© 1985 S.

Karger A G , Basel
Gynecol, obstet. Invest. 20: 78-83 (1985) 0378-7346/85/0202-007852.75/0

Calcium Blockade as a Rapid Pharmacological Test to Evaluate

Primary Dysmenorrhea
U. Ulmsten
Department of Obstetrics and Gynecology, Malmö General Hospital, University of Lund, Malmö, Sweden

Key Words. Calcium antagonists • Nifedipine • Myometrial hyperactivity • Dysmenorrhea

Abstract. The calcium antagonist, nifedipine, was used to identify patients with primary
dysmenorrhea caused by myometrial hyperactivity. Twelve patients with severe primary dys­
menorrhea received an oral loading dose of 30 mg nifedipine on the first day of menstruation.
Nine patients reported prompt relief of the menstrual cramps (within 15-60 min). In 3
patients no pain relief was obtained. In 2 of these subjects, subsequent laparoscopy revealed
obvious signs of endometriosis and previous pelvic inflammatory disease as the cause of these
patients pain. Moreover, intrauterine pressure recording with microtransducers displayed
normal uterine activity in these patients. It is concluded that, due to its prominent tocolytic
effect, nifedipine can be used as a simple pharmacologic test to identify patients suffering from
severe primary dysmenorrhea. In addition it indicates a subsequent way to treat the dis­
order.

Introduction different therapeutic principles have been

Abnormally increased smooth muscle ac­
tivity is considered to be the cause of several
gynecological disorders. Today there is, for
example, a common opinion that primary
dysmenorrhea is due in most cases to an
abnormally increased uterine activity result­
ing in myometrial ischemia, recognized by
the patients as menstrual cramps [1-3]. Al­
suggested, compounds that have the ability
to block the production of uterine contrac­
tions should be recognized as possible thera­
peutic alternatives in the treatment of pri­
mary dysmenorrhea.
Slow channel blockers or calcium antago­
nists are a new group of compounds recently
introduced into clinical medicine, primarily
for the treatment of cardiac dysfunction [4],
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though the ethiology of this myometrial hy­ In a long series of investigations both in vitro
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peractivity may be multifactorial and hence and in vivo we have explored the aspects of
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Calcium Blockade in Primary Dysmenorrhea
calcium blockade as a therapeutic principle
in obstetrics and gynecology. Among calcium
blockers presently available we found nifedi­
pine to exert pronounced relaxation of both
the non-pregnant and pregnant myometrium
[5, 6], In both healthy and dysmenorrheic
patients oral intake of 30-40 mg nifedipine
markedly reduced or abolished uterine con­
tractions in almost all patients, as objectively
verified by intrauterine pressure recordings
[6, 7], Simultaneously with the decreased
uterine activity, which occurred within 15-
20 min of drug intake, the dysmenorrheic
patients reported relief of their menstrual
cramps (fig. 1). Based on these results which
recognize nifedipine as an extraordinarily po­
tent tocolytic drug, we were interested in dis­
covering whether the compound could be
used as an indirect diagnostic test to identify
primary dysmenorrhea - characterized by an
abnormally increased uterine activity - and
at the same time indicate a way to treat the
disorder.
Material and Methods
Twelve nulliparous patients seen in the outpa­
tient’s clinic with severe menstrual cramps on the first
day of their periods were randomly enrolled in the
study. The patients had a mean age of 16 years (range
14 22 years) and a typical history of severe primary
dysmenorrhea. They all had regular periods, and none
was on medication. Oral intake of conventional salicy­
lates had affected the menstrual cramps little in pre­
vious cycles. Before entering the study all women were
informed of the procedures involved and agreed to
participate.
After elicitation of the medical history and a care­
ful gynecological examination to rule out other possi­
ble causes of the menstrual cramps which would dis­
qualify the patient from participation in the study, all
women were given 30 mg nifedipine (Adalat®) orally.
Blood pressure and pulse rate were monitored at drug
intake and subsequently every 30 min up to 3 h. All
79
patients were asked to rest in the clinic until the
cramps had abated. They were also instructed to note
the positive or negative effects of the drug on a special
chart. When satisfactory pain relief had been obtained
the subjects were released from the clinic and in­
structed to take another 20 mg of nifedipine if pain
recurred. This second dose was not allowed until 6 h
had elapsed from ingestion of the loading dose. Pa­
tients with effective pain relief were allowed to use
nifedipine on their own during the next two menstrual
periods. After that time they were asked to re-visit the
clinic to discuss the outcome of the treatment. In the
case of no pain relief within 2 h of intake of the loading
dose, the patient was subjected to intrauterine pressure
recordings (IUP) with microtransducers, according to
the technique shown in figure I and described in detail
previously (6-8). If the IUP recordings revealed nor­
mal uterine activity the patient was recommended to
undergo laparoscopy to rule out other possible causes
of the dysmenorrheic pains.
Results
Nine of the 12 patients reported a prompt
and marked decrease of the menstrual pains
within 20 min of drug intake. Six of these
9 patients declared that they were completely
cured within half an hour and then asked to
be released from the clinic. The other 3 pa­
tients reported considerable pain relief after
that time and were released from the hospital
after a resting period of 1 h. According to
their reports the pain relief in these 9 patients
was sustained for 5 h. Further intake of
20 mg nifedipine then alleviated recurring
menstrual cramps for another 5-hour period.
In 3 of the patients nifedipine medication
had to be repeated the next day. No patient
required therapy on day 3. During the follow­
ing two menstrual periods all 9 patients had
similarly effective pain relief after nifedipine
intake.
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In 3 patients the drug test was negative,
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i.e. nifedipine did not alleviate the menstrual
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80 Ulmsten

Fig. 1. a Intrauterine pressure

recording from a patient with pri­
mary dysmenorrhea on the first day
of menstruation. Pressure is re­
corded from fundus uteri with a mi­
crotransducer catheter (b). Note the
high contraction amplitudes some­
times exceeding 200 mm Hg. The
arrow indicates peroral intake of 30
mg nifedipine. Within 15 min after
drug intake the uterine contractions
abate and simultaneously the patient
reports pain relief, b The microtrans-
duccr catheter used for the record­
ings. Pressure can be obtained from
three sections simultaneously: I, 2
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and 3 corresponding to fundus, isth­

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mus and cervix uteri, respectively.

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Calcium Blockade in Primary Dysmenorrhea
lO O ynfflH g I 1
' .
*1V;!A
■*1 .
a
V
v'""v
.\ v<\ >\
Tt \ '<
'
Fig. 2. Intrauterine pressure recordings from a dysmenorrheic patient who did not respond to nifedipine
intake. The recordings were obtained about 2 h after drug intake. As seen there are still high contraction ampli­
tudes from fundus uteri (upper tracing), the lower tracing indicates the pressures at the internal os.
cramps. In 1 patient the subsequent IUP re­
cording revealed abnormally increased myo­
métrial activity 2 h after drug intake (fig. 2).
In the other 2 patients uterine activity was
almost normal (fig. 3). Despite this the pa­
tients reported severe lower abdominal pain.
Although the vaginal examination did not
reveal any abnormalities in these 2 women,
subsequent laparoscopy showed obvious
signs of endometriosis in 1 patient and in the
other signs of previous pelvic inflammatory
disease.
All but 1 patient (the one with uterine
hyperactivity but no pain relief) experienced
warmness in the skin and facial flush starting
81
L .. I i il, 11
n\ ivA V v- ^ ■
k Mi.
about 15 min after drug intake. A slight de­
crease in blood pressure was recorded from a
mean of 120/80 mm Hg (range 130/90 to
110/60) to a mean of I 10/60 mm Hg (range
120/90 to 100/50) within half an hour of drug
intake. No hypotensive episodes were ob­
served (also tested in upright position). The
pulse rate was unaffected.
Seven of the 9 subjects with good pain
relief afier nifedipine intake were interested
in continuing with the treatment. Two
women who experienced headache starting
shortly after drug intake asked for another
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remedy after the three period trial had been
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completed.
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82
Fig. 3. Intrauterine pressure recordings from a patient complaining of primary dysmenorrhea 2 h after intake
of nifedipine. As can be seen there is a normal contraction pattern within both fundus (upper tracing) and
isthmus (lower tracing).
Comments
As reported in previous investigations, ni­
fedipine seems to have potent relaxing effects
on the uterus. Consistent with previous re­
sults, the majority of our patients reported
almost complete relief of menstrual pain
shortly after drug intake. In this study nifedi­
pine failed to alleviate the menstrual cramps
in 3 subjects. In 2 the laparoscopic findings
revealed that these patients most certainly
suffered from secondary dysmenorrhea due
to endometriosis and pelvic inflammatory
disease. In the remaining subject the reason
for the ‘negative’ drug response might have
been insufficient absorption of the com­
pound from the gastrointestinal tract. This
suggestion is supported by the fact that the
patient did not experience any warmness of
the skin or facial flush, common side effects
in almost all subjects after nifedipine intake,
as reported previously and as recognized by
the other 11 patients in this study [6, 9],
Due to these well-recognized side effects it
is extremely difficult to carry out double­
blind controlled studies with nifedipine. The
Ulmsten
frequency of other side effects, i.e. headache,
was of the same order as that reported pre­
viously, and may in some patients prevent
the regular use of nifedipine for the treatment
of dysmenorrhea [9].
Based on the findings in the present study,
it seems justified to conclude that infedipine
could be worth trying as a simple and rapid
diagnostic test to indicate whether a patient
suffers from primary dysmenorrhea due to
increased myometrial activity. In the vast
majority of these patients considerable uter­
ine relaxation with subsequent pain relief can
be expected to occur within half an hour of
oral intake of 30 mg of the drug.
The use of the drug test is of special value
in patients in whom conventional therapy
has failed to alleviate the menstrual cramps.
Due to its potent tocolytic effect, a positive
nifedipine response strongly indicates myo­
metrial hyperactivity as the main cause of the
patients cramps. These women can in the fol­
lowing cycles be subjected to tocolytic ther­
apy according to the choice of the gynecolo­
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gist. In the event of a negative response to the
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drug the patient should be subjected to fur­
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Calcium Blockade in Primary Dysmenorrhea
ther investigations to discover the cause of
the menstrual dysfunction. The test de­
scribed here is easily and safely carried out on
an outpatient basis. It provides a diagnostic
tool that may reduce the risks of using incor­
rect or ineffective drugs for long-term treat­
ment of primary dysmenorrhea. Moreover, it
may facilitate the detection of other disorders
causing the pain which, if undiagnosed, may
lead to further problems in these young pa­
tients in the future, c.g. infertility.
Although the etiology of myometrial hy­
peractivity in patients with menstrual cramps
is not absolutely clear, inreased synthesis of
prostaglandins is considered to be an impor­
tant factor. Hence, the drugs of choice, apart
from contraceptive pills, should be prosta­
glandin inhibitors. However, despite the an­
noying side effect of headache in some pa­
tients, calcium blockers like nifedipine might
also be considered as a therapeutic alterna­
tive in patients suffering from severe primary
dysmenorrhea, when conventional therapy
has failed to bring about sufficient uterine
relaxation and alleviation of the dysmen-
orrhcic cramps. Nifedipine can then be used
alone or in combination with prostaglandin
inhibitors [10].
References
1 Akcrlund, M.: Studies on myometrial activity and
endometrial blood flow in the non-pregnant hu­
man uterus; thesis Lund (1977).
2 Ulmsten, U.: Uterine activity and blood flow in
normal and dysmenorrheic women; in Dawood,
McGuire. Demers. Premenstrual syndrome and
dysmenorrhea, pp. 103-124 (Urban & Schwarzen-
berg. Baltimore 1985).
83
3 Lumsden. M.A.; Baird. D.T.: Intrauterine pressure
in dysmenorrhea. Acta obstet. Gyncc. scand. 64:
139-143 (1985).
4 Fleckenstein, A.: Specific pharmacology of cal­
cium in myocardium, cardiac pacemakers and vas­
cular smooth muscle. Annu. Rev. Pharmacol.
Toxicol. 17: 149-166 (1977).
5 Maigaard, S.; Forman, A.; Andersson, K.-E.;
Ulmsten, U.: Comparison of the effects of nicardi­
pine and nifedipine on isolated human myome­
trium. Gynecol, obstet. Invest. 16: 354-366
(1983).
6 Ulmsten. U.; Andersson, K.-E.; Forman, A.: Re­
laxing effects of nifedipine on the non-pregnant
human uterus in vitro and in vivo. Obstet. Gynec.,
N.Y. 52: 436-441 (1978).
7 Andersson, K.-E.; Ulmsten, U.: Effects of nifedi­
pine on myometrial activity and lower abdominal
pain in women with primary dysmenorrhea. Br. J.
Obstet. Gynaec. 85: 142-148 (1978).
8 Ulmsten. U.; Andersson, K.-E.: Multi-channel in-
tra-utcrine pressure recording by means of micro­
transducer. Acta obstet. gynec. scand. 58: 115-119
(1979).
9 Sandahl, B.; Ulmsten, U.; Andersson, K.-E.: Trial
of the calcium antagonist nifedipine in the treat­
ment of primary dysmenorrhea. Arch. Gynaek.
227: 147-151 (1979).
10 Forman. A.; Ulmsten, U.; Andersson, K.-E.: As­
pects of inhibition of myometrial hyperactivity in
primary dysmenorrhea. Acta obstet. gynec. scand.,
Suppl. 113, pp. 71-76 (1983).
Received: March. 22. 1985
Accepted: April 9, 1985
U.Ulmsten. MD,
Department of Obstetrics and Gynecology,
Malmö General Hospital.
University of Lund.
S—214 01 Malmö (Sweden)
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