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Obstetrics & Gynecology 2004;103:347-351
© 2004 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Anesthetic Effect of Intrauterine Lidocaine Plus Naproxen Sodium in Endometrial Biopsy

Erbil Dogan, MD, Murat Celiloglu, MD, Evrim Sarihan, MD and Ahmet Demir, MD

From the Department of Obstetrics and Gynecology, Dokuz Eylül University Faculty of Medicine, zmir, Turkey.

Address reprint requests to: Dr. Erbil Dogan, Dokuz Eylül University Faculty of Medicine, Department of Obstetrics and Gynecology, 35340 nciralti zmir, Turkey; e-mail: erbil.dogan{at}deu.edu.tr.


   ABSTRACT
TOP
ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE: To compare the efficacy of intrauterine lidocaine with oral naproxen sodium on pain perception of the patients during endometrial biopsy using the Pipelle instrument and to investigate their effects when used in combination.

METHODS: One-hundred twenty women were randomly assigned to receive either 5 mL of intrauterine 2% lidocaine or saline and either 550 mg of naproxen sodium or a similar-appearing placebo tablet. Subsequently, each woman completed a 10-cm visual analog scale for subjective pain experience and a physician scored visible signs of the women’s distress during the procedure using a 3-point observer scale.

RESULTS: There was no statistically significant difference between the 4 groups in age, vaginal parity, history of chronic pelvic pain, menopausal status, tenaculum use, previous endometrial biopsy, or difficulty in passing the cervical os. The mean pain scores of the women in the naproxen only (5.8 ± 2.2) and lidocaine only (5.9 ± 2.2) groups were not significantly different compared with placebo group (7.1 ± 2.0). However, the mean pain score in the lidocaine plus naproxen group (4.6 ± 1.8) compared with the placebo group showed significant reduction in pain (P < .05). Pain rated by the physician was significantly lower in the lidocaine plus naproxen group compared with other groups, and a significant correlation was noted between the visual analog pain score and the patients’ distress recorded by the physician (r = .791, P < .001). One patient in the naproxen-only group had vasovagal syncope after the procedure.

CONCLUSION: Intrauterine lidocaine instillation significantly decreases pain associated with Pipelle endometrial biopsy when used in combination with oral naproxen sodium.

LEVEL OF EVIDENCE: I

Endometrial biopsy using the Pipelle (Unimar, Wilton, CT) device is one of the most common outpatient gynecologic procedures. It has a wide range of indications, such as abnormal uterine bleeding, postmenopausal bleeding, abnormal cytology, monitoring hormone replacement therapy, and infertility. Although it is reported to be less painful than conventional methods of endometrial sampling, nearly half of the patients experience moderate-to-severe pain during the procedure.1 Only a few studies have evaluated possible methods of pain relief during endometrial biopsy by using Pipelle.2 Intrauterine instillation of a topical anesthetic is an easy and promising technique for adequate pain relief during endometrial biopsy. Most of the previous studies addressed intrauterine anesthesia in women who had concurrent office hysteroscopies and endometrial biopsies. Most but not all of these studies reported reduced pain during the procedure.3–6

Naproxen sodium is a nonsteroidal anti-inflammatory drug that blocks prostaglandin synthesis and has been shown to be effective in the relief of mild-to-moderate pain related with various obstetrics and gynecology syndromes and procedures, such as dysmenorrhea, intra-uterine device insertion, suction curettage, postpartum pain, gynecologic surgery, and menorrhagia.7 When naproxen sodium is used 1–2 hours before the procedure in combination with paracervical 1% lidocaine solution for first-trimester abortions, it can provide effective analgesia for pain associated with uterine contractions during and after the curettage.8 The aim of this study was to compare the efficacy of intrauterine lidocaine instillation with oral naproxen sodium on pain perception of the patients during endometrial biopsy and to investigate their effects when used in combination.


   MATERIALS AND METHODS
TOP
ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This was a randomized, double-blind, placebo-controlled study with women recruited from our outpatient gynecology clinic. Women who needed endometrial biopsies for various reasons were invited to participate in the study. Exclusion criteria were severe medical illness (eg, heart failure, hypertension), cervical stenosis, known allergy to lidocaine, pregnancy, acute cervicitis, need for coincident endocervical curettage, peptic ulcer disease, and known sensitivity to naproxen sodium. A total of 139 patients was assessed for eligibility between January 2003 and June 2003. Nineteen patients were excluded from the study, of which 4 refused to participate in the study and 15 did not meet the inclusion criteria (8 cervical stenosis, 3 acute cervicitis, 3 peptic ulcer, and 1 hypertension). The study group consisted of 120 patients. A written informed consent was obtained for each patient. The study was approved by Human Ethics Committee of Dokuz Eylül University.

Before the procedure, each woman completed a demographics form. Then, using a random number list, we randomly assigned patients with a predetermined randomization chart to 1 of the 4 groups (groups A–D) before endometrial biopsy. Each group consisted of 30 patients, assuming that a large effect size between groups will result in 96% power with an {alpha} error of .05. Each patient received either 5 mL of intrauterine 2% lidocaine (Jetokain simplex ampule; Adeka Pharmaceutical Company, Istanbul, Turkey) or saline by transcervical 18-gauge angiocatheter and either 550 mg of oral naproxen sodium (Aprol; Bilim Pharmaceutical Company, Istanbul, Turkey) or similar-appearing placebo tablets 60 minutes before the procedure. The groups are shown in Figure 1Go. Biopsies were performed with the Pipelle, which is a 3.1-mm diameter flexible polypropylene suction canula. To maintain consistency and limit confounding variables, a single physician (E.S.) used the same technique to sample the endometrium. The cervix and vagina were cleansed with Betadine (Purdue Pharma LP, Stamford, CT), and 5 mL of unlabeled test solution was instilled through the endocervix into the uterine cavity with an 18-gauge angiocatheter advanced to the hub. The angiocatheter was left in place for 3 minutes before it was withdrawn to limit backflow and to allow the anesthetic to reach its effect. The Pipelle was then pushed into the uterine cavity for a minimum of 3 passes to ensure complete sampling. When a tenaculum was used and/or cervix was passed with difficulty, it was noted.



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  		Figure 1. Patient enrollment and randomization to groups. Patient numbers are in parentheses. NSAID = nonsteroidal anti-inflammatory drug.

Dogan. Naproxen and Intrauterine Lidocaine. Obstet Gynecol 2004.

 
After the procedure, each woman reported her greatest pain on a form. A nurse instructed the patients how to score their pain before the procedure. The form contained a visual analog scale for women to report their responses.9 On the other side of the scale, there was a 10-cm numeric scale on which 0 represented no pain and 10 represented excruciating pain. Patients were asked to report any symptoms before and after the procedure. The physician recorded and scored visible signs of the women’s distress during the procedure (moaning, body movement, grabbing the table) using a 3-point observer scale for each of the parameters in which 0 was no response, 1 was mild response, and 2 was severe response. The pain experienced and its correlation with the difficulty of introducing the instrument were recorded. Lidocaine and saline were packaged in identical bottles, and oral placebo tablets were similar to naproxen sodium tablets. Both the physician performing the procedure and the patient were blinded to the treatment assignment.

Statistical analysis was performed with the Mann-Whitney U test and {chi}2 test where appropriate. Nonparametric analysis of variance test (Kruskal-Wallis) was used to evaluate the differences of the mean pain scores between the groups. Spearman rank correlation analysis was used for the correlation between visual analog scale and the physician pain scores. P < .05 was considered statistically significant.


   RESULTS
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ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Before the study, the analysis of specimens by pathologists blinded to lidocaine or saline revealed no histological effect on the ability to interpret endometrial biopsies. Histological specimens also were not affected in any of the 120 patients enrolled in this study. There were no statistically significant differences among groups in age, vaginal parity, history of chronic pelvic pain, menopausal status, use of tenaculum, previous endometrial biopsy, or difficulty in passing the cervical os, as shown in Table 1Go.


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  		Table 1. Patient Characteristics and Pain Scores of the Groups
 
Pain perceived by the patients in lidocaine-only and naproxen-only groups was 17% and 18% less than the placebo group, respectively, but the difference was not statistically significant (P > .05). However, when lidocaine and naproxen were used in combination (group D), pain perception was 35% less compared with the placebo group, and this difference was statistically significant (P < .001). Combined use of lidocaine and naproxen was superior to either drug when they were used alone. However, the difference did not reach a statistical significance (P > .05). The mean visual analog scale pain scores of each group are shown in Figure 2Go. Postmenopausal women were analyzed separately. In this group of patients, both the lidocaine-only (6.2 ± 2.2) and naproxen-only (6.2 ± 2.0) groups had similar pain scores compared with placebo (7.0 ± 2.0). The most significant pain relief in postmenopausal patients was also obtained by combined use of lidocaine and naproxen sodium (4.0 ± 1.9, P < .05).



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  		Figure 2. Mean pain scores of the groups. NSAID = nonsteroidal anti-inflammatory drug.

Dogan. Naproxen and Intrauterine Lidocaine. Obstet Gynecol 2004.

 
Pain rated by the physician during the procedure was significantly lower in group D than the other groups (Table 1Go). There was a significant positive correlation between the visual analog scale pain score and the patients distress recorded by the physician (r = .791 P < .001). There were no reported side effects in the lidocaine groups. Only 1 patient in the naproxen-only group experienced vasovagal syncope after the procedure.


   DISCUSSION
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The data of the present study demonstrate that lidocaine and naproxen sodium, when used alone, equally attenuate pain experienced by the patient during endometrial biopsy compared with placebo but that a significant decrease in pain perception is obtained by the combined use of these drugs. To our knowledge, this is the first randomized, double-blind, placebo-controlled study comparing the effects of a local anesthetic and a nonsteroidal anti-inflammatory drug for endometrial biopsy. We propose that they may have synergistic effects because their mechanism of action is by different ways. Lidocaine reduces pain by blocking the nerve endings within the endometrial mucosa, and naproxen sodium inhibits prostaglandin synthesis. This way, both a systemic and a local analgesic–anesthetic effect are achieved.

Evaluation of pain as a symptom is difficult because it is a subjective feeling and composed of sensory, emotional, and cognitive components. Pain tolerance is profoundly influenced by culture. Pain from the cervix and lower portion of the uterus is felt in the pelvic splanchnics (S2–4), whereas pain from the fundus and body of the uterus travels up the hypogastric nerves to the lower thoracic segments.10 Therefore, cervical anesthesia will be effective in reducing the sensitivity of cervix but will be ineffective at blocking the innervation to the body and fundus. This was recently confirmed by the study by Lau et al11 in which paracervical lidocaine was found to be ineffective in reducing pain and carried a risk of inducing bradycardia and hypotension. Therefore, paracervical technique is of limited use for endometrial biopsy. There are advantages of intrauterine instillation of anesthetic over intracervical or paracervical injection. The application is painless, and there is no danger of bleeding or intravasation.

Most of the studies on intrauterine topical anesthesia evaluated its use with combined hysteroscopy and endo-metrial biopsy, which is a potentially more uncomfortable procedure than endometrial biopsy alone. In a randomized trial, Cicinelli et al4 evaluated pain management in postmenopausal women undergoing office hysteroscopy and biopsy comparing 2 mL of 2% intrauterine mepivacaine with normal saline. Pain scores were significantly reduced with mepivacaine; however, the reduction was limited to only parous women. Another study, performed by Zupi et al,3 showed similar trends. Contrary to these, Davies et al5 reported that intrauterine application of lidocaine spray during hysteroscopy significantly reduced pain only during grasping of the cervix but not during endometrial biopsy. Similarly, Lau et al12 found no pain relief in patients receiving 5 mL of 2% intrauterine lidocaine for outpatient diagnostic hysteroscopy and endometrial biopsy, and additionally, lidocaine did not prevent the occurrence of vasovagal reaction. The only study that used intrauterine lidocaine for endometrial biopsy with Pipelle is by Trolice et al,2 who revealed a statistically significant reduction in pain over placebo. This was contrary to our results, in which the lidocaine-only group did not have a significant pain relief over placebo. The possible explanation of this could be that our patients were mostly postmenopausal (63%) and were expected to experience more pain because of genital atrophy. Another explanation could be the ethnic and cultural differences between the patient populations, which may affect pain perception and tolerance.

Using a Vabra (Berkeley Medevices, Berkeley, CA) endometrial sampler, which is considered a more painful procedure than Pipelle, Kozman et al13 did not find any beneficial effects of intrauterine application of 2% lidocaine gel on pain perception. Similarly, when naproxen sodium (550 mg) was administered 1 hour before Vabra curettage, it did not reduce the severity of the pain associated with the procedure, but it significantly reduced the cramps immediately after the procedure and 30 and 60 minutes later.14 Likewise, naproxen sodium when used alone was also found to be ineffective for pain relief in our study.

Intrauterine local anesthetics also were investigated for the pain relief during hysterosalpingography. Costello et al15 found no difference in pain scores between 2 mL of 2% lidocaine and placebo and, unexpectedly at 10 minutes after the procedure, the lidocaine group experienced more pain. Similarly, in a prospective cohort study, Lorino et al16 failed to find a statistically significant difference in pain during hysterosalpingography between lidocaine and saline. However, when orally administered naproxen was combined with either 2% intrauterine lidocaine with or without 20% benzocaine gel, pain was reduced only immediately after the procedure. The results of Lorino et al16 are consistent with the results of our study in that the most significant pain reduction is with the combined use of a local anesthetic and a nonsteroidal anti-inflammatory drug. Hysterosal-pingography may be considered a more painful procedure than Pipelle endometrial biopsy because of pain secondary to uterine distention with contrast media and pain caused by peritoneal irritation as a result of contrast spill into peritoneal cavity can increase the discomfort of the patient.

In conclusion, our study showed that the most effective method for pain relief in endometrial biopsy is achieved with the combined use of lidocaine and naproxen. We believe that this will increase the patient acceptability and compliance with the procedure.


   Footnotes
 
The authors thank the Adeka and Bilim pharmaceutical companies for supplying lidocaine and naproxen and their placebo forms used in this study.

doi: 10.1097/01.AOG.0000109519.74229.30

Received August 16, 2003. Received in revised form October 5, 2003. Accepted October 9, 2003.


   REFERENCES
TOP
ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Silver MM, Miles P, Rosa C. Comparison of Novak and Pipelle endometrial biopsy instruments. Obstet Gynecol 1991;78:828–30.[Abstract/Free Full Text]

2. Trolice MP, Fishburne C Jr, McGrady S. Anesthetic efficacy of intrauterine lidocaine for endometrial biopsy: a randomized double-masked trial. Obstet Gynecol 2000; 95:345–7.[Abstract/Free Full Text]

3. Zupi E, Luciano AA, Valli E, Marconi D, Maneschi F, Romanini C. The use of topical anesthesia in diagnostic hysteroscopy and endometrial biopsy. Fertil Steril 1995; 63:414–6.[Medline]

4. Cicinelli E, Didonna T, Ambrosi G, Schonauer LM, Fiore G, Matteo MG. Topical anaesthesia for diagnostic hysteroscopy and endometrial biopsy in postmenopausal women: a randomised placebo-controlled double-blind study. Br J Obstet Gynaecol 1997;104:316–9.[Medline]

5. Davies A, Richardson RE, O’Connor H, Baskett TF, Nagele F, Magos AL. Lidocaine aerosol spray in outpatient hysteroscopy: a randomized double-blind placebo-controlled trial. Fertil Steril 1997;67:1019–23.[Medline]

6. Soriano D, Ajaj S, Chuong T, Deval B, Fauconnier A, Darai E. Lidocaine spray and outpatient hysteroscopy: randomized placebo-controlled trial. Obstet Gynecol 2000;96:661–4.[Abstract/Free Full Text]

7. Edgren RA, Morton CJ. Naproxen sodium for OB/GYN use, with special reference to pain states: a review. Int J Fertil 1986;31:135–42.[Medline]

8. Suprapto K, Reed S. Naproxen sodium for pain relief in first-trimester abortion. Am J Obstet Gynecol 1984;150: 1000–1.[Medline]

9. Revill SI, Robinson JO, Rosen M, Hogg MI. The reliability of a linear analogue for evaluating pain. Anaesthesia 1976;31:1191–8.[Medline]

10. Last RJ. Anatomy: regional and applied. 7th ed. New York (NY): Churchill Livingstone; 1984. p. 336.

11. Lau WC, Lo WK, Tam WH, Yuen PM. Paracervical anaesthesia in outpatient hysteroscopy: a randomised double-blind placebo-controlled trial. Br J Obstet Gynaecol 1999;106:356–9.[Medline]

12. Lau WC, Tam WH, Lo WK, Yuen PM. A randomised double-blind placebo-controlled trial of transcervical intra-uterine local anaesthesia in outpatient hysteroscopy. Br J Obstet Gynaecol 2000;107:610–3.

13. Kozman E, Collins P, Howard A, Akanmu T, Gibbs A, Frazer M. The effect of an intrauterine application of two percent lidocaine gel on pain perception during Vabra endometrial sampling: a randomised double-blind, placebo-controlled trial. Br J Obstet Gynaecol 2001;108:87–90.

14. Siddle NC, Young O, Sledmere CM, Reading AE, White-head MI. A controlled trial of naproxen sodium for relief of pain associated with Vabra suction curettage. Br J Obstet Gynaecol 1983;90:864–9.[Medline]

15. Costello MF, Horrowitz S, Steigrad S, Saif N, Bennett M, Ekangaki A. Transcervical intrauterine topical local anesthetic at hysterosalpingography: a prospective, randomized, double-blind, placebo-controlled trial. Fertil Steril 2002;78:1116–22.[Medline]

16. Lorino C, Prough S, Aksel S, Abuzeid M, Alexander S, Wiebe R. Pain relief in hysterosalpingography. J Reprod Med 1990;35:533–6.[Medline]




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