Management of Dysmenorrhea

Dysmenorrhea: A significant concern in women

Dysmenorrhea – referred to as painful menstrual cramps of uterine origin¹Proctor M, Farquhar C. Diagnosis and management of dysmenorrhea. BMJ 2006;332:1134-8.   – is an extremely common condition for women of reproductive age.²Lefebvre G, Pinsonneault O, Antao V, Black A, Burnett M, Feldman K, Lea R, Robert M; SOGC. Primary dysmenorrhea consensus guideline. J Obstet Gynaecol Can. 2005 Dec;27(12):1117-46.   In fact, it is one of the most common causes of pelvic pain in young women and adolescents, negatively affects patient’s quality-oflife,and may even results in activity restriction. These painful abdominal cramps, occurring with menstruation, are frequently accompanied by general premenstrual symptoms, such as nausea, vomiting, diarrhea and headache.¹Proctor M, Farquhar C. Diagnosis and management of dysmenorrhea. BMJ 2006;332:1134-8.   ³Harada T. Dysmenorrhea and Endometriosis in Young Women. Yonago Acta medica 2013;56:81-84.  

Dysmenorrhea can be seen in women of all ages and races, but prevalence is highest in the adolescent; prevalence rates vary widely, and are as high as 90%;⁴Nasir L, Bope ET. Management of Pelvic Pain from Dysmenorrhea or Endometriosis. J Am Board Fam Pract 2004;17:S43-7.   ⁵Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014 Mar 1;89(5):341-6.   ⁶French L. Dysmenorrhea. Am Fam Physician. 2005 Jan 15;71(2):285-91.   ⁷Thomas B, Magos A. Modern management of dysmenorrhea. Trends in Urology, Gynaecology & Sexual Health 2009;14(5):25-29.   In this regard, evidence derived from large epidemiological studies suggests that over a half of the population of young women suffers from dysmenorrhea, and this makes it a significant concern for women.⁸Mrugacz G, Grygoruk C, Sieczynski P, Grusza M, Bolkun I, Pietrewicz P. Etiopathogenesis of dysmenorrhea. Med Wieku Rozwoj. 2013 Jan- Mar;17(1):85-9.   A number of risk factors have been identified for the development of dysmenorrhea, of which heavy menstrual flow and premenstrual symptoms seem most prominent (Table 1).⁵Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014 Mar 1;89(5):341-6.  ⁶French L. Dysmenorrhea. Am Fam Physician. 2005 Jan 15;71(2):285-91.  Even so, a favorable point for those affected could be that most patients usually have no underlying pathology, and therefore management is aimed at reassurance and symptom relief; referral may sometimes be necessary where underlying disease is suspected.⁷Thomas B, Magos A. Modern management of dysmenorrhea. Trends in Urology, Gynaecology & Sexual Health 2009;14(5):25-29.  

Primary vs. secondary dysmenorrhea

Dysmenorrhea can be categorized into two different types based on the etiology – primary dysmenorrhea and secondary dysmenorrhea. Herein, while any degree of perceived cramping pain during menstruation in absence of detectable pelvic pathology indicates primary dysmenorrhea; secondary dysmenorrhea represents the clinical situation where menstrual pain can be related to an underlying disease, disorder, or structural abnormality either within or outside the uterus.¹Proctor M, Farquhar C. Diagnosis and management of dysmenorrhea. BMJ 2006;332:1134-8.   ³Harada T. Dysmenorrhea and Endometriosis in Young Women. Yonago Acta medica 2013;56:81-84.   ⁵Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014 Mar 1;89(5):341-6.   ⁸Mrugacz G, Grygoruk C, Sieczynski P, Grusza M, Bolkun I, Pietrewicz P. Etiopathogenesis of dysmenorrhea. Med Wieku Rozwoj. 2013 Jan- Mar;17(1):85-9.   ⁹Dawood MY. Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstet Gynecol 2006;108:428-41.  

As such, diagnosis of primary dysmenorrhea is frequently based on clinical history and physical examination, with characteristic symptoms including lower abdominal or pelvic pain with or without radiation to the back or legs; pain typically lasts 8-72 hours and usually occurs at the onset of menstrual flow. In contrast, features representative of secondary dysmenorrhea in individual cases may include abnormal uterine bleeding, dyspareunia, non-cyclic pain, changes in intensity and duration of pain, and abnormal pelvic examination findings.⁵Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014 Mar 1;89(5):341-6.  As follows, patients expected to be having secondary dysmenorrhea would often require further investigation, such as transvaginal ultrasonography, to identify the underlying cause and manage the condition accordingly (Figure 1). Other investigations that might be useful in secondary dysmenorrhea include a urinary human chorionic gonadotropin (hCG) pregnancy test; vaginal and endocervical swabs, a complete hemogram including erythrocyte sedimentation rate (ESR), and urinalysis. Generally, endometriosis is the most common cause of secondary dysmenorrhea, with features including changes in timing and intensity of the pain, i.e., pelvic pain not limited to the menstrual period,⁶French L. Dysmenorrhea. Am Fam Physician. 2005 Jan 15;71(2):285-91.  or dyspareunia, and symptoms and signs of adenomyosis include dysmenorrhea, menorrhagia, and a uniformly enlarged uterus.⁵Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014 Mar 1;89(5):341-6.  

The time of onset also varies according to whether the dysmenorrhea is primary or secondary. In general, the onset of primary dysmenorrhea is 6-12 months after menarche, with peak prevalence seen in late teens or early twenties and then decreasing with increasing age – a longitudinal study of a representative sample of young women demonstrated that prevalence of dysmenorrhea was lower at 24 years of age than at 19 years of age.¹⁰Sundell G, Milsom I, Andersch B. Factors influencing the prevalence and severity of dysmenorrhoea in young women. Br J Obstet Gynaecol. 1990 Jul;97(7):588-94.   Secondary dysmenorrhea, on the other hand, tends to present later at any time after menarche, usually in women in their 30s, and may be suspected in women with symptoms like menorrhagia, dyspareunia, intermenstrual bleeding, postcoital bleeding, and infertility, and no history of dysmenorrhea until proven otherwise.¹Proctor M, Farquhar C. Diagnosis and management of dysmenorrhea. BMJ 2006;332:1134-8.  ⁵Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014 Mar 1;89(5):341-6.  As such, the list of differential diagnoses for secondary dysmenorrhea could be extensive (Box 1). Primary dysmenorrhea often improves in the after childbirth; but relation between prognosis of secondary dysmenorrhea and severity of underlying disease is unclear.¹Proctor M, Farquhar C. Diagnosis and management of dysmenorrhea. BMJ 2006;332:1134-8.  

Etiopathogenesis of (primary) dysmenorrhea

The exact cause of dysmenorrhea is not completely understood, and it possibly includes multiple factors with unexplained mechanisms. However, there are certain known factors that seem to play significant roles in its pathogenesis; most important among these factors include excessive uterine contractility, disturbances in uterine blood supply, synthesis of prostaglandins, and anatomical abnormalities of the female reproductive tract.⁸Mrugacz G, Grygoruk C, Sieczynski P, Grusza M, Bolkun I, Pietrewicz P. Etiopathogenesis of dysmenorrhea. Med Wieku Rozwoj. 2013 Jan- Mar;17(1):85-9.  During menstruation in eumenorrheic women,the uterine basal tone is minimal (10 mmHg), elevated active pressures (> 120 mmHg), increased number of contractions per 10 minutes (> 4 or 5), and non-rhythmic or incoordinate uterine contractions. These contraction abnormalities reduce uterine blood flow, leading to poor uterine reperfusion and oxygenation, and thus causing pain. Furthermore, the abnormalities, when present in combination, 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.⁹Dawood MY. Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstet Gynecol 2006;108:428-41.   The severe secondary dysmenorrhea of endometriosis patients may also be the result of abnormal uterine contractions; though endometriotic lesions and adhesions may also cause the deep pelvic pain associated with endometriosis. For instance, Bulletti et al11 demonstrated that frequency, amplitude and basal pressure tone of uterine contractions in women with endometriosis were higher than in those without, accounting for higher dysmenorrhea score in patients with endometriosis than in controls.

Likewise, the effect of reduced blood flow has also been specifically evaluated in dysmenorrhea, wherein studies showed significantly higher pulsatility index and resistance index of both uterine arteries and arcuate artery on the 1st day of menstruation in women with primary dysmenorrhea, thereby indicating increased blood flow impedance and suggesting uterine vasoconstriction as a cause of the pain.⁹Dawood MY. Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstet Gynecol 2006;108:428-41.  

Role of prostaglandins in (primary) dysmenorrhea

An excessive or imbalanced amount of prostanoids and possibly eicosanoids released from the endometrium during menstruation is implicated in the increased uterine contractions seen in dysmenorrhea.⁹Dawood MY. Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstet Gynecol 2006;108:428-41.   The uterus is induced to contract frequently and dysrhythmically, with increased basal tone and increased active pressure. Then, uterine hypercontractility, reduced uterine blood flow, and increased peripheral nerve hypersensitivity result in induction of pain (Figure 2). Together, symptoms such as nausea, vomiting, and diarrhea that occur in ≥ 60% of patients are similar to the adverse effects of prostaglandins; they occur as sequel of influx of prostaglandins and its derivatives into systemic circulation.²Lefebvre G, Pinsonneault O, Antao V, Black A, Burnett M, Feldman K, Lea R, Robert M; SOGC. Primary dysmenorrhea consensus guideline. J Obstet Gynaecol Can. 2005 Dec;27(12):1117-46.    ³Harada T. Dysmenorrhea and Endometriosis in Young Women. Yonago Acta medica 2013;56:81-84.  

In isolation, the mechanism of prostaglandin for pain could be implicated in both primary and secondary dysmenorrhea; prostaglandins cause myometrial contractility that, when excessive, leads to uterine hypoxia and ischemia and pain.¹Proctor M, Farquhar C. Diagnosis and management of dysmenorrhea. BMJ 2006;332:1134-8.   Studies have shown that in most women with primary dysmenorrhea, there is increased endometrial secretion of menstrual prostaglandin E2 (PGE2) and prostaglandin F_2a (PGF_2a) during the menstrual phase; among prostaglandins, PGF_2a is considered the most potent causal factor of pain.²Lefebvre G, Pinsonneault O, Antao V, Black A, Burnett M, Feldman K, Lea R, Robert M; SOGC. Primary dysmenorrhea consensus guideline. J Obstet Gynaecol Can. 2005 Dec;27(12):1117-46.   ³Harada T. Dysmenorrhea and Endometriosis in Young Women. Yonago Acta medica 2013;56:81-84.   ⁹Dawood MY. Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstet Gynecol 2006;108:428-41.  

The release of prostaglandins into menstrual fluid is a continuous discontinuous process, depicting that the amount of menstrual fluid and prostaglandins varies throughout any window of time. Regardless, the intensity of the menstrual cramps and associated symptoms of dysmenorrhea seems directly proportional to the amount of PGF_2a released.⁹Dawood MY. Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstet Gynecol 2006;108:428-41.   It has been seen that the symptoms of primary dysmenorrhea lasts only 2-3 days, with pains most intense on the 1st or 2nd day of the menstrual flow, consistent with the time of maximal prostaglandin release into the menstrual fluid.⁹Dawood MY. Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstet Gynecol 2006;108:428-41.  

Overall, based on above applications of prostaglandins in dysmenorrhea, therapies accounting for a reduced level of prostaglandins in the menstrual fluid have been evaluated to provide symptom alleviation, in which nonsteroidal anti-inflammatory drugs (NSAIDs) constitute a typical example.¹²Ylikorkala O, Dawood MY. New concepts in dysmenorrhea. Am J Obstet Gynecol. 1978 Apr 1;130(7):833-47.   When an NSAID is taken during menstruation, the menstrual fluid prostaglandins are significantly reduced to levels similar to or lower than those found in eumenorrheic women, and clinical relief is obtained with return of the uterine activity to a pattern similar to normal pain-free menstruation.⁹Dawood MY. Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstet Gynecol 2006;108:428-41.  

The involvement of vasopressin in pathogenesis of primary dysmenorrhea is controversial.⁹Dawood MY. Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstet Gynecol 2006;108:428-41.   However, it may play a role in causing pain in women with primary dysmenorrhea, those reported to have elevated vasopressin levels, by increasing uterine contractility and causing ischemic pain because of vasoconstriction.⁶French L. Dysmenorrhea. Am Fam Physician. 2005 Jan 15;71(2):285-91.  

Management of (primary) dysmenorrhea

Management options for dysmenorrhea include NSAIDs and hormonal contraceptives; the latter are first-line treatment for secondary dysmenorrhea caused by endometriosis.⁵Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014 Mar 1;89(5):341-6.  

onetheless, as pain could be the primary concern in most women – pain and lower abdominal cramps are among the most common causes for gynecological referral, much of the initial effort is directed at alleviating the pain through diverse measures, both pharmacological and non-pharmacological, such as topical heat; however, by far, the pharmacological approach has been better documented for efficacy.⁹Dawood MY. Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstet Gynecol 2006;108:428-41.  

In such settings, empiric therapy can be initiated based on a typical history of painful menses (suprapubic pains with radiation into the inner thighs) and a negative physical examination leading to a presumptive diagnosis of primary dysmenorrhea (Box 2).⁴Nasir L, Bope ET. Management of Pelvic Pain from Dysmenorrhea or Endometriosis. J Am Board Fam Pract 2004;17:S43-7.   ⁶French L. Dysmenorrhea. Am Fam Physician. 2005 Jan 15;71(2):285-91.   ⁷Thomas B, Magos A. Modern management of dysmenorrhea. Trends in Urology, Gynaecology & Sexual Health 2009;14(5):25-29.   Usually, the symptoms peak with maximum blood flow and last less than one day, but pain may persist up to 2 to 3 days.²Lefebvre G, Pinsonneault O, Antao V, Black A, Burnett M, Feldman K, Lea R, Robert M; SOGC. Primary dysmenorrhea consensus guideline. J Obstet Gynaecol Can. 2005 Dec;27(12):1117-46.  

NSAIDs in dysmenorrhea

Following the need discussed above, there is strong evidence to support NSAIDs as the initial therapy of choice in patients with presumptive primary dysmenorrhea; they being best-established initial therapy for dysmenorrhea.⁵Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014 Mar 1;89(5):341-6.   ⁶French L. Dysmenorrhea. Am Fam Physician. 2005 Jan 15;71(2):285-91.  These drugs exert a direct analgesic effect through inhibition of prostaglandin synthesis and are believed to act by decreasing prostaglandin-induced myometrial contractility and restoring blood flow to normal.⁶French L. Dysmenorrhea. Am Fam Physician. 2005 Jan 15;71(2):285-91.   ⁷Thomas B, Magos A. Modern management of dysmenorrhea. Trends in Urology, Gynaecology & Sexual Health 2009;14(5):25-29.   ⁹Dawood MY. Primary Dysmenorrhea. Advances in Pathogenesis and Management. Obstet Gynecol 2006;108:428-41.  Effective treatment is initiated one to two days before the anticipated onset of menses or with the onset of bleeding and/or associated symptoms, and continued for 2 to 3 days.²Lefebvre G, Pinsonneault O, Antao V, Black A, Burnett M, Feldman K, Lea R, Robert M; SOGC. Primary dysmenorrhea consensus guideline. J Obstet Gynaecol Can. 2005 Dec;27(12):1117-46.   NSAIDs may be most effective when therapy is started before the onset of menstrual pain and flow.⁵Osayande AS, Mehulic S. Diagnosis and initial management of dysmenorrhea. Am Fam Physician. 2014 Mar 1;89(5):341-6.   ⁶French L. Dysmenorrhea. Am Fam Physician. 2005 Jan 15;71(2):285-91.  However, if dysmenorrhea remains uncontrolled with initial approaches, pelvic imaging should be performed and a gynecological referral should be considered to timely exclude secondary causes of dysmenorrhea.⁶French L. Dysmenorrhea. Am Fam Physician. 2005 Jan 15;71(2):285-91.  

Aceclofenac: Aceclofenac is an oral NSAID that has shown effectiveness in treatment of multiple painful and inflammatory diseases, including gynecological pain and lower back pain, and has been used by millions of patients worldwide.¹³Legrand E. Aceclofenac in the management of inflammatory pain. Expert Opin Pharmacother. 2004 Jun;5(6):1347-57.   A possible factor for this favored position is that while being high effective, the drug appears to be particularly well tolerated amongst the NSAIDs, with a lower incidence of gastrointestinal adverse effects, most of them being minor and reversible.¹⁴Dooley M, Spencer CM, Dunn CJ. Aceclofenac: a reappraisal of its use in the management of pain and rheumatic disease. Drugs. 2001;61(9):1351-78.   As gastrointestinal effects (nausea, vomiting, and/or diarrhoea) are of particular concern with NSAIDs,¹Proctor M, Farquhar C. Diagnosis and management of dysmenorrhea. BMJ 2006;332:1134-8.   the good overall and gastrointestinal tolerability profile of aceclofenac relative to other NSAIDs would be beneficial in routine practice by results of a reduced withdrawal rate and hence greater compliance with the treatment.¹³Legrand E. Aceclofenac in the management of inflammatory pain. Expert Opin Pharmacother. 2004 Jun;5(6):1347-57.   The rationale is that if an NSAID is offered, a gastroprotective agent may be useful.

A double-blind, prospective, multicentre, randomized, three-way, crossover study determined the analgesic efficacy and safety of a single oral dose of aceclofenac 100 mg in comparison to placebo and naproxen 500 mg in women with primary dysmenorrhea, and found that aceclofenac was significantly more effective than placebo in treating pain associated with primary dysmenorrhea.¹⁵Letzel H, Megard Y, Lamarca R, Raber A, Fortea J. The efficacy and safety of aceclofenac versus placebo and naproxen in women with primary dysmenorrhoea. Eur J Obstet Gynecol Reprod Biol. 2006 Dec;129(2):162-8.   Per protocol, women were randomly assigned to receive one of six treatment sequences, comprising single oral doses of aceclofenac 100 mg, naproxen 500 mg or placebo, when menstrual pain reached a predetermined level of severity. A single dose of the assigned study medication was taken on 3 menstrual periods; a different medication was taken on each treatment day. The results of the study showed that aceclofenac was significantly more effective than placebo in terms of total pain relief scores. The finding was further supported by secondary endpoints, including sum of pain intensity differences (SPID/8), peak analgesia (peak pain intensity and peak pain relief ), and participant’s and investigator’s overall evaluation of effectiveness. Aceclofenac treatment thus eased menstrual pain as assessed by various pain relief criteria.

Mefenamic acid: Mefenamic acid is another NSAID with potential application in gynecological pain that inhibits cyclooxygenase enzyme and exerts its anti-inflammatory and analgesic action by inhibiting prostagl and in synthesis.¹⁶Sharma JB, Aruna J, Kumar P, Roy KK, Malhotra N, Kumar S.Comparison of efficacy of oral drotaverine plus mefenamic acid with paracervical block and with intravenous sedation for pain relief during hysteroscopy and endometrial biopsy. Indian J Med Sci. 2009 Jun;63(6):244-52.   Similar to aceclofenac, the drug is widely used to treat gynecological pain of dysmenorrhea and menorrhagia. In a study, 35 patients (16-23 years old) who had severe primary dysmenorrhea were each treated with 500 mg of mefenamic acid every 8 hours for a maximum of 3 days during menstruation for 3 consecutive cycles.¹⁷Kintis GA, Coutifaris B. Treatment of primary dysmenorrhea with mefenamic acid. Int J Gynaecol Obstet. 1980;18(3):172-5.   In all, 194 treated cycles could be evaluated, 110 cycles with mefenamic acid and 84 with placebo. The results showed that mefenamic acid produced complete relief of all the symptoms of dysmenorrhea in 31 (88.6%) patients in all 98 treated cycles and, in another two patients, moderate relief in 5/6 cycles. In contrast, only five patients (13%) from the placebo group experienced moderate to slight relief in 11/15 cycles. Mefenamic acid was thus demonstrated to be effective and well tolerated in most patients for relief of primary dysmenorrhea, thus representing a rational short-term therapy for this syndrome.

In another indication, evaluating efficacy of mefenamic acid in patients with a complaint of menorrhagia, there was a mean reduction of 28.1% in menstrual blood loss between placebo and mefenamic acid cycles, and a significant shortening of duration of bleeding. Herein, of the 69 patients with history of menorrhagia, who completed a 4-cycle double blind randomized placebocontrolled crossover trial of mefenamic acid taken during menstruation, 30 patients had objective menorrhagia with a measured menstrual loss > 80ml during the placebo cycles, but remainder reported passing clots and/or using two pads at a time.¹⁸Fraser IS, Pearse C, Shearman RP, Elliott PM, McIlveen J, Markham R. Efficacy of mefenamic acid in patients with a complaint of menorrhagia. Obstet Gynecol. 1981 Nov;58(5):543-51.   Overall, results showed a mean reduction of 28.1% in menstrual blood loss between placebo and mefenamic acid cycles. The greatest reduction recorded was 80%, with most of the large percentage reductions seen in patients with high loss during placebo cycles. Significant reductions in blood loss were seen in patients with ovulatory dysfunctional uterine bleeding and menorrhagia that developed after tubal interruption. In addition, there was also an indication that mefenamic acid could reduce blood loss in women with anovulatory dysfunctional uterine bleeding, fibroids, and intrauterine devices. Furthermore,there was a significant shortening of duration of bleeding. In another study of menorrhagia subjects, who completed a double-blind clinical study on effectiveness of mefenamic acid in lowering menstrual blood loss, 9 out of 10 exhibited statistically significant reduction in endometrial prostaglandin levels. Furthermore, a decrease in menstrual blood loss was also noted during mefenamic acid treatment in these patients.19 The investigators noted that menorrhagic subjects had significantly higher levels of endometrial prostaglandins of E and F series as compared to eumenorrheics; particularly prostaglandin E levels were markedly higher than prostaglandin F. These findings were consistent with the concept that abnormally high levels of uterine prostaglandin may be an important etiologic factor in gynecological pain, again supporting the outlook that one of the mechanisms of action of NSAIDs is inhibition of endometrial prostaglandin production.

Role of antispasmodics in dysmenorrhea

Dysmenorrhea is characterized by crampy pelvic pain, that in case of primary dysmenorrhea begin shortly before or at the onset of menses and last 1-3 days.⁶French L. Dysmenorrhea. Am Fam Physician. 2005 Jan 15;71(2):285-91.   As follows, medications reliving spasms could be of definite use in dysmenorrhea. Drotaverine – an isoquinoline derivative – can be used in such instances, it being a highly potent and effective spasmolytic agent suited for oral administration and capable of relieving spasms related to a myriad of indications. Drotaverine acts directly on the smooth muscles by inhibiting phosphodiesterase activity – being a selective inhibitor of phosphodiesterase isoenzyme IV, this mechanism accompanied by a mild Ca-channel blocking effect and no anticholinergic effect.

The latter property of drotaverine of being devoid of anticholinergic side effects²⁰Rai RR, Dwivedi M, Kumar N. Efficacy and Safety of Drotaverine Hydrochloride in Irritable Bowel Syndrome: A Randomized Double- Blind Placebo-Controlled Study. Saudi J Gastroenterol. 2014 Nov-Dec; 20(6):378-382.   is important as those can be concerning in certain patient groups as noted in Figure 3.²¹DeMaagd G. Urinary incontinence. US Pharm. 2007;32(6):34-44.   Another important property is that the antispasmodic and pain-relieving effect of drotaverine does not mask the symptoms of “acute abdomen”, and hence it does not affect association of correct diagnosis;²²Blasko G. Pharmacology, mechanism of action and clinical significance of a convenient antispasmodic agent- drotaverine. JAMA India-The physician update;vol 4(12).   this may be especially relevant in cases. In addition, as it does not have any morphine or dextropropoxyphene like effect, it does not result in addiction. These favored effects of drotaverine have been identified for over 35 years by clinical studies on thousands of patients. In daily practice, drotaverine is generally used in combination with an analgesic drug, thus potentiating the spasmolytic effect in desired indications.²³Romics I, Molnar DL, Timberg G, Mrklic B, Jelakovic B, Koszegi G, Blasko G. The effect of drotaverine hydrochloride in acute colicky pain caused by renal and ureteric stones. BJU International 2003;92(1):92-96.  

Drotaverine combination therapy for dysmenorrhea

A combination of drotaverine hydrochloride with NSAIDs (aceclofenac or mefenamic acid) is expected to provide a synergistic effect and better effectiveness in relieving the pain of dysmenorrhea, because of the complimentary mechanisms of action of different active ingredients.¹⁶Sharma JB, Aruna J, Kumar P, Roy KK, Malhotra N, Kumar S.Comparison of efficacy of oral drotaverine plus mefenamic acid with paracervical block and with intravenous sedation for pain relief during hysteroscopy and endometrial biopsy. Indian J Med Sci. 2009 Jun;63(6):244-52.   ²⁴Pareek A, Chandurkar NB, Patil RT, Agrawal SN, Uday RB, Tambe SG. Efficacy and safety of aceclofenac and drotaverine fixeddose combination in the treatment of primary dysmenorrhoea: a double-blind, double-dummy, randomized comparative study with aceclofenac. Eur J Obstet Gynecol Reprod Biol. 2010 Sep;152(1):86-90.   It has been demonstrated that drotaverine allays early-onset pain and further potentiates the sustained analgesic effect of the NSAID mefenamic acid; peak plasma concentration of drotaverine is attained within 1 hour, and that of mefenamic acid is attained in 2 to 4 hours.¹⁶Sharma JB, Aruna J, Kumar P, Roy KK, Malhotra N, Kumar S.Comparison of efficacy of oral drotaverine plus mefenamic acid with paracervical block and with intravenous sedation for pain relief during hysteroscopy and endometrial biopsy. Indian J Med Sci. 2009 Jun;63(6):244-52.  

Drotaverine + aceclofenac

The fixed-dose combination of drotaverine and aceclofenac may be a suitable, effective and well welltolerated treatment option in primary dysmenorrhea as shown in Indian study.²⁴Pareek A, Chandurkar NB, Patil RT, Agrawal SN, Uday RB, Tambe SG. Efficacy and safety of aceclofenac and drotaverine fixeddose combination in the treatment of primary dysmenorrhoea: a double-blind, double-dummy, randomized comparative study with aceclofenac. Eur J Obstet Gynecol Reprod Biol. 2010 Sep;152(1):86-90.   The double blind, double dummy, randomized, comparative, multicentric study evaluated efficacy and safety of aceclofenac-drotaverine combination against aceclofenac alone in women (100 in each arm; 18-35 years of age) with primary dysmenorrhea.²⁴Pareek A, Chandurkar NB, Patil RT, Agrawal SN, Uday RB, Tambe SG. Efficacy and safety of aceclofenac and drotaverine fixeddose combination in the treatment of primary dysmenorrhoea: a double-blind, double-dummy, randomized comparative study with aceclofenac. Eur J Obstet Gynecol Reprod Biol. 2010 Sep;152(1):86-90.   Patients were randomly allocated to either aceclofenac 100mg-drotaverine 80 mg thrice daily or aceclofenac 100mg alone thrice daily for a maximum of three days. The results of the study showed that both treatments were well tolerated and effective and significantly improved the baseline values in all efficacy parameters. However, the combination therapy was found to be superior to monotherapy in terms of the primary efficacy parameters that were total area under pain relief (PR) score up to 4 and 8 hour (TOPAR/4 and TOPAR/8). Similar trend for superiority of the combination was seen for secondary efficacy measurements that included sum of pain-intensity difference (PID) over 4 and 8 hour (SPID/4 and SPID/8), peak PID over 4 hour (PID/4) and peak PR over 4 hour (PR/4). At the end of 8 hour, both treatments were comparable regarding peak PID/8 and peak PR/8. Furthermore, the total number of doses consumed by patients treated with combination therapy was less than with monotherapy. Most importantly, the combination was significantly superior to monotherapy with respect to both patient’s and investigator’s global evaluation of the efficacy. Thus, the study convincingly establishes the efficacy of drotaverine-aceclofenac combination in patients with primary dysmenorrhea, and proposes that aceclofenac and drotaverine combination should be considered a suitable, effective and well-tolerated treatment option for primary dysmenorrhea.

Drotaverine + mefenamic acid

Likewise, the fixed-dose combination of drotaverine and mefenamic acid could be another suitable alternative in dysmenorrhea patients as shown by its effectiveness in related gynecological setting. An open randomized study, conducted in gynecological department of All India Institute of Medical Sciences (AIIMS) New Delhi, to evaluate the effect of oral drotaverine + mefenamic acid on pain perception during hysteroscopy and endometrial biopsy, found that oral combination of drotaverine with mefenamic acid was more effective in relieving pain during hysteroscopy and endometrial biopsy as compared to paracervical bock and intravenous sedation.16 The combination effectively decreased the pain during the procedure, and its effect lasted longer than that of paracervical block or intravenous sedation. The combination therapy can hence be suitable extended to women with other gynecological pains, including dysmenorrhea.

Conclusion

Dysmenorrhea is a common complaint seen in young women and adolescents. A vast majority of these patients usually has no underlying pathology, and may be managed empirically based on history and examination alone. Alleviation of the spasm and pain is particularly important in all cases, and NSAIDs have a definite role here. Drugs like aceclofenac and mefenamic acid have been shown effective in such varied cases of gynecological pain. However, a synergistic effect and improved symptom alleviation may be achieved when these drugs are used in combination with the spasmolytic drotaverine. A gynecological referral may occasionally be required in cases of secondary dysmenorrhea to manage the underlying pathology.

References

1. Proctor M, Farquhar C. Diagnosis and management of dysmenorrhea. BMJ 2006;332:1134-8.
2. Lefebvre G, Pinsonneault O, Antao V, Black A, Burnett M, Feldman K, Lea R, Robert M; SOGC. Primary dysmenorrhea consensus guideline. J Obstet Gynaecol Can. 2005 Dec;27(12):1117-46.
3. Harada T. Dysmenorrhea and Endometriosis in Young Women. Yonago Acta medica 2013;56:81-84.
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