Acta Obstet Gynecol Scand 2005: 84: 951955 Printed in UK.

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Acta Obstetricia et Gynecologica Scandinavica

ORIGINAL ARTICLE

Diclofenac pyrrolidine versus Ketoprofen for the relief of pain from episiotomy: A randomized controlled trial
FABIO FACCHINETTI1, MARIA LUISA CASINI2, LOREDANA COSTABILE3, BARBARA MALAVASI1
AND

VITTORIO UNFER3

From the 1Mother-Infant Department, Unit of Obstetrics and Gynecology, University of Modena and Reggio Emilia, Modena, 2Department of Human Physiology and Pharmacology Vittorio Erspamer, University La Sapienza, and 3 A.G.UN.CO. Obstetrics and Gynaecology Center, Rome, Italy

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Acta Obstet Gynecol Scand 84 2005

Background. The treatment of pain from episiotomy or from tearing of perineal tissues during childbirth is often unapplied, although discomfort may be severe. We performed a randomized double-blind controlled trial to compare the effectiveness and side-effects of two analgesics in the management of postpartum perineal pain. Patient preference toward the two medications was also analyzed. Methods. A total of 261 women were randomly assigned to receive either Diclofenac hydroxyethyl pyrrolidine (100 mg) (n 133) or Ketoprofen (100 mg) (n 128), both given orally every 12 hr up to 48 hr, as necessary. Inclusion criteria were vaginal birth with episiotomy and/or a second- to third-degree tear. Pain ratings were recorded before the administration of the drugs and at 1, 4, 12, and 24 hr after the first dose, according to a 10-cm visual-analog scale. Side-effects and overall opinion on the two treatments were assessed at 24 hr. Results. Diclofenac hydroxyethyl pyrrolidine and Ketoprofen had similar analgesic properties in the first 24 hr postpartum [mean pain rating 3.1 1.8 and 3.4 2.0, mean number of doses in 24 hr 1.4 1.4 and 1.3 1.5, and proportion of treatment failures 12.8% (17/133) and 16.4% (21/128), respectively]. Significantly fewer subjects in the Diclofenac hydroxyethyl pyrrolidine group than in the Ketoprofen group experienced side-effects (6.8% versus 15.6%; p 0.038) with an odd risk 0.39(95% C.I. 0.160.95). There were no significant differences in overall patient satisfaction between the two groups. Conclusions. No main differences were found concerning the relief of pain between the two treatments. Diclofenac hydroxyethyl pyrrolidine may be the preferred choice because it is associated with less adverse reactions, together with a faster action in the relief of pain. Key words: Diclofenac hydroxyethyl pyrrolidine; episiotomy pain; Ketoprofen; postpartum analgesia; vaginal birth Submitted 12 July, 2004 Accepted 31 October, 2004

The use of episiotomy has been often debated, because it is associated with significant pain, infection, and loss of mobility during the immediate postpartum period (1). However, in Italy this surgical procedure is largely utilized. According
Abbreviations: NSAIDs: non-steroidal antiinammatory drugs; VAS: Visual Analogue Scale.

to a national survey, >60% of women in the 58.3% of the surveyed hospitals received such procedure (2). On the other hand, also secondand third-degree tears represent a significant cause of morbidity during the postpartum period (1). Pain from perineal injury, because of episiotomy or tears, is often poorly treated, though it may be severe (3,4).
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F. Facchinetti et al.
liver impairment, and asthma. Women with postpartum bleeding or any other major postpartum complication were also excluded. The Institutional Review Board approved the protocol, and all patients signed an informed consent soon after delivery and before entering in the study. Patients were randomized according to a computer-generated randomization list when they first asked for an analgesic to relieve the pain due to episiotomy and/or tears. Patients who did not request postpartum analgesia were, therefore, not assigned to any of the groups. Socio-demographic information was provided by the patients on a data form completed after childbirth.

Codeine, alone or in combination with acetaminophen, is frequently used, but side-effects, such as constipation, nausea, vomiting, stomach pain, and dizziness limit its appeal (57). NSAIDs have also been utilized after episiotomy and have been found effective in the management of pain, with lower associated side-effects (812). Studies comparing various NSAIDs with opioid-containing compounds or other anti-inammatory drugs have, however, often been limited by small samples (79,13,14), observation periods of less than 6 hr (5,6,810,14), lack of standardized or validated pain assessment (5,8,10,15), omission of measurement of side-effects (5,9), and of -patient preference (510,1315). In our institution, the management of postpartum pain is usually performed with 100 mg Ketoprofen or Diclofenac hydroxyethyl pyrrolidine on patients request, for a maximum of four doses over a 24-hr period. These particular choices for analgesia have not been rigorously studied, although both Ketoprofen and Diclofenac salts are commonly used and found effective in the treatment of moderate to severe postoperative pain (16) after major surgery (17), gynecologic surgery (1820), as well as orthopaedic (21,22) and dental surgery (23,24). The purpose of this study was to compare the two NSAIDs, Diclofenac hydroxyethyl pyrrolidine and Ketoprofen, in a randomized blinded study over an observation period of 24 hr, in terms of pain relief after episiotomy or the occurrence of second- and third-degree tears following childbirth. The occurrence of side-effects and the measurement of patient satisfaction according to a visual-analogical scale were other two outcomes of the study.
Materials and methods

Study design
Patients were treated with oral Diclofenac hydroxyethyl pyrrolidine (100 mg, Molfenac, IBSA; Lugano, Switzerland) or oral Ketoprofen (100 mg, Orudis, Aventis Pharma; Linate, Italy) every 12 hr up to 24 hr. While Ketoprofen is available worldwide, Diclofenac hydroxyethyl pyrrolidine is on the market only in Italy, Switzerland, Lebanon, and eastern European countries. Both the patient and the medical investigator who administered and treated the data of the questionnaire were blinded as far as the group allocation of the single patient was concerned.

Outcomes
The severity of pain, rated on a 10-cm visual-analog scale from 0 (no pain) to 10 (worst pain ever) represented the primary outcome of the study (23). The baseline value of pain was recorded before the subject took the first dose of drug. Pain was evaluated again at 1, 4, 12, and 24 hr after the first dose. Each patient was asked to answer the questionnaire with the visual-analog scale at the requested time. A nurse participating in the study was asked to remind the patients to answer the questionnaire at the appropriate time. Secondary outcomes relating to pain were evaluated: the number of doses of medication, dosing intervals, and treatment failures, if any, were retrieved from the patients charts 24 hr after childbirth. If the patient indicated that analgesia was inadequate during the first 24 hr, the treatment was considered a failure. Patients were monitored thereafter to ensure that the rescue medication (ketorolac tromethamine, 10 mg p.o., Toradol, Recordati, Italy) was effective. Another outcome measured was the occurrence of sideeffects, including stomach pain, gastro-intestinal discomfort, nausea, diarrhoea, headache, vertigo, dizziness, drowsiness, insomnia, and rashes. The subjects completed a written questionnaire about side-effects at the end of treatment. Finally, the subjects were asked to indicate their overall level of satisfaction with their study drug on a 10-cm visual-analog scale ranging from 0 (very dissatisfied) to 10 (very satisfied).

Patients
During the study period, 1982 women underwent a vaginal birth (either spontaneous or induced). Among them 33.9% received episiotomy, whereas 11.0% had a second- to thirddegree tear. Analgesia was required only by 406 women, of whom 145 were not considered for participation in the study because of logistical reasons (e.g. delivery at night or on weekends, when an investigator was not on-site), maternal exhaustion, or an insufficient number of nurses during the night shift. Mean age and rate of nulliparity was similar in women non-participating to the study and in those who were later randomized. Thus, 261 women participated in the study. Inclusion criteria were vaginal birth and a subsequent requirement of analgesia for episiotomy and/or the occurrence of a secondto third-degree tear. Exclusion criteria included known hypersensitivity to NSAIDs, history of drug dependence, regular use of analgesic drugs before or during pregnancy, and any medical condition known to be potentially exacerbated by NSAIDs, including bleeding, significant renal or
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Statistical analysis
Power analysis indicated that a sample of 104 subjects per study arm was required to achieve 80% power with a type I error set at 0.05 to determine a 30% difference in pain severity. In a pilot analysis, a sample of women who received Diclofenac hydroxyethyl pyrrolidine for perineal pain had a mean pain rating on the visual-analog scale 3 cm lower, after than before taking the medication. An additional decrease of 1 cm was considered clinically important, representing a relative difference of 30%.

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Analysis proceeded according to the intention to treat. We compared categorical variables, such as presence of sideeffects, using the chi-square test and compared continuous variables, such as overall satisfaction as measured on the visual-analog scale, using Students t-test. Sequential measures on visual analog pain scales were compared between groups with the use of a general linear model for repeated measures. The initial pain rating before the patient received the first dose of medication was included as a covariate in the model.
10 8 VAS cm 6 4 2 PAIN INTENSITY

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Results

baseline

1 hour

4 hours

12 hours

24 hours

According to the study protocol 261 women were randomized, 133 received Diclofenac hydroxyethyl pyrrolidine, and 128 received Ketoprofen. Errors were made in the dosing interval when administering the study drug to one subject in the Diclofenac hydroxyethyl pyrrolidine group, whereas another one in the Ketoprofen group was withdrawn because of a major postpartum bleeding. The results for these subjects were retained in the analysis. The two groups were comparable in sociodemographic characteristics as well as in gravidity and parity. There was no difference in the use of episiotomy or in the incidence of second- to third-degree tears between the groups (Table I). The mean ratings of pain at baseline were of medium intensity, overlapping among groups (Fig. 1). The absolute mean value of Visual Analogue Scale (VAS) was similar to that previously recorded in the pilot study. Pain levels did not differ between the groups at 4, 12, and 24-hr post-treatment while a statistically significant difference was found at 1 hr (P < 0.05), where Diclofenac hydroxyethyl pyrrolidine seemed to show a faster action than Ketoprofen (Fig. 1). The mean number of doses in 24 hr was 1.4 1.4 for the Diclofenac hydroxyethyl pyrrolidine group and 1.3 1.5 for the Ketoprofen group. The proportion of treatment failures in the two groups was 12.8 (17/133) and 16.4% (21/128), respectively.

Diclofenac pyrrolidine

Ketoprofen

Fig. 1. Changes in pain intensity measures (Mean SD) in the two treatment groups. Either treatment values recorded since the fourth hour were significantly lower than at Baseline. Asterisks denotes a P < 0.05 difference between treatments group at that time-point.

Significantly fewer subjects in the Diclofenac hydroxyethyl pyrrolidine group (6.8%) experienced side-effects than those in the Ketoprofen group (15.6%, chi-square 4.32, P 0.038) with an odd risk 0.39 (95% C.I. 0.160.95). Such a difference was mostly due to fewer subjects with gastro-intestinal discomfort, stomach pain, and nausea in the Diclofenac hydroxyethyl pyrrolidine group (Table II). Overall satisfaction with the study drug, as measured with the visual analog scale, did not differ between the two groups (7.1 2.8 for the Diclofenac hydroxyethyl pyrrolidine group and 6.3 2.7 for the Ketoprofen group).

Discussion

In this study, where a repeated-measures analysis controlling for initial expression of pain had been performed, we found no main differences in perineal pain ratings between women treated
Table II. Frequency of side-effects in the two groups of treatment. The values are n of patients (with percentages in brackets)

Table I. Socio-demographic and clinical features among the two study groups. The values are mean SD or n (% in brackets) of women. No statistically signicant differences were found between the two groups Diclofenac pyrrolidine (n 133) 31.7 4.9 43 (32.3) 27 (20.3) 104 (78.2) 113 (85) 6 (4.5) 14 (11) Ketoprofen (n 128) 32.6 5.1 37 (28.9) 32 (25.0) 94 (73.4) 105 (82) 7 (6) 16 (12)

Side-effects Stomach pain Gastro-intestinal discomfort Nausea Diarrhoea Headache Vertigo Dizziness Drowsiness Insomnia Rashes Any side-effect

Diclofenac pyrrolidine (n 133) 2 (1.5) 6 (1.1) 2 (1.5) 0 1 (0.8) 1 (0.8) 0 0 0 1 (0.8) 9 (6.8)

Ketoprofen (n 128) 9 (7.0) 18 (14.1)* 6 (4.7) 1 (0.8) 2 (1.6) 3 (2.3) 1 (0.8) 5 (3.9) 1 (0.8) 6 (4.7) 20 (15.6)*

Variable Age (years) Educational level High school graduate University graduate Nulliparity Episiotomy Episiotomy with tear Second- or third-degree tear

*A statistically significant difference (P < 0.05).

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F. Facchinetti et al. dissolved in the gelly phase and, therefore, readily available for absorption; and (b) its hydrophobic characteristic allows an active interaction of the molecule with membrane components such as lecithins and consequently a rapid absorption. Both these pharmaceutical features can explain the faster action in relieving pain observed at first hour in the Diclofenac hydroxyethyl pyrrolidine group in comparison to Ketoprofen group. Moreover, the enteric coating reduces the risk of occurrence of gastric complication, as shown by the lower number of gastrointestinal side-effect experienced by the patients of the Diclofenac hydroxyethyl pyrrolidine group. In conclusion, we found that Diclofenac hydroxyethyl pyrrolidine and Ketoprofen were quite similar in efficacy for the treatment of postpartum pain from episiotomy or second- to third-degree tears. However, the profile of tolerability was slightly better for the former drug, although with similar overall patients satisfaction among groups.
References
1. Klein MC, Gauthier RJ, Robbins JM, Kaczorowski J, Jorgensen SH, Franco ED et al. Relationship of episiotomy to perineal trauma and morbidity, sexual dysfunction, and pelvic floor relaxation. Am J Obstet Gynecol 1994; 171: 5918. 2. Basevi V, Cerrone L, Gori G. Resistance to changes of medical procedures in obstetrics. The role of mass media and community medicine. Epidemiol Prev 1994; 18: 1949. 3. Reading AE, Sledmere CM, Cox DN, Campbell S. How women view post-episiotomy pain. BMJ 1982; 284: 2436. 4. Macarthur A, Macarthur C. Perineal trauma and postpartum perineal pain (abstract). Am J Obstet Gynecol 1997; 176: S121. 5. Laska E, Sunshine A. Fenoprofen and codeine analgesia. Clin Pharmacol Ther 1981; 29: 60616. 6. Norman SL, Jeavons BI, OBrien PMS, Johnson IR. A doubleblind comparison of a new Diclofenac pyrrolidine-codeine phosphate combination, codeine phosphate, and placebo in the relief of postepisiotomy pain. Clin Ther 1985; 7: 54954. 7. Bloomfield S, Barden T, Mitchell J. Naproxen, aspirin, and codeine in postpartum uterine pain. Clin Pharmacol Ther 1983; 34: 41421. 8. Sunshine A, Roure C, Olson N, Laska E, Zorrilla C, Rivera J. Analgesic efficacy of two Diclofenac pyrrolidinecodeine combinations for the treatment of postepisiotomy and postoperative pain. Clin Pharmacol Ther 1987; 42: 37480. 9. Schachtel B, Thoden W, Baybutt R. Diclofenac pyrrolidine and acetaminophen in the relief of postpartum episiotomy pain. J Clin Pharmacol 1989; 29: 5503. 10. Yonkeura M, Turner J, diZerega G. Double-blind comparison of meclofenamate sodium with codeine and placebo for the pain of episiotomy. Clin Ther 1987; 9: 57893. 11. Olson NZ, Sunshine A, Zighelboim I, DeCastro A. Onset and duration of analgesia of diclofenac potassium in the treatment of postepisiotomy pain. Am J Ther 1997; 4: 23946. 12. Facchinetti F, De Pietri R, Giunchi M, Genazzani AR. Use of meclofenamic acid in gynecology and obstetrics: effects on postsurgical stress. Clin J Pain 1991; 7: S603. 13. Vangen O, Doessland S, Lindbaek E. Comparative study of ketorolac and paracetamol/codeine in alleviating pain following gynaecological surgery. J Int Med Res 1988; 16: 44351.

with Ketoprofen and those treated with Diclofenac hydroxyethyl pyrrolidine Moreover, Diclofenac hydroxyethyl pyrrolidine seemed to show a faster action, significantly reducing pain already after the first hour of assumption. Furthermore, significantly fewer subjects in the Diclofenac hydroxyethyl pyrrolidine group reported adverse reactions than in Ketoprofen study group. The strengths of our study include the use of a randomized, blinded design, the measurement of a variety of side-effects, but it was limited by its small sample. Although the sample was larger than those in many studies published to date, the repeated-measures analysis included only 111 subjects at 24th hour. Unfortunately, many women chose to stop rating when their pain management was satisfactory and they were no longer requesting analgesia. To allow repeated-measures analysis, all subjects have to complete the scale at each time interval. However, it has to be taken into account that even the analysis of shorter time intervals (12 hr), which allow more subjects to be included, did not reveal any significant differences in perception of pain intensity between the treatment groups. On the other hand, it seems of particular relevancetheobservationthatDiclofenachydroxyethyl pyrrolidine was associated with a better tolerance profile, namely inducing less gastrointestinal discomfort. Moreover, the faster action of Diclofenac in respect with Ketoprofen should also be highlighted in view of maternal cares, in a ward that allows a 24-hr rooming-in of the neonates. Such pharmacological features of the action of Diclofenac hydroxyethyl pyrrolidine were in part expected, also considering the characteristics of this Diclofenac salt and the pharmaceutical form of the preparation. Their impact on clinical practice, however, should not be emphasized in view of the relatively small sample of the actual study. Diclofenac hydroxyethyl pyrrolidine (diclofenac N-(2-hydroxyethyl)pyrrolidine) is a Diclofenac salt prepared recently (25), with balanced hydrophilic and hydrophobic properties (26). This characteristic is important in the perspective of achieving both a good dissolution and a valid absorption rate. Moreover, the molecule of Diclofenac hydroxyethyl pyrrolidine shows a surface activity, unique among NSAIDs salts, that allows the preparation of solutions that can overcome the critical concentration value (26) (probably forming micelles). Such features are fully exploited in the pharmaceutical form of coated gelly capsules of the Diclofenac hydroxyethyl pyrrolidine preparation. Indeed, (a) the active component is concentrated and completely
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14. Walters B, Smith V, De Swiet M. Pain relief after episiotomy a comparative study of suprofen and dihydrocodeine. Br J Obstet Gynaecol 1985; 92: 11603. 15. Jacobson J, Bertilson S. Analgesic efficacy of paracetamol/ codeine and paracetamol/dextropropoxyphene in pain after episiotomy and ruptures in connection with childbirth. J Int Med Res 1987; 15: 8995. 16. Barden J, Edwards J, Moore R, McQuay H. Single dose oral diclofenac for postoperative pain. Cochrane Database Syst Rev 2004: 2: CD004768. 17. Forrest JB, Camu F, Greer IA, Kehlet H, Abdalla M, Bonnet F et al. Ketorolac, diclofenac, and ketoprofen are equally safe for pain relief after major surgery. Br J Anaesth 2002; 88: 22733. 18. Sunshine A, Olson NZ. Analgesic efficacy of ketoprofen in postpartum, general surgery, and chronic cancer pain. J Clin Pharmacol 1988; 28: S4754. 19. Searles JA, Pring DW. Effective analgesia following perineal injury during childbirth: a placebo controlled trial of prophylactic rectal diclofenac. Br J Obstet Gynaecol 1998; 105: 62731. 20. Tuncer S, Pirbudak L, Balat O, Capar M. Adding ketoprofen to intravenous patient-controlled analgesia with tramadol after major gynecological cancer surgery: a double-blinded, randomized, placebo-controlled clinical trial. Eur J Gynaecol Oncol 2003; 24: 1814. 21. Benhamou D, Bouaziz H, Zerrouk N, Preaux N. Audit of ketoprofen prescribing after orthopedic and general surgery. Can J Anaesth 1999; 46: 10913.

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22. Alexander R, El-Moalem HE, Gan TJ. Comparison of the morphine-sparing effects of diclofenac sodium and ketorolac tromethamine after major orthopedic surgery. J Clin Anesth 2002; 14: 18792. 23. Valanne J, Korttila K, Ylikorkala O. Intravenous diclofenac sodium decreases prostaglandin synthesis and postoperative symptoms after general anaesthesia in outpatients undergoing dental surgery. Acta Anaesthesiol Scand 1987; 31: 7227. 24. Cooper SA. Ketoprofen in oral surgery pain: a review. J Clin Pharmacol 1988; 28: S406. 25. Fini A, Fazio G, Rapaport I. Diclofenac/N-(2-hydroxyethyl) pyrrolidine: a new salt for an old drug. Drugs Exp Clin Res 1993; 19: 818. 26. Fini A, Fazio G, Orienti I, Zecchi V, Rapaport I. Chemical properties-dissolution relationship. IV. Behaviour in solution of the diclofenac/N-(2-hydroxyethyl) pyrrolidine salt (DHEP). Pharm Acta Helv 1991; 66: 2013.

Address for correspondence: Fabio Facchinetti U.O Ostetricia e Ginecologia Dip. Materno Infantile Via del Pozzo 71 41100 Modena Italy e-mail: facchi@unimore.it

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