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 concom-
itant 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)
P
rimary dysmenorrhea is defined as painful men-
strual 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 4050% 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
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 mod-
erate 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 pri-
mary dysmenorrhea to targeted young populations.
The prevalence of primary dysmenorrhea de-
creases 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 cy-
cles.
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
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
428 VOL. 108, NO. 2, AUGUST 2006 OBSTETRICS & GYNECOLOGY
CLINICAL FEATURES
Primary dysmenorrhea presents with or shortly after
menarche. It may start within 6 months after men-
arche because it occurs only during ovulatory cycles,
which may not always be evident at menarche. Al-
though 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 men-
strual 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 2436 hours, consis-
tent 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 es-
sentially normal.
The typical history and absence of any positive
findings in the physical examination are key diagnos-
tic features. The diagnostic history includes the prox-
imities of the onset of primary dysmenorrhea with
menarche, the onset of symptoms with the onset of
menstrual flow, and the duration of menstrual cramp-
ing and its characteristic description. Thus, primary
dysmenorrhea should be diagnosed as a specific
entity, but there is no laboratory test for it.
PATHOPHYSIOLOGY
Advances in the last three decades and current un-
derstanding suggest that in primary dysmenorrhea
there is abnormal and increased prostanoid and pos-
sibly eicosanoid secretion, which in turn induces
abnormal uterine contractions. The contractions re-
duce 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) substan-
tial evidence demonstrating and correlating the
amount of menstrual prostanoids in women with
primary dysmenorrhea compared with eumenorrheic
women, and 3) many clinical trials demonstrating the
efficacy of cyclooxygenase (COX) inhibitors in reliev-
ing the pain of primary dysmenorrhea through pros-
taglandin suppression and quantitative decrease of
menstrual fluid prostaglandins.
Prostanoids
In primary dysmenorrhea, there is increased abnor-
mal uterine contractility, similar to uterine contractil-
ity 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 colleagues
6,7
postulated that men-
strual stimulant or prostaglandins were elevated in
menstrual extracts of women with primary dysmen-
orrhea compared with eumenorrheic women.
8
With
availability of radioimmunoassay and specific anti-
serum, several laboratories, including ours, were able
to measure small quantities of prostanoids in endo-
metrium and menstrual fluid with greater preci-
sion.
915
In most but not all women with primary
dysmenorrhea, there is increased endometrial secre-
tion of menstrual prostaglandin F
2
(PGF
2
) 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 PGF
2
released
4,13
(Fig. 1).
Fig. 1. Correlation between the amounts of prostaglandins
in prostaglandin F
2
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 dysmenor-
rhea. 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.
VOL. 108, NO. 2, AUGUST 2006 Dawood Advances in Primary Dysmenorrhea 429
When a nonsteroidal anti-inflammatory drug
(NSAID) such as ibuprofen is taken during menstru-
ation, the menstrual fluid prostaglandins are signifi-
cantly 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 proges-
tin), her menstrual fluid prostaglandins are signifi-
cantly 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 pa-
tients with normal laparoscopic finding and severe
dysmenorrhea who do not have elevated menstrual
PGF
2
to account for the severe cramping.
11
The
prevalence of such patients is currently not known.
The role of prostanoids such as thromboxane A
2
,
prostacyclin, and leukotrienes in the pathogenesis
of primary dysmenorrhea is neither fully under-
stood nor adequately explored. Prostacyclin, a po-
tent 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 en-
zyme pathway rather than the COX pathway may
account for some forms of primary dysmenorrhea
that are not responsive to NSAIDs.
23
The 5-lipoxy-
genase 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-lipoxy-
genase pathway and that leukotrienes are involved
in myometrial contractions.
24
In women with pri-
mary dysmenorrhea, there are significantly higher
concentrations of menstrual leukotrienes,
25,26
espe-
cially 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 biosynthe-
sized 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, proges-
terone levels decline during the late luteal phase.
This causes labilization of lysosomes and release of
their phospholipase enzyme, which then hydro-
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
In-
creased levels of circulating vasopressin during men-
struation reported in women with primary dysmenor-
rhea
31
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
Fig. 2. The lipoxygenase (5-lipoxygenase and 12-lipoxygen-
ase) pathways for biosynthesis of hydroxyperoxyeicosatet-
raenoic (HPETE) acid. Leukotrienes A, B, and C are even-
tually 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 dysmenor-
rhea not responding to NSAID therapy.
Dawood. Advances in Primary Dysmenorrhea. Obstet Gynecol
2006.
430 Dawood Advances in Primary Dysmenorrhea OBSTETRICS & GYNECOLOGY
vasopressin and relieve dysmenorrhea.
31,32
Other in-
vestigators could not confirm elevated plasma vaso-
pressin 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 well-
defined 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.
16,1820,31,3335
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 34 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
labor with pushing), and the contractions are synchro-
nous and rhythmical. In patients with primary dys-
menorrhea, four contraction abnormalities alone or in
combination have been reported. They include ele-
vated basal tone (more than 10 mmHg), which is
frequently seen,
36
elevated active pressures (more
than 120 mmHg, often more than 150180 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, electro-
magnetic flowmeters, and the microsphere methods.
Fig. 3. The arachidonic acid
cascade showing the cycloox-
ygenase (COX) pathway, the
biosynthesis of cyclic endoper-
oxides PGG and PGH, and the
final products: prostacyclin,
prostaglandins F (PGF) and E
(PGE), and thromboxane A
2
(TxA
2
). The enzymes are shown
in italics. Thus, COX inhibitors
block early in the COX path-
way. Prostaglandin F, PGE, and
TxA induce smooth muscle
contractions (uterine contrac-
tility, vasoconstriction) and hy-
persensitization of pain nerve
fibers.
Dawood. Advances in Primary
Dysmenorrhea. Obstet Gynecol
2006.
VOL. 108, NO. 2, AUGUST 2006 Dawood Advances in Primary Dysmenorrhea 431
Thermoelectric blood flow recordings based on ther-
modilution have been used for assessing changes in
uterine pressure and variations in blood flow.
3741
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 myome-
trial 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 dysmen-
orrhea, 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, nonphar-
macological, and surgical. By far, the pharmacologi-
cal 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 3540% 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 symp-
toms, functionality as measured by reduction in ab-
senteeism ,and qualitative improvement in perfor-
mance).
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 diag-
nosis 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, in-
volving 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-
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 pros-
taglandins can be reliably compared.
Pharmacological Agents
Nonsteroidal Anti-Inflammatory Drugs
(NSAIDs)
In women with dysmenorrhoea, NSAIDs are signifi-
cantly 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 signif-
icantly more common (OR 1.52, 95% CI 1.092.12).
There was insufficient power to detect differences
between different NSAIDs because most individual
comparisons were based on a few small trials unsuit-
able for meta-analysis. Thus there is insufficient evi-
dence to determine which (if any) individual NSAID
is the most safe and effective for treatment of dysmen-
orrhoea. 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, random-
ized, 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-
432 Dawood Advances in Primary Dysmenorrhea OBSTETRICS & GYNECOLOGY
theless, cost considerations, lack of superiority, and
concerns about the adverse effects of COX-II inhibi-
tors do not support them as a first-line NSAID for
treatment of primary dysmenorrhea. Several NSAIDs
have been approved and are available as OTC med-
ications, including ibuprofen, naproxen sodium,
45
and
ketoprofen.
47,48
Nonsteroidal anti-inflammatory drugs relieve pri-
mary dysmenorrhea by inhibiting endometrial pros-
taglandin production
4
but also have direct analgesic
properties at the central nervous system level. Non-
steroidal anti-inflammatory drugs do not appear to
affect the development of the endometrium when
given during the menstrual phase for primary dys-
menorrhea but directly inhibit COX activity and
therefore suppress endometrial prostaglandin biosyn-
thesis 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
Accom-
panying the decrease in menstrual fluid prostaglan-
dins 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 gastrointesti-
nal symptoms, central nervous system symptoms,
nephrotoxic and hepatotoxic effects, hematologic ab-
normalities, 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. Inter-
estingly, in most of the clinical trials, there are re-
ported 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 en-
doperoxides involves catalytic conversion by the en-
zyme 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 gastroduo-
denal ulcers. More specific COX II inhibitors are now
available, but concerns about their adverse effects
have recently attracted attention. Rofecoxib,
49
valde-
coxib,
50,51
and lumiracoxib
52
are effective for treating
primary dysmenorrhea. Thus far, COX II inhibitors
are equally effective but not better than naproxen
sodium.
49,50,52
Given the above considerations, con-
cerns about safety of COX II inhibitors, the short
duration of therapy for relieving primary dysmenor-
rhea, 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
patients
53
. 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 con-
traceptive pills (OCPs) with medium-dose estrogen
and first-/second-generation progestogens are more
effective than placebo for relief of primary dysmen-
orrhea.
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 differ-
ence in the prevalence rate of dysmenorrhea between
users of these preparations,
58
but the observations are
indirect. A recent randomized, double-blind, placebo-
controlled trial of adolescents confirmed that low-
dose (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 extended-
use OCP found that few studies reported on men-
strual pain, but the regimen fared slightly better than
cyclic use.
60
There is insufficient information about
long-acting progestational contraceptives and pri-
mary dysmenorrhea.
Glyceryl Trinitrate
Diminished levels of nitric oxide induce myometrial
contractions while nitric oxide causes uterine relax-
ation. 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-
VOL. 108, NO. 2, AUGUST 2006 Dawood Advances in Primary Dysmenorrhea 433
cantly reduces the pain in primary dysmenorrhea.
61
A
pilot uncontrolled study found that satisfactory-to-
excellent relief was obtained in 90% of patients with
primary dysmenorrhea.
62
In a multinational, double-
blind, 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 2026% 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 effec-
tive, but the dose and regime were widely variable.
Magnesium has been given as magnesium pidolate.
66
In one study, magnesium reduced menstrual fluid
PGF
2
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.
6870
By blocking calcium entry into
smooth muscle cell, intracellular free calcium is
reduced, the muscle relaxes, contractions are re-
duced, vasodilatation is promoted, and ionic stim-
ulation of prostanoids release is decreased. Adverse
effects reported from the studies include transient
facial flush, increased pulse rate, palpitations, and
headache.
Vitamin B
One small trial found vitamin B6 was more effective
at reducing menstrual pain than placebo or a combi-
nation of magnesium and vitamin B6.
65
A combina-
tion of magnesium and vitamin B6 was no different
from placebo. One large trial found that100 mg
vitamin B1 daily was more effective than placebo.
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, place-
bo-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, prob-
ably through prostaglandin biosynthesis, but there is
no data on menstrual fluid PGF
2a
and uterine contrac-
tility. In vitro and in vivo studies in mice suggest that
prostaglandin production is affected. Vitamin E in-
creases the production of vasodilator prostacyclin and
prostaglandin E
2
(PGE
2
), as well as a dose-dependent
upregulation of phospholipase A
2
and arachidonic
acid release, but inhibits COX posttranslational activ-
ity
74
. In macrophages, vitamin E abrogates peroxyni-
trite induction of COX
75
and significantly suppresses
arachidonic acid metabolism and prostaglandin pro-
duction through inhibition of PLA
2
and COX.
7678
In
short, vitamin E and its analogues suppress phospho-
lipase A
2
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 dysmenor-
rhea.
81
Currently there is insufficient evidence to
recommend the use of herbal and dietary therapies
for dysmenorrhea.
Nonpharmacologic Approaches
Transcutaneous Electrical Nerve Stimulation
(TENS)
A recent Cochrane review analyzed seven random-
ized 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-
434 Dawood Advances in Primary Dysmenorrhea OBSTETRICS & GYNECOLOGY
rhea than placebo TENS
8390
. 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 signifi-
cantly better than placebo TENS.
83
Thirty percent of
severe dysmenorrheic cycles can be effectively re-
lieved 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 stim-
ulation 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 con-
fers 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 electri-
cal nerve stimulation also stimulates release of endor-
phins from the peripheral nerves and the spinal cord,
thus providing another avenue of partial pain attenu-
ation. 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 Co-
chrane analysis and review
82
found one small trial
showing acupuncture to be significantly more effec-
tive 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 acupunc-
ture 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,
controlled, larger, and more definitive trials are
needed.
The therapeutic efficacy of acupressure was con-
sidered similar to that of ibuprofen in relief of dys-
menorrhea.
96
Acupressure (both administered and
self-applied) at Sanyinjiao significantly reduced men-
strual 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 appli-
cation for relief of primary dysmenorrhea.
98
This can
be used by patients or as an adjunct to other better
evidence-based therapies. A randomized, placebo-
controlled study found significant relief of primary
dysmenorrhea pain with magnet (2,500 gauss) com-
pared 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 utero-
sacral 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 evi-
dence to recommend surgical nerve interruption for
the management of primary dysmenorrhea. Adverse
events were more common with presacral neurec-
tomy. Because uterosacral nerve ablation essentially
transects postganglionic sensory fibers, they are likely
to regenerate with time and the pain returns. Suffi-
ciently 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 effec-
tive for treatment of primary dysmenorrhea.
101,102
Four trials of high-velocity, low-amplitude manipula-
tion suggest that it was no more effective than sham
manipulation for the treatment of dysmenorrhoea.
VOL. 108, NO. 2, AUGUST 2006 Dawood Advances in Primary Dysmenorrhea 435
Three of the smaller trials favored high-velocity,
low-amplitude manipulation, but one trial with an
adequate sample size found no difference. The Toft-
ness technique was shown to be more effective than
sham treatment by one small trial.
Management Algorithm
A simplified algorithmic approach has been devel-
oped 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 dysmen-
orrhea 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 estro-
gen-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
supraoral 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. 4. Pathway for the selection of prostaglandin synthetase
inhibitor compared with oral contraceptive in the manage-
ment of primary dysmenorrhea.
Dawood. Advances in Primary Dysmenorrhea. Obstet Gynecol
2006.
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
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 unneces-
sary 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, 8090% 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 as-
needed basis. Table 1 summarizes the types of
NSAIDs , their doses, and clinical efficacy in the relief
of primary dysmenorrhea. Nonsteroidal anti-inflam-
matory drugs given at the time of menstruation do not
appear to affect the development of the endometrium
but inhibit COX activity and reduce prostaglandin
Fig. 6. Algorithm for managing primary dysmenor-
rhea with prostaglandin synthetase inhibitor.
Dawood. Advances in Primary Dysmenorrhea. Obstet
Gynecol 2006.
Table 1. Clinical Efficacy of Prostaglandin Synthetase Inhibitors and Doses Used for Treatment of
Primary Dysmenorrhea
Prostaglandin Synthetase Inhibitor Group Medication Dose (Times per Day) Clinical Relief (%)*
Indole acetic acid derivatives Indomethacin 25 mg (36) 7390
Fenamates Flufenamic acid 100200 mg (3) 7782
Mefenamic acid 250500 mg (4) 93
Tolfenamic acid 133 mg (3) 88
Arylpropionic acid derivatives Ibuprofen

400 mg (4) 66100

Naproxen sodium

275 mg (4) 7990

Ketoprofen

50 mg (3) 90
12.52.5 mg (4) 8788
Miscellaneous Suprofen

200 mg (4) 6080

Piroxicam 1020 mg (12) 7080
Nimesulide 50100 mg (12) 7883
Specific cyclooxygenase II (COX II inhibitors)

Rofecoxib 25 mg (2) Not available

Valdecoxib 2040 mg (2) Not available
Lumiracoxib 400 mg (1) Not available
* 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 men-
strual 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 contra-
ceptive 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 sup-
port relief of endometriosis with monthly cyclic use of
oral contraceptive. If pelvic disease causing the dys-
menorrhea is found at laparoscopy, appropriate ther-
apy is directed to the underlying pathology so that
relief of the secondary dysmenorrhea may be at-
tained. If no pelvic pathology is found, multimodal
therapy, using some of the partially evidence-sup-
ported or less well-established therapies discussed
above, may be tried.
Cervical dilation and hysteroscopy are recom-
mended at the time of laparoscopy to ensure com-
pleteness 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 men-
strual fluid prostaglandin contact with the myome-
trium. Additionally, cervical dilation may induce
paracervical neurapraxia or partial disruption of the
paracervical innervations. However, there is no pub-
lished evidence about the efficacy of cervical dilation,
even for the short term.
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