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DECEMBERJOGC DCEMBRE 2005

SOGC CLINICAL PRACTICE GUIDELINE

No 169, December 2005

Primary Dysmenorrhea ConsensusGuideline

CO-CHAIRS

Guylaine Lefebvre, MD, FRCSC, Ottawa ON

Odette Pinsonneault, MD, FRCSC, Sherbrooke QC

CO-AUTHORS

Viola Antao, MD, CCFP, MHSc, Toronto ON

Amanda Black, MD, FRCSC, Ottawa ON

Margaret Burnett, MD, MA, CCFP, FRCSC, Winnipeg MB

Kymm Feldman, MD, CCFP, MHSc, Toronto ON

Robert Lea, MD, FRCSC, Halifax NS

Magali Robert, MD, FRCSC, Calgary AB

Abstract

Methods: Members of this consensus group were selected based onindividual expertise to represent a range of practical and academicexperience both in terms of location in Canada and type ofpractice, as well as subspecialty expertise along with generalgynaecology backgrounds. The consensus group reviewed allavailable evidence through the English and French medicalliterature and available data from a survey of Canadian women.Recommendations were established as consensus statements.The final document was reviewed and approved by the Executiveand Council of the SOGC.

Results: This document provides a summary of up-to-date evidenceregarding the diagnosis, investigations, and medical and surgicalmanagement of dysmenorrhea. The resulting recommendationsmay be adapted by individual health care workers when servingwomen who suffer from this condition.

Conclusions: Dysmenorrhea is an extremely common andsometimes debilitating condition for women of reproductive age.

A multidisciplinary approach involving a combination of lifestyle,medications, and allied health services should be used to limit theimpact of this condition on activities of daily living. In somecircumstances, surgery is required to offer the desired relief.

Outcomes: This guideline discusses the various options in managingdysmenorrhea. Patient information materials may be derived fromthese guidelines in order to educate women in terms of theiroptions and possible risks and benefits of various treatment

strategies. Women who find an acceptable management strategyfor this condition may benefit from an improved quality of life.

Key Words: Primary dysmenorrhea, pelvic pain, menstrual pain,

crampy suprapubic pain, endometriosis, menorrhagia, menstrual

cramps, length of cycles, regularity of cycles, duration of menses,

pelvic examination, management of dysmenorrhea

Evidence: MEDLINE and Cochrane databases were searched forarticles in English and French on subjects related to primarydysmenorrhea, menstrual pain and pelvic pain from January 1990to December 2004 in order to prepare a Canadian consensusguideline on the management of primary dysmenorrhea.

Values: The quality of evidence is rated using the criteria described inthe Report of the Canadian Task Force on the Periodic HealthExamination. Recommendations for practice are ranked accordingto this method.

Sponsors: The development of this consensus guideline wassupported by unrestricted educational grants from Pfizer Canada

Inc., Janssen-Ortho, Wyeth, Organon Canada Ltd., and BerlexCanada Inc.

Recommendations

Section 3: Diagnosis / Differential Diagnosis / Investigations

1. In adolescents experiencing dysmenorrhea in the first 6 monthsfrom the start of menarche, and when an anovulatory patientcomplains of dysmenorrhea, the diagnosis of obstructingmalformation of the genital tract should be considered. (III-A)

2. The diagnosis of secondary dysmenorrhea should be consideredwhen symptoms appear after many years of painless menses.(III-A)

3. In view of the high prevalence of dysmenorrhea, and evidence thatmany women do not seek medical attention for this problem, healthcare providers should include specific questions regardingmenstrual pain when obtaining a woman's medical history. (III-B)

4. In an adolescent who has never been sexually active and has atypical history of mild to moderate dysmenorrhea, a pelvicexamination is not necessary. (III-D)

5. A pelvic examination is indicated in all patients not responding toconventional therapy of dysmenorrhea or when an organicpathology is suspected. (III-B)

Section 4: Non-medicinal Therapeutic Options

1. Unlike low-frequency TENS, high-frequency TENS provides moreeffective dysmenorrhea pain relief compared with placebo.High-frequency TENS may be considered as a supplementarytreatment in women unable to tolerate medication. (II-B)

2. Women who inquire about alternatives to relieve dysmenorrhea,may be instructed that, at the present time, there is limitedevidence that acupuncture may be of benefit (II-B), there is no

evidence to support spinal manipulation as an effective treatment(II-D), and there is limited evidence to support topical heat therapy (II-B).

Section 5: Medicinal Therapeutic Options

1. Women suffering from primary dysmenorrhea should be offeredNSAIDs as a first-line treatment for the relief of pain and improveddaily activity unless they have a contraindication to the use ofNSAIDs. (I-A)

These guidelines reflect emerging clinical and scientific advances as of the date issued and are subject to change. The information

should not be construed as dictating an exclusive course of treatment or procedure to be followed. Local institutions can dictate

amendments to these opinions. They should be well documented if modified at the local level. None of these contents may be

reproduced in any form without prior written permission of the SOGC.

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SOGC CLINICAL PRACTICE GUIDELINES

Table 1. Criteria for quality of evidence assessment and classification of recommendations

Level of evidence* Classification of recommendations

I: Evidence obtained from at least one properly designedrandomized controlled trial.

II-1: Evidence from well-designed controlled trials without

randomization.II-2: Evidence from well-designed cohort (prospective or

retrospective) or case-control studies, preferably frommore than one centre or research group.

II-3: Evidence from comparisons between times or places withor without the intervention. Dramatic results fromuncontrolled experiments (such as the results of treatmentwith penicillin in the 1940s) could also be included in thiscategory.

III: Opinions of respected authorities, based on clinicalexperience, descriptive studies, or reports of expertcommittees.

A. There is good evidence to support the recommendation foruse of a diagnostic test, treatment, or intervention.

B. There is fair evidence to support the recommendation for

use of a diagnostic test, treatment, or intervention.C. There is insufficient evidence to support the recommen-

dation for use of a diagnostic test, treatment, or inter-vention.

D. There is fair evidence not to support the recommendationfor a diagnostic test, treatment, or intervention.

E. There is good evidence not to support the recommendationfor use of a diagnostic test, treatment, or intervention.

The quality of evidence reported in these guidelines has been adapted from the Evaluation of Evidence criteria described in the Canadian Task Forceon the Periodic Health Exam.

126

Recommendations included in these guidelines have been adapted from the Classification of Recommendations criteria described in the Canadian

Task Force on the Periodic Health Exam.126

2. Oral contraceptives may be recommended for the treatment ofprimary dysmenorrhea. The added contraceptive advantage maymake oral contraceptives a first-line therapy for some women. (1-

A)

3. Consideration may be given to continuous use of oral contraceptivepills for withdrawal bleeding and the associated dysmenorrhea. (1-

A)

4. Depot medroxyprogesterone acetate and levonorgestrelintrauterine system have been shown to be effective in thetreatment of dysmenorrhea and therefore can be considered astreatment options in the management of primary dysmenorrhea. (II-

B)

Section 6: Surgical Options

1. Surgery constitutes the final diagnostic and therapeutic option inthe management of dysmenorrhea. Laparoscopy should beconsidered in women who have persistent dysmenorrhea despitemedical therapy of NSAIDs and/or oral contraceptives. (III-C)

2. Hysterectomy may be considered for the management ofdysmenorrhea when medical alternatives have been refused orfailed and fertility is no longer possible or desired. (II-B)

3. As there is limited evidence for use of presacral neurectomy in themanagement of primary dysmenorrhea, the risks must be carefullyweighed against the expected benefits. (III-C)

4. Laparoscopic uterosacral ligament resection has not been shown toreduce dysmenorrhea and therefore should not be advocated as a

mainstream treatment option. (III-C)

Section 7: Complementary and Alternative Medicine (CAM)

1. The following CAM has limited support and may be considered inthe treatment of primary dysmenorrhea, though further study is

required:

Vitamin B1 (I-B)

2. The following CAMs showed an initial positive response for the

treatment of primary dysmenorrhea and merit further study:

Vitamin E (I-C)

Fish oil / Vitamin B12 combination (I-C)

Magnesium (II-1 C)

Vitamin B6; (II-1 C)

Toki-shakuyaku-san (II-1 C)

Fish oil (II-3 C)

Neptune krill oil (II-3 C)

3. The following CAMs have not been shown to have any benefit inthe treatment of primary dysmenorrhea and may need further

study:

Vitamin B6 / Magnesium combination (II-1)

Vitamin E (daily) in addition to Ibuprofen (during menses) (II-3)

Fennel (II-3)

J Obstet Gynaecol Can 2005;27(12):11171130

SECTION 1: DEFINITION AND PATHOPHYSIOLOGY

Dysmenorrhea is derived from a Greekroot translating to difficult menstrual flow.Dysmenorrhea can be divided into 2 broadcategories of primary and secondary.Primary dysmenorrhea is defined asrecurrent, crampy pain occur- ring with

menses in the absence of identifiable pelvicpathology. Secondary dysmenorrhea ismenstrual pain associated with underlyingpelvic pathology such as endometriosis.Primary dysmenorrhea usually begins in

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Primary Dysmenorrhea Consensus GuidelineP

adolescence after the establishment ofovulatory cycles.1,2

Primary dysmenorrhea is caused bymyometrial activity resulting in uterineischemia causing pain.1 This myometrialactivity is modulated and augmented byprostaglandin synthesis (Figure 1). Uterinecontractions can last many minutes andmay produce uterine pressures greaterthan60 mm Hg. Multiple other factors may play arole in the perception and the severity of thepain.

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Figure 1. Pathophysiology of primary dysmenorrhea

Estrogenprogesterone PGF2a

PGE2Sensitization of afferent nerves

Vasopressin Myometrial contraction

PAIN Otherfactors

Altered blood flow( constriction of arterioles)

Uterine ischemia

Cervical obstruction Unknown factors

SECTION 2: RISK FACTORS

Dysmenorrhea is the most commongynaecological symptom reported bywomen. Ninety percent of women pre-senting for primary care suffer from somemenstrual pain.3

Population surveys suggest that, althoughprevalence rates vary considerably bygeographical location, complaints ofdysmenorrhea are widespread in diversepopulations.410

Furthermore, one third to one half of thesewomen report moderate or severesymptoms. Symptoms are frequentlyassociated with time lost from school, work,or other activities.11 In spite of thefrequency and severity of dysmenorrhea,most women do not seek medical treatment

for this condition.4,12

Age is a determinant of menstrual pain12

with symptoms being more pronounced inadolescents than in older women.9,12,13

Associated factors for more severe episodesof dysmenorrhea may include earlymenarche,6,14,15 heavy

and increased duration of menstrual flow14,15

and family history.15 There is someevidence that parous women have lesssevere dysmenorrhea.6,13,14,16

The evidence that smoking worsens primarymenstrual pain is convincing.12,13,1517 Onerecent prospective study found thatdysmenorrhea is also associated withincreased exposure to environmentaltobacco smoke.18

There is some suggestion that more frequentlife changes, fewer social supports, andstressful close relationships may beassociated with increased dysmenorrhea.19

There may be an increased prevalence ofdysmenorrhea in lower socioeconomic

groups.3

There is controversy about the association ofobesity,6,14,17 physical activity,14,17 andalcohol6,14,16,17 with primary dysmenorrhea.

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SECTION 3: DIAGNOSIS / DIFFERENTIAL DIAGNOSIS / INVESTIGATIONS

DIAGNOSIS OF PRIMARY DYSMENORRHEA

Typically, primary dysmenorrhea ischaracterized by a crampy suprapubic painthat begins somewhere between severalhours before and a few hours after the onsetof the menstrual bleeding. Symptoms peak

with maximum blood flow20 and usually lastless than one day, but the pain may persistup to 2 to 3 days. Symptoms are more orless repro- ducible from one menstrualperiod to the other.21 The pain ischaracteristically colicky and located in themidline of the

lower abdomen but may also be describedas dull and may extend to both lowerquadrants, the lumbar area, and the thighs.Frequently associated symptoms includediarrhea, nausea and vomiting, fatigue, light-headedness, headache, dizziness and,

rarely, syncope and fever.20,2225

These asso-ciated symptoms have been attributed toprostaglandin release.1,2

Onset of dysmenorrhea soon after menarcheor in a patient who is clearly anovulatoryshould alert the physician to the

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possibility of an obstructing malformation ofthe genital tract. Occasionally adolescentsmay experience menstrual pain with theirfirst periods without any demonstrableunderlying cause, especially when thebleeding is heavy and accompanied by

clots.22

Menstrual pain appearing afterseveral years of painless periods issuggestive of secondary dysmenorrhea.

Differential diagnosis

The differential diagnosis of primarydysmenorrhea is sum- marized in Table 2.Endometriosis is certainly one of the mostfrequent causes of secondary dysmenorrheaand is a disease that can also affect youngerpatients. In adolescent girls undergoinglaparoscopy for chronic pelvic pain not

responding to NSAIDs and oralcontraceptives, endometriosis is found witha prevalence of approximately70%.26,27 In parous women, adenomyosisshould be considered as a possiblediagnosis, especially in the presence ofmenorrhagia and of a uniformly enlargeduterus. Pedunculated submucosalleiomyomas and endometrial polyps maycause obstruction of the cervical canal andtrig- ger painful menstrual cramps. In

patients with a history of surgical proceduresof the cervix such as a cerclage, acryotherapy, or a conization, cervicalstenosis is a possibility. Whendysmenorrhea occurs suddenly in patientswho normally have no or mild menstrualpain, pelvic inflammatory disease orpregnancy complications should be ruledout. Congenital obstructing malformations ofthe mllerian ducts should be consideredwhen dysmenorrhea appears before theestablishment of ovulatory menstrual

cycles.21,24Other causes of chronic pelvic pain (chronicpelvic inflammatory disease, pelvicadhesions, bowel inflammatory dis- eases,irritable bowel syndrome, interstitial cystitis)may be symptomatic during menses.28

CLINICAL APPROACH

History

Many women consider menstrual pain, even

severe and incapacitating, as inevitable.Women suffering from primarydysmenorrhea may not seek medicalassistance and frequently do not make useof the prescription therapies that areavailable.12,22

When a health care provider identifiesmenstrual pain on history, an attempt shouldthen be made to differentiate betweenprimary and secondary dysmenorrhea. Thehistory should focus on menstrual history,including age at menarche, length andregularity of cycles, dates of last twomenses, and duration and amount of thebleeding. The length of time elapsedbetween menarche and the beginning ofdysmenorrhea should be established. The

pain should be clearly defined in terms oftype, location, radiation, and

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associated symptoms, as well as thechronology of the onset of pain in relation toonset of menstrual bleeding. The severityand duration of symptoms, the progressionover time, and the degree of the patientsdisability should be established. Significantgastrointestinal or urinary symptoms or thepresence of pelvic pain not related to the

menstrual cycle may suggest other causesof pelvic pain.

In obtaining a thorough history, it isimportant to inquire about sexual activity,dyspareunia, and contraception. Manyadolescents use dysmenorrhea as a pretextto obtain contraception.24 Past obstetric andgynaecologic history, in particular, sexuallytransmitted infections, pelvic infection,infertility, and pelvic surgery, as well asother medical prob- lems should berecorded. A family history of endometriosisshould also be sought.

The patient should also be asked about alltypes of therapy tried in the past. Sincemany patients do not use medication inadequate dose, it is essential to inquireabout the way every medication wasutilized. Campbell and McGrath report thatin a group of high school girls aged 14 to21 years using over-the-counter medications

for menstrual discomfort, only 31% tookthem at the recommended daily dosage. Ofthose using a prescription drug, 13%reported using less than the prescribeddose. In the same study, par- ticipantswaited a median of 30 minutes after theonset of dysmenorrhea before taking theirmedication and only 16% of them took itprophylactically.29 Many patients who statethat oral contraceptives are ineffective didnot try them for a long enough period toobtain the maximum effectiveness in painrelief.

PHYSICAL EXAMINATION

Women suffering from primarydysmenorrhea are expected to have anormal pelvic examination. However, anormal pelvic examination does notsystematically rule out the presence of apelvic pathology.

An abdominal examination should be done inevery patient to rule out palpable pathology.In an adolescent who has never beensexually active and presents with a typicalhis- tory of mild to moderate primarydysmenorrhea, pelvic examination is notnecessary.21,2224 However, some authorsrecommend inspecting the external genitalia

of all patients to exclude an abnormality ofthe hymen.23 On the other hand, whenhistory is suggestive of organic disease orcon- genital malformation of the genitaltract, or when the patient does not respondto the conventional therapy of primarydysmenorrhea, a complete pelvicexamination is indicated.

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Table 2. Differential diagnosis of dysmenorrhea

Primary dysmenorrhea

Secondary dysmenorrhea

Endometriosis

Adenomyosis

Uterine myomas

Endometrial polyps

Cervical stenosis

Obstructive malformations of the genital tract

Other causes of pain

Chronic pelvic inflammatory disease

Pelvic adhesions

Irritable bowel syndrome

Inflammatory bowel disease

Interstitial cystitis

Sudden onset of dysmenorrhea

Pelvic inflammatory disease

Unrecognized ectopic pregnancy or spontaneous abortion

INVESTIGATIONS

Laboratory testing or imaging is not requiredto make a diagnosis of primary

dysmenorrhea. Complementary inves-tigations may be ordered when secondarydysmenorrhea is suspected.

There is no evidence for the routine use ofultrasound in the evaluation of primarydysmenorrhea. For women who suffer fromdysmenorrhea refractory to first-linetherapy, or in women who have a clinicalabnormality on pelvic examination,ultrasound may identify causes ofsecondary dysmenorrhea. In adolescents in

whom a pelvic examination is impossible orunsatisfactory, ultrasound may uncover apelvic mass or an obstructing mllerianmalformation. Ultrasonography cannotdetect subtle signs of organic dis- easessuch as uterosacral ligament tenderness ornodules and cervical motion tenderness.Ultrasound will not replace a thoroughbimanual examination.

Magnetic resonance imaging has been

shown to be an inter- esting diagnostic toolfor adenomyosis but since a precisediagnosis of this pathology is rarely essentialto therapeutic

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decisions, this expensive test has limitedclinical usefulness.28,30

Hysteroscopy and saline sonohysterographyare helpful in the diagnosis of endometrialpolyps and submucosal leiomyomas.30,31

Laparoscopy is the only procedure that willestablish a defi- nite diagnosis of

endometriosis, pelvic inflammatory disease,or pelvic adhesions. It should be performedwhen these pathologies are stronglysuspected or when first-line therapy hasfailed. In adolescent girls who do notrespond to therapy, a diagnostic laparoscopyshould not be post- poned unduly becausethe prognosis of endometriosis may beimproved by an early diagnosis.32

Gynaecologists are usually experienced withthe laparoscopic diagnosis of endometriosisin adult women. In adolescents, however, the

appearance of endometriotic implants mayhave vari- able morphology. In theseyounger patients, red flame, white, andclear lesions are more frequently seen thanthe classical blue-black and powder burnlesions found in adults.33 Laufer has proposedthat using fluid as a distension mediumduring laparoscopy facilitates theidentification of clear lesions that can beeasily missed when doing the con- ventionaltechnique of laparoscopy.34 This has notbeen advocated traditionally. Biopsies ofvisible lesions, especially when atypical, arerecommended in order to have histologicalconfirmation of the diagnosis.

Recommendations

1. In adolescents experiencing dysmenorrheain the first six months from the start ofmenarche, and when an anovulatorypatient complains of dysmenorrhea, thediagnosis of obstructing malformation ofthe genital tract should be considered. (III-A)

2. The diagnosis of secondary dysmenorrheashould be considered when symptomsappear after many years of painlessmenses. (III-A)

3. In view of the high prevalence ofdysmenorrhea, and evidence that manywomen do not seek medical attention forthis problem, health care providers shouldinclude specific questions regarding

menstrual pain when obtaining a womansmedical history. (III-B)

4. In an adolescent who has never beensexually active and has a typical history ofmild to moderate dysmenorrhea, a pelvicexamination is not necessary. (III-D)

5. A pelvic examination is indicated in all

patients not responding to conventionaltherapy of dysmenorrhea or when anorganic pathology is suspected. (III-B)

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SECTION 4: NON-MEDICINAL THERAPEUTIC OPTIONS

Non-medicinal approaches such as exercise,heat, behavioural interventions, anddietary/herbal supplements are commonly

utilized by women in an effort to relievedysmenorrhea.35 The data on theeffectiveness of such interventions remaininconclusive and controversial.

EXERCISE

In a review of 4 randomized controlled trialsand 2 observa- tional studies, exercise wasassociated with a reduction in dysmenorrheasymptoms.36 A more recent study foundthat vigorous exercisers (more than 3 times

per week) reported less physical symptomsduring menstruation in comparison withsedentary counterparts.37 In contrast, resultsfrom a retrospective questionnairecompleted by a cohort of nurses indicatedthat although exercise was associated withan improvement in mood and stress, it wasalso associated with a 30% increase indysmenorrhea symptom severity.36,38 Themajority of these early studies had numer-ous methodological flaws (non-blinded,confounding factors, lack of objectivemeasurements for pain or level of activity),making it inappropriate to draw definitiveconclu- sions regarding the use of exerciseas a supplementary treatment fordysmenorrhea. A Cochrane review onexercise and primary dysmenorrhea iscurrently being compiled andrecommendations are expected in 2005.39

TRANSCUTANEOUS ELECTRICAL NERVESTIMULATION (TENS) / ACUPUNCTURE

TENS involves use of electrodes to stimulatethe skin at various frequencies andintensities in an attempt to diminish painperception. TENS may be divided into highand low frequency. Low-frequency TENSinvolves pulses delivered between 1 and 4Hz and high-frequency TENS consists ofpulses delivered between 50 and 120 Hz.40,41

Acupuncture also involves stimulating nervefibre receptors in an attempt to block painimpulses. A Cochrane review examined 9

randomized controlled trials on the use ofTENS or acupuncture for the treatment ofprimary dysmenorrhea.42 Overall data

indicated that high-frequency TENS providesmore effective pain relief when comparedwith placebo TENS.40,41,43 Adverseoutcomes associated with high- frequency

TENS including muscle tightness, headaches,nausea, redness or burning of skin werereported in over10% of participants.40 Two trials compared

TENS with medical treatment. Ibuprofen wasfound to be significantly better in relievingpain in comparison than high-frequency

TENS.40 In contrast, no difference in painrelief scores was demonstrated betweennaproxen and high-frequency

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TENS.41,44 Overall results indicate nosignificant differences between low-frequency TENS and placebo TENS orplacebo pill for relief of dysmenorrhea.41,43,4547

Significantly greater pain relief in the

acupuncture group compared with the shamacupuncture group was reported.48 Due tothe limited evidence (only 1 randomizedcontrolled trial), recommendations regardingacupuncture as a treatment fordysmenorrhea must be guarded.

SPINAL MANIPULATION

A Cochrane review included 5 trialsexamining spinal manipulation for the

treatment of dysmenorrhea. Overall resultsprovided no evidence that spinalmanipulation relieves dysmenorrhea.49 Nosignificant differences in adverse effectswere reported by the spinal manipulationgroup in comparison to the sham treatmentgroup.50

BEHAVIOURAL INTERVENTIONS

Behavioural interventions used in the

treatment of dysmenorrhea includeprocedures such as biofeedback,desensitization, Lamaze exercise,hypnotherapy, and relax- ation training.51

Case studies suggest that behavioural inter-ventions may be effective in treatingdysmenorrhea.51

Because of the limited studies norecommendation can be formulated at thistime. A Cochrane protocol examiningbehavioural interventions for primary andsecondary dysmenorrhea was published in

2000, but has since been withdrawn frompublication.52

TOPICAL HEAT

A randomized placebo-controlled trialcompared the effectiveness of topicallyapplied heat for dysmenorrhea with the useof oral ibuprofen and placebo treatments.Results indicate that the 3 treatment groups

heated patch plus ibuprofen, heated patchplus placebo pill, and unheated patch plusibuprofen demonstrated significantlygreater pain relief than the unheated patchplus placebo pill control(P < 0.001). Low-level topical heat therapywas as effective as ibuprofen for thetreatment of dysmenorrhea. Further- more,

there was faster improvement in pain reliefwhen heat was applied with ibuprofencompared with the ibuprofen and unheatedpatch control.53

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Recommendations

1. Unlike low-frequency TENS, high-frequency TENS provides more effectivedysmenorrhea pain relief than placebo.High-frequency TENS may be consideredas a supplementary treatment in women

unable to tolerate medication. (II-B)

2. Women who inquire about alternatives torelieve dysmenorrhea may be instructedthat, at the present time, there is limitedevidence that acupuncture may be ofbenefit (II-B), there is no evidence tosupport spinal manipulation as an

effective treatment (II-D), and there islimited evidence to support topical heattherapy. (II-B)

SECTION 5: MEDICINAL THERAPEUTIC OPTIONS

5.1 NON-HORMONAL MEDICAL TREATMENT

Many drugs are commercially available andapproved for the use in treatment of primarydysmenorrhea.

Over-the-counter (OTC) medications

OTC medications available to treatdysmenorrhea in Canada includeacetaminophen (Tylenol), acetaminophenplus pamabrom (Midol), acetylsalicylic acid(Aspirin), and ibuprofen (Advil, Motrin).

Acetaminophen is an analgesic/antipyreticdrug, not a peripheral prostaglandinsynthetase inhibitor, and is a weak

cyclooxygenase (COX) inhibitor in thepresence of high peroxide concentrationsthat are present in inflammatory tissues.Acetaminophen produces analgesia byraising the pain threshold. It is a safe drugwhen used in therapeutic dosages with agood gastrointestinal tolerance and no effecton hemostasis. Acetaminophen can causeliver damage after three or more alcoholicdrinks per day54 and can cross-react withASA to produce analgesic-induced asthma.55

The one randomized controlled trial of

acetaminophen showed it to be no betterthan placebo, but the trial was small andalso failed to show aspirin to be effective.56

In many analyses of effectiveness ofmedications for relief of primarydysmenorrhea, acetaminophen is used asthe control.

Acetaminophen and pamabrom are indicatedto provide temporary relief of dysmenorrhea.Pamabrom is a mild and short-acting diuretic

that relieves water retention. The avail- ableinformation concerning the efficacy ofacetaminophen in primary dysmenorrhea islimited and not conclusive with respect to

other non-steroidal anti-inflammatory drugs(NSAIDs) or even placebo. The clinicalevidence regarding the association withpamabrom is even more scarce.57

Adolescents who experience lessmenstrual discomfort, shorter duration ofmenstrual discomfort, and less severedisability were more likely to be associatedwith the use of OTC medications. More thanhalf (56%) of the adolescents who used OTCmedications took the pills less often than the

maximum daily recommendation.29

Therewas a greater

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frequency of OTC medication use amongyoung women aged 16 to 21 years thanamong girls aged 12 to 14 years.58

NSAIDs

Non-selective NSAIDs

Research has identified the over-production

of uterine prostaglandins (higher levels ofprostaglandins F2 and E2) as a contributingfactor to primary dysmenorrhoea. NSAIDsare analgesics which inhibit thecyclooxygenase (COX) enzymes, therebyinhibiting the production ofprostaglandins.

A meta-analysis of 56 trials59 confirmsbeyond doubt that all4 NSAIDs evaluated (naproxen, ibuprofen,

mefenamic acid and aspirin) are effective inprimary dysmenorrhea. In the systematicreview, both naproxen and ibuprofenappeared to be better than aspirin. On a risk-benefit assessment, ibuprofen was betterthan naproxen because of the side effects ofnaproxen. All 4 NSAIDs reduced restriction ofdaily life better than placebo, but only withibuprofen and naproxen was this statisticallysignificant.

In a review of 63 randomized controlled

trials60

in women with primarydysmenorrhea, NSAIDs were found signifi-cantly more effective for pain relief thanplacebo (OR 7.91;95% CI 5.6511.09), although overalladverse effects were also significantlymore common (OR 1.52; 95% CI1.092.12). When NSAIDs were comparedwith each other or with acetaminophen,there was little evidence of superi- ority ofany NSAIDs with regard to either efficacy orsafety. Women taking NSAIDs were

significantly less likely to report restriction ofdaily activities and absenteeism from workor school than women taking placebo.

Effective treatment is initiated with theonset of bleeding and/or associatedsymptoms and should not be necessary formore than 2 to 3 days. Recommendedmaximum dosing includes starting with aninitial loading dose followed by divided dosesover 24 hours.

The adverse effects of NSAIDs can includegastrointestinal intolerance, headaches, anddrowsiness. It is important for women takingNSAIDs to be aware of the need to take the

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Table. 3 Examples of NSAIDs

Class of NSAIDs Medications

Acetic acid derivatives (including indole derivatives) Diclofenac potassium (Voltaren Rapide)

Indomethacin (Indocid)

Cyclooxygenase-2 (COX-2) inhibitors Celecoxib (Celebrex)

Meloxicam (Mobicox)

Fenamates Mefenamic acid (Ponstan, Mefenamic)

Oxicams Meloxicam (Mobicox)

Propionic acid derivatives Ibuprofen (Advil, Motrin)

Naproxen (Naprosyn)

Naproxen sodium (Anaprox)

Salicylic acid derivatives Acetylsalicylic acid (Aspirin)

medications with food. Aspirin is notrecommended for children and adolescents

with influenza or chicken pox because of itsassociation with the onset of Reyessyndrome.61

COX-2 inhibitors

Prostaglandin synthesis is mediatedprimarily by 2 distinct isoforms ofcyclooxygenase (COX-1 and COX-2), whichcatalyze the metabolism of arachidonate toprostaglandin H2. Conventional NSAIDs arenon-selective inhibitors of both isoforms ofCOX. It has been proposed that the thera-

peutic efficacy of NSAIDs is primarily theresult of cyclooxygenase-2 (COX-2)inhibition, whereas their well-recognizedgastrointestinal toxicity and disruption ofplatelet function is derived from inhibition ofthe cyclooxygenase-1 (COX-1) activity.

In a double-blind study62 comparingmeloxicam 7.5 mg and15 mg once a day with mefenamic acid 500mg three times a day, both of the dailydoses of meloxicam were comparable to

mefenamic acid t.i.d. in relievingdysmenorrhea symptoms, and meloxicamhad a better gastrointestinal tolerabilityprofile.

Both rofecoxib (Vioxx) and valdecoxib(Bextra) have been withdrawn from themarket because of cardiovascular con- cerns(rofecoxib, valdecoxib) and potentially life-threatening skin reactions (valdecoxib).

Transdermal glyceryl trinitrate

Transdermal glyceryl trinitrate has a relaxingeffect on myometrium. In a study

comparing glyceryl trinitrate patch withdiclofenac,63 both treatments significantlyreduced the pain intensity score by 30minutes. However, diclofenac continued tobe effective in reducing pelvic pain for 2hours whereas glyceryl trinitrate did not.Headache was significantly increased byglyceryl trinitrate. This study indicates thatglyceryl trinitrate has a reduced efficacy and

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tolerability by comparison with diclofenac inthe treatment of primary dysmenorrhea.

When the glyceryl trinitrate patch wascompared with a placebo patch, the painintensity differences from 1 to 6 hours werestatistically significant in favour of the activetreat- ment. The incidence of headache was26% for the active drug and 6.1% forplacebo.64

5.2 HORMONAL MEDICAL TREATMENT

Combined oral contraceptive(COC)

As early as 1937, researchers showed thatdysmenorrhea responds favourably toinhibition of ovulation.65 Research suggeststhat the COC suppresses ovulation andendometrial tissue growth, therebydecreasing menstrual fluid volume andprostaglandin secretion6668 with subse-quent decrease in intrauterine pressure67

and uterine cramping.69

COCs are considered an effective treatmentfor primary dysmenorrhea. Observationalstudies support an association betweenCOC use and decreased dysmenorrhea.12,7077

The lack of a placebo control group is amajor limitation of all of these studies. Onlyfive double-blinded, randomized, placebo-

controlled trials have examined theeffectiveness of COCs in the treatment ofprimary dysmenorrhea. A2003 Cochrane Collaborative Review, whichincluded 4 of these studies in its analysis,determined that COCs with more than 35mcg of ethinyl estradiol were more effectivethan placebo for pain relief during menses(OR 2.01; 95% CI 1.173.33).66 However,when data were analyzed with a randomeffects model, the results were notstatistically significant (OR 1.68; 95% CI0.299.81). Treatment with COCscompared with placebo did appear tosignificantly decrease absences from workor school (OR 0.43; 95% CI0.190.99). Only 1 randomized, double-blinded, placebo- controlled study has beenconducted using a low-dose COC

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preparation. Hendrix et al. found asignificant reduction in painful menstrualcramping in users of a COC containing20 mg of ethinyl estradiol compared withplacebo (P0.001)

.78

When given in a continuous fashion, the COCmay have a number of advantages, includinga decreased incidence ofdysmenorrhea.79,80,81

Progestin regimens

Depot medroxyprogesterone acetate (DMPA)works primarily by suppressing ovulation.82

It also can induce endometrial atrophy.83

One of its non-contraceptive benefits isamenorrhea with a resultant reduction in theincidence of dysmenorrhea. Amenorrhearates are 55% to60% at 12 months and 68% at 24 months.84

For this reason, DMPA may be considered inthe treatment of dysmenorrhea.8587

The progestin only pill (POP) may decreasemenstrual flow, and up to 10% of POP userswill develop amenorrhea. Menstrualcramping may be decreased; however, nostudies have been done to date.

Levonorgestrel intrauterine system (LN-IUS)LN-IUS (Mirena) is an intrauterine device thatreleases progestin locally inside theuterine cavity. Although

ovulation is not suppressed, the LN-IUS has alocal effect on the endometrium, whichbecomes atrophic and inac- tive.88 Menstrualblood loss is reduced by 74% to 97%8992 and16% to 35% of LN-IUS users will becomeamenorrheic after 1 year of use.9396

Dysmenorrhea has been shown to improvein LN-IUS users.90,97

Recommendations

1. Women suffering from primarydysmenorrhea should be offered NSAIDsas a first-line treatment for the relief ofpain and improved daily activity unlessthey have a contraindication to the use ofNSAIDs. (I-A)

2. Oral contraceptives may be recommendedfor the treatment of primarydysmenorrhea. The added contracep- tiveadvantage may make oral contraceptivesa first-line therapy for some women. (I-A)

3. Consideration may be given to continuoususe of oral contraceptives for withdrawalbleeding and associated dysmenorrhea. (I-A)

4. Depot medroxyprogesterone acetate andlevonorgestrel intrauterine system have

been shown to be effective in thetreatment of dysmenorrhea and thereforecan be considered as treatment options inthe management of primarydysmenorrhea. (II-B)

SECTION 6: SURGICAL OPTIONS

For a small number of women, thedysmenorrhea will per- sist despite medicalmanagement, and in this group of women it

is appropriate to consider surgical options.Surgery therefore constitutes the finaldiagnostic and therapeutic option in themanagement of dysmenorrhea.98,99

LAPAROSCOPY

In women who do not obtain adequate painrelief with NSAIDs and oral contraceptives,the likelihood of pelvic pathology such asendometriosis is high. In one study of100 women with pelvic pain who did not

have adequate pain relief with NSAIDs, 80%were found to have endometriosis atlaparoscopy.100

Endometriosis is present at laparoscopy in12% to 32% of women undergoinglaparoscopy to determine the cause of pelvicpain,101,102 but it is found in up to 50% ofteenagers undergoing laparoscopy forevaluation of chronic pelvic pain ordysmenorrhea.103,104 The lesions ofendometriosis may be cauterized or resectedat the time of laparoscopy followed bymedical suppressive therapy.

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In women who experience relief of theirdysmenorrhea with NSAIDs or oralcontraceptives, there is a possibility of

underlying endometriosis, but the risks oflaparoscopic documentation of the diseasemust be weighed against the predictedadvantages of having a diagnosis of endo-metriosis when the symptoms are controlledwithout surgery.

HYSTERECTOMY

Pelvic pain should be carefully investigatedprior to considering a hysterectomy.

There is a case for hysterectomy when anunderlying disease, amenable tohysterectomy, is demonstrated and thepatient has completed her family.Hysterectomy may offer permanent relief forthe woman who has pain confined to hermenses, and therefore there is goodevidence for excellent patient satisfactionfollowing hysterectomy in this context.105108

PRESACRAL NEURECTOMY

Presacral neurectomy (PSN) involves thetotal transection of the presacral nerveslying within the boundaries of the interiliactriangle. PSN seems to be the method ofpelvic denervation that is associated withthe major long-term effectiveness in painrelief.109,110 In one study, 126 womenunderwent laparoscopic management forpain associated

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with endometriosis: 63 were randomized toundergo PSN; the other women underwentconservative ablation of visi- bleendometriosis lesions. No difference inintraoperative complications was observedbetween groups. The 6- and

12-month follow-up visits revealed improvedrelief with regard to the severity ofdysmenorrhea in patients who were treatedwith laparoscopic PSN.111 This improvedrelief was also present and statisticallysignificant (P 0.05) at 24 monthsfollowing treatment.111 Some of thecomplicationsof this procedure may include constipationas well as uri-nary urgency which is unlikely to respond tomedical treatment. This adverse event was

observed in 5% of women treated withPSN.112

LAPAROSCOPIC UTEROSACRALNERVE ABLATION (LUNA)

Resection of the uterosacral ligamentsachieves in theory a more complete uterinedenervation than presacral neurectomy. Theintervention carries the risk for complica-tions such as bleeding, ureteral lesions, andpelvic support disorders. The efficacy of

relieving pain associated with endometriosiswas not confirmed in a recent meta-analysis.112,113 In one study involving 180women scheduled to undergo laparoscopyfor pain and endometriosis, 78

women had uterosacral ligament resection.One year later,29% of women in this group had persistentdysmenorrhea. Of the 78 women who hadconservative surgery only, 27% hadrecurrent dysmenorrhea. Addition of

uterosacral ligament resection did notappear to reduce dysmenorrhea.114

Recommendations

1. Surgery constitutes the final diagnosticand therapeutic option in the managementof dysmenorrhea. Laparos- copy shouldbe considered in women who have persis-tent dysmenorrhea despite medicaltherapy of NSAIDs and/or oralcontraceptives. (III-C)

2. Hysterectomy may be considered for themanagement of dysmenorrhea whenmedical alternatives have been refused orfailed and fertility is no longer possible ordesired. (II-B)

3. As there is limited evidence for use ofpresacral neurectomy in themanagement of primarydysmenorrhea, the risks must be carefullyweighed against the expected benefits.(III-C)

4. Laparoscopic uterosacral nerve resectionhas not been shown to reducedysmenorrhea and therefore should not beadvocated as a mainstream treatmentoption. (III-C)

SECTION 7: COMPLEMENTARY AND ALTERNATIVE MEDICINES (CAM)

In considering complementary andalternative medicine (CAM) treatments for

primary dysmenorrhea, a search of theconventional medical literature wasundertaken. Though there may be CAMsother than those mentioned below which areused for dysmenorrhea, we are not aware ofwell-designed, published studies thatdemonstrate efficacy. When advisingpatients about CAM for primarydysmenorrhea, care should be taken toconsider uncertainty about long-termefficacy, interactions, and possible harm.

Evidence is limited by small study sizes.

According to one large randomizedcontrolled trial, vitamin B1 at 100 mg daily isan effective treatment for primarydysmenorrhea.114

Vitamin E taken 2 days before and 3 daysafter onset of menses (500 mg/day)significantly improved primarydysmenorrhea in a small study ofadolescents.115 Daily vitamin E, however,taken with ibuprofen during menses only,showed no significant difference.116

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A small trial showed that fish oil (2.5 g/day)in combination with vitamin B12 (7.5mg/day) may be helpful in reducingdysmenorrhea.117 There is some suggestionthat both fish oil and Neptune krill oil (2g/day) may produce improvement frombaseline with the Neptune krill oil requiring

fewer additional analgesics.118 Other smallstudies of fish oil have shown promise119,120

and further studies are recommended.

Overall, magnesium was more effective thanplacebo in improving pain control inprimary dysmenorrhea.121,122

Results are tempered by high participantwithdrawal from the studies as well asdifferent doses prescribed differently.

In a small study, vitamin B6 alone (200mg/day) was helpful and even better thana combination of vitamin B6 (200mg/day) with magnesium (500 mg/day) inreducing dysmenorrhea and the use ofadditional medications. No differences wereseen between vitamin B6 alone (200 mg/day)and magnesium alone (500 mg/day).123

One study of 40 participants showed

that Toki- shakuyaku-san, a combinationJapanese herbal remedy (7.5 mg/day individed doses), reduced pain and decreasedadditional diclofenac use during a 2-monthtreatment period and a further 2-monthuntreated follow-up. These findings may belimited by differences between Eastern andWestern diagnostic techniques.124

In a small study, mefenamic acid (250 mgq6h) was superior to essence of Fennel'sfruit ([2%] 25 gtts po q4h). There was,however, no placebo group in this study.125

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Recommendations

1. The following CAM has limited support andmay be considered in the treatmentof primary dysmenorrhea,

though further study is

required: Vitamin B1 (I-B)2. The following CAMs showed an initial

positive response for the treatment ofprimary dysmenorrhea and merit

further study:

Vitamin E (I-C)

Fish oil / Vitamin B12 combination (I-C)Magnesium (II-1 C)

Vitamin B6 (II-1 C)

Toki-shakuyaku-san (II-1 C)

Fish oil (II-3 C)Neptune krill oil (II-3 C)

3. The following CAMs have not shown tohave any benefit in the treatment of

primary dysmenorrhea and may need

further study:

Vitamin B6/magnesium combination (II-1)Vitamin E (daily) in addition to ibuprofen

(during menses)

(II-3) Fennel (II-3)

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