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Pre-emptive effect of ibuprofen versus placebo on pain relief and success rates of medical abortion: a double-blind, randomized, controlled study
ORIGINAL ARTICLES: CONTRACEPTION
Pre-emptive effect of ibuprofen versus placebo on pain relief and success rates of medical abortion: a double-blind, randomized, controlled study Sarit Avraham, B.M.Sc., Itai Gat, M.D., Nir-Ram Duvdevani, M.D., Jigal Haas, M.D., Yair Frenkel, M.D., and Daniel S. Seidman, M.D. Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, affiliated with the Sackler School of Medicine, Tel-Aviv University, Tel Hashomer, Israel
Objective: To determine the efficacy of pre-emptive administration of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen vs. a placebo on pain relief during medical abortion and to evaluate whether NSAIDs interfere with the action of misoprostol. Design: Prospective, double-blind, randomized, controlled study. Setting: University-affiliated tertiary hospital. Patient(s): Sixty-one women who underwent first-trimester termination of pregnancy. Intervention(s): Patients received 600 mg mifepristone orally, followed by 400 mg oral misoprostol 2 days later. They were randomized to receive preemptively two tablets of 400 mg ibuprofen orally or a placebo, when taking the misoprostol. The patients completed a questionnaire about side effects and pain score and returned for an ultrasound follow-up examination 10–14 days after the medical abortion. Main Outcome Measure(s): Significant pain, assessed by the need for additional analgesia, and failure rates, defined by a need for surgical intervention. Result(s): Pre-emptive ibuprofen treatment was found to be more effective than a placebo in pain prevention, as determined by a significantly lower need for additional analgesia: 11 of 29 (38%) vs. 25 of 32 (78%), respectively. Treatment failure rate was not statistically different between the ibuprofen and placebo groups: 4 of 28 (14.2%) vs. 3 of 31 (9.7%), respectively. History of menstrual pain was predictive for the need of additional analgesia. Conclusion(s): Pre-emptive use of ibuprofen had a statistically significant beneficial effect on the need for pain relief during a mifepristone and misoprostol regimen for medical abortion. Ibuprofen did not adversely affect the outcome of medical abortion. Clinical Trial Registration Number: NCT00997074. (Fertil SterilÒ 2012;97:612–5. Ó2012 by American Society for Reproductive Medicine.) Key Words: Pain, medical abortion, ibuprofen, mifepristone, misoprostol, analgesics, pre-emptive, placebo
M
ifepristone, a P antagonist, is currently the drug most widely used to induce medical abortion (1). Most protocols combine the use of 200–600 mg of oral mifepristone with misoprostol, a prostaglandin (PG) E1 analogue, usually in an oral or buccal dose of 400 mg (1, 2). High efficacy rates are usually reported, with success rates of up to 97.5% (3). Pain is the most common
side effect during medical abortion, mainly after PG administration, and is recognized as an important factor in women’s decisions regarding whether to resort to surgical or medical abortion (4). Penney (5), in a review concerning medical abortion, reported that approximately 75% of women need to use narcotic analgesics to obtain pain relief during early medical abortion with PG
Received September 19, 2011; revised December 17, 2011; accepted December 21, 2011; published online January 20, 2012. S.A. has nothing to disclose. I.G. has nothing to disclose. N.-R.D. has nothing to disclose. J.H. has nothing to disclose. Y.F. has nothing to disclose. D.S.S. has nothing to disclose. Reprint requests: Daniel S. Seidman, M.D., Chaim Sheba Medical Center, Department of Obstetrics and Gynecology, 52621 Tel Hashomer, Israel (E-mail: [email protected]). Fertility and Sterility® Vol. 97, No. 3, March 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2011.12.041 612
administration. Increasing gestation, young age, white race, and nulliparity were associated with increased need for analgesia (5, 6). We have previously reported the results of a double-blind, randomized trial, in which ibuprofen and paracetamol were compared for pain relief during medical abortion using a mifepristone and misoprostol protocol (7). We found that ibuprofen was superior to paracetamol in pain reduction and also reduced the need for additional analgesia. In that study, analgesia was administered at the onset of pain. However, because pain and fear of it are described by many women as their greatest concerns regarding the medical abortion procedure (8), we chose to VOL. 97 NO. 3 / MARCH 2012
Fertility and Sterility® investigate a new protocol for pain relief whereby ibuprofen is administered pre-emptively at the same time as the misoprostol. The use of pre-emptive analgesia may offer a means to reduce the pain experienced after a medical procedure. For instance, pre-emptive local anesthesia was shown in a randomized blinded trial to successfully lower pain levels 24 hours after laparoscopic surgery (9). Little has been reported to date regarding the use of pre-emptive analgesia for pain management during medical abortion (10). Weib (11) used an uncommon protocol of methotrexate combined with vaginal misoprostol. He found no difference in pain scores after pre-emptive administration of acetaminophen and codeine, ibuprofen, or placebo. No differences in maximal pain levels were also reported after the use of preemptive acetaminophen, alverine, or placebo, before a no longer used protocol combining mifepristone with a sulprostone injection (12). To date no studies have been reported regarding the use of pre-emptive analgesia during the most commonly implemented mifepristone and misoprostol protocol. The aim of this study was to investigate the pre-emptive administration of analgesia to allow a less painful experience during medical abortion. Because pain score data are often difficult to compare, owing to little or no information about the distribution of error (13), we decided to use as our primary outcome variable the need for additional analgesia, because this could serve as a good proxy for significant pain experienced after taking misoprostol.
received two placebo tablets. The tablets of ibuprofen and the placebo were of the exact same size, shape, and color. Information about the effect of the analgesics on pain and on the course of the medical abortion was prospectively gathered from three questionnaires, filled out by all women participating in the study. The first was a demographic questionnaire, and the second documented side effects after mifepristone. In the third questionnaire the women were asked to document the level of pain 1 and 2 hours after misoprostol ingestion, as well as the need for another analgesic and any side effects that they experienced during the 6 hours of hospital observation (e.g., fever, headache, vaginal bleeding, nausea, vomiting, diarrhea, dizziness, or shivering). Pain was assessed using an 11-point numeric pain scale, from 0 (no pain) to 10 (the most severe pain). Time and need for another analgesic was also recorded by the nurses. The second-line analgesic was dipyrone (Drop Optalgin, 1 g; Teva), given at any time at patient request. Dipyrone or metamizole sodium is banned in more than 30 countries (including United States, Japan, Australia, and several of the European Union member nations) because of the associated risk of agranulocytosis. The women returned for a follow-up by ultrasound examination after 10–14 days. Endometrial thickness >15 mm was considered a failure of the medical abortion, and these patients were referred for a surgical evacuation. Under any suspicion for retained products of gestation, women were invited for another follow-up after menstrual period and evaluated for the need for intervention (14).
MATERIALS AND METHODS
Statistical Analysis
In a randomized, placebo-controlled, double-blind trial we studied 61 women who chose to undergo a medical abortion. The study protocol was approved by our medical center’s review board for human investigation. The medical abortion regimen used was 600 mg mifepristone given orally (Mifegyne; Exelgyn) followed by an oral dose of 400 mg misoprostol after 36–48 hours (Cytotec; Searle), given under medical supervision for 6 hours in the hospital. The women were sent home between the treatments.
The groups were compared in frequency tables, using the appropriate statistical tests. Dichotomous variables were analyzed using the Pearson c2 test with linear step-up correction for multiple analyses. When asymptotics could not be assumed, Fisher’s exact test was used. Student’s t test was used for normally distributed metric variables, and numeric ones were analyzed with the Wilcoxon rank test. To adjust for interaction between independent variables and pain levels or demand for additional analgesia, a logistic regression model was used. Statistical significance was defined as a P value < .05.
Study Group The study group comprised women aged 18–45 who had chosen to undergo a medical abortion, with an ultrasounddocumented intrauterine pregnancy of up to 7 weeks’ gestation, after approval from the Ministry of Health’s committee for termination of pregnancy. Women with chronic disease, renal insufficiency, or known allergy to misoprostol or nonsteroidal anti-inflammatory drugs were excluded.
Study Process The 61 women were randomized at the time of misoprostol administration into two treatment groups by providing a sealed envelope, using a computer-generated random list, with serial numbers from 1 to 61. One group received two tablets of ibuprofen 400 mg (Adex; Dexon), and the second group VOL. 97 NO. 3 / MARCH 2012
RESULTS Sixty-one women participated in the study. Twenty nine were randomized to receive ibuprofen at the time of misoprostol administration, and 32 received placebo pills. Four women did not fill out the questionnaires properly and therefore information about side effects and pain levels was not complete. Another woman did not report on menstrual pain. Information about the need for analgesia (recorded by the nurse at real time), demographics, and success of the treatment was taken from their medical files. Two women, one in each group, did not show up for follow-up, and data about the success of the abortion were not established. They were considered in our analysis as failure of the medical abortion. There was no significant difference between the two groups regarding marital status, age, parity, religion, 613
ORIGINAL ARTICLE: CONTRACEPTION socioeconomic state, usual menstrual pain, cigarette smoking, week of gestation, and previous abortions. There was also no significant difference in adverse side effects reported by women in both groups. The side effects reported included abdominal pain (79.3%), headache (17.5%), nausea (67.2%), dizziness (28%), vomiting (19.3%), bleeding (78.6%), and shivering (31.6%). Headache and vomiting were reported by fewer women in the study group compared with the placebo group, but the difference did not reach statistical significance after correcting for multiple comparisons (Table 1). Success of the medical abortion was recorded at the follow-up visit in 85.2% of the patients. The failure rate was not significantly different between the study and the placebo groups: 5 of 29 (17.2%) vs. 4 of 32 (12.5%) patients. Two women in each group required additional misoprostol to complete the medical abortion without surgical intervention. A statistically significant difference was found between the two groups regarding the need for additional analgesia. Twenty-five women from the group that received placebo pills with the administration of misoprostol (78%) demanded additional pain relief, compared with only 11 (38%) women in the ibuprofen group (P< .001). Of the women who received ibuprofen, 15.5% reported being free of any pain (¼0), compared with 5.2% of the placebo group (P¼ .52). Mean (SD) pain levels after 1 and 2 hours in the ibuprofen group were 4.00 3.80 and 2.98 2.98, respectively, and were higher in the placebo group by approximately 1.5 points, although this difference was not statistically significant (Table 2). To evaluate pain levels after 2 hours more accurately, we excluded the women who received additional analgesia by that time. Twenty-six women in the ibuprofen group, compared with 22 women in the placebo group, were still free of additional analgesia. A significant difference was found between the groups regarding their mean (SD) pain levels: 4.81 3.30 in the placebo group and 2.09 þ 3.09 in the ibuprofen group (P¼ .024). Data about success of the medical abortion, pain levels, and additional use of analgesia are shown in Table 2. Using a logistic regression model we found that a patient who reported that she usually suffered from menstrual pain was more likely to demand additional analgesia. Any increase by a single point in menstrual level pain raised the probability of additional analgesia request (odds ratio 1.47, 95% confidence
TABLE 1 Rate of side effects in patients receiving pre-emptive analgesia with ibuprofen vs. a placebo during 6 hours of observation. Adverse effect Headache Nausea Dizziness Vomiting Bleeding Shivering
Placebo group (n [ 32)
Ibuprofen group (n [ 29)
P value
7 (12.3) 19 (32.8) 8 (14.0) 9 (15.8) 23 (41.1) 7 (12.3)
3 (5.3) 20 (34.5) 8 (14.0) 2 (3.5) 21 (37.5) 11 (19.3)
.15 .78 .93 < .02 .89 .29
Note: Values are number (percentage). Avraham. Ibuprofen for pain relief in medical abortion. Fertil Steril 2012.
614
TABLE 2 Abortion success rate and pain relief achieved in patients receiving pre-emptive analgesia with ibuprofen vs. a placebo. Measure Abortion success Required additional misoprostol Patients with no pain (¼0) at 1 or 2 h Required additional analgesia Pain level (1 h) Pain level (2 h) Pain level without analgesia (2 h)
Placebo group Ibuprofen group (n [ 32) (n [ 29) P value 28 (87.5) 2 (6.3)
24 (82.8) 2 (6.9)
.72 1.00
3 (5.2)
9 (15.5)
.05
25 (78) 5.40 3.90 4.46 3.20 4.81 3.30
11 (38) 4.00 3.80 2.98 2.98 2.09 3.09
.001 .18 .07 .02
Note: Values are number (percentage) or mean SD. Avraham. Ibuprofen for pain relief in medical abortion. Fertil Steril 2012.
interval 1.11–1.93). Previous abortion adversely affected the demand for additional analgesia (odds ratio 0.21, 95% confidence interval 0.06–0.79).
DISCUSSION Our study is, to the best of our knowledge, the first to show a beneficial effect on the need for pain relief for the preemptive use of ibuprofen during a mifepristone and misoprostol regimen for medical abortion. The most clear and significant difference was a remarkably lower demand for additional pain relief in the ibuprofen group. Among women who received pre-emptive ibuprofen, 62% of the patients did not require additional analgesia, compared with only 22% in the group that received a placebo. This is in agreement with the lower levels of pain reported by the women in the ibuprofen group, who did not receive additional analgesia after 2 hours, compared with the matching placebo group. Mean pain levels 1 hour after misoprostol administration were 5.4 in the placebo group and 4.0 in the ibuprofen group. These pain levels were substantially lower than those reported in our previous study that was conducted at the same hospital, using a similar protocol for medical abortion and identical pain scores, but that compared ibuprofen with paracetamol given only at the onset of pain, after misoprostol administration (7). It seems that our new data not only demonstrate the beneficial effect of pre-emptive ibuprofen but also suggest a significant effect for pre-emptive placebo. A higher demand for additional pain relief was found among women who reported more painful periods. This finding is consistent with results of a recent study showing that menstrual pain correlates positively with pain during medical abortion (15). A previous study of the methotrexate and misoprostol protocol reported mean pain levels of 6–6.5 after the use of a placebo or different analgesia regimens, when administrated with misoprostol (11). The women in that study received the analgesia for home use. This might suggest a more comfortable and supporting experience in the hospital setting. A recent systemic review, comparing home medical abortion with clinic-based abortion, found no differences in VOL. 97 NO. 3 / MARCH 2012
Fertility and Sterility® acceptability between these two approaches. Yet the study did show that pain lasted longer among women who took misoprostol at home (16). We are aware of the limited size of our study sample. However, our results do suggest that it may be appropriate to offer a woman who is about to undergo medical abortion preemptive use of ibuprofen, especially if she is at increased risk for experiencing severe pain or strongly afraid of a potentially painful procedure. We believe that the fact that most of the women who received pre-emptive analgesia did not ask for additional pain relief is a strong indicator of improved comfort and less pain and will likely allow more patients an easier choice favoring the less-invasive medical abortion protocol. Nonsteroidal anti-inflammatory drugs, such as ibuprofen, were previously avoided in protocols studied for medical abortion because of concern over their potential inhibition of PG-induced uterine contractions. The present study adds support to our previous report (7) by demonstrating that ibuprofen does not diminish the success rates of medical abortion. In conclusion, we found in a prospective, double-blind, randomized, controlled study that pre-emptive ibuprofen use, in a mifepristone and misoprostol protocol for medical abortion, can significantly reduce pain levels and the need for additional analgesia compared with placebo.
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Ashok PW, Penny GC, Flett GM, Templeton A. An effective regimen for early medical abortion: a report of 2000 consecutive cases. Hum Reprod 1998;13: 2962–5. Niinimaki M, Jouppila P, Martikainen H, Talvensaari-Mattila A. A randomized study comparing efficacy and patient satisfaction in medical or surgical treatment of miscarriage. Fertil Steril 2006;86:367–72. Penney G. Treatment of pain during medical abortion. Contraception 2006; 74:45–7. Hamoda H, Ashok PW, Flett GM, Templeton A. Analgesia requirements and predictors of analgesia use for women undergoing medical abortion up to 22 weeks of gestation. BJOG 2004;111:996–1000. Livshits A, Machtinger R, David LB, Spira M, Moshe-Zahav A, Seidman DS. Ibuprofen and paracetamol for pain relief during medical abortion: a double-blinded randomized controlled trial. Fertil Steril 2009;91:1877–80. Winikoff B, Ellerston C, Elul B, Sivin I. Acceptability and feasibility of early pregnancy termination by mifepristone-misoprostol. Results of a large multicenter trial in the United States. Arch Fam Med 1998;7:360–6. Ke RW, Portera SG, Lincoln SR. A randomized blinded trial of preemptive local anesthesia in laparoscopy. Prim Care Ob Gyns 1998;5:197–8. Jacson E, Kapp N. Pain control in first-trimester and second-trimester medical termination of pregnancy: a systemic review. Contraception 2011;83: 116–26. Weib E. Pain control in medical abortion. Int J Gynecol Obstet 2001;74:275–80. Weber B, Fontan JE, Scheller E, Debu E, Dufour B, Majorel P, et al. Abortion induced by mifepristone and sulprostone combination: attempting analgesia with acetaminophen or dipropyline. Contracept Fertil Sex 1990;18: 1073–6. Williamson A, Hoggart B. Pain: a review of three commonly used pain rating scales. J Clin Nurs 2005;14:798–804. Machtinger R, Seidman DS, Goldenberg M, Stockheim D, Schiff E, Shulman A. Transvaginal ultrasound and operative hysteroscopy in women undergoing medical termination of pregnancy as part of routine follow-up. Fertil Steril 2005;84:1536–8. Suhonen S, Tikka M, Kivinen S, Kauppila T. Pain during medical abortion: predicting factors from gynecologic history and medical staff evaluation of severity. Contraception 2011;83:357–61. Ngo TD, Park MH, Shakur H, Free C. Comparative effectiveness, safety and acceptability of medical abortion at home and in the clinic: a systemic review. Bull World Health Organ 2011;89:360–70.
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Pre-emptive effect of ibuprofen versus placebo on pain relief and success rates of medical abortion: a double-blind, randomized, controlled study Sarit Avraham, B.M.Sc., Itai Gat, M.D., Nir-Ram Duvdevani, M.D., Jigal Haas, M.D., Yair Frenkel, M.D., and Daniel S. Seidman, M.D. Department of Obstetrics and Gynecology, Chaim Sheba Medical Center, affiliated with the Sackler School of Medicine, Tel-Aviv University, Tel Hashomer, Israel
Objective: To determine the efficacy of pre-emptive administration of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen vs. a placebo on pain relief during medical abortion and to evaluate whether NSAIDs interfere with the action of misoprostol. Design: Prospective, double-blind, randomized, controlled study. Setting: University-affiliated tertiary hospital. Patient(s): Sixty-one women who underwent first-trimester termination of pregnancy. Intervention(s): Patients received 600 mg mifepristone orally, followed by 400 mg oral misoprostol 2 days later. They were randomized to receive preemptively two tablets of 400 mg ibuprofen orally or a placebo, when taking the misoprostol. The patients completed a questionnaire about side effects and pain score and returned for an ultrasound follow-up examination 10–14 days after the medical abortion. Main Outcome Measure(s): Significant pain, assessed by the need for additional analgesia, and failure rates, defined by a need for surgical intervention. Result(s): Pre-emptive ibuprofen treatment was found to be more effective than a placebo in pain prevention, as determined by a significantly lower need for additional analgesia: 11 of 29 (38%) vs. 25 of 32 (78%), respectively. Treatment failure rate was not statistically different between the ibuprofen and placebo groups: 4 of 28 (14.2%) vs. 3 of 31 (9.7%), respectively. History of menstrual pain was predictive for the need of additional analgesia. Conclusion(s): Pre-emptive use of ibuprofen had a statistically significant beneficial effect on the need for pain relief during a mifepristone and misoprostol regimen for medical abortion. Ibuprofen did not adversely affect the outcome of medical abortion. Clinical Trial Registration Number: NCT00997074. (Fertil SterilÒ 2012;97:612–5. Ó2012 by American Society for Reproductive Medicine.) Key Words: Pain, medical abortion, ibuprofen, mifepristone, misoprostol, analgesics, pre-emptive, placebo
M
ifepristone, a P antagonist, is currently the drug most widely used to induce medical abortion (1). Most protocols combine the use of 200–600 mg of oral mifepristone with misoprostol, a prostaglandin (PG) E1 analogue, usually in an oral or buccal dose of 400 mg (1, 2). High efficacy rates are usually reported, with success rates of up to 97.5% (3). Pain is the most common
side effect during medical abortion, mainly after PG administration, and is recognized as an important factor in women’s decisions regarding whether to resort to surgical or medical abortion (4). Penney (5), in a review concerning medical abortion, reported that approximately 75% of women need to use narcotic analgesics to obtain pain relief during early medical abortion with PG
Received September 19, 2011; revised December 17, 2011; accepted December 21, 2011; published online January 20, 2012. S.A. has nothing to disclose. I.G. has nothing to disclose. N.-R.D. has nothing to disclose. J.H. has nothing to disclose. Y.F. has nothing to disclose. D.S.S. has nothing to disclose. Reprint requests: Daniel S. Seidman, M.D., Chaim Sheba Medical Center, Department of Obstetrics and Gynecology, 52621 Tel Hashomer, Israel (E-mail: [email protected]). Fertility and Sterility® Vol. 97, No. 3, March 2012 0015-0282/$36.00 Copyright ©2012 American Society for Reproductive Medicine, Published by Elsevier Inc. doi:10.1016/j.fertnstert.2011.12.041 612
administration. Increasing gestation, young age, white race, and nulliparity were associated with increased need for analgesia (5, 6). We have previously reported the results of a double-blind, randomized trial, in which ibuprofen and paracetamol were compared for pain relief during medical abortion using a mifepristone and misoprostol protocol (7). We found that ibuprofen was superior to paracetamol in pain reduction and also reduced the need for additional analgesia. In that study, analgesia was administered at the onset of pain. However, because pain and fear of it are described by many women as their greatest concerns regarding the medical abortion procedure (8), we chose to VOL. 97 NO. 3 / MARCH 2012
Fertility and Sterility® investigate a new protocol for pain relief whereby ibuprofen is administered pre-emptively at the same time as the misoprostol. The use of pre-emptive analgesia may offer a means to reduce the pain experienced after a medical procedure. For instance, pre-emptive local anesthesia was shown in a randomized blinded trial to successfully lower pain levels 24 hours after laparoscopic surgery (9). Little has been reported to date regarding the use of pre-emptive analgesia for pain management during medical abortion (10). Weib (11) used an uncommon protocol of methotrexate combined with vaginal misoprostol. He found no difference in pain scores after pre-emptive administration of acetaminophen and codeine, ibuprofen, or placebo. No differences in maximal pain levels were also reported after the use of preemptive acetaminophen, alverine, or placebo, before a no longer used protocol combining mifepristone with a sulprostone injection (12). To date no studies have been reported regarding the use of pre-emptive analgesia during the most commonly implemented mifepristone and misoprostol protocol. The aim of this study was to investigate the pre-emptive administration of analgesia to allow a less painful experience during medical abortion. Because pain score data are often difficult to compare, owing to little or no information about the distribution of error (13), we decided to use as our primary outcome variable the need for additional analgesia, because this could serve as a good proxy for significant pain experienced after taking misoprostol.
received two placebo tablets. The tablets of ibuprofen and the placebo were of the exact same size, shape, and color. Information about the effect of the analgesics on pain and on the course of the medical abortion was prospectively gathered from three questionnaires, filled out by all women participating in the study. The first was a demographic questionnaire, and the second documented side effects after mifepristone. In the third questionnaire the women were asked to document the level of pain 1 and 2 hours after misoprostol ingestion, as well as the need for another analgesic and any side effects that they experienced during the 6 hours of hospital observation (e.g., fever, headache, vaginal bleeding, nausea, vomiting, diarrhea, dizziness, or shivering). Pain was assessed using an 11-point numeric pain scale, from 0 (no pain) to 10 (the most severe pain). Time and need for another analgesic was also recorded by the nurses. The second-line analgesic was dipyrone (Drop Optalgin, 1 g; Teva), given at any time at patient request. Dipyrone or metamizole sodium is banned in more than 30 countries (including United States, Japan, Australia, and several of the European Union member nations) because of the associated risk of agranulocytosis. The women returned for a follow-up by ultrasound examination after 10–14 days. Endometrial thickness >15 mm was considered a failure of the medical abortion, and these patients were referred for a surgical evacuation. Under any suspicion for retained products of gestation, women were invited for another follow-up after menstrual period and evaluated for the need for intervention (14).
MATERIALS AND METHODS
Statistical Analysis
In a randomized, placebo-controlled, double-blind trial we studied 61 women who chose to undergo a medical abortion. The study protocol was approved by our medical center’s review board for human investigation. The medical abortion regimen used was 600 mg mifepristone given orally (Mifegyne; Exelgyn) followed by an oral dose of 400 mg misoprostol after 36–48 hours (Cytotec; Searle), given under medical supervision for 6 hours in the hospital. The women were sent home between the treatments.
The groups were compared in frequency tables, using the appropriate statistical tests. Dichotomous variables were analyzed using the Pearson c2 test with linear step-up correction for multiple analyses. When asymptotics could not be assumed, Fisher’s exact test was used. Student’s t test was used for normally distributed metric variables, and numeric ones were analyzed with the Wilcoxon rank test. To adjust for interaction between independent variables and pain levels or demand for additional analgesia, a logistic regression model was used. Statistical significance was defined as a P value < .05.
Study Group The study group comprised women aged 18–45 who had chosen to undergo a medical abortion, with an ultrasounddocumented intrauterine pregnancy of up to 7 weeks’ gestation, after approval from the Ministry of Health’s committee for termination of pregnancy. Women with chronic disease, renal insufficiency, or known allergy to misoprostol or nonsteroidal anti-inflammatory drugs were excluded.
Study Process The 61 women were randomized at the time of misoprostol administration into two treatment groups by providing a sealed envelope, using a computer-generated random list, with serial numbers from 1 to 61. One group received two tablets of ibuprofen 400 mg (Adex; Dexon), and the second group VOL. 97 NO. 3 / MARCH 2012
RESULTS Sixty-one women participated in the study. Twenty nine were randomized to receive ibuprofen at the time of misoprostol administration, and 32 received placebo pills. Four women did not fill out the questionnaires properly and therefore information about side effects and pain levels was not complete. Another woman did not report on menstrual pain. Information about the need for analgesia (recorded by the nurse at real time), demographics, and success of the treatment was taken from their medical files. Two women, one in each group, did not show up for follow-up, and data about the success of the abortion were not established. They were considered in our analysis as failure of the medical abortion. There was no significant difference between the two groups regarding marital status, age, parity, religion, 613
ORIGINAL ARTICLE: CONTRACEPTION socioeconomic state, usual menstrual pain, cigarette smoking, week of gestation, and previous abortions. There was also no significant difference in adverse side effects reported by women in both groups. The side effects reported included abdominal pain (79.3%), headache (17.5%), nausea (67.2%), dizziness (28%), vomiting (19.3%), bleeding (78.6%), and shivering (31.6%). Headache and vomiting were reported by fewer women in the study group compared with the placebo group, but the difference did not reach statistical significance after correcting for multiple comparisons (Table 1). Success of the medical abortion was recorded at the follow-up visit in 85.2% of the patients. The failure rate was not significantly different between the study and the placebo groups: 5 of 29 (17.2%) vs. 4 of 32 (12.5%) patients. Two women in each group required additional misoprostol to complete the medical abortion without surgical intervention. A statistically significant difference was found between the two groups regarding the need for additional analgesia. Twenty-five women from the group that received placebo pills with the administration of misoprostol (78%) demanded additional pain relief, compared with only 11 (38%) women in the ibuprofen group (P< .001). Of the women who received ibuprofen, 15.5% reported being free of any pain (¼0), compared with 5.2% of the placebo group (P¼ .52). Mean (SD) pain levels after 1 and 2 hours in the ibuprofen group were 4.00 3.80 and 2.98 2.98, respectively, and were higher in the placebo group by approximately 1.5 points, although this difference was not statistically significant (Table 2). To evaluate pain levels after 2 hours more accurately, we excluded the women who received additional analgesia by that time. Twenty-six women in the ibuprofen group, compared with 22 women in the placebo group, were still free of additional analgesia. A significant difference was found between the groups regarding their mean (SD) pain levels: 4.81 3.30 in the placebo group and 2.09 þ 3.09 in the ibuprofen group (P¼ .024). Data about success of the medical abortion, pain levels, and additional use of analgesia are shown in Table 2. Using a logistic regression model we found that a patient who reported that she usually suffered from menstrual pain was more likely to demand additional analgesia. Any increase by a single point in menstrual level pain raised the probability of additional analgesia request (odds ratio 1.47, 95% confidence
TABLE 1 Rate of side effects in patients receiving pre-emptive analgesia with ibuprofen vs. a placebo during 6 hours of observation. Adverse effect Headache Nausea Dizziness Vomiting Bleeding Shivering
Placebo group (n [ 32)
Ibuprofen group (n [ 29)
P value
7 (12.3) 19 (32.8) 8 (14.0) 9 (15.8) 23 (41.1) 7 (12.3)
3 (5.3) 20 (34.5) 8 (14.0) 2 (3.5) 21 (37.5) 11 (19.3)
.15 .78 .93 < .02 .89 .29
Note: Values are number (percentage). Avraham. Ibuprofen for pain relief in medical abortion. Fertil Steril 2012.
614
TABLE 2 Abortion success rate and pain relief achieved in patients receiving pre-emptive analgesia with ibuprofen vs. a placebo. Measure Abortion success Required additional misoprostol Patients with no pain (¼0) at 1 or 2 h Required additional analgesia Pain level (1 h) Pain level (2 h) Pain level without analgesia (2 h)
Placebo group Ibuprofen group (n [ 32) (n [ 29) P value 28 (87.5) 2 (6.3)
24 (82.8) 2 (6.9)
.72 1.00
3 (5.2)
9 (15.5)
.05
25 (78) 5.40 3.90 4.46 3.20 4.81 3.30
11 (38) 4.00 3.80 2.98 2.98 2.09 3.09
.001 .18 .07 .02
Note: Values are number (percentage) or mean SD. Avraham. Ibuprofen for pain relief in medical abortion. Fertil Steril 2012.
interval 1.11–1.93). Previous abortion adversely affected the demand for additional analgesia (odds ratio 0.21, 95% confidence interval 0.06–0.79).
DISCUSSION Our study is, to the best of our knowledge, the first to show a beneficial effect on the need for pain relief for the preemptive use of ibuprofen during a mifepristone and misoprostol regimen for medical abortion. The most clear and significant difference was a remarkably lower demand for additional pain relief in the ibuprofen group. Among women who received pre-emptive ibuprofen, 62% of the patients did not require additional analgesia, compared with only 22% in the group that received a placebo. This is in agreement with the lower levels of pain reported by the women in the ibuprofen group, who did not receive additional analgesia after 2 hours, compared with the matching placebo group. Mean pain levels 1 hour after misoprostol administration were 5.4 in the placebo group and 4.0 in the ibuprofen group. These pain levels were substantially lower than those reported in our previous study that was conducted at the same hospital, using a similar protocol for medical abortion and identical pain scores, but that compared ibuprofen with paracetamol given only at the onset of pain, after misoprostol administration (7). It seems that our new data not only demonstrate the beneficial effect of pre-emptive ibuprofen but also suggest a significant effect for pre-emptive placebo. A higher demand for additional pain relief was found among women who reported more painful periods. This finding is consistent with results of a recent study showing that menstrual pain correlates positively with pain during medical abortion (15). A previous study of the methotrexate and misoprostol protocol reported mean pain levels of 6–6.5 after the use of a placebo or different analgesia regimens, when administrated with misoprostol (11). The women in that study received the analgesia for home use. This might suggest a more comfortable and supporting experience in the hospital setting. A recent systemic review, comparing home medical abortion with clinic-based abortion, found no differences in VOL. 97 NO. 3 / MARCH 2012
Fertility and Sterility® acceptability between these two approaches. Yet the study did show that pain lasted longer among women who took misoprostol at home (16). We are aware of the limited size of our study sample. However, our results do suggest that it may be appropriate to offer a woman who is about to undergo medical abortion preemptive use of ibuprofen, especially if she is at increased risk for experiencing severe pain or strongly afraid of a potentially painful procedure. We believe that the fact that most of the women who received pre-emptive analgesia did not ask for additional pain relief is a strong indicator of improved comfort and less pain and will likely allow more patients an easier choice favoring the less-invasive medical abortion protocol. Nonsteroidal anti-inflammatory drugs, such as ibuprofen, were previously avoided in protocols studied for medical abortion because of concern over their potential inhibition of PG-induced uterine contractions. The present study adds support to our previous report (7) by demonstrating that ibuprofen does not diminish the success rates of medical abortion. In conclusion, we found in a prospective, double-blind, randomized, controlled study that pre-emptive ibuprofen use, in a mifepristone and misoprostol protocol for medical abortion, can significantly reduce pain levels and the need for additional analgesia compared with placebo.
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