis of 8 of 11 trials (2 did not
meet criteria)100 included five for laparoscopic uterosacral nerve ablation, two for laparoscopic presacral
neurectomy, and two for open presacral neurectomy.
There was some evidence for efficacy of laparoscopic
uterosacral nerve ablation-resection over placebo or
no treatment, and long-term presacral neurectomy
was significantly better than laparoscopic uterosacral
nerve ablation. However, there is insufficient evidence to recommend surgical nerve interruption for
the management of primary dysmenorrhea. Adverse
events were more common with presacral neurectomy. Because uterosacral nerve ablation essentially
transects postganglionic sensory fibers, they are likely
to regenerate with time and the pain returns. Sufficiently powered, future, randomized controlled trials
are needed.
Spinal Manipulation
A Cochrane analysis and its follow-up found no
evidence to suggest that spinal manipulation is effective for treatment of primary dysmenorrhea.101,102
Four trials of high-velocity, low-amplitude manipulation suggest that it was no more effective than sham
manipulation for the treatment of dysmenorrhoea.

Dawood

Advances in Primary Dysmenorrhea

435

Fig. 4. Pathway for the selection of prostaglandin synthetase


inhibitor compared with oral contraceptive in the management of primary dysmenorrhea.
Dawood. Advances in Primary Dysmenorrhea. Obstet Gynecol
2006.

Three of the smaller trials favored high-velocity,


low-amplitude manipulation, but one trial with an
adequate sample size found no difference. The Toftness technique was shown to be more effective than
sham treatment by one small trial.

Management Algorithm
A simplified algorithmic approach has been developed by me for the management of dysmenorrhea. I

have used it for more than 20 years of practice, and it


has seldom let me down. We employ the rule of two,
which is easy to remember, with each step of the
algorithm having only two choices to select from..
When a patient presents with chronic pelvic pain, it is
important to distinguish between pain associated with
menstruation and pain that occurs at other times. If it
is associated with menstruation, it is dysmenorrhea,
which then has to be separated into primary dysmenorrhea and secondary dysmenorrhea. The typical
history of primary dysmenorrhea and the normal
pelvic examination findings would sort out primary
from secondary dysmenorrhea. However, in some
cases of endometriosis presenting during the teenage
years and with no pelvic abnormalities, there can be
a striking similarity with primary dysmenorrhea.
Once the diagnosis of primary dysmenorrhea is
arrived at, the most effective treatment of choice
remains between an NSAID and the combined estrogen-progestin oral contraceptive (Fig. 4). If the patient
wants to use oral contraceptive as a method of birth
control, a combined oral contraceptive is prescribed
for her birth control needs, and she can be expected
to obtain relief of her primary dysmenorrhea (vide
supra oral contraceptive). The choice of 3 months
can be construed as arbitrary, but sufficient time must
be given to test efficacy of the medication because

Fig. 5. Algorithm for managing


primary dysmenorrhea with
oral contraceptive.
Dawood. Advances in Primary
Dysmenorrhea. Obstet Gynecol
2006.

436

Dawood

Advances in Primary Dysmenorrhea

OBSTETRICS & GYNECOLOGY

Fig. 6. Algorithm for managing primary dysmenorrhea with prostaglandin synthetase inhibitor.
Dawood. Advances in Primary Dysmenorrhea. Obstet
Gynecol 2006.

intensity of primary dysmenorrhea can fluctuate from


cycle to cycle. On the other hand, waiting for even
more cycles of trying with the medication is unnecessary and subjects the women to a trial of endurance. If
dysmenorrhea is not adequately relieved by oral
contraceptives after three cycles, consider adding an
appropriate NSAID during the menstrual phase (Fig.
5). Thereafter, the management is similar to that of
the patient initially given an NSAID. With birth
control pills, 80 90% or more of women can be
satisfactorily relieved of primary dysmenorrhea if the
diagnosis is correct.
If contraception is not desired or if the patient
prefers other nonoral contraception, the medication
of choice for relief of her primary dysmenorrhea is a

NSAID. Patients with gastroduodenal ulcer or who


are allergic to NSAIDs should be recommended to
use an oral contraceptive and not given NSAID (Fig.
6). To obtain maximum and continuous relief from
painful menstrual cramping and to avoid exposing a
potential very early pregnancy, NSAIDs should be
taken with the onset of menstruation and continually
for the first 23 days of menstrual flow so as to inhibit
prostaglandin production, rather than on an asneeded basis. Table 1 summarizes the types of
NSAIDs , their doses, and clinical efficacy in the relief
of primary dysmenorrhea. Nonsteroidal anti-inflammatory drugs given at the time of menstruation do not
appear to affect the development of the endometrium
but inhibit COX activity and reduce prostaglandin

Table 1. Clinical Efficacy of Prostaglandin Synthetase Inhibitors and Doses Used for Treatment of
Primary Dysmenorrhea
Prostaglandin Synthetase Inhibitor Group
Indole acetic acid derivatives
Fenamates

Arylpropionic acid derivatives

Miscellaneous
Specific cyclooxygenase II (COX II inhibitors)

Medication

Dose (Times per Day)

Clinical Relief (%)*

Indomethacin
Flufenamic acid
Mefenamic acid
Tolfenamic acid
Ibuprofen
Naproxen sodium
Ketoprofen

25 mg (36)
100200 mg (3)
250500 mg (4)
133 mg (3)
400 mg (4)
275 mg (4)
50 mg (3)
12.52.5 mg (4)
200 mg (4)
1020 mg (12)
50100 mg (12)
25 mg (2)
2040 mg (2)
400 mg (1)

7390
7782
93
88
66100
7990
90
8788
6080
7080
7883
Not available
Not available
Not available

Suprofen
Piroxicam
Nimesulide
Rofecoxib
Valdecoxib
Lumiracoxib

* Percentage of women obtaining relief.

Also available as over-the-counter medication in United States.

Withdrawn from the market.

Effective compared with naproxen.

VOL. 108, NO. 2, AUGUST 2006

Dawood

Advances in Primary Dysmenorrhea

437

production and release. Thus, the menstrual fluid


volume remains relatively unchanged, but the menstrual fluid prostaglandins are markedly reduced to
the level obtained in a normal pain-free menstrual
cycle or even below normal levels.4,11,14,16,18,20
If relief is inadequate, combination oral contraceptive can be tried for up to another three cycles.
Because NSAIDs provide relief in as many as 80
85% of dysmenorrheic patients if judiciously used,
laparoscopy becomes necessary only in a small group
of women who have a history suggesting primary
dysmenorrhea (Fig. 6). Patients with endometriosis
are not relieved by NSAIDs (vide supraCOX II
inhibitor).53 There is no published evidence to support relief of endometriosis with monthly cyclic use of
oral contraceptive. If pelvic disease causing the dysmenorrhea is found at laparoscopy, appropriate therapy is directed to the underlying pathology so that
relief of the secondary dysmenorrhea may be attained. If no pelvic pathology is found, multimodal
therapy, using some of the partially evidence-supported or less well-established therapies discussed
above, may be tried.
Cervical dilation and hysteroscopy are recommended at the time of laparoscopy to ensure completeness of excluding secondary dysmenorrhea and
for any temporary relief that dilation may confer on
some patients by widening the cervical canal and
promoting menstrual flow and thereby reducing menstrual fluid prostaglandin contact with the myometrium. Additionally, cervical dilation may induce
paracervical neurapraxia or partial disruption of the
paracervical innervations. However, there is no published evidence about the efficacy of cervical dilation,
even for the short term.
REFERENCES
1. Ylikorkala O, Dawood MY. New concepts in dysmenorrhea.
Am J Obstet Gynecol 1978;130:83347.
2. Burnett MA, Antao V, Black A, Feldman K, Grenville A, Lea
R, et al. Prevalence of primary dysmenorrhea in Canada. J
Obstet Gynaecol Can 2005;27:76570.
3. Dawood MY. Dysmenorrhea. Infertil Reprod Med Clin N
Am 1995;6:36377.
4. Dawood MY. Hormones, prostaglandin and dysmenorrhea.
In: Dawood MY, editor. Dysmenorrhea. Baltimore (MD):
Williams and Wilkins; 1981. p. 2052.
5. Golomb LM, Solidum AA, Warren MP. Primary dysmenorrhea and physical activity. Med Sci Sports Exerc 1998;30:
9069.
6. Pickles VR. A plain muscle stimulant in the menstruum.
Nature 1957;180:11989.
7. Eglinton G, Rahael RA, Smith GN, Hall WJ, Pickles VR.
Isolation and identification of two smooth muscle stimulants
from menstrual fluid. Nature 1963;200:960.

438

Dawood

Advances in Primary Dysmenorrhea

8. Pickles VR, Hall WJ, Best FA, Smith GN. Prostaglandin in


endometrium and menstrual fluid from normal and dysmenorrhoeic subjects. J Obstet Gynaecol Br Commonw 1965;72:
18592.
9. Lundstrom V, Green K. Endogenous levels of prostaglandin
F2a and its main metabolites in plasma and endometrium in
normal and dysmenorrheic women. Am J Obstet Gynecol
1978;130:6406.
10. Chan WY, Hill JC. Determination of menstrual prostaglandin
levels in non-dysmenorrheic and dysmenorrheic subjects.
Prostaglandins 1978;15:36575.
11. Chan WY, Dawood MY, Fuchs F. Relief of dysmenorrhea
with the prostaglandin synthetase inhibitor ibuprofen: effect
on prostaglandin levels in menstrual fluid. Am J Obstet
Gynecol 1979;135:1028.
12. Chan WY, Dawood MY. Prostaglandin levels in menstrual
fluid of non-dysmenorrheic and of dysmenorrheic subjects
with and without oral contraceptives or ibuprofen therapy.
Adv Prostaglandin Thromboxane Res 1980;8:14437.
13. Chan WY, Dawood MY, Fuchs F. Prostaglandins in primary
dysmenorrhea. Comparison of prophylactic and nonprophylactic treatment with ibuprofen and use of oral contraceptives.
Am J Med 1981;70:53541.
14. Chan WY, Fuchs F, Powell AM. Effects of naproxen sodium
on menstrual prostaglandins and primary dysmenorrhea.
Obstet Gynecol 1983;61:28591.
15. Powell AM, Chan WY, Alvin P, Litt IF. Menstrual-PGF2
alpha, PGE2 and TXA2 in normal and dysmenorrheic
women and their temporal relationship to dysmenorrhea.
Prostaglandins 1985;29:27390.
16. Dawood MY. Dysmenorrhoea and prostaglandins: pharmacological and therapeutic considerations. Drugs 1981;22:
4256.
17. Chan WY. Prostaglandins and nonsteroidal antiinflammatory
drugs in dysmenorrhea. Annu Rev Pharmacol Toxicol 1983;
23:13149.
18. Dawood MY. Ibuprofen and dysmenorrhea. Am J Med
1984;77:8794.
19. Dawood MY. Dysmenorrhea. J Reprod Med 1985;30:
15467.
20. Dawood MY. Nonsteroidal antiinflammatory drugs and
reproduction. Am J Obstet Gynecol 1993;169:125565.
21. Creatsas G, Deligeoroglou E, Zachari A, Loutradis D, Papadimitriou T, Miras K, et al. Prostaglandins: PGF2 alpha, PGE2,
6-keto-PGF1 alpha and TXB2 serum levels in dysmenorrheic
adolescents before, during and after treatment with oral
contraceptives. Eur J Obstet Gynecol Reprod Biol 1990;36:
2928.
22. Wiqvist N, Lindblom B, Wilhelmsson L. The pathophysiology of primary dysmenorrhea. Res Clin Forums 1979;1:
4754.
23. Demers LM, Hahn DW, McGuire JL. Newer concepts in
dysmenorrheal research: leukotrienes and calcium channel
blockers. In: Dawood MY, McGuire JL, Demers LM, editors.
Premenstrual syndrome and dysmenorrhea. Baltimore (MD):
Urban and Schwarzenberg; 1985. p. 205.
24. Carraher R, Hahn DW, Ritchie DM, McGuire JL. Involvement of lipoxygenase products in myometrial contractions.
Prostaglandins 1983;26:2332.
25. Rees MCP, DiMarzo V, Tippins JR, Morris HR, Turnbull
AC. Leukotriene release by endometrium and myometrium
throughout the menstrual cycle in dysmenorrhea and menorrhagia. J Endocrinol 1987;113:2915.

OBSTETRICS & GYNECOLOGY

26. Bieglmayer C, Hofer G, Kainz C, Reinthaller A, Kopp B,


Janisch H. Concentrations of various arachidonic acid metabolites in menstrual fluid are associated with menstrual pain
and are influenced by hormonal contraceptives. Gynecol
Endocrinol 1995;9:30712.
27. Nigam S, Benedetto C, Zonca M, Leo-Rossberg I, Lubbert H,
Hammerstein J. Increased concentrations of eicosanoids and
platelet-activating factor in menstrual blood from women
with primary dysmenorrhea. Eicosanoids 1991;4:13741.
28. Mitchell MD, Grzyboski CF. Arachidonic acid metabolism
by lipoxygenase pathways in intrauterine tissues of women at
term of pregnancy. Prostaglandins Leukot Med 1987;28:
30312.
29. Akerlund M, Stromberg P, Forsling ML. Primary dysmenorrhea and vasopressin. Br J Obstet Gynaecol 1979;86:4847.
30. Valentin L, Sladkevicius P, Kindahl H, Broeders A, Marsal K,
Melin P. Effects of a vasopressin antagonist in women with
dysmenorrhea. Gynecol Obstet Invest 2000;50:1707.
31. Akerlund M. Pathophysiology of dysmenorrhea. Acta Obstet
Gynecol Scand 1979;87 suppl:2732.
32. Brouard R, Bossmar T, Fournie-Lloret D, Chassard D, Akerlund M. Effect of SR49059, an orally active V1a vasopressin
receptor antagonist, in the prevention of dysmenorrhoea.
BJOG 2000;107:6149.
33. Ulmsten U, Anderssen KE. Mutichannel intrauterine pressure
recording by means of microtransducers. Acta Obstet
Gynecol Scand 1979;58:11520.
34. Andersson KE, Ulmsten U. Effects of nifedipine on myometrial activity and lower abdominal pain in women with
primary dysmenorrhea. Br J Obstet Gynaecol 1978;85:1428.
35. Lundstrom V, Green K, Wiqvist N. Prostaglandins, indomethacin and dysmenorrhea. Prostaglandins 1976;11:
893907.
36. Csapo AI, Pinto-Dantas CR. The cyclic activity of the nonpregnant human uterus: a new method for recording intrauterine pressure. Fertil Steril 1966;17:348.
37. Csapo AI, Pulkkinen MO, Henzl MR. The effect of naproxen
sodium on the intrauterine pressure and menstrual pain of
dysmenorrheic patients. Prostaglandins 1977;13:1939.
38. Brotanek V, Kazda S, Roth L. A method for studying uterine
blood flow in pregnant women. Physiol Bohemoslov 1962;
11:35863.
39. Brotanek V, Hendricks CH, Yoshida T. Changes in uterine
blood flow during uterine contractions. Am J Obstet Gynecol
1969;103:110816.
40. Akerlund M, Andersson KE, Ingemarsson I. Effects of terbutaline on myometrial activity, uterine blood flow, and
lower abdominal pain in women with primary dysmenorrhoea. Br J Obstet Gynaecol 1976;83:6738.
41. Ulmsten U. Uterine activity and blood flow in normal and
dysmenorrheic women. In: Dawood MY, McGuire JL, Demers LM, editors. Premenstrual syndrome and dysmenorrhea.
Baltimore (MD): Urban and Schwarzenberg; 1985. p.
103124.
42. Altunyurt S, Gol M, Altunyurt S, Sezer O, Demir N. Primary
dysmenorrhea and uterine blood flow: a color Doppler study.
J Reprod Med 2005;50:2515.
43. Dawood MY. Dysmenorrhea. In: Max M, Portenoy R, Laska
E, editors. The design of analgesic clinical trials. New York
(NY): Raven Press; 1991. p. 42943.
44. Marjoribanks J, Proctor ML, Farquhar C. Nonsteroidal antiinflammatory drugs for primary dysmenorrhoea (Cochrane
Review). In: The Cochrane Library, Issue 4, 2003. Oxford:
Update Software.

VOL. 108, NO. 2, AUGUST 2006

45. Milsom I, Minic M, Dawood MY, Akin MD, Spann J, Niland


NF, 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;24:1384400.
46. Akerlund M, Stromberg P. Comparison of ketoprofen and
naproxen in the treatment of dysmenorrhoea, with special
regard to the time of onset of pain relief. Curr Med Res Opin
1989;11:48590.
47. Dawood MY. Multi-center, randomized double-blind, crossover study comparing ketoprofen 12.5 mg and 25 mg,
ibuprofen 200 mg and placebo in the treatment of primary
dysmenorrhea. Miles Medical Research Report No. 1245,
1994.
48. Fulmer RI. A randomized, double-blind, cross-over study
comparing 12.5 mg and 25 mg, ibuprofen 200 mg and
placebo in the treatment of primary dysmenorrhea. Miles
Medical Report No. 1238, 1994.
49. Morrison BW, Daniels SE, Kotey P, Cantu N, Seidenberg B.
Rofecoxib, a specific cyclooxygenase-2 inhibitor, in primary
dysmenorrhea: a randomized controlled trial. Obstet
Gynecol 1999;94:5048.
50. Daniels SE, Talwalker S, Torri S, Snabes MC, Recker DP,
Verburg KM. Valdecoxib, a cyclooxygenase-2-specific inhibitor, is effective in treating primary dysmenorrhea. Obstet
Gynecol 2002;100:3508.
51. Daniels SE, Torri S, Desjardins PJ. Valdecoxib for treatment
of primary dysmenorrhea: a randomized, double-blind comparison with placebo and naproxen. J Gen Intern Med
2005;20:627.
52. Bitner M, Kattenhorn J, Hatfield C, Gao J, Kellstein D.
Efficacy and tolerability of lumiracoxib in the treatment of
primary dysmenorrhoea. Int J Clin Pract 2004;58:3405.
53. Allen C, Hopewell S, Prentice A. Non-steroidal anti-inflammatory drugs for pain in women with endometriosis
(Cochrane Review). In: The Cochrane Library, Issue 4, 2005.
Oxford: Update Software.
54. Kauppila A, Ronnberg L. Naproxen sodium in dysmenorrhea
secondary to endometriosis. Obstet Gynecol 1985;65:
37983.
55. Ylikorkala O, Viinikka L. Prostaglandins and endometriosis.
Acta Obstet Gynecol Scand Suppl 1983;113:1057.
56. Proctor ML, Roberts H, Farquhar CM. Combined oral
contraceptive pill (OCP) as treatment for primary dysmenorrhoea (Cochrane Review). In: The Cochrane Library, Issue 4,
2001. Oxford: Update Software.
57. Ekstrom P, Akerlund M, Forsling M, Kindahl H, Laudanski
T, Mrugacz G. Stimulation of vasopressin release in women
with primary dysmenorrhea and after oral contraceptive
treatment: effect on uterine contractility. Br J Obstet Gynaecol 1992;99:6804.
58. Milsom I, Sundell G, Andersch B. The influence of different
combined oral contraceptives on the prevalence and severity
of dysmenorrhea. Contraception 1990;42:497506.
59. Davis AR, Westhoff C, OConnell K, Gallagher N. Oral
contraceptives for dysmenorrhea in adolescent girls: a randomized trial. Obstet Gynecol 2005;106:97104.
60. Edelman AB, Gallo MF, Jensen JT, Nichols MD, Schulz KF,
Grimes DA. Continuous or extended cycle vs. cyclic use of
combined oral contraceptives for contraception (Cochrane
Review). In: The Cochrane Library, Issue 3, 2005. Oxford:
Update Software.

Dawood

Advances in Primary Dysmenorrhea

439

61. Morgan PJ, Kung R, Tarshis J. Nitroglycerin as a uterine


relaxant: a systematic review. J Obstet Gynaecol Can 2002;
24:4039.

78. Ali M, Gudbranson CG, McDonald JW. Inhibition of human


platelet cyclooxygenase by alpha-tocopherol. Prostaglandins
Med 1980;4:7985.

62. Transdermal nitroglycerine in the management of pain associated with primary dysmenorrhoea: a multinational pilot
study. The Transdermal Nitroglycerine/Dysmenorrhoea
Study Group. J Int Med Res 1997;25:414.

79. Tseng YF, Chen CH, Yang YH. Rose tea for relief of
primary dysmenorrhea in adolescents: a randomized controlled trial in Taiwan. J Midwifery Womens Health 2005;
50:e517.

63. Moya RA, Moisa CF, Morales F, Wynter H, Ali A, Narancio


E. Transdermal glyceryl trinitrate in the management of
primary dysmenorrhea. Int J Gynaecol Obstet 2000;69:
1138.

80. Namavar JB, Tartifizadeh A, Khabnadideh S. Comparison of


fennel and mefenamic acid for the treatment of primary
dysmenorrhea. Int J Gynaecol Obstet 2003;80:1537.

64. Facchinetti F, Sgarbi L, Piccinini F, Volpe A. A comparison of


glyceryl trinitrate with diclofenac for the treatment of primary
dysmenorrhea: an open, randomized, cross-over trial.
Gynecol Endocrinol 2002;16:3943.
65. Wilson ML, Murphy PA. Herbal and dietary therapies for
primary and secondary dysmenorrhoea (Cochrane Review).
In: The Cochrane Library, Issue 3, 2001. Oxford: Update
Software.
66. Benassi L, Barletta FP, Baroncini L, Bertani D, Filippini F,
Beski L, et al. Effectiveness of magnesium pidolate in the
prophylactic treatment of primary dysmenorrhea. Clin Exp
Obstet Gynecol 1992;19:1769.
67. Seifert B, Wagler P, Dartsch S, Schmidt U, Nieder J.
Magnesiuma new therapeutic alternative in primary dysmenorrhea. Zentralbl Gynakol 1989;111:75560.
68. Sandahl B, Ulmsten U, Andersson KE. Trial of the calcium
antagonist nifedipine in the treatment of primary dysmenorrhoea. Arch Gynecol 1979;227:14751.
69. Andersson KE, Ulmsten U. Effects of nifedipine on myometrial activity and lower abdominal pain in women with
primary dysmenorrhoea. Br J Obstet Gynaecol 1978;85:
1428.
70. Ulmsten U. Calcium blockade as a rapid pharmacological test
to evaluate primary dysmenorrhea. Gynecol Obstet Invest
1985;20:7883.
71. Butler EB, McKnight E. Vitamin E in the treatment of
primary dysmenorrhea. Lancet 1955;268:8447.
72. Ziaei S, Faghihzadeh S, Sohrabvand F, Lamyian M, Emamgholy T. A randomized placebo-controlled trial to determine
the effect of vitamin E in treatment of primary dysmenorrheal. BJOG 2001;108:11813.
73. Ziaei S, Zakeri M, Kazemnejad A. A randomized controlled
trial of vitamin E in the treatment of primary dysmenorrhoea.
BJOG 2005;112:4669.
74. Wu D, Liu L, Meydani M, Meydani SN. Vitamin E increases
production of vasodilator prostanoids in human aortic endothelial cells through opposing effects on cyclooxygenase-2
and phospholipase A2. J Nutr 2005;135:184753.

81. Sampalis F, Bunea R, Pelland MF, Kowalski O, Duguet N,


Dupuis S. Evaluation of the effects of Neptune Krill Oil on the
management of premenstrual syndrome and dysmenorrhea.
Altern Med Rev 2003;8:1719.
82. Proctor ML, Smith CA, Farquhar CM, Stones RW. Transcutaneous electrical nerve stimulation and acupuncture for
primary dysmenorrhoea (Cochrane Review). In: The
Cochrane Library, Issue 1, 2002. Oxford: Update Software.
83. Dawood MY, Ramos J. Transcutaneous electrical nerve stimulation (TENS) for the treatment of primary dysmenorrhea: a
randomized crossover comparison with placebo TENS and
ibuprofen. Obstet Gynecol 1990;75:65660.
84. Lewers D, Clelland JA, Jackson JR, Varner RE, Bergman J.
Transcutaneous electrical nerve stimulation in the relief of
primary dysmenorrhea. Phys Ther 1989;69:39.
85. Lundeberg T, Bondesson L, Lundstrom V. Relief of primary
dysmenorrhea by transcutaneous electrical nerve stimulation.
Acta Obstet Gynecol Scand 1985;64:4917.
86. Mannheimer JS, Whalen EC. The efficacy of transcutaneous
electrical nerve stimulation in dysmenorrhea. Clin J Pain
1985;1:7583
87. Milsom I, Hedner N, Mannheimer C. A comparative study of
the effect of high-intensity transcutaneous nerve stimulation
and oral naproxen on intrauterine pressure and menstrual
pain in patients with primary dysmenorrhea. Am J Obstet
Gynecol 1994;170:1239.
88. Neighbours LE, Clelland J, Jackson JR, Bergman J, Orr J.
Transcutaneous electrical nerve stimulation for pain relief in
primary dysmenorrhea. Clin J Pain 1987;3:1722.
89. Santiesteban AJ, Burnham TL, George KL, Kita PJ, Mehring
EA. Primary spasmodic dysmenorrhea: the use of TENS on
acupuncture points. Am J Acupunct 1985;13:35 42.
90. Walker JB, Katz RL. Peripheral nerve stimulation in the
management of dysmenorrhea. Pain 1981;11:35561.
91. Golding JF, Ashton H, Marsh R, Thompson JW. Transcutaneous electrical nerve stimulation produces variable changes
in somatosensory evoked potentials, sensory perception and
pain threshold: clinical implications for pain relief. J Neurol
Neurosurg Psychiatry 1986;49:1397406.

75. Beharka AA, Wu D, Serafini M, Meydani SN. Mechanism of


vitamin E inhibition of cyclooxygenase activity in macrophages from old mice: role of peroxynitrite. Free Radic Biol
Med 2002;32:50311.

92. Melzack R, Wall PD. Pain mechanisms: a new theory.


Science 1965;150:9719.

76. Sakamoto W, Fujie K, Nishihira J, Mino M, Morita I, Minota


S. Inhibition of PGE2 production in macrophages from
vitamin E-treated rats. Prostaglandins Leukot Essent Fatty
Acids 1991;44:8992.

94. Habek D, Cerkez Habek J, Bobic-Vukovic M, Vujic B.


Efficacy of acupuncture for the treatment of primary
dysmenorrhea. Gynakol Geburtshilfliche Rundsch 2003;
43:2503.

77. Pentland AP, Morrison AR, Jacobs SC, Hruza LL, Herbert JS,
Packer L. Tocopherol analogs suppress arachidonic acid
metabolism via phospholipase inhibition. J Biol Chem 1992;
267:1557884.

95. Wang L, Cardini F, Zhao W, Regalia AL, Wade C, Forcella


E, et al. Vitamin K acupuncture pint injection for severe
primary dysmenorrhea: an international pilot study. MedGenMed 2004;6:45.

440

Dawood

Advances in Primary Dysmenorrhea

93. Helms JM. Acupuncture for the management of primary


dysmenorrhea. Obstet Gynecol 1987;69:516.

OBSTETRICS & GYNECOLOGY

96. Pouresmail Z, Ibrahimzadeh R. Effects of acupressure and


ibuprofen on the severity of primary dysmenorrhea. J Tradit
Chin Med 2002;22:20510.
97. Chen HM, Chen CH. Effects of acupressure at the Sanyinjiao
point on primary dysmenorrhoea. J Adv Nurs 2004;48:3807.
98. Akin M, Price W, Rodriguez G Erasala G, Hurley G, Smith
RP. Continuous, low-level, topical heat wrap therapy as
compared to acetaminophen for primary dysmenorrhea.
J Reprod Med 2004;49:73945.
99. Eccles NK. A randomized, double-blinded, placebo-controlled pilot study to investigate the effectiveness of a static
magnet to relieve dysmenorrhea. J Altern Complement Med
2005;11:6817.

100. Proctor M, Latthe P, Farquhar C, Khan K, Johnson N,


Proctor M. Surgical interruption of pelvic nerve pathways
for primary and secondary dysmenorrhoea (Cochrane
Review). In: The Cochrane Library, Issue 4, 2005. Oxford:
Update Software.
101. Proctor ML, Hing W, Johnson TC, Murphy PA. Spinal
manipulation for primary and secondary dysmenorrhoea
(Cochrane Review). In: The Cochrane Library, Issue 4, 2001.
Oxford: Update Software.
102. Proctor ML, Hing W, Johnson TC, Murphy PA. Spinal
manipulation for primary and secondary dysmenorrhoea
(Cochrane Review). In: The Cochrane Library, Issue 3, 2004.
Oxford: Update Software.

Continuing Medical Education Credits Now Available for the


Clinical Expert Series
Continuing medical education (CME) credits are now being awarded for the Clinical
Expert Series.* Follow these steps to receive credit:
1. Log on to www.greenjournal.org or the Members-Only area on www.acog.org to access the
most recent journal issue
2. Read the Clinical Expert Series article (quizzes are available for articles published since
August 2005)
3. Download the quiz (in Microsoft Word format)
4. Complete the quiz and save your answers
5. E-mail the completed quiz to cognates@acog.org as an attachment or fax the quiz to
202-484-1586
*ACCME Accreditation: The American College of Obstetricians and Gynecologists (ACOG) is accredited by the
Accreditation Council for Continuing Medical Education to provide continuing medical education for
physicians.
AMA PRA Category 1 CreditTM and ACOG Cognate Credit: The American College of Obstetricians and
Gynecologists (ACOG) designates this educational activity for a maximum of 2 AMA PRA Category 1
CreditsTM or up to a maximum of 2 category 1 ACOG cognate credits. Physicians should only claim credit
commensurate with the extent of their participation in the activity.

VOL. 108, NO. 2, AUGUST 2006

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