IJG-08362; No of Pages 4 International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
5Q2
Tarek Shokeir a,⁎, Sherif Mousa b
6 7
a
8
a r t i c l e
9 10 11 12
Article history: Received 10 December 2014 Received in revised form 18 March 2015 Accepted 22 May 2015
13 14 15 16 17
Keywords: Bupivacaine Endometriosis Hysteroscopy Pelvic pain
i n f o
R O
Department of Obstetrics and Gynecology, Mansoura University Hospital, Mansoura Faculty of Medicine, Mansoura, Egypt Department of Anaesthesia and Intensive Care, Mansoura University Hospital, Mansoura Faculty of Medicine, Mansoura, Egypt
a b s t r a c t
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 © 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics. 34
Objective: To assess the effectiveness of hysteroscopic-guided pertubal diluted bupivacaine infusion for endometriosis-associated chronic pelvic pain (CPP). Methods: Between June 2010 and July 2013, a randomized, placebo-controlled, double-blind study was undertaken at Mansoura University Hospital, Mansoura, Egypt. Patients meeting inclusion criteria (laparoscopically confirmed endometriosis, patent fallopian tubes, ≥6 months CPP, pain score on visual analogue scale [VAS] N 5) were randomly assigned using a computer-generated randomization sequence to receive either office hysteroscopic-guided pertubal diluted bupivacaine infusion (0.25%) or placebo. Response to treatment was assessed using subjective data for scores on VAS and a monthly verbal rating scale (VRSmonthly) at baseline and at 1, 2, and 3 months of follow-up. Additionally, women completed a questionnaire to evaluate the overall satisfaction at 3 months. Results: Thirty patients were assigned to each group. In the bupivacaine group, VAS and VRSmonthly scores were significantly lower at 1, 2, and 3 months than at baseline (P b 0.05 for all). Additionally, scores were significantly lower in the bupivacaine group than in the placebo group at 1, 2, and 3 months (P b 0.05 for all). At 3 months, 22 (73%) women in the bupivacaine group expressed satisfaction, compared with 2 (7%) in the placebo group (P = 0.18). Conclusion: Office pertubal hysteroscopicguided diluted bupivacaine infusion could be used to manage endometriosis-associated CPP for at least 3 months. AEARCTR-0000573
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A randomized, placebo-controlled, double-blind study of hysteroscopic-guided pertubal diluted bupivacaine infusion for endometriosis-associated chronic pelvic pain
2Q1
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38
1. Introduction
40
The successful treatment of endometriosis-associated chronic pelvic pain (CPP) typically requires surgical and medical interventions. Some pharmacologic treatments inhibit the growth and activity of endometrial implants, such as combination oral contraceptives, danazol (an androgenic agent), gonadotropin-releasing hormone analogues, progestins, aromatase inhibitors, selective estrogen receptor modulators, and selective progesterone receptor modulators [1–4]. Locally long-acting pharmacologic agents that can specifically target the endometrial implants rather than systemically reducing estrogen levels have not yet been assessed fully in clinical practice. However, pertubation with lignocaine has been shown to be an effective non-hormonal treatment option for women with dysmenorrhea and pelvic endometriosis [5–7]. In an open-label preliminary observational pilot study at Mansoura University Hospital, Mansoura, Egypt, office hysteroscopic-guided
43 44 45 46 47 48 49 50 51 52 53
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⁎ Corresponding author at: Department of Obstetrics and Gynecology, Mansoura University Hospital, Mansoura Faculty of Medicine, Mansoura 11271, Egypt. Tel.: +20 50 2331118; fax: +20 50 2319922. E-mail address: [email protected] (T. Shokeir).
pertubal bupivacaine infusion (0.25%) was shown to reduce CPP intensity in women with stage I–IV pelvic endometriosis (unpublished data). Bupivacaine is more cardiotoxic than are other local anesthetics [4]. Most of its adverse effects are caused by accelerated absorption from the injection site, unintentional intravascular injection, or slow metabolic degradation. However, several clinical trials have confirmed the safety of this local anesthetic drug [8–10]. Notably, the effectiveness of pertubal diluted bupivacaine infusion (0.25%) has not been tested against placebo. The aim of the present study was to assess the short-term effectiveness of the office hysteroscopic-guided pertubal diluted bupivacaine infusion (0.25%) for endometriosis-associated CPP in a randomized, placebo-controlled trial.
54
2. Materials and methods
67
Between June 1, 2010, and July 30, 2013, a randomized, placebocontrolled, double-blind study was conducted at Mansoura University Hospital. Women were eligible when they had experienced CPP for at least 6 months, had a pain score on the visual analogue scale (VAS) of more than 5 (0–10 scale), had laparoscopically confirmed stage I–IV
68 69
http://dx.doi.org/10.1016/j.ijgo.2015.03.043 0020-7292/© 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
Please cite this article as: Shokeir T, Mousa S, A randomized, placebo-controlled, double-blind study of hysteroscopic-guided pertubal diluted bupivacaine infusion..., Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.043
55 56 57 58 59 60 61 62 63 64 65 66
70 71 72
2
T. Shokeir, S. Mousa / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Assessed for eligibility (n=76) Excluded (n=14) Did not meet inclusion criteria (n=10) Declined to participate (n=4)
Randomization (n=62)
Assigned to receive placebo (n=30)
Assigned to receive bupivacaine (n=32)
Analyzed (n=30) Fig. 1. Study profile.
89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117
118 119
3. Results
136
A total of 76 patients were enrolled. Data from 60 were included in analyses (Fig. 1). After identification, the baseline clinical characteristics for both groups were comparable in terms of age, parity, body mass index, and laparoscopic endometriosis staging (Table 1). In the bupivacaine group, VAS and VRSmonthly scores were significantly lower at 1, 2, and 3 months than at baseline (Table 2). Additionally, the scores on both scales were significantly lower in the bupivacaine group than in the placebo group at 1, 2, and 3 months
137
Table 1 Baseline characteristics.a
t1:1 t1:2
E
D
P
ruler in the diary. Mean VAS scores for the month were calculated for each patient. At monthly follow-up appointments, participants were asked to provide a monthly pain score on a verbal rating scale (VRSmonthly), on which a score of 0 indicated no pain and 100 indicated the maximum pain. After 3 months, participants were asked to complete a multiplechoice questionnaire that assessed overall patient satisfaction independent of age, duration or severity of the symptoms. Sample size was calculated using Epi Info version 6.0 (Centers for Disease Control and Prevention, Atlanta, GA, USA), setting the type I error (α) at 0.05 and the power (1–β) at 0.8. Using data from previous studies [5–7] and a 95% confidence interval, a minimum sample size of 60 patients was established. Epi Info version 6.0 was used to record and analyze the data. Only women who completed 3 months of follow-up were included in analyses. The paired t test, Mann–Whitney U test, and Wilcoxon and Friedman two-way ANOVA tests were used as appropriate. P b 0.05 was deemed significant.
T
C
87 88
E
85 86
R
83 84
R
81 82
O
79 80
C
77 78
N
75 76
pelvic endometriosis, and had patent fallopian tubes. Exclusion criteria were age younger than 18 years, any hormonal therapy in the previous 3 months, a desire to conceive within 1 year, occluded fallopian tubes with or without pelvic adhesions, non-gynecologic causes of CPP (intestinal, urinary, or musculoskeletal), and known hypersensitivity or contraindications to bupivacaine or any amide local anesthetic agent. The institutional ethics committee approved the study. All participants provided written informed consent. Patients were asked to stop any analgesic medications before enrollment into the study. Potential participants underwent a complete pelvic examination and high-resolution transvaginal ultrasonography. Basic work-up investigations were done whenever indicated to exclude concomitant non-gynecologic causes of CPP, including mid-stream urine analysis, stool analysis, intravenous urography, and full blood count. At the time of office recruitment, participants were randomly assigned to receive bupivacaine or placebo in a 1:1 ratio according to a computer-generated randomization sequence using numbered, sealed envelopes. All patients and investigators were masked to group allocation, including during data analysis. Procedures were undertaken as a day-case in an endoscopic suite. One treatment was to be given before ovulation on day 7–12 of their cycle. Under paracervical block and using Ringer solution as a uterine distending medium (Hysteromat, Karl Storz, Tuttlingen, Germany), an office hysteroscope (2.7 mm; Karl Storz, Tuttlingen, Germany) was passed and one tubal orifice was identified. Under hysteroscopic guidance, a 3-Fr ureteric catheter was introduced, cannulated through the tubal ostium, and passed proximally for 2–3 cm. After successful cannulation, participants assigned to the bupivacaine group received 10 mL diluted bupivacaine (0.25%; Marcaine, AstraZenica, Istanbul, Turkey) plus 100 mL Ringer solution, which was infused through the catheter over 15–20 minutes. Participants assigned to the placebo group received a 10-mL placebo infusion (sterile water) plus 100 mL Ringer solution. The allocated study solution was provided to the surgeon intraoperatively by senior nursing staff. Solutions were indistinguishable and were preloaded into identical unlabeled Ringer solution bottles. None of the patients used any adjunctive measures or analgesics following the original treatment. Follow-up visits were arranged after 1, 2, and 3 months. Patients were advised to stop any analgesic medications and to use barrier contraception for these 3 months. All patients completed a daily diary about pain during the month preceding the procedure and follow-up visits. These diaries were collected at each visit; new ones for the next month were provided. As part of the diary, participants were asked to provide a subjective assessment of the severity of pelvic pain on a VAS, on which 0 indicated no pain and 10 indicated severe pain. It was recorded daily on a 10-cm
U
73 74
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Analyzed (n=30)
O
F
Lost to follow-up (n=2)
120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135
138 139 140 141 142 143 144
Measure
Bupivacaine group (n = 30)
Placebo group (n = 30)
P valueb
t1:3
Age, y Parity Body mass indexc Laparoscopic staging Stage I Stage II Stage III Stage IV
32.8 ± 5.0 2.7 ± 1.2 27.2 ± 2.1
33.0 ± 2.6 3.0 ± 1.1 29 ± 1.0
0.63 0.39 0.65 0.90
14 (47) 10 (33) 4 (13) 2 (7)
16 (53) 8 (27) 4 (13) 2 (7)
t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11
a
Values are given as mean ± SD or number (percentage), unless indicated otherwise. Continuous data analyzed using t test when normally distributed and Wilcoxon ranksum test when not normally distributed. Categorical data analyzed using Fisher exact test. c Calculated as weight in kilograms divided by the square of the height in meters. b
Please cite this article as: Shokeir T, Mousa S, A randomized, placebo-controlled, double-blind study of hysteroscopic-guided pertubal diluted bupivacaine infusion..., Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.043
t1:12 t1:13 t1:14 t1:15
T. Shokeir, S. Mousa / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Outcome measures
Bupivacaine group (n = 30)
t2:4 t2:5 t2:6
Visual analogue scale (1–10) Verbal rating scale (1–100)
t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13
a
150 151
f g
Baseline
1 month
2 months
3 months
7.7 (7.9–8.2) 90.2 (90.5–91.9)
6.1 (5.5–6.3)b 35.4 (29.3–41.6)b
5.6 (5.8–6.0)c 34.2 (28.6–39.8)c
5.4 (4.9–5.0)d 38.6 (32.4–44.8)d
7.9 (8.2–6.8) 91.8 (91.3–92.3)
7.4 (7.5–6.7)e 91.2 (90.5–91.9)e
7.5 (7.9–6.8)f 89.9 (92.1–93.1)f
7.7 (7.5–6.6)g 90.2 (92.0–88.9)g
Values are given as mean (95% confidence interval). Comparison with baseline using the Wilcoxon rank sum test: P b 0.05. Comparison with baseline using the Wilcoxon rank sum test: P b 0.01. Comparison with baseline using the Wilcoxon rank sum test: P b 0.001. Comparison with bupivacaine group using the Wilcoxon rank sum test: P b 0.05. Comparison with bupivacaine group using the Wilcoxon rank sum test: P b 0.01. Comparison with bupivacaine group using the Wilcoxon rank sum test: P b 0.001.
(Table 2). In the placebo group, changes during follow-up were unremarkable. On the multiple-choice questionnaire, more women in the bupivacaine group than in the placebo group expressed satisfaction, although the difference was not significant (P = 0.18) (Table 3). The procedures were well tolerated by all patients without any adverse effects. No technical hysteroscopic cannulation failures were reported.
4. Discussion
153 154
181 182
The present study has shown that a 0.25% diluted bupivacaine pertubal infusion can relieve endometriosis-related CPP, with significant reductions in scores on the VAS and VRSmonthly between baseline and 3-month follow-up. The findings indicate that the drug had a greater benefit than did placebo. The explanation for this observation could be related to our small sample size. The present results are in line with those reported by other authors who investigated the action of pertubal lignocaine (5%) infusion in patients with endometriosis-related CPP [5–7]. In one placebo-controlled randomized trial [5], 41.7% of patients who received lignocaine achieved a reduction of 50% of more in the score on the VAS scale, compared with 16.7% of those who received placebo, and 44% of patients had a persistent therapeutic effect after 9 months. Lignocaine and bupivacaine are in the same pharmacologic group (amino amide group) and have an almost identical mechanism of action [11]. Therefore, office perturbation with diluted bupivacaine (0.25%) seems to be a promising alternative, minimally invasive, non-hormonal, short-term treatment. The exact mode of action of pertubal bupivacaine infusion is not clear. The perturbation treatment with bupivacaine might affect the pathologic endometrial foci during the instillation procedure. Additionally, bupivacaine could affect inflammatory cells (e.g. macrophages) and their activation status [12–14]. Several mechanisms by which the drug might have local anesthetic action on inflammatory cells have been suggested, but only a few targets have been specified [13]. Macrophages have contradictory actions: they can switch from pro-inflammatory to anti-inflammatory states, and can contribute to both the induction and the resolution of inflammation [15,16]. In chronic inflammatory diseases, inhibition of the apoptotic program could promote monocyte survival, which could account for the accumulation of macrophages and the persistence of an inflammatory milieu [17]. Neurologically, it
t3:1 t3:2
Table 3 Overall satisfaction at 3 months.
167 168 169 170 171 172 173 174 175 176 177 178 179 180
C
E
165 166
R
163 164
R
161 162
N C O
159 160
U
157 158
T
152
155 156
F
e
3 months
t3:3 t3:4
Degree of satisfaction
Bupivacaine group (n = 30)a
Placebo group (n = 30)a
P value b
t3:5 t3:6 t3:7
Satisfied Uncertain Dissatisfied
22 (73) 4 (13) 4 (13)
2 (7) 2 (7) 26 (87)
0.18 0.32 0.36
t3:8 t3:9
a b
Values are given as number (percentage). χ2 test.
has been suggested that bupivacaine exerts effects on sensory nerves in the peritoneum, peritoneal lesions, and eutopic endometrium [18]. In the present study, 10 mL diluted bupivacaine (0.25%) was introduced into the fallopian tubes. Similarly, Wickström et al. [5] passed a study solution of lignocaine (5%) through the uterine cavity and the fallopian tubes via an intracervical balloon catheter. Such procedures ensure that most of the solution used will pass directly into the pelvic cavity and directly target the endometriotic implants. Dose-ranging studies using this kind of therapy are needed. The present findings that 73% of patients who received bupivacaine were satisfied with their treatment confirm the efficacy and tolerability of the office perturbation treatment with diluted bupivacaine. Patients can be treated with repeated outpatient infusions on a symptomatic basis, which could mean that they would not need hormonal therapy, opioid analgesia, or surgical interventions such as hysterectomy with bilateral salpingo-oophorectomy [2–4,19]. However, an experienced hysteroscopist is needed to perform the procedure. The present study is limited by the small sample size. However, in view of the findings of previous studies, it is likely that similar results would be achieved in larger trials. The sample size needed to achieve a power of 0.85 would probably be large, and it would be impracticable to recruit such a large number of patients with endometriosisassociated CPP. Nevertheless, further multicenter randomized controlled trials are needed. In conclusion, the present results provide evidence to support the feasibility and the beneficial effect of office pertubal hysteroscopicguided bupivacaine (0.25%) infusion therapy for women with endometriosis-associated CPP. It offers a safe, minimally invasive, and cost-effective alternative to current treatments. The procedure can be repeated and is well tolerated by patients.
183
Conflict of interest
213
O
148 149
d
2 months
R O
146 147
c
1 month
P
145
b
Placebo group (n = 30)
Baseline
D
t2:3
Table 2 Outcomes.a
E
t2:1 t2:2
3
The authors have no conflicts of interest.
References [1] Jacobson TZ, Duffy JM, Barlow D, Koninckx PR, Garry R. Laparoscopic surgery for pelvic pain associated with endometriosis. Cochrane Database Syst Rev 2009;4: CD001300. [2] Bernardi LA. Pavone ME Endometriosis: an update on management. Womens Health (Lond Engl) 2013;9(3):233–50. [3] Triolo O, Laganà AS, Sturlese E. Chronic pelvic pain in endometriosis: an overview. J Clin Med Res 2013;5(3):153–63. [4] Taylor RN, Hummelshoj L, Stratton P, Vercellini P. Pain and endometriosis: Etiology, impact, and therapeutics. Middle East Fertil Soc J 2012;17(4):221–5. [5] Wickström K, Bruse C, Sjösten A, Spira J, Edelstam G. Pertubation with lignocaine as a new treatment of dysmenorrhea due to endometriosis: a randomized controlled trial. Hum Reprod 2012;27(3):695–701. [6] Edelstam G, Sjösten A, Jablonowska B, Kjellberg S, Spira J. Pertubation with lidocaine—a non-hormonal, long-term treatment of dysmenorrhea due to endometriosis. Sex Reprod Health 2012;3(2):93–4. [7] Edelstam GA, Sjösten AC, Salamon CW. Pertubation with lignocaine—a possible new treatment for women with endometriosis and impaired fertility. Ups J Med Sci 2001; 106(1):51–7.
Please cite this article as: Shokeir T, Mousa S, A randomized, placebo-controlled, double-blind study of hysteroscopic-guided pertubal diluted bupivacaine infusion..., Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.043
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[14] Parihar A, Eubank TD, Doseff AI. Monocytes and macrophages regulate immunity through dynamic networks of survival and cell death. J Innate Immun 2010;2(3): 204–15. [15] Porcheray F, Viaud S, Rimaniol AC, Léone C, Samah B, Dereuddre-Bosquet N, et al. Macrophage activation switching: an asset for the resolution of inflammation. Clin Exp Immunol 2005;142(3):481–9. [16] Devor M, Wall PD, Catalan N. Systemic lidocaine silences ectopic neuroma and DRG discharge without blocking nerve conduction. Pain 1992;48(2):261–8. [17] Tremont-Lukats IW, Challapalli V, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetics to relieve neuropathic pain: a systematic review and meta-analysis. Anesth Analg 2005;101(6):1738–49. [18] Medina MG, Lebovic DI. Endometriosis-associated nerve fibers and pain. Acta Obstet Gynecol Scand 2009;88(9):968–75. [19] Quinn MJ. "Endometriosis"—the role of radical surgery in a regional pain syndrome. Ann Surg 2013;257(6):e17.
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[8] Ebrahimifard F, Nooraei N. Postoperative pain after laparoscopic cholecystectomy: a randomized clinical trial comparing intraperitoneal bupivacaine versus intravenous pethidine. Surg Laparosc Endosc Percutan Tech 2013;23(1):88–92. [9] Arden D, Seifert E, Donnellan N, Guido R, Lee T, Mansuria S. Intraperitoneal instillation of bupivacaine for reduction of postoperative pain after laparoscopic hysterectomy: a double-blind randomized controlled trial. J Minim Invasive Gynecol 2013; 20(5):620–6. [10] Malhotra N, Chanana C, Roy KK, Kumar S, Rewari V, Sharma JB. To compare the efficacy of two doses of intraperitoneal bupivacaine for pain relief after operative laparoscopy in gynecology. Arch Gynecol Obstet 2007;276(4):323–6. [11] Rossi S. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook Pty; 2006. [12] van Furth R, Cohn ZA. The origin and kinetics of mononuclear phagocytes. J Exp Med 1968;128(3):415–35. [13] Hollman MW, Durieux ME. Local anesthetics and the inflammatory response: a new therapeutic indication? Anesthesiology 2000;93(3):858–75.
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Please cite this article as: Shokeir T, Mousa S, A randomized, placebo-controlled, double-blind study of hysteroscopic-guided pertubal diluted bupivacaine infusion..., Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.043
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Contents lists available at ScienceDirect
International Journal of Gynecology and Obstetrics journal homepage: www.elsevier.com/locate/ijgo
CLINICAL ARTICLE
5Q2
Tarek Shokeir a,⁎, Sherif Mousa b
6 7
a
8
a r t i c l e
9 10 11 12
Article history: Received 10 December 2014 Received in revised form 18 March 2015 Accepted 22 May 2015
13 14 15 16 17
Keywords: Bupivacaine Endometriosis Hysteroscopy Pelvic pain
i n f o
R O
Department of Obstetrics and Gynecology, Mansoura University Hospital, Mansoura Faculty of Medicine, Mansoura, Egypt Department of Anaesthesia and Intensive Care, Mansoura University Hospital, Mansoura Faculty of Medicine, Mansoura, Egypt
a b s t r a c t
18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 © 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics. 34
Objective: To assess the effectiveness of hysteroscopic-guided pertubal diluted bupivacaine infusion for endometriosis-associated chronic pelvic pain (CPP). Methods: Between June 2010 and July 2013, a randomized, placebo-controlled, double-blind study was undertaken at Mansoura University Hospital, Mansoura, Egypt. Patients meeting inclusion criteria (laparoscopically confirmed endometriosis, patent fallopian tubes, ≥6 months CPP, pain score on visual analogue scale [VAS] N 5) were randomly assigned using a computer-generated randomization sequence to receive either office hysteroscopic-guided pertubal diluted bupivacaine infusion (0.25%) or placebo. Response to treatment was assessed using subjective data for scores on VAS and a monthly verbal rating scale (VRSmonthly) at baseline and at 1, 2, and 3 months of follow-up. Additionally, women completed a questionnaire to evaluate the overall satisfaction at 3 months. Results: Thirty patients were assigned to each group. In the bupivacaine group, VAS and VRSmonthly scores were significantly lower at 1, 2, and 3 months than at baseline (P b 0.05 for all). Additionally, scores were significantly lower in the bupivacaine group than in the placebo group at 1, 2, and 3 months (P b 0.05 for all). At 3 months, 22 (73%) women in the bupivacaine group expressed satisfaction, compared with 2 (7%) in the placebo group (P = 0.18). Conclusion: Office pertubal hysteroscopicguided diluted bupivacaine infusion could be used to manage endometriosis-associated CPP for at least 3 months. AEARCTR-0000573
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A randomized, placebo-controlled, double-blind study of hysteroscopic-guided pertubal diluted bupivacaine infusion for endometriosis-associated chronic pelvic pain
2Q1
F
1
R
38
1. Introduction
40
The successful treatment of endometriosis-associated chronic pelvic pain (CPP) typically requires surgical and medical interventions. Some pharmacologic treatments inhibit the growth and activity of endometrial implants, such as combination oral contraceptives, danazol (an androgenic agent), gonadotropin-releasing hormone analogues, progestins, aromatase inhibitors, selective estrogen receptor modulators, and selective progesterone receptor modulators [1–4]. Locally long-acting pharmacologic agents that can specifically target the endometrial implants rather than systemically reducing estrogen levels have not yet been assessed fully in clinical practice. However, pertubation with lignocaine has been shown to be an effective non-hormonal treatment option for women with dysmenorrhea and pelvic endometriosis [5–7]. In an open-label preliminary observational pilot study at Mansoura University Hospital, Mansoura, Egypt, office hysteroscopic-guided
43 44 45 46 47 48 49 50 51 52 53
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41 42
N C O
39
⁎ Corresponding author at: Department of Obstetrics and Gynecology, Mansoura University Hospital, Mansoura Faculty of Medicine, Mansoura 11271, Egypt. Tel.: +20 50 2331118; fax: +20 50 2319922. E-mail address: [email protected] (T. Shokeir).
pertubal bupivacaine infusion (0.25%) was shown to reduce CPP intensity in women with stage I–IV pelvic endometriosis (unpublished data). Bupivacaine is more cardiotoxic than are other local anesthetics [4]. Most of its adverse effects are caused by accelerated absorption from the injection site, unintentional intravascular injection, or slow metabolic degradation. However, several clinical trials have confirmed the safety of this local anesthetic drug [8–10]. Notably, the effectiveness of pertubal diluted bupivacaine infusion (0.25%) has not been tested against placebo. The aim of the present study was to assess the short-term effectiveness of the office hysteroscopic-guided pertubal diluted bupivacaine infusion (0.25%) for endometriosis-associated CPP in a randomized, placebo-controlled trial.
54
2. Materials and methods
67
Between June 1, 2010, and July 30, 2013, a randomized, placebocontrolled, double-blind study was conducted at Mansoura University Hospital. Women were eligible when they had experienced CPP for at least 6 months, had a pain score on the visual analogue scale (VAS) of more than 5 (0–10 scale), had laparoscopically confirmed stage I–IV
68 69
http://dx.doi.org/10.1016/j.ijgo.2015.03.043 0020-7292/© 2015 Published by Elsevier Ireland Ltd. on behalf of International Federation of Gynecology and Obstetrics.
Please cite this article as: Shokeir T, Mousa S, A randomized, placebo-controlled, double-blind study of hysteroscopic-guided pertubal diluted bupivacaine infusion..., Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.043
55 56 57 58 59 60 61 62 63 64 65 66
70 71 72
2
T. Shokeir, S. Mousa / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Assessed for eligibility (n=76) Excluded (n=14) Did not meet inclusion criteria (n=10) Declined to participate (n=4)
Randomization (n=62)
Assigned to receive placebo (n=30)
Assigned to receive bupivacaine (n=32)
Analyzed (n=30) Fig. 1. Study profile.
89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117
118 119
3. Results
136
A total of 76 patients were enrolled. Data from 60 were included in analyses (Fig. 1). After identification, the baseline clinical characteristics for both groups were comparable in terms of age, parity, body mass index, and laparoscopic endometriosis staging (Table 1). In the bupivacaine group, VAS and VRSmonthly scores were significantly lower at 1, 2, and 3 months than at baseline (Table 2). Additionally, the scores on both scales were significantly lower in the bupivacaine group than in the placebo group at 1, 2, and 3 months
137
Table 1 Baseline characteristics.a
t1:1 t1:2
E
D
P
ruler in the diary. Mean VAS scores for the month were calculated for each patient. At monthly follow-up appointments, participants were asked to provide a monthly pain score on a verbal rating scale (VRSmonthly), on which a score of 0 indicated no pain and 100 indicated the maximum pain. After 3 months, participants were asked to complete a multiplechoice questionnaire that assessed overall patient satisfaction independent of age, duration or severity of the symptoms. Sample size was calculated using Epi Info version 6.0 (Centers for Disease Control and Prevention, Atlanta, GA, USA), setting the type I error (α) at 0.05 and the power (1–β) at 0.8. Using data from previous studies [5–7] and a 95% confidence interval, a minimum sample size of 60 patients was established. Epi Info version 6.0 was used to record and analyze the data. Only women who completed 3 months of follow-up were included in analyses. The paired t test, Mann–Whitney U test, and Wilcoxon and Friedman two-way ANOVA tests were used as appropriate. P b 0.05 was deemed significant.
T
C
87 88
E
85 86
R
83 84
R
81 82
O
79 80
C
77 78
N
75 76
pelvic endometriosis, and had patent fallopian tubes. Exclusion criteria were age younger than 18 years, any hormonal therapy in the previous 3 months, a desire to conceive within 1 year, occluded fallopian tubes with or without pelvic adhesions, non-gynecologic causes of CPP (intestinal, urinary, or musculoskeletal), and known hypersensitivity or contraindications to bupivacaine or any amide local anesthetic agent. The institutional ethics committee approved the study. All participants provided written informed consent. Patients were asked to stop any analgesic medications before enrollment into the study. Potential participants underwent a complete pelvic examination and high-resolution transvaginal ultrasonography. Basic work-up investigations were done whenever indicated to exclude concomitant non-gynecologic causes of CPP, including mid-stream urine analysis, stool analysis, intravenous urography, and full blood count. At the time of office recruitment, participants were randomly assigned to receive bupivacaine or placebo in a 1:1 ratio according to a computer-generated randomization sequence using numbered, sealed envelopes. All patients and investigators were masked to group allocation, including during data analysis. Procedures were undertaken as a day-case in an endoscopic suite. One treatment was to be given before ovulation on day 7–12 of their cycle. Under paracervical block and using Ringer solution as a uterine distending medium (Hysteromat, Karl Storz, Tuttlingen, Germany), an office hysteroscope (2.7 mm; Karl Storz, Tuttlingen, Germany) was passed and one tubal orifice was identified. Under hysteroscopic guidance, a 3-Fr ureteric catheter was introduced, cannulated through the tubal ostium, and passed proximally for 2–3 cm. After successful cannulation, participants assigned to the bupivacaine group received 10 mL diluted bupivacaine (0.25%; Marcaine, AstraZenica, Istanbul, Turkey) plus 100 mL Ringer solution, which was infused through the catheter over 15–20 minutes. Participants assigned to the placebo group received a 10-mL placebo infusion (sterile water) plus 100 mL Ringer solution. The allocated study solution was provided to the surgeon intraoperatively by senior nursing staff. Solutions were indistinguishable and were preloaded into identical unlabeled Ringer solution bottles. None of the patients used any adjunctive measures or analgesics following the original treatment. Follow-up visits were arranged after 1, 2, and 3 months. Patients were advised to stop any analgesic medications and to use barrier contraception for these 3 months. All patients completed a daily diary about pain during the month preceding the procedure and follow-up visits. These diaries were collected at each visit; new ones for the next month were provided. As part of the diary, participants were asked to provide a subjective assessment of the severity of pelvic pain on a VAS, on which 0 indicated no pain and 10 indicated severe pain. It was recorded daily on a 10-cm
U
73 74
R O
Analyzed (n=30)
O
F
Lost to follow-up (n=2)
120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135
138 139 140 141 142 143 144
Measure
Bupivacaine group (n = 30)
Placebo group (n = 30)
P valueb
t1:3
Age, y Parity Body mass indexc Laparoscopic staging Stage I Stage II Stage III Stage IV
32.8 ± 5.0 2.7 ± 1.2 27.2 ± 2.1
33.0 ± 2.6 3.0 ± 1.1 29 ± 1.0
0.63 0.39 0.65 0.90
14 (47) 10 (33) 4 (13) 2 (7)
16 (53) 8 (27) 4 (13) 2 (7)
t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10 t1:11
a
Values are given as mean ± SD or number (percentage), unless indicated otherwise. Continuous data analyzed using t test when normally distributed and Wilcoxon ranksum test when not normally distributed. Categorical data analyzed using Fisher exact test. c Calculated as weight in kilograms divided by the square of the height in meters. b
Please cite this article as: Shokeir T, Mousa S, A randomized, placebo-controlled, double-blind study of hysteroscopic-guided pertubal diluted bupivacaine infusion..., Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.043
t1:12 t1:13 t1:14 t1:15
T. Shokeir, S. Mousa / International Journal of Gynecology and Obstetrics xxx (2015) xxx–xxx
Outcome measures
Bupivacaine group (n = 30)
t2:4 t2:5 t2:6
Visual analogue scale (1–10) Verbal rating scale (1–100)
t2:7 t2:8 t2:9 t2:10 t2:11 t2:12 t2:13
a
150 151
f g
Baseline
1 month
2 months
3 months
7.7 (7.9–8.2) 90.2 (90.5–91.9)
6.1 (5.5–6.3)b 35.4 (29.3–41.6)b
5.6 (5.8–6.0)c 34.2 (28.6–39.8)c
5.4 (4.9–5.0)d 38.6 (32.4–44.8)d
7.9 (8.2–6.8) 91.8 (91.3–92.3)
7.4 (7.5–6.7)e 91.2 (90.5–91.9)e
7.5 (7.9–6.8)f 89.9 (92.1–93.1)f
7.7 (7.5–6.6)g 90.2 (92.0–88.9)g
Values are given as mean (95% confidence interval). Comparison with baseline using the Wilcoxon rank sum test: P b 0.05. Comparison with baseline using the Wilcoxon rank sum test: P b 0.01. Comparison with baseline using the Wilcoxon rank sum test: P b 0.001. Comparison with bupivacaine group using the Wilcoxon rank sum test: P b 0.05. Comparison with bupivacaine group using the Wilcoxon rank sum test: P b 0.01. Comparison with bupivacaine group using the Wilcoxon rank sum test: P b 0.001.
(Table 2). In the placebo group, changes during follow-up were unremarkable. On the multiple-choice questionnaire, more women in the bupivacaine group than in the placebo group expressed satisfaction, although the difference was not significant (P = 0.18) (Table 3). The procedures were well tolerated by all patients without any adverse effects. No technical hysteroscopic cannulation failures were reported.
4. Discussion
153 154
181 182
The present study has shown that a 0.25% diluted bupivacaine pertubal infusion can relieve endometriosis-related CPP, with significant reductions in scores on the VAS and VRSmonthly between baseline and 3-month follow-up. The findings indicate that the drug had a greater benefit than did placebo. The explanation for this observation could be related to our small sample size. The present results are in line with those reported by other authors who investigated the action of pertubal lignocaine (5%) infusion in patients with endometriosis-related CPP [5–7]. In one placebo-controlled randomized trial [5], 41.7% of patients who received lignocaine achieved a reduction of 50% of more in the score on the VAS scale, compared with 16.7% of those who received placebo, and 44% of patients had a persistent therapeutic effect after 9 months. Lignocaine and bupivacaine are in the same pharmacologic group (amino amide group) and have an almost identical mechanism of action [11]. Therefore, office perturbation with diluted bupivacaine (0.25%) seems to be a promising alternative, minimally invasive, non-hormonal, short-term treatment. The exact mode of action of pertubal bupivacaine infusion is not clear. The perturbation treatment with bupivacaine might affect the pathologic endometrial foci during the instillation procedure. Additionally, bupivacaine could affect inflammatory cells (e.g. macrophages) and their activation status [12–14]. Several mechanisms by which the drug might have local anesthetic action on inflammatory cells have been suggested, but only a few targets have been specified [13]. Macrophages have contradictory actions: they can switch from pro-inflammatory to anti-inflammatory states, and can contribute to both the induction and the resolution of inflammation [15,16]. In chronic inflammatory diseases, inhibition of the apoptotic program could promote monocyte survival, which could account for the accumulation of macrophages and the persistence of an inflammatory milieu [17]. Neurologically, it
t3:1 t3:2
Table 3 Overall satisfaction at 3 months.
167 168 169 170 171 172 173 174 175 176 177 178 179 180
C
E
165 166
R
163 164
R
161 162
N C O
159 160
U
157 158
T
152
155 156
F
e
3 months
t3:3 t3:4
Degree of satisfaction
Bupivacaine group (n = 30)a
Placebo group (n = 30)a
P value b
t3:5 t3:6 t3:7
Satisfied Uncertain Dissatisfied
22 (73) 4 (13) 4 (13)
2 (7) 2 (7) 26 (87)
0.18 0.32 0.36
t3:8 t3:9
a b
Values are given as number (percentage). χ2 test.
has been suggested that bupivacaine exerts effects on sensory nerves in the peritoneum, peritoneal lesions, and eutopic endometrium [18]. In the present study, 10 mL diluted bupivacaine (0.25%) was introduced into the fallopian tubes. Similarly, Wickström et al. [5] passed a study solution of lignocaine (5%) through the uterine cavity and the fallopian tubes via an intracervical balloon catheter. Such procedures ensure that most of the solution used will pass directly into the pelvic cavity and directly target the endometriotic implants. Dose-ranging studies using this kind of therapy are needed. The present findings that 73% of patients who received bupivacaine were satisfied with their treatment confirm the efficacy and tolerability of the office perturbation treatment with diluted bupivacaine. Patients can be treated with repeated outpatient infusions on a symptomatic basis, which could mean that they would not need hormonal therapy, opioid analgesia, or surgical interventions such as hysterectomy with bilateral salpingo-oophorectomy [2–4,19]. However, an experienced hysteroscopist is needed to perform the procedure. The present study is limited by the small sample size. However, in view of the findings of previous studies, it is likely that similar results would be achieved in larger trials. The sample size needed to achieve a power of 0.85 would probably be large, and it would be impracticable to recruit such a large number of patients with endometriosisassociated CPP. Nevertheless, further multicenter randomized controlled trials are needed. In conclusion, the present results provide evidence to support the feasibility and the beneficial effect of office pertubal hysteroscopicguided bupivacaine (0.25%) infusion therapy for women with endometriosis-associated CPP. It offers a safe, minimally invasive, and cost-effective alternative to current treatments. The procedure can be repeated and is well tolerated by patients.
183
Conflict of interest
213
O
148 149
d
2 months
R O
146 147
c
1 month
P
145
b
Placebo group (n = 30)
Baseline
D
t2:3
Table 2 Outcomes.a
E
t2:1 t2:2
3
The authors have no conflicts of interest.
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Please cite this article as: Shokeir T, Mousa S, A randomized, placebo-controlled, double-blind study of hysteroscopic-guided pertubal diluted bupivacaine infusion..., Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.043
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Please cite this article as: Shokeir T, Mousa S, A randomized, placebo-controlled, double-blind study of hysteroscopic-guided pertubal diluted bupivacaine infusion..., Int J Gynecol Obstet (2015), http://dx.doi.org/10.1016/j.ijgo.2015.03.043
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