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

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

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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

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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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-

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.
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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

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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

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.

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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.

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-

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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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

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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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 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.

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
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-

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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,

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.

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Fig. 4. Pathway for the selection of prostaglandin synthetase inhibitor compared with oral contraceptive in the management of primary dysmenorrhea.
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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.

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Fig. 6. Algorithm for managing primary dysmenorrhea with prostaglandin synthetase inhibitor.
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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

Medication
Indomethacin Flufenamic acid Mefenamic acid Tolfenamic acid Ibuprofen Naproxen sodium Ketoprofen Suprofen Piroxicam Nimesulide Rofecoxib Valdecoxib Lumiracoxib

Dose (Times per Day)

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)

Clinical Relief (%)*

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

Arylpropionic acid derivatives

Miscellaneous Specific cyclooxygenase II (COX II inhibitors)

* Percentage of women obtaining relief. Also available as over-the-counter medication in United States. Withdrawn from the market. Effective compared with naproxen.

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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.

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.

438

Dawood

Advances in Primary Dysmenorrhea

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.

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.

VOL. 108, NO. 2, AUGUST 2006

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. 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. 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. 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. 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. 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. 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.

78. Ali M, Gudbranson CG, McDonald JW. Inhibition of human platelet cyclooxygenase by alpha-tocopherol. Prostaglandins Med 1980;4:7985. 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. 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. 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. 92. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150:9719. 93. Helms JM. Acupuncture for the management of primary dysmenorrhea. Obstet Gynecol 1987;69:516. 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. 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

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.

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