Primary Dysmenorrhea Advances in Pathogenesis and.29

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Clinical Expert Series

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Primary DysmenorrheaAdvances in Pathogenesis and Management M. Yusoff Dawood, MD

Primary dysmenorrhea is painful menstrual cramps without any evident pathology to account forthem, and it occurs in up to 50% of menstruating females and causes significant disruption inquality of life and absenteeism. Current understanding implicates an excessive or imbalancedamount of prostanoids and possibly eicosanoids released from the endometrium duringmenstruation. The uterus is induced to contract frequently and dysrhythmically, with increasedbasal tone and increased active pressure. Uterine hypercontractility, reduced uterine blood flow,

and increased peripheral nerve hypersensitivity induce pain. Diagnosis rests on a good historywith 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 anddecrease menstrual prostanoids. An algorithm is provided for a simple approach to themanagement of primary dysmenorrhea.(Obstet Gynecol 2006;108:428–41)

P

rimary dysmenorrhea is defined as painful men-

strual cramps without any evident pathology toaccount for them. It refers to any degree of perceivedcramping pain during menstruation.

PREVALENCEA widely prevalent and common complaint among young women, primary dysmenorrhea is estimatedto be present in 40–50% of them,1 with severeforms giving rise to work or school absenteeism in15% and the mild forms requiring no medication oroccasional 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 thedysmenorrheic 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 availableOTC and prescription medications, or there isinsufficient dissemination of information about pri-mary dysmenorrhea to targeted young populations.

The prevalence of primary dysmenorrhea de-creases with increasing age: prevalence is highest inthe 20- to 24-year-old age group and decreases

progressively thereafter.3 There appears to be norelationship with parity when age is factored in.Dysmenorrhea is increased with smoking.2 Primarydysmenorrhea occurs only during ovulatory cy-cles.4 Limited studies have suggested a decline indysmenorrhea with physical exercises, but criticalanalysis and other studies do not support anyevidence-based relationship between exercise andprimary 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: [email protected].

© 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins.

ISSN: 0029-7844/06

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CLINICAL FEATURESPrimary dysmenorrhea presents with or shortly aftermenarche. 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 raisesuspicion 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 theonset of menstrual flow, the symptoms of primarydysmenorrhea lasts only 2–3 days. The pains are most intense on the first or second day of the menstrualflow, or more precisely the first 24 –36 hours, consis-tent with the time of maximal prostaglandin releaseinto the menstrual fluid (vide infra). The pains aresuprapubic in location with radiation into the inneraspects of the thighs. The cramps are frequently

accompanied by backache, nausea, vomiting, anddiarrhea in a high percentage of cases.1 With severepains, the sufferers may be absent from school orwork for a day or two. In the severe forms, the painmay present as an intense acute abdominal episodeand may mimic the presentation of an acute ectopicpregnancy. General and pelvic examinations are es-sentially normal.

The typical history and absence of any positivefindings 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, primarydysmenorrhea should be diagnosed as a specificentity, but there is no laboratory test for it.

PATHOPHYSIOLOGYAdvances 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 inducesabnormal 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 theclinical symptoms of primary dysmenorrhea and theuterine contractions and adverse effects observed inprostaglandin-induced abortion and labor, 2) substan-tial evidence demonstrating and correlating theamount of menstrual prostanoids in women with

primary dysmenorrhea compared with eumenorrheicwomen, and 3) many clinical trials demonstrating theefficacy 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 forlabor or abortion. Symptoms such as nausea, vomiting,and diarrhea occur in 60% or more of patients and aresimilar to the adverse effects of prostaglandins.

Pickles and his colleagues6,7 postulated that “men-strual stimulant” or prostaglandins were elevated inmenstrual extracts of women with primary dysmen-orrhea compared with eumenorrheic women.8 Withavailability 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.9–15 In most but not all women with primarydysmenorrhea, there is increased endometrial secre-tion of menstrual prostaglandin F2 (PGF2) during themenstrual phase.10,11 The release of prostaglandinsinto the menstrual fluid is a continuous discontinuousprocess,4 that is, the amount of menstrual fluid andprostaglandins varies throughout any window of time.The intensity of the menstrual cramps and associatedsymptoms of dysmenorrhea are directly proportionalto the amount of PGF2 released4,13 (Fig. 1).

Fig. 1. Correlation between the amounts of prostaglandinsin prostaglandin F2 equivalents released per hour duringmenstruation and the severity of the dysmenorrhea asreflected by the dysmenorrhea score in a woman withprimary dysmenorrhea. Reproduced with permission fromDawood 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.

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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 thanthose found in eumenorrheic women,11–20 and clinicalrelief 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 reductionin menstrual fluid volume/bleeding and concomitant relief of pain compared with cycles given placebo orno medication.3,12,16,19,21

Despite advances with prostaglandins in theetiology of primary dysmenorrhea, there are pa-tients with normal laparoscopic finding and severedysmenorrhea who do not have elevated menstrualPGF2 to account for the severe cramping.11 Theprevalence 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 under-stood nor adequately explored. Prostacyclin, a po-tent vasodilator and uterine relaxant, appears to bereduced in primary dysmenorrhea.22 This heightensthe uterine activity and vasoconstriction becausethe uteronic and vasoconstrictive effects of theother prostaglandins are less impeded. Increasedleukotriene produced by the 5-lipoxygenase en-zyme pathway rather than the COX pathway mayaccount 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 andmyometrium can synthesize leukotrienes,23 thusconfirming the functional activity of the 5-lipoxy-genase pathway and that leukotrienes are involvedin myometrial contractions.24 In women with pri-mary dysmenorrhea, there are significantly higherconcentrations of menstrual leukotrienes,25,26 espe-cially leukotriene C4 and leukotriene D4, than inwomen without dysmenorrhea.27 Because specificbinding sites for leukotriene C4 are demonstrablein myometrial cells,28 it is likely that leukotrienescontribute to the uterine hypercontractility seen in

primary dysmenorrhea.Prostaglandins and prostanoids are biosynthe-

sized from arachidonic acid through the COXpathway after production of arachidonic acid fromhydrolysis 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 generatearachidonic acid as well as icosatetraenoic acid.These compounds then serve as the precursors forthe COX and lipoxygenase pathways.

VasopressinInvolvement 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 contractionsthat reduce uterine blood flow and cause uterinehypoxia. In limited studies, vasopressin antagonistswere 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. Theenzymes involved are shown in italics. Thus, blockade with

cyclo-oxygenase inhibitors, as happens with nonsteroidalanti-inflammatory drugs (NSAIDs), have no effect on thelipoxygenase 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.

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vasopressin and relieve dysmenorrhea.31,32 Other in-vestigators could not confirm elevated plasma vaso-

pressin in women with primary dysmenorrhea andfound that the vasopressin antagonist atosiban had noeffect on menstrual pain, intrauterine pressure, oruterine artery pulsatility index in dysmenorrheicwomen.30

Uterine ContractionsIn normal eumenorrheic women, the uterus has well-defined contraction patterns that are influenced bysex steroids, prostaglandins, and other uterotonicsubstances throughout the menstrual cycle. Details of the pattern have been well described.16,18–20,31,33–35 Of

particular interest and relevance to the pathogenesisof primary dysmenorrhea is the uterine contractionpattern during menstruation when the symptoms of dysmenorrhea occur. During menstruation in normalwomen, the uterine basal tone is minimal (less than 10mm Hg), there are 3–4 contractions during each10-minute interval with active pressures at the peak of a contraction reaching up to 120 mmHg (comparableto 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 incombination have been reported. They include ele-vated basal tone (more than 10 mmHg), which isfrequently seen,36 elevated active pressures (morethan 120 mmHg, often more than 150–180 mmHg),increased number of contractions per 10 minutes(more than 4 or 5), and nonrhythmic or incoordinateuterine contractions. These abnormalities lead to pooruterine reperfusion and oxygenation, thus giving riseto pain. If more than one contraction abnormality ispresent, they synergize with each other so that thepain threshold is exceeded with much smaller

changes in each parameter than if only one anomalywere present.

Uterine Blood FlowStudies to determine uterine blood flow in womenhave been difficult because of the highly invasivemethods and technically challenging requirementsinvolving hydrogen clearance, nitrous oxide, electro-magnetic flowmeters, and the microsphere methods.

Fig. 3. The arachidonic acidcascade showing the cycloox-ygenase (COX) pathway, thebiosynthesis of cyclic endoper-oxides PGG and PGH, and thefinal products: prostacyclin,prostaglandins F (PGF) and E(PGE), and thromboxane A2(TxA2). The enzymes are shownin italics. Thus, COX inhibitorsblock early in the COX path-way. Prostaglandin F, PGE, andTxA induce smooth musclecontractions (uterine contrac-tility, vasoconstriction) and hy-persensitization of pain nervefibers.Dawood. Advances in Primary Dysmenorrhea. Obstet Gynecol 2006.



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Thermoelectric blood flow recordings based on ther-modilution have been used for assessing changes inuterine pressure and variations in blood flow.37–41 Ineumenorrheic women the uterine contractions do not affect uterine blood flow. By contrast, the strong andabnormal uterine contractions in dysmenorrheicwomen reduce uterine blood flow and cause myome-trial ischemia, resulting in pain. Such changes can be

produced with pharmacologically induced uterinecontractions which, if excessive, will reduce bloodflow and produce cramplike pains. Administration of an uterolytic, such as a calcium channel blocker orNSAID, abrogates the hypercontractility and restoresblood flow to normal.

These earlier studies are now supported byDoppler flow studies.42 The pulsatility index andresistance index of both uterine arteries and thearcuate 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.

MANAGEMENTThere 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 variableevidence.

In evaluating treatment efficacy, it is criticallyimportant 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 timeto relief of pain (rapidity of onset) and onset of peakpain relief, the duration of pain relief, and secondaryoutcome 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 elsewherein 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 oralcontraceptives should be excluded, although a fewtrials have included them.

In primary dysmenorrhea, all trials should beprospective, double-blind, and placebo-controlled, in-volving several cycles, with each treatment given for2–3 cycles. After ibuprofen was shown to be effective,it is now the gold standard against which new drugs ortreatment modalities are evaluated. Because of intra-

individual cycle-to-cycle variability of dysmenorrhea symptoms, it is preferable to use a parallel rather thana crossover study design for trials using only a limitednumber of cycles (2–3 cycles).43 There is little or nocrossover effect because primary dysmenorrhea isconfined to only 3 days or less, over which time thepathophysiology (vide supra) occurs and clears off. Acrossover (blinded and random) from one treatment or placebo to another is the optimum study designbecause patients can act as their own controls ortreatment comparisons and the menstrual fluid pros-taglandins can be reliably compared.

Pharmacological AgentsNonsteroidal 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]

5.65–11.09).44 Overall adverse effects were also signif-icantly more common (OR 1.52, 95% CI 1.09–2.12).There was insufficient power to detect differencesbetween different NSAIDs because most individualcomparisons were based on a few small trials unsuit-able for meta-analysis. Thus there is insufficient evi-dence to determine which (if any) individual NSAIDis the most safe and effective for treatment of dysmen-orrhoea. My personal preference is to select anNSAID that has been around for a long time, iscurrently available as a generic and therefore isrelatively inexpensive, and has many randomized

double-blinded clinical trials with data on time toonset of relief with the first dose, in addition to overallefficacy. Such NSAIDs are ibuprofen, sodiumnaproxen, or ketoprofen. Thus far, trials have shownibuprofen, naproxen, ketoprofen, mefenamic acid,and nimesulide to be significantly better than placeboor comparably as effective as ibuprofen or naproxensodium. In our study, naproxen 400 mg providesgreater pain relief than placebo and acetaminophenwithin 30 minutes and is maintained at 6 hours afteradministration.45 Ketoprofen (100 mg) was reportedmore 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 12.5and 25 mg ketoprofen and 200 mg ibuprofen weresignificantly 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-IIspecific inhibitors, should not be considered. Never-

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theless, cost considerations, lack of superiority, andconcerns about the adverse effects of COX-II inhibi-tors do not support them as a first-line NSAID fortreatment of primary dysmenorrhea. Several NSAIDshave been approved and are available as OTC med-ications, including ibuprofen, naproxen sodium,45 andketoprofen.47,48

Nonsteroidal anti-inflammatory drugs relieve pri-

mary dysmenorrhea by inhibiting endometrial pros-taglandin production4 but also have direct analgesicproperties at the central nervous system level. Non-steroidal anti-inflammatory drugs do not appear toaffect the development of the endometrium whengiven during the menstrual phase for primary dys-menorrhea but directly inhibit COX activity andtherefore suppress endometrial prostaglandin biosyn-thesis and release. Thus, menstrual fluid volumes arenot affected, but menstrual fluid prostaglandin levelsare significantly reduced to or even below levelsfound in normal pain-free cycles.4,12–14,16,18,19 Accom-

panying the decrease in menstrual fluid prostaglan-dins is a return of the uterine activity to a patternsimilar 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, andedema, but with a 3-day regimen used in primarydysmenorrheics who are usually young and healthy,adverse effects are infrequent, well tolerated, andusually 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 7–11% with placebo-treatedcycles and a slightly higher incidence of 15–16% withthe medications.

Cyclooxygenase II InhibitorsThe 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 basallywhereas 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 respondsto stimuli, the COX II inhibitors are deemed morespecific and, therefore, unlikely to induce gastroduo-denal ulcers. More specific COX II inhibitors are nowavailable, but concerns about their adverse effectshave recently attracted attention. Rofecoxib,49 valde-coxib,50,51 and lumiracoxib52 are effective for treating primary dysmenorrhea. Thus far, COX II inhibitors

are equally effective but not better than naproxensodium.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 asibuprofen and naproxen, it is prudent to recommendestablished NSAIDs with track records of long-termsafety as the preferred pharmacologic agent.

A Cochrane analysis found two trials on NSAIDfor endometriosis but analyzed only one involving 24patients53. There is no evidence that NSAIDs areeffective for pain in endometriosis.53 Earlier smallerstudies gave conflicting conclusions.54,55

Oral ContraceptiveA Cochrane analysis in 2001 concluded from fourrandomized controlled trials that combined oral con-traceptive pills (OCPs) with medium-dose estrogenand first-/second-generation progestogens are moreeffective than placebo for relief of primary dysmen-

orrhea.56 We have shown that such OCPs (estrogenand progestin) reduce menstrual fluid volume andprostaglandins to within, or even below, normalrange,4,12,13 with concomitant clinical relief during that cycle. The relief and the reduction in prostaglandinsare confined only to that particular cycle, with nocarry-over effect after stopping the OCP.4,12,13 Oralcontraceptive pills may also lower the elevatedplasma vasopressin levels found in dysmenorrheicwomen and lead to attenuation of the excessiveuterine activity.57 Monophasic and triphasic OCPs areequally effective because there is no significant differ-

ence in the prevalence rate of dysmenorrhea betweenusers of these preparations,58 but the observations areindirect. A recent randomized, double-blind, placebo-controlled trial of adolescents confirmed that low-dose (20 g ethinyl estradiol) OCP is also clinicallyeffective in relieving primary dysmenorrhea,59 albeit the Moos Menstrual Distress Questionnaire, whichdoes 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 thancyclic use.60 There is insufficient information about long-acting progestational contraceptives and pri-

mary dysmenorrhea.

Glyceryl TrinitrateDiminished levels of nitric oxide induce myometrialcontractions while nitric oxide causes uterine relax-ation. Thus glyceryl trinitrate as a source of nitricoxide can be expected to relax the exaggeratedmyometrial contractions in primary dysmenorrhea. Arecent review concluded that nitroglycerin signifi-



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cantly reduces the pain in primary dysmenorrhea.61 Apilot uncontrolled study found that satisfactory-to-excellent relief was obtained in 90% of patients withprimary dysmenorrhea.62 In a multinational, double-blind, placebo-controlled, randomized crossoverstudy, transdermal glyceryl trinitrate 0.1 mg/h wasfound to be significantly more effective during thefirst 6 hours of treatment and demonstrated greateroverall efficacy than placebo.63 A comparison of transdermal glyceryl trinitrate with diclofenac sodiumin an open, randomized, crossover trial found bothtreatments to be effective during the first 2 hours aftermedication but with slightly, but not significantly,reduced efficacy for glyceryl trinitrate.64 In all thestudies, there is low tolerability for glyceryl trinitratebecause of headache occurring in 20–26% of patients.The doses of glyceryl trinitrate patches used werefrom 0.1 to 0.2 mg/h.

MagnesiumA Cochrane data analysis in 2001 found three smalltrials 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 fluidPGF2 to 45% of its pretreatment levels,67 whichprovides a mechanistic rationale for this therapy.Currently, it is not clear what dose, preparation, andregime to use for magnesium in treating primarydysmenorrhea. Further studies are needed.

Calcium AntagonistsNifedipine, a calcium channel blocker, inhibitsmyometrial contractility, thereby relieving primarydysmenorrhea.68–70 By blocking calcium entry intosmooth muscle cell, intracellular free calcium isreduced, the muscle relaxes, contractions are re-duced, vasodilatation is promoted, and ionic stim-ulation of prostanoids release is decreased. Adverseeffects reported from the studies include transient facial flush, increased pulse rate, palpitations, and

headache.

Vitamin BOne small trial found vitamin B6 was more effectiveat 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 ETreatment of primary dysmenorrhea with vitamin Ewas reported in 1995,71 but evidence for its efficacy islimited. In a recent randomized, double-blind, place-bo-controlled trial, 500 international units vitamin Eand placebo were effective with more marked effectsfor vitamin E, suggesting a potentially large placeboeffect.72 Recently, the same investigators found 100mg vitamin E given for 5 days around menstruationsignificantly reduced the severity and duration of menstrual pain and blood loss than placebo.73 Moredefinitive trials are needed.

Vitamin E relieves primary dysmenorrhea, prob-ably through prostaglandin biosynthesis, but there isno data on menstrual fluid PGF2a 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 andprostaglandin E2 (PGE2), as well as a dose-dependent upregulation of phospholipase A2 and arachidonicacid release, but inhibits COX posttranslational activ-ity74. In macrophages, vitamin E abrogates peroxyni-trite induction of COX75 and significantly suppressesarachidonic acid metabolism and prostaglandin pro-duction through inhibition of PLA2 and COX.76–78 Inshort, vitamin E and its analogues suppress phospho-lipase A2 and COX activities to inhibit prostaglandinproduction but promote vasodilator and uterine musclerelaxing prostanoids such as prostacyclin.

Herbs

Adolescents who drank rose tea (n

70) perceived lessmenstrual pain and distress at 1, 3, and 6 months,compared with controls (n60).79 Other herbs, suchas extracts of sweet fennel seeds (Foeniculum vulgare ),are less potent than naproxen for relief of primarydysmenorrhea.80 A Cochrane analysis concluded that a small trial showed fish oil (mega-3 fatty acids) to bemore effective than placebo.65 Krill oil significantlyreduces the number of analgesics used for dysmenor-rhea.81 Currently there is insufficient evidence torecommend the use of herbal and dietary therapiesfor dysmenorrhea.

Nonpharmacologic ApproachesTranscutaneous Electrical Nerve Stimulation(TENS)A recent Cochrane review analyzed seven random-ized controlled trials of transcutaneous electricalnerve stimulation (TENS) compared with placebo orno treatment.82 Overall, high-frequency TENS ismore effective for pain relief in primary dysmenor-

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rhea than placebo TENS83–90. Low-frequency TENS isno more effective than placebo TENS. Our owndouble-blind, randomized, placebo-controlled studiesusing 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 theremaining 70% of cycles was significantly less thanwithout TENS. Transcutaneous electrical nerve stim-ulation is a noninvasive and effective method forrelief of primary dysmenorrhea and empowers thewoman to control her treatment because she canregulate 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 thelarge diameter A sensory fibers of the same nerveroot, TENS raises the threshold for pain signals by

lowering the “gate,” thus blocking signal receptionalong the same root from the uterine hypoxia andhypercontractility.91,92 Thus, the uterine signals areless 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 neutralizethis effect.86

Acupuncture and AcupressureBoth acupuncture and acupressure have been tried

for relief of primary dysmenorrhea. However, thelimited trials and variable techniques and designsused render systematic analysis difficult.93–95 A Co-chrane analysis and review82 found one small trialshowing acupuncture to be significantly more effec-tive for pain relief than placebo acupuncture and twono-treatment control groups. Given weekly for threemenstrual cycles, acupuncture reduced analgesicmedication by 41% compared with placebo acupunc-ture in women with primary dysmenorrhea.93 In a recent study, acupuncture was successful in primarydysmenorrhea (defined as no recurrence of symptoms

for 2 years or more and no need for medication) in93% of patients, compared with only 3.7% in theplacebo group.94 In an uncontrolled internationalpilot study, acupuncture point injection with vitaminK alleviated primary dysmenorrhea with extension of relief into nontreatment follow-up cycles.95 Thus,there is some suggestive evidence that acupuncturemay play a role in the nonpharmacologic relief of primary dysmenorrhea. However, well-designed,

controlled, larger, and more definitive trials areneeded.

The therapeutic efficacy of acupressure was con-sidered similar to that of ibuprofen in relief of dys-menorrhea.96 Acupressure (both administered andself-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 TherapyContinuous, low-level, heat-wrap therapy applied tothe suprapubic region is significantly superior toacetaminophen throughout the first 8 hours of appli-cation for relief of primary dysmenorrhea.98 This canbe used by patients or as an adjunct to other betterevidence-based therapies. A randomized, placebo-controlled study found significant relief of primarydysmenorrhea pain with magnet (2,500 gauss) com-pared with placebo magnet–treated cycles.99

Surgical or Manipulative ApproachesNerve AblationObservational studies support the use of uterosacralnerve ablation and presacral neurectomy for primarydysmenorrhoea. Both surgical procedures interrupt the cervical sensory pain fibers in the pelvic area. ACochrane meta-analysis of 8 of 11 trials (2 did not meet criteria)100 included five for laparoscopic utero-sacral nerve ablation, two for laparoscopic presacralneurectomy, and two for open presacral neurectomy.

There was some evidence for efficacy of laparoscopicuterosacral nerve ablation-resection over placebo orno treatment, and long-term presacral neurectomywas significantly better than laparoscopic uterosacralnerve ablation. However, there is insufficient evi-dence to recommend surgical nerve interruption forthe management of primary dysmenorrhea. Adverseevents were more common with presacral neurec-tomy. Because uterosacral nerve ablation essentiallytransects postganglionic sensory fibers, they are likelyto regenerate with time and the pain returns. Suffi-ciently powered, future, randomized controlled trials

are needed.

Spinal ManipulationA Cochrane analysis and its follow-up found noevidence 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 shammanipulation for the treatment of dysmenorrhoea.



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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 Toft-ness technique was shown to be more effective thansham treatment by one small trial.

Management AlgorithmA 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 thealgorithm having only two choices to select from..When a patient presents with chronic pelvic pain, it isimportant to distinguish between pain associated withmenstruation 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 typicalhistory of primary dysmenorrhea and the normalpelvic examination findings would sort out primaryfrom secondary dysmenorrhea. However, in somecases of endometriosis presenting during the teenageyears and with no pelvic abnormalities, there can bea striking similarity with primary dysmenorrhea.

Once the diagnosis of primary dysmenorrhea isarrived at, the most effective treatment of choiceremains 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 birthcontrol, a combined oral contraceptive is prescribedfor her birth control needs, and she can be expectedto obtain relief of her primary dysmenorrhea (videsupra–oral contraceptive). The choice of 3 monthscan 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 synthetaseinhibitor compared with oral contraceptive in the manage-ment of primary dysmenorrhea.Dawood. Advances in Primary Dysmenorrhea. Obstet Gynecol 2006.

Fig. 5. Algorithm for managingprimary dysmenorrhea withoral contraceptive.Dawood. Advances in Primary Dysmenorrhea. Obstet Gynecol 2006.

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intensity of primary dysmenorrhea can fluctuate fromcycle 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 oralcontraceptives after three cycles, consider adding anappropriate NSAID during the menstrual phase (Fig.5). Thereafter, the management is similar to that of the patient initially given an NSAID. With birthcontrol pills, 80–90% or more of women can besatisfactorily relieved of primary dysmenorrhea if thediagnosis 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 whoare allergic to NSAIDs should be recommended to

use an oral contraceptive and not given NSAID (Fig.6). To obtain maximum and continuous relief frompainful menstrual cramping and to avoid exposing a potential very early pregnancy, NSAIDs should betaken with the onset of menstruation and continuallyfor the first 2–3 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 (3–6) 73–90Fenamates Flufenamic acid 100–200 mg (3) 77–82

Mefenamic acid 250–500 mg (4) 93Tolfenamic acid 133 mg (3) 88

Arylpropionic acid derivatives Ibuprofen† 400 mg (4) 66–100Naproxen sodium† 275 mg (4) 79–90Ketoprofen† 50 mg (3) 90

12.5–2.5 mg (4) 87–88Miscellaneous Suprofen‡ 200 mg (4) 60–80Piroxicam 10–20 mg (1–2) 70–80Nimesulide 50–100 mg (1–2) 78–83

Specific cyclooxygenase II (COX II inhibitors)§ Rofecoxib 25 mg (2) Not availableValdecoxib 20–40 mg (2) Not availableLumiracoxib 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.



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production and release. Thus, the menstrual fluidvolume remains relatively unchanged, but the men-strual fluid prostaglandins are markedly reduced tothe level obtained in a normal pain-free menstrualcycle 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 groupof women who have a history suggesting primarydysmenorrhea (Fig. 6). Patients with endometriosisare not relieved by NSAIDs (vide supra–COX IIinhibitor).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, multimodaltherapy, using some of the partially evidence-sup-ported or less well-established therapies discussedabove, may be tried.

Cervical dilation and hysteroscopy are recom-mended at the time of laparoscopy to ensure com-pleteness of excluding secondary dysmenorrhea andfor any temporary relief that dilation may confer onsome patients by widening the cervical canal andpromoting menstrual flow and thereby reducing men-strual fluid prostaglandin contact with the myome-trium. Additionally, cervical dilation may induceparacervical neurapraxia or partial disruption of theparacervical innervations. However, there is no pub-lished evidence about the efficacy of cervical dilation,even for the short term.

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