- Email: [email protected]
Comparison between lidocaine-prilocaine cream (EMLA) and mepivacaine infiltration for pain relief during perineal repair after childbirth: a randomized trial
Research
www. AJOG.org
OBSTETRICS
Comparison between lidocaine-prilocaine cream (EMLA) and mepivacaine infiltration for pain relief during perineal repair after childbirth: a randomized trial Massimo Franchi, MD; Antonella Cromi, PhD; Stefano Scarperi, MD; Francesca Gaudino, RM; Gabriele Siesto, MD; Fabio Ghezzi, MD OBJECTIVE: The purpose of this study was to compare the effective-
ness of topically applied lidocaine-prilocaine (EMLA) cream with local anesthetic infiltration in the reduction of pain during perineal suturing after childbirth. STUDY DESIGN: Sixty-one women with either an episiotomy or a perineal laceration after vaginal delivery were assigned randomly to receive either the application of EMLA cream (n ⫽ 31) or infiltration with mepivacaine (n ⫽ 30) before perineal suturing. Primary outcome was pain during perineal repair. RESULTS: Women in the EMLA group had lower pain scores than
those in the mepivacaine group (1.7 ⫾ 2.4 vs 3.9 ⫾ 2.4; P ⫽ .0002).
The proportion of women who needed additional anesthesia was similar in the 2 groups (3/30 vs 5/31; P ⫽ .71). A significantly higher proportion of women expressed satisfaction with anesthesia method in the EMLA group, compared with the mepivacaine group (83.8% vs 53.3%; P ⫽ .01) CONCLUSION: EMLA cream appears to be an effective and satisfactory
alternative to local anesthetic infiltration for the relief of pain during perineal repair. Key words: EMLA, lidocaine-prilocaine cream, pain, perineal suturing, vaginal delivery
Cite this article as: Franchi M, Cromi A, Scarperi S, et al. Comparison between lidocaine-prilocaine cream (EMLA) and mepivacaine infiltration for pain relief during perineal repair after childbirth: a randomized trial. Am J Obstet Gynecol 2009;201:186.e1-5.
P
erineal infiltration with local anesthetics is the most common technique to provide anesthesia during perineal suturing. Although infiltrative anesthesia remains a mainstay for pain relief goals during minor surgical procedures, topical anesthetics in the form of sprays, gels, and ointments have emerged as a valuable alternative in several medical specialties.1-6 The advanFrom the Departments of Obstetrics and Gynecology, University of Verona, Verona (Drs Franchi, Scarperi, and Gaudino), and University of Insubria, Varese (Drs Cromi, Siesto, and Ghezzi), Italy. Received Sept. 28, 2008; revised Nov. 23, 2008; accepted April 9, 2009. Reprints: Fabio Ghezzi, MD, Department of Obstetrics and Gynecology, University of Insubria, Piazza Biroldi 1, 21100 Varese, Italy. [email protected]. Authorship and contribution to the article is limited to the 6 authors indicated. There was no outside funding or technical assistance with the production of this article. 0002-9378/$36.00 © 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2009.04.023
186.e1
tages of using topical anesthetics include their localized action with negligible systemic absorption, ease of administration, painless application, and absence of edema at the surgical site that distorts wound margins in laceration repair. Previous published trials on topically applied anesthetics that were used to reduce perineal pain yielded conflicting results; most of the trials addressed pain during the second stage of labor7 or in the early puerperium period,8-11 rather than pain during suturing. Lidocaine-prilocaine cream (EMLA cream; AstraZeneca, Basiglio, Italy) is an eutectic mixture of 2.5% lidocaine and 2.5% prilocaine that is used widely as topical anesthetic for pediatric, dermatologic, reconstructive, and gynecologic minor procedures. Absorption from the genital mucosa is rapid, and onset time is between 5 and 10 minutes with an average duration of effective analgesia from 15-20 minutes; however, on intact skin, the cream should be applied for at least 1 hour to provide satisfactory dermal analgesia.12
American Journal of Obstetrics & Gynecology AUGUST 2009
We sought to assess in a randomized controlled trial whether the topical application of EMLA cream is an effective method for alleviating pain that is experienced during perineal repair. We therefore compared the effectiveness of EMLA cream vs conventional local infiltrative anesthesia with mepivacaine in the reduction of pain during suturing of an episiotomy or a naturally occurring tear after vaginal delivery.
M ATERIALS AND M ETHODS The trial was designed as a prospective, randomized controlled trial with recruitment from August through September 2007. The trial was conducted at a referring academic institution after the approval from the institutional review board. Inclusion criteria included gestational age ⬎ 37 weeks, uncomplicated pregnancy, singleton gestation, and vertex fetal presentation. Women were excluded because of epidural analgesia request, operative delivery, intact perineum, previous fourth-degree perineal tear, previous adverse reaction to a local anesthetic, and insufficient Italian lan-
Obstetrics
www.AJOG.org guage knowledge to prevent adequate consent. Neither systemic opioids nor inhalational methods are used for intrapartum pain control at our institution. Pudendal block is never used to relieve pain in the second and third stages of labor. Written and verbal information about the study were given to all potentially eligible women during antenatal visits. Patients were enrolled on hospital admission in labor or for labor induction. Written informed consent was obtained from all women who agreed to participate in the trial before study entry. Patients who were enrolled in the study were guaranteed to obtain additional anesthesia during perineal repair whenever pain exceeded the tolerability threshold. Volunteers were assigned randomly to have either local injection of mepivacaine or application of EMLA cream for pain relief during perineal repair. Allocation was on 1:1 basis with the use of a block-randomized computer-generated list. The allocation arm was written in a card that was sealed in sequentially numbered opaque envelopes. In the mepivacaine group, 20 mL of 1% mepivacaine solution (Mepiforan) that was associated with adrenaline tartrate 1:200,000 was injected slowly along the lines of the edges of the perineal tears or episiotomy after placental delivery, with frequent aspirations to avoid intravascular injection. The suture procedure was delayed 10 minutes after the injection of the anesthetic. In the mepivacaine group, if an episiotomy was indicated, it was performed after infiltration of perineal tissue with 10 mL of 1% mepivacaine solution. Women who were assigned randomly to receive EMLA cream had a 5-g dose of cream applied to the intact surface of the perineum, and the area was covered with an occlusive dressing (a patch of Tegaderm; 3M, St. Paul, MN, or clear plastic wrap) to facilitate penetration through the stratum corneum. EMLA cream was applied 1 hour before the expected time of birth. With the assistance at birth, the residue of cream was removed to prevent contact with the fetus, because sodium hydroxide, which is a component of the cream, can cause fetal eye irritation.13 No additional anesthetic was applied if epi-
siotomy was necessary. After birth and placental delivery, an additional 5-g dose of EMLA cream was applied to the intact tissue around each laceration for 10 minutes before suturing occurred to have time to take effect. Before commencement of perineal repair, any residual cream was wiped off. All episiotomies were performed at the top of contraction as mediolateral episiotomies. In all cases, perineal trauma was repaired with a loose, continuous, nonlocking suture to close the vaginal mucosa and the muscular layer of the perineum; the skin was closed with the same continuous suture to approximate the subcutaneous tissue. The same suturing material, a rapid-absorption polyglactin 910 suture (2-0 Vicryl rapid; Ethicon Inc, Somerville, NJ) was used. Women were placed in lithotomy position for repair. All the procedures were performed by senior midwifes or by resident obstetricians. Before leaving the delivery suite (approximately 2 hours after delivery), each patient was asked to record the severity of pain that she had experienced during perineal repair in a 10-cm visual analog scale, where 0 cm means no pain and 10 cm means unbearable pain.14 The patient was asked to mark the point that best indicated the perception of her pain on the visual analog scale. The level of pain was estimated from the length in millimeters of the space running from the left hand and the point that the patient had marked. Finally, women were asked to express their overall satisfaction with the anesthesia method during perineal repair with “yes” or “no” answers. Maternal demographics, delivery details, and perineal trauma characteristics were recorded in a computerized database. Moreover, the request of additional anesthetic (ie, 10 mL of 1% mepivacaine solution for both groups) was recorded. The primary outcome measure was pain score during the suture of perineal tear. Secondary outcomes included pain by degree of perineal tear, during episiorrhaphy, need for additional anesthetic, and patient’s satisfaction. Power calculation was based on a previous study in which mean pain score during perineal suturing was 4.24 ⫾ 2.78 (SD).15 With ␣
Research
of .05 and  of 80%, 29 patients in each arm were required to demonstrate a 50% difference in pain score between groups. Incorporating a potential 20% attrition rate because of cesarean sections in labor, epidural analgesia request, operative vaginal deliveries, and absence of perineal trauma, the trial was designed to include a total of 70 participants. Statistical analysis was performed with GraphPad Prism software (version 4.00; GraphPad Software, San Diego, CA) and STATA software (version 9.2; Stata Corp, College Station, TX). The t test and the Mann-Whitney U test were performed to compare continuous parametric and nonparametric variables, respectively. Proportions were compared across groups by the Fisher exact test. A probability value of ⬍ .05 was considered to be statistically significant.
R ESULTS During the study period, a total of 70 patients who met the inclusion criteria and agreed to participate were enrolled. Of these, 35 women were assigned to receive local anesthesia with mepivacaine infiltration (mepivacaine group), and 35 women had topical application of EMLA cream (EMLA group). Flow of participants through each stage of the randomized clinical trial is displayed in the Figure. Thirty patients in the mepivacaine group and 31 patients in the EMLA group were available for data analysis. The 2 groups were similar for baseline characteristics and obstetric outcomes (Table 1). Induction of labor was performed in 7 women (23.3%) in the mepivacaine group vs 5 women (16.1%) in the EMLA group (P ⫽ .76); oxytocin augmentation was required in 5 women in each group (P ⫽ 1.0). The median application-todelivery interval in the EMLA group was 56 minutes (range, 25-90 minutes). Ten patients (33.3%) in the mepivacaine group and 13 patients (41.9%) in the EMLA group had first-degree perineal injury (P ⫽ .59); 15 patients (50%) in the mepivacaine group and 14 patients (45.1%) in the EMLA group sustained second-degree injury (P ⫽ .79); 1 patient in each group had third-degree perineal
AUGUST 2009 American Journal of Obstetrics & Gynecology
186.e2
Research
Obstetrics
www.AJOG.org
FIGURE 1
Flow chart Deliveries in the study period (n = 230)
Excluded (n = 160) Enrollment
•
70 randomized
•
Not meeting the inclusion criteria (n = 115) Refused to participate (n = 45)
Allocated to mepivacaine (n = 35)
Allocated to EMLA cream (n = 35)
Did not receive allocated intervention Cesarean delivery (n = 4) Vacuum delivery (n = 1)
Did not receive allocated intervention Cesarean delivery (n = 3) Intact perineum (n = 1)
Allocation
Received allocated intervention (n = 30)
Analyzed (n = 30)
Received allocated intervention (n = 31)
Analysis
Analyzed (n = 31)
Flow of participants through each stage of the trial. Franchi. EMLA cream vs mepivacaine for pain during perineal repair. Am J Obstet Gynecol 2009.
trauma (P ⫽ 1.0). No woman in either group sustained fourth-degree perineal tears. An episiotomy was performed in 7 patients: 4 (13.3%) in the mepivacaine group and 3 (9.7%) in the EMLA group (P ⫽ .69). Pain scores during perineal repair are displayed in Table 2. The proportion of women who required additional analgesia during perineal suturing was similar in the EMLA group and in the mepivacaine group (5/31 women [16.1%] vs 3/30 women [10%]; P ⫽ .7). Satisfaction with anesthesia method was expressed by 83.8% of women in the EMLA group, compared with 53.3% in the mepivacaine group (P ⫽ .01). 186.e3
C OMMENT The findings of this study suggest that a topically applied anesthetic, such as EMLA cream, is more effective in the relief of pain that is experienced during repair of perineal trauma after childbirth than conventional infiltrative anesthesia. Despite thousands of research trials that have addressed the issue of analgesia that is provided to women in labor and in the immediate postpartum period, levels of pain and discomfort that are experienced during perineal suturing have been largely overlooked in the obstetric literature. However, evidence exists that indicates that some women have consid-
American Journal of Obstetrics & Gynecology AUGUST 2009
erable levels of pain during suturing.15,16 Sanders et al17 reported that pain of suture of perineal tears was described as “distressing,” “horrible,” or “excruciating” by 16.5% of women after vaginal delivery. Strategies to reduce perineal trauma and appropriate surgical techniques of suturing are important for avoiding or alleviating pain, but adequate analgesia during surgical repair remains a major contributing factor to reduce feelings of distress and discomfort that are incurred by women. Infiltrative anesthetics are chosen frequently because of their proven safety record, low cost, widespread availability, and rapid onset of action. However, pain
Obstetrics
www.AJOG.org
TABLE 1
Patient demographics and obstetric outcomes Mepivacaine group (n ⴝ 30)
Variable
EMLA group (n ⴝ 31)
P value
Race (n)
.....................................................................................................................................................................................................................................
White
22 (74.6%)
24 (77.4%)
.77
.....................................................................................................................................................................................................................................
Others
8 (26.4%)
7 (22.6%)
31.1 (4.1%)
31.3 (3.7%)
..............................................................................................................................................................................................................................................
Age (y)
.76
.............................................................................................................................................................................................................................................. a
Parity (n)
1 (0-3)
1 (0-4)
.92
.............................................................................................................................................................................................................................................. 2b
27.9 ⫾ 3.5
Body mass index (kg/m )
28.1 ⫾ 2.6
.77
39.2 ⫾ 0.9
.59
.............................................................................................................................................................................................................................................. b
39.1 ⫾ 1.1
Gestational age (wk)
.............................................................................................................................................................................................................................................. b
Length of first stage of labor (min)
183 ⫾ 103
206 ⫾ 133
.44
37 ⫾ 22
46 ⫾ 37
.28
..............................................................................................................................................................................................................................................
Length of second stage of labor (min)b
.............................................................................................................................................................................................................................................. b
3409 ⫾ 390
Neonatal weight (g)
3340 ⫾ 365
.56
.............................................................................................................................................................................................................................................. b
Cranial circumference (cm)
34.4 ⫾ 1.6
34.7 ⫾ 3.2
.77
..............................................................................................................................................................................................................................................
EMLA, lidocaine-prilocaine cream. a
Values are expressed as median (range); proportions were compared by the Fisher exact test; b values are expressed as mean ⫾ SD; means were compared by the Mann-Whitney U test (parity) or the t test (all the other continuous variables).
Franchi. EMLA cream vs mepivacaine for pain during perineal repair. Am J Obstet Gynecol 2009.
of injection that is caused by insertion of the needle and infiltration of the anesthetic into the skin, burning sensation during infusion, distortion of surgical site by edema, and risks of accidental intravascular administration are major drawbacks. Moreover, epinephrine that is used to slow absorption of local anesthetics may cause an exaggerated vasoconstrictor response and arrhythmias in susceptible patients. Safety and efficacy of EMLA cream have been shown consistently in a number of clinical trials across many med-
ical specialties since 1990.1-6,12 EMLA cream provides analgesia by the release of lidocaine and prilocaine, which are 2 amide anesthetics, from the cream into the dermal layers before penetrating the smooth and striated muscle and the individual axons within the nerve. Nerve conduction becomes impeded because an action potential is prevented by an inward flux of sodium ions through the nerve membranes. Although EMLA cream is indicated as a topic anesthetic for use on intact skin, several studies have shown that EMLA cream can also
TABLE 2
Pain scores during perineal suturing that were assessed by a 10-cm visual analog scale Variable
Mepivacaine group, n
Pain score
EMLA group, n
Pain score
P value
Total perineal trauma
30
3.9 ⫾ 2.4
31
1.7 ⫾ 2.4
.0002
..............................................................................................................................................................................................................................................
Degree of laceration
.....................................................................................................................................................................................................................................
First
10
3.2 ⫾ 2.6
13
0.4 ⫾ 0.5
.007
Second
15
3.9 ⫾ 2.3
14
1.3 ⫾ 1.7
.005
..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................
Third
1
5
1
8
—
Episiotomy
4
4.6 ⫾ 3.6
3
4.0 ⫾ 4.0
.85
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Values are expressed as mean ⫾ SD; means were compared by the t test. EMLA, lidocaine-prilocaine cream. Franchi. EMLA cream vs mepivacaine for pain during perineal repair. Am J Obstet Gynecol 2009.
Research
be used effectively for laceration repair.18,19 Moreover, EMLA cream has been shown to work effectively on genital mucosa during minor gynecologic surgical procedures, such as laser treatment of condylomata acuminata.20-22 Typically, for the topical anesthetic creams, the systemic blood levels are well below the concentration that would cause toxicity. If 60 g of EMLA cream is placed on a 400-cm2 area for 4 hours, the peak blood levels of lidocaine and prilocaine will be 1/20th and 1/36th the toxicity level, respectively.23 There have been reports of rare methemoglobinemia that is limited to infants ⬍ 3 months old who were exposed to high doses of EMLA cream for prolonged periods.23 Localized reactions, generally mild and transient (blanching and erythema because of peripheral vasoconstriction), have been reported after treatment with EMLA cream, but there were no serious reactions that were ascribed to the cream in studies the involved ⬎ 1600 subjects.23 This trial was powered to detect a difference in the primary outcome of perineal pain during suturing of any perineal trauma but was underpowered for subgroup analysis, thus preventing meaningful conclusions on the effects of topically applied EMLA cream for relief of pain that is associated with suturing of episiotomy compared with spontaneous perineal tear or major degree perineal trauma. The reported results might suggest that EMLA cream resulted in a lower pain score in those women who have minimal mucosal involvement. One could speculate that EMLA cream may be less active on the perineal muscular layers than local infiltration of mepivacaine, because of lower depth of action. Depth of anesthesia depends on contact time with EMLA cream, and anesthetic effect has been shown to reach a maximal depth of 3 mm after a 60-minute application and 5 mm after a 120-minute application. Because the median application-to-delivery interval was 56 minutes, even considering the length of the third stage, it seems unlikely that, in most of the women of our study group, the application time exceeded the 2-hour wait
AUGUST 2009 American Journal of Obstetrics & Gynecology
186.e4
Research
Obstetrics
that is required for a deep penetration of the topical anesthetic. The pain scores that were recorded in this trial in the mepivacaine group were similar to those scores that were obtained in previous studies on pain during postdelivery perineal repair.3 The lack of blinding of both participants and investigators because of the nature of the interventions might cast doubts on whether absence of clinical equipoise by proponents of a new treatment have had the effect of diminishing pain scores that were reported by women in the EMLA group. However, most members of our medical and midwifery staff who were involved in recruitment, care, and patient interviews did not participate actively in the research project conception and design, thus satisfying the principle of uncertainty regarding the comparative therapeutic merits of each arm in the trial. It is noteworthy that 39% of eligible patients declined participation in the study, 80% of whom were multiparous women. Although we did not record methodically the reasons for not participating in the trial, we believed that most of these women, with negative previous experiences of perineal repair, preferred to avoid “drugs under investigation” because of fear of experiencing pain even worse than they expected, believing that the treatment they would receive in a clinical trial would be less effective than standard care. In conclusion, this study has demonstrated that the application of EMLA cream to the perineum is an effective, highly satisfactory, and easy-to-use alternative to the “standard” injective local anesthesia for perineal repair. When painful injections and “needle anxiety” are avoided, the patient’s distress about perineal suturing could be lessened and
186.e5
www.AJOG.org overall better tolerated. The adequacy of EMLA cream to achieve analgesia, specifically during episiorrhaphy and repair of major perineal tears, remains to be elucidated in further larger randomized trials.1,4 f REFERENCES 1. Kaweski S. Plastic Surgery Educational Foundation Technology Assessment committee: topical anesthetic creams. Plast Reconstr Surg 2008;121:2161-5. 2. Lander JA, Weltman BJ, So SS. EMLA and amethocaine for reduction of children’s pain associated with needle insertion. Cochrane Database Syst Rev 2006;3:CD004236. 3. Brady-Fryer B, Wiebe N, Lander JA. Pain relief for neonatal circumcision. Cochrane Database Syst Rev 2004;4:CD004217. 4. Alster TS. The lidocaine/tetracaine peel: a novel topical anesthetic for dermatologic procedures in adult patients. Dermatol Surg 2007;33:1073-81. 5. Galosi AB, Minardi D, Dell’atti L, Yehia M, Muzzonigro G. Tolerability of prostate transrectal biopsies using gel and local anesthetics: results of a randomized clinical trial. J Endourol 2005;19:738-43. 6. Vickers ER, Marzbani N, Gerzina TM, McLean C, Punnia-Moorthy A, Mather L. Pharmacokinetics of EMLA cream 5% application to oral mucosa. Anesth Prog 1997;44:32-7. 7. Sanders J, Campbell R, Peters TJ. Effectiveness and acceptability of lidocaine spray in reducing perineal pain during spontaneous vaginal delivery: randomised controlled trial. BMJ 2006;333:117. 8. Corkill A, Lavender T, Walkinshaw S, Alfirevic Z. Reducing postnatal pain from perineal tears by using lignocaine gel: a doubleblind randomised controlled trial. Birth 2001; 28:22-7. 9. Hedayati H, Parsons J, Crowther CA. Topically applied anaesthetics for treating perineal pain after childbirth. Cochrane Database Syst Rev 2005;2:CD004223. 10. Minassian VA, Jazayeri A, Prien SD, Timmons RL, Stumbo K. Randomized trial of lidocaine ointment versus placebo for the treatment of postpartum perineal pain. Obstet Gynecol 2002;100:1239-43.
American Journal of Obstetrics & Gynecology AUGUST 2009
11. Seckin B, Avsar F, Parlakygit EE, Aksakal O. Effects of indomethacin suppository and lidocaine pomade for the relief of post-episiotomy pain. Int J Gynaecol Obstet 2002;78:159-61. 12. Friedman PM, Mafong EA, Friedman ES, Geronemus RG. Topical anesthetics update: EMLA and beyond. Dermatol Surg 2001; 27:1019-26. 13. McKinlay JR, Hofmeister E, Ross EV, MacAllister W. EMLA cream-induced eye injury. Arch Dermatol 1999;135:855-6. 14. Ludington E, Dexter F. Statistical analysis of total labor pain using the visual analog scale and application to studies of analgesic effectiveness during childbirth. Anesth Analg 1998;87:723-7. 15. Sanders J, Campbell R, Peters TJ. Effectiveness of pain relief during perineal suturing. BJOG 2002;109:1066-8. 16. Salmon D. A feminist analysis of women’s experiences of perineal trauma in the immediate post-delivery period. Midwifery 1999;15: 247-56. 17. Sanders J, Peters TJ, Campbell R. Techniques to reduce perineal pain during spontaneous vaginal delivery and perineal suturing: a UK survey of midwifery practice. Midwifery 2005;21:154-60. 18. Zempsky WT, Karasic RB. EMLA versus TAC for topical anesthesia of extremity wounds in children. Ann Emerg Med 1997;30:163-6. 19. Singer AJ, Stark MJ. LET versus EMLA for pretreating lacerations: a randomized trial. Acad Emerg Med 2001;8:223-30. 20. Rylander E, Sjöberg I, Lillieborg S, Stockman O. Local anesthesia of the genital mucosa with a lidocaine/prilocaine cream (EMLA) for laser treatment of condylomata acuminata: a placebo-controlled study. Obstet Gynecol 1990; 75:302-6. 21. Frega A, Di Renzi F, Palazzetti PL, Pace S, Figliolini M, Stentella P. Vulvar and penile HPV lesions: laser surgery and topic anaesthesia. Clin Exp Obstet Gynecol 1993;20:76-81. 22. Monsonego J, Semaille C. Local anesthesia of genital mucosa with a lidocaine/prilocaine combination cream before laser therapy of human papillomavirus lesions. Eur J Dermatol 2000;10:607-10. 23. Department of Health and Human Services. EMLA. Available at: http://www.fda.gov/ medwatch/SAFETY/2005/Dec_PI/Emla_PI.pdf 2005. Accessed Sept. 25, 2008.
www. AJOG.org
OBSTETRICS
Comparison between lidocaine-prilocaine cream (EMLA) and mepivacaine infiltration for pain relief during perineal repair after childbirth: a randomized trial Massimo Franchi, MD; Antonella Cromi, PhD; Stefano Scarperi, MD; Francesca Gaudino, RM; Gabriele Siesto, MD; Fabio Ghezzi, MD OBJECTIVE: The purpose of this study was to compare the effective-
ness of topically applied lidocaine-prilocaine (EMLA) cream with local anesthetic infiltration in the reduction of pain during perineal suturing after childbirth. STUDY DESIGN: Sixty-one women with either an episiotomy or a perineal laceration after vaginal delivery were assigned randomly to receive either the application of EMLA cream (n ⫽ 31) or infiltration with mepivacaine (n ⫽ 30) before perineal suturing. Primary outcome was pain during perineal repair. RESULTS: Women in the EMLA group had lower pain scores than
those in the mepivacaine group (1.7 ⫾ 2.4 vs 3.9 ⫾ 2.4; P ⫽ .0002).
The proportion of women who needed additional anesthesia was similar in the 2 groups (3/30 vs 5/31; P ⫽ .71). A significantly higher proportion of women expressed satisfaction with anesthesia method in the EMLA group, compared with the mepivacaine group (83.8% vs 53.3%; P ⫽ .01) CONCLUSION: EMLA cream appears to be an effective and satisfactory
alternative to local anesthetic infiltration for the relief of pain during perineal repair. Key words: EMLA, lidocaine-prilocaine cream, pain, perineal suturing, vaginal delivery
Cite this article as: Franchi M, Cromi A, Scarperi S, et al. Comparison between lidocaine-prilocaine cream (EMLA) and mepivacaine infiltration for pain relief during perineal repair after childbirth: a randomized trial. Am J Obstet Gynecol 2009;201:186.e1-5.
P
erineal infiltration with local anesthetics is the most common technique to provide anesthesia during perineal suturing. Although infiltrative anesthesia remains a mainstay for pain relief goals during minor surgical procedures, topical anesthetics in the form of sprays, gels, and ointments have emerged as a valuable alternative in several medical specialties.1-6 The advanFrom the Departments of Obstetrics and Gynecology, University of Verona, Verona (Drs Franchi, Scarperi, and Gaudino), and University of Insubria, Varese (Drs Cromi, Siesto, and Ghezzi), Italy. Received Sept. 28, 2008; revised Nov. 23, 2008; accepted April 9, 2009. Reprints: Fabio Ghezzi, MD, Department of Obstetrics and Gynecology, University of Insubria, Piazza Biroldi 1, 21100 Varese, Italy. [email protected]. Authorship and contribution to the article is limited to the 6 authors indicated. There was no outside funding or technical assistance with the production of this article. 0002-9378/$36.00 © 2009 Mosby, Inc. All rights reserved. doi: 10.1016/j.ajog.2009.04.023
186.e1
tages of using topical anesthetics include their localized action with negligible systemic absorption, ease of administration, painless application, and absence of edema at the surgical site that distorts wound margins in laceration repair. Previous published trials on topically applied anesthetics that were used to reduce perineal pain yielded conflicting results; most of the trials addressed pain during the second stage of labor7 or in the early puerperium period,8-11 rather than pain during suturing. Lidocaine-prilocaine cream (EMLA cream; AstraZeneca, Basiglio, Italy) is an eutectic mixture of 2.5% lidocaine and 2.5% prilocaine that is used widely as topical anesthetic for pediatric, dermatologic, reconstructive, and gynecologic minor procedures. Absorption from the genital mucosa is rapid, and onset time is between 5 and 10 minutes with an average duration of effective analgesia from 15-20 minutes; however, on intact skin, the cream should be applied for at least 1 hour to provide satisfactory dermal analgesia.12
American Journal of Obstetrics & Gynecology AUGUST 2009
We sought to assess in a randomized controlled trial whether the topical application of EMLA cream is an effective method for alleviating pain that is experienced during perineal repair. We therefore compared the effectiveness of EMLA cream vs conventional local infiltrative anesthesia with mepivacaine in the reduction of pain during suturing of an episiotomy or a naturally occurring tear after vaginal delivery.
M ATERIALS AND M ETHODS The trial was designed as a prospective, randomized controlled trial with recruitment from August through September 2007. The trial was conducted at a referring academic institution after the approval from the institutional review board. Inclusion criteria included gestational age ⬎ 37 weeks, uncomplicated pregnancy, singleton gestation, and vertex fetal presentation. Women were excluded because of epidural analgesia request, operative delivery, intact perineum, previous fourth-degree perineal tear, previous adverse reaction to a local anesthetic, and insufficient Italian lan-
Obstetrics
www.AJOG.org guage knowledge to prevent adequate consent. Neither systemic opioids nor inhalational methods are used for intrapartum pain control at our institution. Pudendal block is never used to relieve pain in the second and third stages of labor. Written and verbal information about the study were given to all potentially eligible women during antenatal visits. Patients were enrolled on hospital admission in labor or for labor induction. Written informed consent was obtained from all women who agreed to participate in the trial before study entry. Patients who were enrolled in the study were guaranteed to obtain additional anesthesia during perineal repair whenever pain exceeded the tolerability threshold. Volunteers were assigned randomly to have either local injection of mepivacaine or application of EMLA cream for pain relief during perineal repair. Allocation was on 1:1 basis with the use of a block-randomized computer-generated list. The allocation arm was written in a card that was sealed in sequentially numbered opaque envelopes. In the mepivacaine group, 20 mL of 1% mepivacaine solution (Mepiforan) that was associated with adrenaline tartrate 1:200,000 was injected slowly along the lines of the edges of the perineal tears or episiotomy after placental delivery, with frequent aspirations to avoid intravascular injection. The suture procedure was delayed 10 minutes after the injection of the anesthetic. In the mepivacaine group, if an episiotomy was indicated, it was performed after infiltration of perineal tissue with 10 mL of 1% mepivacaine solution. Women who were assigned randomly to receive EMLA cream had a 5-g dose of cream applied to the intact surface of the perineum, and the area was covered with an occlusive dressing (a patch of Tegaderm; 3M, St. Paul, MN, or clear plastic wrap) to facilitate penetration through the stratum corneum. EMLA cream was applied 1 hour before the expected time of birth. With the assistance at birth, the residue of cream was removed to prevent contact with the fetus, because sodium hydroxide, which is a component of the cream, can cause fetal eye irritation.13 No additional anesthetic was applied if epi-
siotomy was necessary. After birth and placental delivery, an additional 5-g dose of EMLA cream was applied to the intact tissue around each laceration for 10 minutes before suturing occurred to have time to take effect. Before commencement of perineal repair, any residual cream was wiped off. All episiotomies were performed at the top of contraction as mediolateral episiotomies. In all cases, perineal trauma was repaired with a loose, continuous, nonlocking suture to close the vaginal mucosa and the muscular layer of the perineum; the skin was closed with the same continuous suture to approximate the subcutaneous tissue. The same suturing material, a rapid-absorption polyglactin 910 suture (2-0 Vicryl rapid; Ethicon Inc, Somerville, NJ) was used. Women were placed in lithotomy position for repair. All the procedures were performed by senior midwifes or by resident obstetricians. Before leaving the delivery suite (approximately 2 hours after delivery), each patient was asked to record the severity of pain that she had experienced during perineal repair in a 10-cm visual analog scale, where 0 cm means no pain and 10 cm means unbearable pain.14 The patient was asked to mark the point that best indicated the perception of her pain on the visual analog scale. The level of pain was estimated from the length in millimeters of the space running from the left hand and the point that the patient had marked. Finally, women were asked to express their overall satisfaction with the anesthesia method during perineal repair with “yes” or “no” answers. Maternal demographics, delivery details, and perineal trauma characteristics were recorded in a computerized database. Moreover, the request of additional anesthetic (ie, 10 mL of 1% mepivacaine solution for both groups) was recorded. The primary outcome measure was pain score during the suture of perineal tear. Secondary outcomes included pain by degree of perineal tear, during episiorrhaphy, need for additional anesthetic, and patient’s satisfaction. Power calculation was based on a previous study in which mean pain score during perineal suturing was 4.24 ⫾ 2.78 (SD).15 With ␣
Research
of .05 and  of 80%, 29 patients in each arm were required to demonstrate a 50% difference in pain score between groups. Incorporating a potential 20% attrition rate because of cesarean sections in labor, epidural analgesia request, operative vaginal deliveries, and absence of perineal trauma, the trial was designed to include a total of 70 participants. Statistical analysis was performed with GraphPad Prism software (version 4.00; GraphPad Software, San Diego, CA) and STATA software (version 9.2; Stata Corp, College Station, TX). The t test and the Mann-Whitney U test were performed to compare continuous parametric and nonparametric variables, respectively. Proportions were compared across groups by the Fisher exact test. A probability value of ⬍ .05 was considered to be statistically significant.
R ESULTS During the study period, a total of 70 patients who met the inclusion criteria and agreed to participate were enrolled. Of these, 35 women were assigned to receive local anesthesia with mepivacaine infiltration (mepivacaine group), and 35 women had topical application of EMLA cream (EMLA group). Flow of participants through each stage of the randomized clinical trial is displayed in the Figure. Thirty patients in the mepivacaine group and 31 patients in the EMLA group were available for data analysis. The 2 groups were similar for baseline characteristics and obstetric outcomes (Table 1). Induction of labor was performed in 7 women (23.3%) in the mepivacaine group vs 5 women (16.1%) in the EMLA group (P ⫽ .76); oxytocin augmentation was required in 5 women in each group (P ⫽ 1.0). The median application-todelivery interval in the EMLA group was 56 minutes (range, 25-90 minutes). Ten patients (33.3%) in the mepivacaine group and 13 patients (41.9%) in the EMLA group had first-degree perineal injury (P ⫽ .59); 15 patients (50%) in the mepivacaine group and 14 patients (45.1%) in the EMLA group sustained second-degree injury (P ⫽ .79); 1 patient in each group had third-degree perineal
AUGUST 2009 American Journal of Obstetrics & Gynecology
186.e2
Research
Obstetrics
www.AJOG.org
FIGURE 1
Flow chart Deliveries in the study period (n = 230)
Excluded (n = 160) Enrollment
•
70 randomized
•
Not meeting the inclusion criteria (n = 115) Refused to participate (n = 45)
Allocated to mepivacaine (n = 35)
Allocated to EMLA cream (n = 35)
Did not receive allocated intervention Cesarean delivery (n = 4) Vacuum delivery (n = 1)
Did not receive allocated intervention Cesarean delivery (n = 3) Intact perineum (n = 1)
Allocation
Received allocated intervention (n = 30)
Analyzed (n = 30)
Received allocated intervention (n = 31)
Analysis
Analyzed (n = 31)
Flow of participants through each stage of the trial. Franchi. EMLA cream vs mepivacaine for pain during perineal repair. Am J Obstet Gynecol 2009.
trauma (P ⫽ 1.0). No woman in either group sustained fourth-degree perineal tears. An episiotomy was performed in 7 patients: 4 (13.3%) in the mepivacaine group and 3 (9.7%) in the EMLA group (P ⫽ .69). Pain scores during perineal repair are displayed in Table 2. The proportion of women who required additional analgesia during perineal suturing was similar in the EMLA group and in the mepivacaine group (5/31 women [16.1%] vs 3/30 women [10%]; P ⫽ .7). Satisfaction with anesthesia method was expressed by 83.8% of women in the EMLA group, compared with 53.3% in the mepivacaine group (P ⫽ .01). 186.e3
C OMMENT The findings of this study suggest that a topically applied anesthetic, such as EMLA cream, is more effective in the relief of pain that is experienced during repair of perineal trauma after childbirth than conventional infiltrative anesthesia. Despite thousands of research trials that have addressed the issue of analgesia that is provided to women in labor and in the immediate postpartum period, levels of pain and discomfort that are experienced during perineal suturing have been largely overlooked in the obstetric literature. However, evidence exists that indicates that some women have consid-
American Journal of Obstetrics & Gynecology AUGUST 2009
erable levels of pain during suturing.15,16 Sanders et al17 reported that pain of suture of perineal tears was described as “distressing,” “horrible,” or “excruciating” by 16.5% of women after vaginal delivery. Strategies to reduce perineal trauma and appropriate surgical techniques of suturing are important for avoiding or alleviating pain, but adequate analgesia during surgical repair remains a major contributing factor to reduce feelings of distress and discomfort that are incurred by women. Infiltrative anesthetics are chosen frequently because of their proven safety record, low cost, widespread availability, and rapid onset of action. However, pain
Obstetrics
www.AJOG.org
TABLE 1
Patient demographics and obstetric outcomes Mepivacaine group (n ⴝ 30)
Variable
EMLA group (n ⴝ 31)
P value
Race (n)
.....................................................................................................................................................................................................................................
White
22 (74.6%)
24 (77.4%)
.77
.....................................................................................................................................................................................................................................
Others
8 (26.4%)
7 (22.6%)
31.1 (4.1%)
31.3 (3.7%)
..............................................................................................................................................................................................................................................
Age (y)
.76
.............................................................................................................................................................................................................................................. a
Parity (n)
1 (0-3)
1 (0-4)
.92
.............................................................................................................................................................................................................................................. 2b
27.9 ⫾ 3.5
Body mass index (kg/m )
28.1 ⫾ 2.6
.77
39.2 ⫾ 0.9
.59
.............................................................................................................................................................................................................................................. b
39.1 ⫾ 1.1
Gestational age (wk)
.............................................................................................................................................................................................................................................. b
Length of first stage of labor (min)
183 ⫾ 103
206 ⫾ 133
.44
37 ⫾ 22
46 ⫾ 37
.28
..............................................................................................................................................................................................................................................
Length of second stage of labor (min)b
.............................................................................................................................................................................................................................................. b
3409 ⫾ 390
Neonatal weight (g)
3340 ⫾ 365
.56
.............................................................................................................................................................................................................................................. b
Cranial circumference (cm)
34.4 ⫾ 1.6
34.7 ⫾ 3.2
.77
..............................................................................................................................................................................................................................................
EMLA, lidocaine-prilocaine cream. a
Values are expressed as median (range); proportions were compared by the Fisher exact test; b values are expressed as mean ⫾ SD; means were compared by the Mann-Whitney U test (parity) or the t test (all the other continuous variables).
Franchi. EMLA cream vs mepivacaine for pain during perineal repair. Am J Obstet Gynecol 2009.
of injection that is caused by insertion of the needle and infiltration of the anesthetic into the skin, burning sensation during infusion, distortion of surgical site by edema, and risks of accidental intravascular administration are major drawbacks. Moreover, epinephrine that is used to slow absorption of local anesthetics may cause an exaggerated vasoconstrictor response and arrhythmias in susceptible patients. Safety and efficacy of EMLA cream have been shown consistently in a number of clinical trials across many med-
ical specialties since 1990.1-6,12 EMLA cream provides analgesia by the release of lidocaine and prilocaine, which are 2 amide anesthetics, from the cream into the dermal layers before penetrating the smooth and striated muscle and the individual axons within the nerve. Nerve conduction becomes impeded because an action potential is prevented by an inward flux of sodium ions through the nerve membranes. Although EMLA cream is indicated as a topic anesthetic for use on intact skin, several studies have shown that EMLA cream can also
TABLE 2
Pain scores during perineal suturing that were assessed by a 10-cm visual analog scale Variable
Mepivacaine group, n
Pain score
EMLA group, n
Pain score
P value
Total perineal trauma
30
3.9 ⫾ 2.4
31
1.7 ⫾ 2.4
.0002
..............................................................................................................................................................................................................................................
Degree of laceration
.....................................................................................................................................................................................................................................
First
10
3.2 ⫾ 2.6
13
0.4 ⫾ 0.5
.007
Second
15
3.9 ⫾ 2.3
14
1.3 ⫾ 1.7
.005
..................................................................................................................................................................................................................................... .....................................................................................................................................................................................................................................
Third
1
5
1
8
—
Episiotomy
4
4.6 ⫾ 3.6
3
4.0 ⫾ 4.0
.85
.............................................................................................................................................................................................................................................. ..............................................................................................................................................................................................................................................
Values are expressed as mean ⫾ SD; means were compared by the t test. EMLA, lidocaine-prilocaine cream. Franchi. EMLA cream vs mepivacaine for pain during perineal repair. Am J Obstet Gynecol 2009.
Research
be used effectively for laceration repair.18,19 Moreover, EMLA cream has been shown to work effectively on genital mucosa during minor gynecologic surgical procedures, such as laser treatment of condylomata acuminata.20-22 Typically, for the topical anesthetic creams, the systemic blood levels are well below the concentration that would cause toxicity. If 60 g of EMLA cream is placed on a 400-cm2 area for 4 hours, the peak blood levels of lidocaine and prilocaine will be 1/20th and 1/36th the toxicity level, respectively.23 There have been reports of rare methemoglobinemia that is limited to infants ⬍ 3 months old who were exposed to high doses of EMLA cream for prolonged periods.23 Localized reactions, generally mild and transient (blanching and erythema because of peripheral vasoconstriction), have been reported after treatment with EMLA cream, but there were no serious reactions that were ascribed to the cream in studies the involved ⬎ 1600 subjects.23 This trial was powered to detect a difference in the primary outcome of perineal pain during suturing of any perineal trauma but was underpowered for subgroup analysis, thus preventing meaningful conclusions on the effects of topically applied EMLA cream for relief of pain that is associated with suturing of episiotomy compared with spontaneous perineal tear or major degree perineal trauma. The reported results might suggest that EMLA cream resulted in a lower pain score in those women who have minimal mucosal involvement. One could speculate that EMLA cream may be less active on the perineal muscular layers than local infiltration of mepivacaine, because of lower depth of action. Depth of anesthesia depends on contact time with EMLA cream, and anesthetic effect has been shown to reach a maximal depth of 3 mm after a 60-minute application and 5 mm after a 120-minute application. Because the median application-to-delivery interval was 56 minutes, even considering the length of the third stage, it seems unlikely that, in most of the women of our study group, the application time exceeded the 2-hour wait
AUGUST 2009 American Journal of Obstetrics & Gynecology
186.e4
Research
Obstetrics
that is required for a deep penetration of the topical anesthetic. The pain scores that were recorded in this trial in the mepivacaine group were similar to those scores that were obtained in previous studies on pain during postdelivery perineal repair.3 The lack of blinding of both participants and investigators because of the nature of the interventions might cast doubts on whether absence of clinical equipoise by proponents of a new treatment have had the effect of diminishing pain scores that were reported by women in the EMLA group. However, most members of our medical and midwifery staff who were involved in recruitment, care, and patient interviews did not participate actively in the research project conception and design, thus satisfying the principle of uncertainty regarding the comparative therapeutic merits of each arm in the trial. It is noteworthy that 39% of eligible patients declined participation in the study, 80% of whom were multiparous women. Although we did not record methodically the reasons for not participating in the trial, we believed that most of these women, with negative previous experiences of perineal repair, preferred to avoid “drugs under investigation” because of fear of experiencing pain even worse than they expected, believing that the treatment they would receive in a clinical trial would be less effective than standard care. In conclusion, this study has demonstrated that the application of EMLA cream to the perineum is an effective, highly satisfactory, and easy-to-use alternative to the “standard” injective local anesthesia for perineal repair. When painful injections and “needle anxiety” are avoided, the patient’s distress about perineal suturing could be lessened and
186.e5
www.AJOG.org overall better tolerated. The adequacy of EMLA cream to achieve analgesia, specifically during episiorrhaphy and repair of major perineal tears, remains to be elucidated in further larger randomized trials.1,4 f REFERENCES 1. Kaweski S. Plastic Surgery Educational Foundation Technology Assessment committee: topical anesthetic creams. Plast Reconstr Surg 2008;121:2161-5. 2. Lander JA, Weltman BJ, So SS. EMLA and amethocaine for reduction of children’s pain associated with needle insertion. Cochrane Database Syst Rev 2006;3:CD004236. 3. Brady-Fryer B, Wiebe N, Lander JA. Pain relief for neonatal circumcision. Cochrane Database Syst Rev 2004;4:CD004217. 4. Alster TS. The lidocaine/tetracaine peel: a novel topical anesthetic for dermatologic procedures in adult patients. Dermatol Surg 2007;33:1073-81. 5. Galosi AB, Minardi D, Dell’atti L, Yehia M, Muzzonigro G. Tolerability of prostate transrectal biopsies using gel and local anesthetics: results of a randomized clinical trial. J Endourol 2005;19:738-43. 6. Vickers ER, Marzbani N, Gerzina TM, McLean C, Punnia-Moorthy A, Mather L. Pharmacokinetics of EMLA cream 5% application to oral mucosa. Anesth Prog 1997;44:32-7. 7. Sanders J, Campbell R, Peters TJ. Effectiveness and acceptability of lidocaine spray in reducing perineal pain during spontaneous vaginal delivery: randomised controlled trial. BMJ 2006;333:117. 8. Corkill A, Lavender T, Walkinshaw S, Alfirevic Z. Reducing postnatal pain from perineal tears by using lignocaine gel: a doubleblind randomised controlled trial. Birth 2001; 28:22-7. 9. Hedayati H, Parsons J, Crowther CA. Topically applied anaesthetics for treating perineal pain after childbirth. Cochrane Database Syst Rev 2005;2:CD004223. 10. Minassian VA, Jazayeri A, Prien SD, Timmons RL, Stumbo K. Randomized trial of lidocaine ointment versus placebo for the treatment of postpartum perineal pain. Obstet Gynecol 2002;100:1239-43.
American Journal of Obstetrics & Gynecology AUGUST 2009
11. Seckin B, Avsar F, Parlakygit EE, Aksakal O. Effects of indomethacin suppository and lidocaine pomade for the relief of post-episiotomy pain. Int J Gynaecol Obstet 2002;78:159-61. 12. Friedman PM, Mafong EA, Friedman ES, Geronemus RG. Topical anesthetics update: EMLA and beyond. Dermatol Surg 2001; 27:1019-26. 13. McKinlay JR, Hofmeister E, Ross EV, MacAllister W. EMLA cream-induced eye injury. Arch Dermatol 1999;135:855-6. 14. Ludington E, Dexter F. Statistical analysis of total labor pain using the visual analog scale and application to studies of analgesic effectiveness during childbirth. Anesth Analg 1998;87:723-7. 15. Sanders J, Campbell R, Peters TJ. Effectiveness of pain relief during perineal suturing. BJOG 2002;109:1066-8. 16. Salmon D. A feminist analysis of women’s experiences of perineal trauma in the immediate post-delivery period. Midwifery 1999;15: 247-56. 17. Sanders J, Peters TJ, Campbell R. Techniques to reduce perineal pain during spontaneous vaginal delivery and perineal suturing: a UK survey of midwifery practice. Midwifery 2005;21:154-60. 18. Zempsky WT, Karasic RB. EMLA versus TAC for topical anesthesia of extremity wounds in children. Ann Emerg Med 1997;30:163-6. 19. Singer AJ, Stark MJ. LET versus EMLA for pretreating lacerations: a randomized trial. Acad Emerg Med 2001;8:223-30. 20. Rylander E, Sjöberg I, Lillieborg S, Stockman O. Local anesthesia of the genital mucosa with a lidocaine/prilocaine cream (EMLA) for laser treatment of condylomata acuminata: a placebo-controlled study. Obstet Gynecol 1990; 75:302-6. 21. Frega A, Di Renzi F, Palazzetti PL, Pace S, Figliolini M, Stentella P. Vulvar and penile HPV lesions: laser surgery and topic anaesthesia. Clin Exp Obstet Gynecol 1993;20:76-81. 22. Monsonego J, Semaille C. Local anesthesia of genital mucosa with a lidocaine/prilocaine combination cream before laser therapy of human papillomavirus lesions. Eur J Dermatol 2000;10:607-10. 23. Department of Health and Human Services. EMLA. Available at: http://www.fda.gov/ medwatch/SAFETY/2005/Dec_PI/Emla_PI.pdf 2005. Accessed Sept. 25, 2008.