Department of Woman and Child Health, Division for Obstetrics and Gynaecology, Karolinska Institute/Hospital, S-171 76 Stockholm, Sweden
1 To whom correspondence should be addressed. e-mail: kristina.gemzell@kbh.ki.se
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Abstract |
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Key words: misoprostol/pregnancy/sublingual administration/uterine contractility
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Introduction |
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In early pregnancy, the effect on uterine contractility after oral administration is limited. However, the effect of misoprostol is enhanced after pre-treatment with the antiprogestin, mifepristone (Norman et al., 1991). The combination of mifepristone and oral misoprostol is a highly effective method to terminate pregnancy at least up to 49 days of amenorrhoea (Peyron et al., 1993
) but less effective in more advanced pregnancy (McKinley et al., 1993
). More recent clinical studies have shown that vaginal administration of misoprostol is more effective than oral treatment in combination with mifepristone to terminate early pregnancy (El-Refaey et al., 1995
). The higher efficacy of vaginal in comparison with oral administration has also been demonstrated in second trimester pregnancy termination (Ho et al., 1997
).
The reason for the higher efficacy of vaginal administration seems to be a longer duration of elevated plasma levels in comparison with oral administration, resulting in more regular and long-lasting increase in uterine contractility (Zieman et al., 1997; Gemzell Danielsson et al., 1999
). The vaginal route of administration may not be acceptable to many women due to religious and social reasons. The degree of absorption also showed a pronounced individual variation (Gemzell Danielsson et al., 1999
). It has recently been shown that sublingual administration could effectively terminate pregnancy and results in plasma concentrations of misoprostol which are significantly greater than following both oral and vaginal administration (Tang et al., 2001
, 2002
).
The aim of the present study was to compare the effect of oral, vaginal and sublingual administration of misoprostol on uterine contractility in women in the first trimester of pregnancy.
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Materials and methods |
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Elevation of uterine tonus, above the resting level, in mmHg and uterine activity in Montevideo Units (Caldeyro-Barcia et al., 1959), were calculated before and for 10 min intervals after misoprostol administration in each subject.
t-Test was used for assessing the significance of differences between two means under assumption of normal distribution. For several means, one-way analysis of variance (ANOVA) was employed. In the latter case, appropriate comparisons of the means were calculated (Snedecor et al., 1973). The limit of significance was set at P < 0.05. A sample size of at least six subjects in each group was chosen to detect a 35% difference in the time to start of tonus elevation and time to maximum effect, assuming a coefficient of variance of 25%.
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Results |
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The only side-effect reported was abdominal pain. For women receiving oral treatment the pain was regarded as mild or moderate. Following vaginal treatment three women had strong abdominal pain and one received opioid analgesic. The same was true also for sublingual administration when the 0.4 mg dose was used.
One noteworthy finding, though incidental to the study, was that all patients had a dilated cervical canal at the time of vacuum aspiration.
In the patients who were treated vaginally, remaining parts of the tablets were found at the pre-operative vaginal washing which, however, did not seem to influence the effect on the uterus. Following sublingual administration the mean time needed for the tablets to dissolve was 16.3 min (0.2 mg) and 17.6 min (0.4 mg). In one woman in the 0.4 mg group this was not the case and the tablets remained unaffected after 3 h. In this woman there was no effect on uterine contractility. This patient was excluded from the calculation of uterine activity.
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Discussion |
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As indicated in Table II, the time from start of treatment to start of effect (increase in tonus) was the same following both oral and sublingual administration (between 7.8 and 11.5 min) but was significantly more prolonged following vaginal administration as established by one-way ANOVA. The time to maximum tonus elevation was also the same following oral and sublingual administration and significantly shorter than following vaginal administration of misoprostol. These results correspond well with the plasma levels reported by Tang et al. (2002), who found that the time to peak concentration of misoprostol in plasma was 26.0 and 27.5 min following sublingual and oral administration respectively, and between 72.0 and 75.0 min following vaginal administration. The increase in uterine tonus was most pronounced following sublingual administration of 0.4 mg misoprostol and significantly higher than that following oral administration of the same dose of misoprostol, which is also in accordance with the pharmacokinetic results (Tang et al., 2002
).
The typical effect of a single oral administration of misoprostol is an increase in uterine tonus (Norman et al., 1991; Gemzell Danielsson et al., 1999
). It is only following repeated treatment that regular uterine contractions appear. The effect of vaginal administration of misoprostol on uterine contractility is initially similar to that of oral administration; an increase in uterine tonus. However, after 12 h regular uterine contractions appear lasting at least up to 4 h after the start of treatment. The effect of sublingual administration was the same as following vaginal treatment and significantly more pronounced than after oral treatment as shown in Figure 2. One explanation can be that following both sublingual and vaginal treatment with misoprostol, the plasma levels of misoprostol are significantly elevated for a longer period of time than following oral treatment (Tang et al., 2002
). It is possible that this prolonged duration of stimulation is able to overcome the so-called progesterone block which otherwise prevents the myometrium from regular activity. With sublingual administration of 0.4 mg misoprostol, uterine contractility tended to decrease at the end of the recording period. This is also in accordance with the pharmacokinetic data which demonstrated a more rapid decline in plasma levels following sublingual than following vaginal administration.
Both oral and vaginal administration of misoprostol is used to dilate the cervix prior to vacuum aspiration (Ngai et al., 1999). Although it was not the aim of the study, the outcome indicates that sublingual administration might be equally effective. In eight out of the 12 women treated by this route the cervical canal allowed the introduction of an 8 mm size vacuum curette without prior dilatation.
It may be concluded from the present study that sublingual administration of misoprostol with regard to effect on the uterus acts as rapid as oral administration and the effect on uterine contractility is similar to that following vaginal administration.
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Acknowledgements |
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References |
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Submitted on June 3, 2003; accepted on August 17, 2003.