ORIGINAL ARTICLE: CONTRACEPTION
Novel topical formulation of lidocaine provides significant pain relief for intrauterine device insertion: pharmacokinetic evaluation and randomized placebo-controlled trial Sara Tornblom-Paulander, M.D.,a Berith K. Ting aker, M.D., Ph.D.,a Agneta Werner, M.D.,b Caroline Liliecreutz, M.D., Ph.D.,c Peter Conner, M.D., Ph.D.,a Hans Wessel, M.D., Ph.D.,a and Gunvor Ekman-Ordeberg, M.D., Ph.D.a a
Division of Obstetrics and Gynecology, Department of Woman and Child Health, Karolinska Institute, Stockholm; € ping; and c Department of Clinical and Experimental Medicine, Department of Obstetrics and Gynecology, Norrko € ping University, Linko € ping, Sweden Obstetrics and Gynecology, Linko b
Objective: To investigate the pharmacokinetics, safety, and analgesic efficacy of a novel topical formulation of lidocaine at insertion of an intrauterine device (IUD). Design: Randomized controlled trial; phase-I and phase-II studies. Setting: University and public hospitals. Patient(s): Women aged R18 years who wanted to receive an IUD. Four women were parous in phase I; all in phase II were nulliparous. Intervention(s): A single, 8.5-mL dose of lidocaine formulation (SHACT) was administered (to the portio, cervix, and uterus) with a specially designed applicator. Main Outcome Measure(s): The phase-I study (single-arm) was designed for pharmacokinetic assessment; the phase-II study (randomized) was intended for investigation of efficacy and safety. Result(s): From the phase-I study (15 participants), mean pharmacokinetic values were: maximum plasma concentration: 351 205 ng/mL; time taken to reach maximum concentration: 68 41 minutes; and area under the concentration–time curve from 0 to 180 minutes: 717 421 ng*h/mL. Pain relief was observed with lidocaine vs. placebo in the phase-II study (218 women, randomized). Mean visual analog scale score for maximum pain during the first 10 minutes after IUD insertion was 36% lower with lidocaine than with placebo (28.3 24.6 vs. 44.2 26.0). Pain intensity was also significantly lower in the lidocaine group at 30 minutes. On average, 3 of 4 patients will have less pain with lidocaine than with placebo. Adverse events were similar in the placebo and lidocaine groups. No serious adverse events were reported. Conclusion(s): Lidocaine provides pain relief lasting for 30–60 minutes for women undergoing IUD insertion, without any safety concerns. Further studies of this lidocaine formulation, for IUD insertion and other clinical applications, are planned. Use your smartphone Clinical Trial Registration Number: 2011-005660-18 and 2011-006220-20 (EudraCT). (Fertil to scan this QR code SterilÒ 2015;103:422–7. Ó2015 by American Society for Reproductive Medicine.) and connect to the Key Words: Intrauterine device, lidocaine, pain, pharmacokinetics, topical anesthetic Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/tornblompaulanders-lidocaine-pain-intrauterine-device-insertion/
Received August 4, 2014; revised and accepted October 14, 2014; published online November 20, 2014. S.T.-P. has nothing to disclose. B.K.T. owns 12,020 shares in Pharmanest AB. A.W. has nothing to disclose. C.L. has nothing to disclose. P.C. has nothing to disclose. H.W. has nothing to disclose. G.E.-O. owns 13,322 shares in Pharmanest AB. Supported by Pharmanest AB (Solna, Sweden). Reprint requests: Gunvor Ekman-Ordeberg, M.D., Ph.D., Division of Obstetrics and Gynecology, Department of Woman and Child Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden (E-mail: [email protected]). Fertility and Sterility® Vol. 103, No. 2, February 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.10.026 422
discussion forum for this article now.*
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I
ntrauterine devices (IUDs) provide reliable, long-term contraception from a single insertion procedure (1, 2). However, the insertion of an IUD can be associated with significant levels of pain, which for many women is a major obstacle to IUD use (3). This VOL. 103 NO. 2 / FEBRUARY 2015
Fertility and Sterility® method of contraception is considered to be underutilized, with only 7.6% of women of reproductive age in developed countries adopting the IUD, and 14.5% in developing countries (4). The role of the capsaicin and heat receptor transient receptor potential vanilloid (TRPV1) has been explored in the human cervix and the uterus. This work identified peripheral sensory innervations in both the cervix and uterus in nonpregnant women (5), strengthening the rationale for using topical anesthetic for IUD insertion. Few studies have provided robust evidence that topical anesthetics provide pain relief for women undergoing IUD insertion (6). Two Cochrane reviews showed a lack of clinically relevant pain relief with the available pharmacologic therapies, although topical lidocaine was identified as warranting further investigation (7, 8). More recent reviews of intrauterine anesthesia, published in 2012 and 2013, also found insufficient evidence for its use in IUD insertion (3, 9). One randomized study was identified, with a significantly lower pain score among women treated with 2% lidocaine (Instillagel) vs. either placebo or no treatment (10). However, the results need further substantiation, because the investigators were not blinded, and the authors considered the study to be only preliminary. In 2012, a randomized trial of 1% lidocaine paracervical block for IUD insertion showed only a trend toward a reduced visual analog scale (VAS) pain score with the lidocaine, compared with no anesthetic (11). A novel topical formulation of lidocaine (short-acting 4% viscous solution; SHACT) has been developed (Pharmanest AB) for gynecologic application. The viscosity of this formulation increases with increasing temperature, so that leakage after gynecologic administration is minimized, and delivery of lidocaine to the intended tissues is prolonged. We performed phase I and phase II studies to investigate the pharmacokinetics, efficacy, and safety of this formulation of lidocaine as an anesthetic for IUD insertion.
MATERIALS AND METHODS Phase I: Single-Arm Pharmacokinetic Study This single-center study was performed at the Karolinska University Hospital, Stockholm, Sweden in accordance with the Declaration of Helsinki and Good Clinical Practice. The study was reviewed and approved by the Stockholm Regional Ethical Review. Women aged R18 years who wanted to receive an IUD were eligible to participate, with no restrictions based on previous childbirth. Exclusion criteria included cervical infection, current pregnancy, pelvic inflammation disease within the last month, intolerance to acetaminophen, cervical or uterine cancer, and intake of analgesics within the 24 hours preceding IUD insertion. No restriction was put on the type of IUD. All participants provided signed informed consent after receiving verbal and written information about the study. The lidocaine was administered 5 minutes before IUD insertion, as a single, 8.5-mL dose. A speculum, and an applicator with a diameter of 3.7 mm, were used for application: 1 mL was put onto the surface of the portio; 2 mL were put into the cervical canal; and 5.5 mL were put into the uterine cavity. After VOL. 103 NO. 2 / FEBRUARY 2015
administration, but before IUD insertion, the degree of discomfort was ascertained by asking: ‘‘Did you experience any discomfort associated with administration of the study drug?’’ Participants were asked to choose their answer from the following options: ‘‘no,’’ ‘‘a little,’’ ‘‘some,’’ ‘‘high level,’’ and ‘‘very high level.’’ The insertion of IUDs was performed according to the recommendations of their manufacturers. Blood samples (4 mL) were taken at baseline, and at 5, 10, 20, 30, 45, 60, 120, and 180 minutes after administration. In each sample, the plasma level of lidocaine was determined, to calculate the following pharmacokinetic parameters: maximum plasma concentration (Cmax), time taken to reach maximum concentration (tmax), and area under the concentration–time curve from 0 to 180 minutes (AUC0–180). Lidocaine concentration was determined using a validated liquid chromatography-mass spectrometry/mass spectometry (LCMS/MS) method, with a quantitation limit of 1.0 ng/ml, accuracy of 90% of nominal value, and repeatability coefficient of variation of 12%, both at 1 ng/ml. Plasma pharmacokinetics calculations for lidocaine were performed by standard noncompartmental analysis using WinNonlin software (version 3.1, Certara). Pain was assessed on a 100-mm VAS at 10 minutes (maximum pain experienced within 10 minutes of IUD insertion), 1 hour, 2 hours, 1 day, 2 days, and 3 days after IUD insertion. An additional oral analgesic (acetaminophen) was provided, and participants recorded their use of this medication over the 4-day period after IUD insertion. Adverse events were recorded by active questioning at 3 time points: just before IUD insertion, and at 15 minutes and 2 hours after lidocaine administration. Diary entries enabled further adverseevent reporting on days 2–4.
Phase-I Statistics A sample size of 15 was chosen, as this number should enable pharmacokinetic parameters to be determined with reasonable accuracy. Individuals with incomplete blood sampling were replaced, to ensure that the 15 study participants had complete blood sampling. The primary variables were Cmax, tmax, and AUC0–180. All study results are presented as mean SD or absolute values; no statistical comparisons were performed.
Phase II: Randomized, Double-Blind, PlaceboControlled Study of Pain Relief The phase II study was performed at 3 Swedish hospitals: Karolinska University Hospital, University Hospital of Linkoping, and Vrinnevi Hospital in Norrkoping. The study was reviewed and approved by the Stockholm Regional Ethical Review Board (2012/801-32). The methods and ethical standards for phase 2 were fundamentally similar to those for phase I. However, women who had previously given birth were excluded from phase II, although they were permitted in phase I. Study participants were randomized 1:1 to receive the lidocaine or a placebo gel with similar appearance and viscosity. A randomization list was generated by the study statistician, using nQuery Advisor (Statistical Solutions Ltd.). Code 423
ORIGINAL ARTICLE: CONTRACEPTION numbers from the list were assigned to participants, and based on the list, the contract manufacturing organization prepared labeled vials to be sent to the hospital pharmacies. The randomization list was concealed from all study personnel until study completion. The procedures for applying the lidocaine and inserting the UID were the same as in phase I. No restriction was placed on the type of IUD. Insertion of IUDs took place within 5 minutes of lidocaine administration. Pain was assessed at the clinic on a 100-mm VAS at 10 minutes, 30 minutes, and 1 hour after insertion. For the first of these time points, patients were asked to rate their maximum pain level during the insertion of the IUD, reporting within 10 minutes of the insertion; for the second 2 time points, they were asked to rate their pain at that time. Further assessments of pain were recorded in a diary, on day 1 (2 hours after IUD insertion) and on days 2–4. An additional oral analgesic (acetaminophen) was provided, and participants recorded their use of this medication over the 4-day period after IUD insertion. An ultrasound scan was performed before patients left the clinic, to ensure correct IUD placement. Adverse events were recorded by active questioning of participants 10 minutes and 1 hour after IUD insertion; in addition, participants were asked to report any adverse events occurring up to 10 days postinsertion. The following protocol changes were made to the study methods after commencement of the study: [1] assessment of pain on the VAS 30 minutes after IUD insertion; [2] for a woman with regular menstruation, she had to be in day 1–6 of menstruation at insertion, or pregnancy had to be reliably excluded; [3] menstrual pain, abdominal pain, or abdominal discomfort related solely to IUD insertion were not reported as adverse events; [4] previous pregnancy with >13 weeks' gestation was added as an exclusion criterion; and [5] University Hospital of Linkoping, and Vrinnevi Hospital in Norrkoping, were added as study centers.
Phase-II Statistics Based on data from a pilot study, the SD for maximum pain intensity within 10 minutes was assumed to be 40 mm. Assuming a VAS pain score difference of 20 mm between lidocaine and placebo, a sample size of 86 individuals per group was calculated to provide statistical significance at the 5% level, and 90% power. To allow for withdrawals, the overall recruitment target was 200 study participants. The primary efficacy analysis was comparison of the maximum pain reported within 10 minutes of IUD insertion, with lidocaine vs. placebo, as assessed by the VAS score. Statistical comparison was performed using analysis of variance (ANOVA), stratified by study center, and expressed as mean difference with 95% confidence interval (CI). A stratified ANOVA was performed to investigate the relationships between VAS pain and IUD type, midwife, volume of lidocaine administered, and degree of discomfort. Secondary efficacy variables were the time course of pain, need for additional oral analgesia, and degree of discomfort. Data are presented as mean SD, or as absolute values, and no missing data were imputed. 424
The full analysis set, on which the primary efficacy analysis was based, comprised all randomized participants who received the study treatment and whose 10-minute VAS evaluation was available, as a minimum for data collected. All randomized individuals who received the study product were included in the safety set.
RESULTS Phase I: Single-Arm Pharmacokinetic Study Seventeen women were enrolled in the study; one was withdrawn from all analyses (uterine anomaly before lidocaine administration), and one was withdrawn from all analyses except safety and tolerability (predose blood sample not taken before lidocaine administration). The first patient entered the study on April 28, 2012, and the last patient completed the study on June 4, 2012. For the 15 participants included in the primary analysis, the mean age was 26.4 5.8 years; mean height was 167.9 6.1 cm; and mean weight was 60.2 8.8 kg. Four women were parous remaining nulliparous, and no gynecologic abnormalities were apparent. Pharmacokinetic parameters, based on results from all 15 study participants, were as follows: Cmax: 351 205 ng/mL; tmax: 68 41 minutes; and AUC0–180: 717 421 ng*h/mL. Changes in plasma lidocaine levels over time are shown in Figure 1. In all participants, plasma lidocaine concentration remained elevated at the last time point, meaning that AUC0–180 does not provide an accurate estimation of total exposure. Overall pharmacokinetic patterns were similar in all 15 participants, but as indicated by the SD values in Figure 1, considerable individual variation in absolute plasma levels was found. The highest value for Cmax observed in this study was 725 ng/mL; the lowest value was 64.7 ng/mL. Pain scores on the VAS were low, with mean values of 350 ng/mL. The number of participants who took the additional oral analgesic was 6 (40%) on day 1; 5 (33%) on day 2; 3 (20%) on day 3; and 1 (7%) on day 4. No serious adverse events or other safety concerns were reported. Six study participants (40%) experienced discomfort
FIGURE 1
Change over time in mean plasma lidocaine level (phase-I study). Error bars represent SD. Tornblom-Paulander. Topical lidocaine for IUD insertion. Fertil Steril 2015.
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Fertility and Sterility® upon administration of the lidocaine; in 4 cases, ‘‘a little’’ discomfort was reported; in 1 case, ‘‘strong’’ discomfort; and in 1 case, ‘‘very strong’’ discomfort. This discomfort was related to the application procedure, rather than to the pharmacologic effects of the study drug. All other adverse events were considered to be unrelated to the lidocaine.
FIGURE 2
Phase II: Randomized, Double-Blind, PlaceboControlled Study of Pain Relief Of 248 women screened for the study, 30 were excluded before randomization, because they did not meet the inclusion criteria. The main reasons for exclusion were: lack of interest in a clinical study; recent unprotected sexual intercourse (meaning pregnancy could not be excluded); intake of analgesic drugs during the preceding 24 hours; ongoing treatment for genital infections; and pregnancy. Nine of the 218 women randomized to treatment were excluded from the efficacy analysis because their uteri were too small for insertion of an IUD. The first patient entered the study on June 11, 2012, and the last patient completed the study on May 30, 2013. Demographic characteristics were similar in the 2 study groups (Table 1). In the lidocaine group, 89 individuals (81%) had never been pregnant, compared with 85 (78%) in the placebo group. Two different IUDs were used during the study: Mirena (Bayer HealthCare AG), used for 70 placebo recipients and 70 lidocaine recipients; and Nova T 380 (Bayer Schering Pharma AG), used for 38 placebo recipients and 40 lidocaine recipients. The mean VAS score for maximum pain within 10 minutes of IUD insertion was significantly lower in the lidocaine group than in the placebo group (28.3 vs. 44.2; P< .0001). The mean between-group difference was 15.9, representing a 36% reduction in VAS score in the lidocaine group. These results are reflected by the distributions of 10-minute VAS scores
Distributions of VAS pain scores in the phase II-study: maximum pain experienced within 10 minutes of insertion of the IUD. Tornblom-Paulander. Topical lidocaine for IUD insertion. Fertil Steril 2015.
in the 2 groups (Fig. 2). Lidocaine recipients tended to have low VAS scores, whereas placebo recipients were spread more evenly across the whole range. A significantly higher percentage of women in the lidocaine group were considered to be essentially pain-free (VAS score %10 mm), and a significantly lower percentage had moderate to severe pain (VAS score >40 mm) (Fig. 3) (12). The stratified ANOVA showed that neither discomfort during administration of the study treatment nor IUD type influenced the effect of the lidocaine. Fifteen midwives were recruited to take part in the study to perform the IUD procedure; for 4 of them, the mean 10-minute VAS score was higher with lidocaine than with the placebo (range: 29.0 to 42.5 mm). Despite this variability, the differences among midwives did not reach statistical significance (P¼ .056). The mean 10-minute VAS score was lower with lidocaine
FIGURE 3
TABLE 1 Participant characteristics in the phase-II study. Characteristic Age (y) Height (cm) Weight (kg) Gynecologic examination Normal Abnormal Menstruation No Yes Hormone contraceptive No Yes Type of IUD Mirena (Bayer HealthCare AG) Nova T 380 (Bayer Schering Pharma AG)
Lidocaine group (n [ 110)
Placebo group (n [ 108)
23.9 4.9 167.0 6.0 64.5 10.6
23.4 4.1 167.9 5.7 64.2 12.1
110 (100) 0 (0)
108 (100) 0 (0)
43 (39) 67 (61)
32 (30) 76 (70)
77 (70) 33 (30)
82 (76) 26 (24)
70 (64)
70 (65)
40 (36)
38 (35)
Note: Data presented as mean SD or n (%).
Percentages of women in the phase-II study considered to be essentially pain-free or to have moderate to severe pain, as assessed by VAS score for maximum pain experienced within 10 minutes of IUD insertion (P99%) and cost-effective birth control without the need for daily medication or cooperation of sexual partners, although IUD insertion can be costly and does require a healthcare professional (15). Pain upon IUD insertion may be a significant barrier to women's preparedness to choose this method of contraception (16). Relief from the pain could increase the number of women who would consider having an IUD inserted, with the possible consequence of reducing unwanted pregnancies. Young women and those who have not given birth are likely to experience more pain during IUD insertion, as a result of having a relatively narrow cervix (16). These women may be considered to have a greater need for pain relief during IUD insertion than women who have previously given birth, and they are likely to benefit more from the effects of lidocaine. Future studies to investigate the efficacy of this lidocaine formulation in various populations would be helpful. The novel thermogel formulation of lidocaine seems to be successful in providing pain relief. The viscosity of the product is designed to ensure continuing delivery of lidocaine to the appropriate tissues after its application; this may not occur with other formulations. The duration of action of lidocaine in humans is dependent on the application site, with various influencing factors, including blood supply. We observed a duration of action of 30–60 minutes, which we consider to be consistent with previously reported values of 70 minutes, for subcutaneous injection (13), and 20 minutes for periodontal scaling/root treatment (17). After 60 minutes in our study, pain intensity was similar for placebo and lidocaine. Lidocaine has a rapid onset of action, reportedly around 2 minutes or less (13, 17). As with duration of action, onset of action is liable to vary among application sites. We allowed 5 minutes to elapse between administration of lidocaine and IUD insertion, and based on the results, this time period is sufficient for the drug to take effect. The range of peak plasma level of lidocaine observed in this study was 64.7–725 ng/mL. Thus, all values were far below the range of 6–10 mg/mL, which represents the VOL. 103 NO. 2 / FEBRUARY 2015
Fertility and Sterility® threshold at which lidocaine toxicities begin to occur (18). This range may therefore explain the lack of lidocaine safety concerns apparent in our study. The adverse events were consistent with those expected to occur after IUD insertion. The overall incidence of adverse events with lidocaine was the same as with placebo, and no adverse events were specifically attributable to pharmacologic effects. These data are consistent with the established safety profile of lidocaine when it is used either locally or intravenously (19, 20). Strengths of the phase-II study include the double-blind design, sufficient statistical power to demonstrate the efficacy of lidocaine vs. placebo, and the inclusion of as many as 15 midwives across 3 centers. This number of midwives should increase the likelihood of the results being representative of those for large-scale clinical practice. Owing to very high levels of interest from potential participants, recruitment could not be stopped at exactly the targeted sample size of 200 participants. This over-recruitment seems unlikely to have influenced the study results. The lack of assessment of efficacy in women who have previously given birth represents a limitation of the phase-II study. In addition, the optimal time interval between lidocaine administration and IUD insertion was not investigated. The fact that lidocaine was shown here to be effective for IUD insertion suggests that it could also be used for other gynecologic procedures, such as biopsies, hysteroscopy, and spontaneous abortion. The duration of anesthesia—at least 30 minutes—should be adequate in a variety of situations. In conclusion, we report 2 early studies suggesting that a short-acting 4% viscous lidocaine solution may be a viable anesthetic for women undergoing IUD insertion, providing highly significant pain relief without any apparent safety concerns. Additional data are needed, but the results are promising, especially given the lack of evidence supporting the use of previously available anesthetics in this setting. In addition, this lidocaine formulation may have potential for other clinical uses. Acknowledgments: The authors thank the following midwives for participating in the study: Eneli Salomonsson, Monica Johansson, Pia Jacobsson, Tuula Ekl€ of, Carina Carlsson, Mari Denckert, Eva Almgren-Lidman, Martina Franck, Tuula Forsberg, Carlotta Bernerstedt, Lina Isaksson, Charlotta Thyden, Karin Zernisson Lagerbrant, Anna-Maria Pettersson, Pia Cederholm. We are similarly grateful to the following doctors for their participation: Esfandiar Nikodell, M.D., Henrik Rabaeus, M.D., Katarina Ernstson, M.D., Niels Fuglede, M.D., Linda J€ager, M.D., Kiriaki Papaikonomou, M.D., Caroline Liliecreutz, M.D., Brynhildsen Jan, M.D., Ph.D. For development of the manuscript, medical writing support was provided by Ken Sutor (Ascendancy Medical Writing Ltd, Cheshire, United Kingdom). Bernhard Huitfeldt, Ph.D. (BH Statistical Consulting, Nykvarn, Sweden) was responsible
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for all statistical aspects of the study, including design, analysis, and reporting of the study results.
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Novel topical formulation of lidocaine provides significant pain relief for intrauterine device insertion: pharmacokinetic evaluation and randomized placebo-controlled trial Sara Tornblom-Paulander, M.D.,a Berith K. Ting aker, M.D., Ph.D.,a Agneta Werner, M.D.,b Caroline Liliecreutz, M.D., Ph.D.,c Peter Conner, M.D., Ph.D.,a Hans Wessel, M.D., Ph.D.,a and Gunvor Ekman-Ordeberg, M.D., Ph.D.a a
Division of Obstetrics and Gynecology, Department of Woman and Child Health, Karolinska Institute, Stockholm; € ping; and c Department of Clinical and Experimental Medicine, Department of Obstetrics and Gynecology, Norrko € ping University, Linko € ping, Sweden Obstetrics and Gynecology, Linko b
Objective: To investigate the pharmacokinetics, safety, and analgesic efficacy of a novel topical formulation of lidocaine at insertion of an intrauterine device (IUD). Design: Randomized controlled trial; phase-I and phase-II studies. Setting: University and public hospitals. Patient(s): Women aged R18 years who wanted to receive an IUD. Four women were parous in phase I; all in phase II were nulliparous. Intervention(s): A single, 8.5-mL dose of lidocaine formulation (SHACT) was administered (to the portio, cervix, and uterus) with a specially designed applicator. Main Outcome Measure(s): The phase-I study (single-arm) was designed for pharmacokinetic assessment; the phase-II study (randomized) was intended for investigation of efficacy and safety. Result(s): From the phase-I study (15 participants), mean pharmacokinetic values were: maximum plasma concentration: 351 205 ng/mL; time taken to reach maximum concentration: 68 41 minutes; and area under the concentration–time curve from 0 to 180 minutes: 717 421 ng*h/mL. Pain relief was observed with lidocaine vs. placebo in the phase-II study (218 women, randomized). Mean visual analog scale score for maximum pain during the first 10 minutes after IUD insertion was 36% lower with lidocaine than with placebo (28.3 24.6 vs. 44.2 26.0). Pain intensity was also significantly lower in the lidocaine group at 30 minutes. On average, 3 of 4 patients will have less pain with lidocaine than with placebo. Adverse events were similar in the placebo and lidocaine groups. No serious adverse events were reported. Conclusion(s): Lidocaine provides pain relief lasting for 30–60 minutes for women undergoing IUD insertion, without any safety concerns. Further studies of this lidocaine formulation, for IUD insertion and other clinical applications, are planned. Use your smartphone Clinical Trial Registration Number: 2011-005660-18 and 2011-006220-20 (EudraCT). (Fertil to scan this QR code SterilÒ 2015;103:422–7. Ó2015 by American Society for Reproductive Medicine.) and connect to the Key Words: Intrauterine device, lidocaine, pain, pharmacokinetics, topical anesthetic Discuss: You can discuss this article with its authors and with other ASRM members at http:// fertstertforum.com/tornblompaulanders-lidocaine-pain-intrauterine-device-insertion/
Received August 4, 2014; revised and accepted October 14, 2014; published online November 20, 2014. S.T.-P. has nothing to disclose. B.K.T. owns 12,020 shares in Pharmanest AB. A.W. has nothing to disclose. C.L. has nothing to disclose. P.C. has nothing to disclose. H.W. has nothing to disclose. G.E.-O. owns 13,322 shares in Pharmanest AB. Supported by Pharmanest AB (Solna, Sweden). Reprint requests: Gunvor Ekman-Ordeberg, M.D., Ph.D., Division of Obstetrics and Gynecology, Department of Woman and Child Health, Karolinska Institutet, SE-171 76 Stockholm, Sweden (E-mail: [email protected]). Fertility and Sterility® Vol. 103, No. 2, February 2015 0015-0282/$36.00 Copyright ©2015 American Society for Reproductive Medicine, Published by Elsevier Inc. http://dx.doi.org/10.1016/j.fertnstert.2014.10.026 422
discussion forum for this article now.*
* Download a free QR code scanner by searching for “QR scanner” in your smartphone’s app store or app marketplace.
I
ntrauterine devices (IUDs) provide reliable, long-term contraception from a single insertion procedure (1, 2). However, the insertion of an IUD can be associated with significant levels of pain, which for many women is a major obstacle to IUD use (3). This VOL. 103 NO. 2 / FEBRUARY 2015
Fertility and Sterility® method of contraception is considered to be underutilized, with only 7.6% of women of reproductive age in developed countries adopting the IUD, and 14.5% in developing countries (4). The role of the capsaicin and heat receptor transient receptor potential vanilloid (TRPV1) has been explored in the human cervix and the uterus. This work identified peripheral sensory innervations in both the cervix and uterus in nonpregnant women (5), strengthening the rationale for using topical anesthetic for IUD insertion. Few studies have provided robust evidence that topical anesthetics provide pain relief for women undergoing IUD insertion (6). Two Cochrane reviews showed a lack of clinically relevant pain relief with the available pharmacologic therapies, although topical lidocaine was identified as warranting further investigation (7, 8). More recent reviews of intrauterine anesthesia, published in 2012 and 2013, also found insufficient evidence for its use in IUD insertion (3, 9). One randomized study was identified, with a significantly lower pain score among women treated with 2% lidocaine (Instillagel) vs. either placebo or no treatment (10). However, the results need further substantiation, because the investigators were not blinded, and the authors considered the study to be only preliminary. In 2012, a randomized trial of 1% lidocaine paracervical block for IUD insertion showed only a trend toward a reduced visual analog scale (VAS) pain score with the lidocaine, compared with no anesthetic (11). A novel topical formulation of lidocaine (short-acting 4% viscous solution; SHACT) has been developed (Pharmanest AB) for gynecologic application. The viscosity of this formulation increases with increasing temperature, so that leakage after gynecologic administration is minimized, and delivery of lidocaine to the intended tissues is prolonged. We performed phase I and phase II studies to investigate the pharmacokinetics, efficacy, and safety of this formulation of lidocaine as an anesthetic for IUD insertion.
MATERIALS AND METHODS Phase I: Single-Arm Pharmacokinetic Study This single-center study was performed at the Karolinska University Hospital, Stockholm, Sweden in accordance with the Declaration of Helsinki and Good Clinical Practice. The study was reviewed and approved by the Stockholm Regional Ethical Review. Women aged R18 years who wanted to receive an IUD were eligible to participate, with no restrictions based on previous childbirth. Exclusion criteria included cervical infection, current pregnancy, pelvic inflammation disease within the last month, intolerance to acetaminophen, cervical or uterine cancer, and intake of analgesics within the 24 hours preceding IUD insertion. No restriction was put on the type of IUD. All participants provided signed informed consent after receiving verbal and written information about the study. The lidocaine was administered 5 minutes before IUD insertion, as a single, 8.5-mL dose. A speculum, and an applicator with a diameter of 3.7 mm, were used for application: 1 mL was put onto the surface of the portio; 2 mL were put into the cervical canal; and 5.5 mL were put into the uterine cavity. After VOL. 103 NO. 2 / FEBRUARY 2015
administration, but before IUD insertion, the degree of discomfort was ascertained by asking: ‘‘Did you experience any discomfort associated with administration of the study drug?’’ Participants were asked to choose their answer from the following options: ‘‘no,’’ ‘‘a little,’’ ‘‘some,’’ ‘‘high level,’’ and ‘‘very high level.’’ The insertion of IUDs was performed according to the recommendations of their manufacturers. Blood samples (4 mL) were taken at baseline, and at 5, 10, 20, 30, 45, 60, 120, and 180 minutes after administration. In each sample, the plasma level of lidocaine was determined, to calculate the following pharmacokinetic parameters: maximum plasma concentration (Cmax), time taken to reach maximum concentration (tmax), and area under the concentration–time curve from 0 to 180 minutes (AUC0–180). Lidocaine concentration was determined using a validated liquid chromatography-mass spectrometry/mass spectometry (LCMS/MS) method, with a quantitation limit of 1.0 ng/ml, accuracy of 90% of nominal value, and repeatability coefficient of variation of 12%, both at 1 ng/ml. Plasma pharmacokinetics calculations for lidocaine were performed by standard noncompartmental analysis using WinNonlin software (version 3.1, Certara). Pain was assessed on a 100-mm VAS at 10 minutes (maximum pain experienced within 10 minutes of IUD insertion), 1 hour, 2 hours, 1 day, 2 days, and 3 days after IUD insertion. An additional oral analgesic (acetaminophen) was provided, and participants recorded their use of this medication over the 4-day period after IUD insertion. Adverse events were recorded by active questioning at 3 time points: just before IUD insertion, and at 15 minutes and 2 hours after lidocaine administration. Diary entries enabled further adverseevent reporting on days 2–4.
Phase-I Statistics A sample size of 15 was chosen, as this number should enable pharmacokinetic parameters to be determined with reasonable accuracy. Individuals with incomplete blood sampling were replaced, to ensure that the 15 study participants had complete blood sampling. The primary variables were Cmax, tmax, and AUC0–180. All study results are presented as mean SD or absolute values; no statistical comparisons were performed.
Phase II: Randomized, Double-Blind, PlaceboControlled Study of Pain Relief The phase II study was performed at 3 Swedish hospitals: Karolinska University Hospital, University Hospital of Linkoping, and Vrinnevi Hospital in Norrkoping. The study was reviewed and approved by the Stockholm Regional Ethical Review Board (2012/801-32). The methods and ethical standards for phase 2 were fundamentally similar to those for phase I. However, women who had previously given birth were excluded from phase II, although they were permitted in phase I. Study participants were randomized 1:1 to receive the lidocaine or a placebo gel with similar appearance and viscosity. A randomization list was generated by the study statistician, using nQuery Advisor (Statistical Solutions Ltd.). Code 423
ORIGINAL ARTICLE: CONTRACEPTION numbers from the list were assigned to participants, and based on the list, the contract manufacturing organization prepared labeled vials to be sent to the hospital pharmacies. The randomization list was concealed from all study personnel until study completion. The procedures for applying the lidocaine and inserting the UID were the same as in phase I. No restriction was placed on the type of IUD. Insertion of IUDs took place within 5 minutes of lidocaine administration. Pain was assessed at the clinic on a 100-mm VAS at 10 minutes, 30 minutes, and 1 hour after insertion. For the first of these time points, patients were asked to rate their maximum pain level during the insertion of the IUD, reporting within 10 minutes of the insertion; for the second 2 time points, they were asked to rate their pain at that time. Further assessments of pain were recorded in a diary, on day 1 (2 hours after IUD insertion) and on days 2–4. An additional oral analgesic (acetaminophen) was provided, and participants recorded their use of this medication over the 4-day period after IUD insertion. An ultrasound scan was performed before patients left the clinic, to ensure correct IUD placement. Adverse events were recorded by active questioning of participants 10 minutes and 1 hour after IUD insertion; in addition, participants were asked to report any adverse events occurring up to 10 days postinsertion. The following protocol changes were made to the study methods after commencement of the study: [1] assessment of pain on the VAS 30 minutes after IUD insertion; [2] for a woman with regular menstruation, she had to be in day 1–6 of menstruation at insertion, or pregnancy had to be reliably excluded; [3] menstrual pain, abdominal pain, or abdominal discomfort related solely to IUD insertion were not reported as adverse events; [4] previous pregnancy with >13 weeks' gestation was added as an exclusion criterion; and [5] University Hospital of Linkoping, and Vrinnevi Hospital in Norrkoping, were added as study centers.
Phase-II Statistics Based on data from a pilot study, the SD for maximum pain intensity within 10 minutes was assumed to be 40 mm. Assuming a VAS pain score difference of 20 mm between lidocaine and placebo, a sample size of 86 individuals per group was calculated to provide statistical significance at the 5% level, and 90% power. To allow for withdrawals, the overall recruitment target was 200 study participants. The primary efficacy analysis was comparison of the maximum pain reported within 10 minutes of IUD insertion, with lidocaine vs. placebo, as assessed by the VAS score. Statistical comparison was performed using analysis of variance (ANOVA), stratified by study center, and expressed as mean difference with 95% confidence interval (CI). A stratified ANOVA was performed to investigate the relationships between VAS pain and IUD type, midwife, volume of lidocaine administered, and degree of discomfort. Secondary efficacy variables were the time course of pain, need for additional oral analgesia, and degree of discomfort. Data are presented as mean SD, or as absolute values, and no missing data were imputed. 424
The full analysis set, on which the primary efficacy analysis was based, comprised all randomized participants who received the study treatment and whose 10-minute VAS evaluation was available, as a minimum for data collected. All randomized individuals who received the study product were included in the safety set.
RESULTS Phase I: Single-Arm Pharmacokinetic Study Seventeen women were enrolled in the study; one was withdrawn from all analyses (uterine anomaly before lidocaine administration), and one was withdrawn from all analyses except safety and tolerability (predose blood sample not taken before lidocaine administration). The first patient entered the study on April 28, 2012, and the last patient completed the study on June 4, 2012. For the 15 participants included in the primary analysis, the mean age was 26.4 5.8 years; mean height was 167.9 6.1 cm; and mean weight was 60.2 8.8 kg. Four women were parous remaining nulliparous, and no gynecologic abnormalities were apparent. Pharmacokinetic parameters, based on results from all 15 study participants, were as follows: Cmax: 351 205 ng/mL; tmax: 68 41 minutes; and AUC0–180: 717 421 ng*h/mL. Changes in plasma lidocaine levels over time are shown in Figure 1. In all participants, plasma lidocaine concentration remained elevated at the last time point, meaning that AUC0–180 does not provide an accurate estimation of total exposure. Overall pharmacokinetic patterns were similar in all 15 participants, but as indicated by the SD values in Figure 1, considerable individual variation in absolute plasma levels was found. The highest value for Cmax observed in this study was 725 ng/mL; the lowest value was 64.7 ng/mL. Pain scores on the VAS were low, with mean values of 350 ng/mL. The number of participants who took the additional oral analgesic was 6 (40%) on day 1; 5 (33%) on day 2; 3 (20%) on day 3; and 1 (7%) on day 4. No serious adverse events or other safety concerns were reported. Six study participants (40%) experienced discomfort
FIGURE 1
Change over time in mean plasma lidocaine level (phase-I study). Error bars represent SD. Tornblom-Paulander. Topical lidocaine for IUD insertion. Fertil Steril 2015.
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Fertility and Sterility® upon administration of the lidocaine; in 4 cases, ‘‘a little’’ discomfort was reported; in 1 case, ‘‘strong’’ discomfort; and in 1 case, ‘‘very strong’’ discomfort. This discomfort was related to the application procedure, rather than to the pharmacologic effects of the study drug. All other adverse events were considered to be unrelated to the lidocaine.
FIGURE 2
Phase II: Randomized, Double-Blind, PlaceboControlled Study of Pain Relief Of 248 women screened for the study, 30 were excluded before randomization, because they did not meet the inclusion criteria. The main reasons for exclusion were: lack of interest in a clinical study; recent unprotected sexual intercourse (meaning pregnancy could not be excluded); intake of analgesic drugs during the preceding 24 hours; ongoing treatment for genital infections; and pregnancy. Nine of the 218 women randomized to treatment were excluded from the efficacy analysis because their uteri were too small for insertion of an IUD. The first patient entered the study on June 11, 2012, and the last patient completed the study on May 30, 2013. Demographic characteristics were similar in the 2 study groups (Table 1). In the lidocaine group, 89 individuals (81%) had never been pregnant, compared with 85 (78%) in the placebo group. Two different IUDs were used during the study: Mirena (Bayer HealthCare AG), used for 70 placebo recipients and 70 lidocaine recipients; and Nova T 380 (Bayer Schering Pharma AG), used for 38 placebo recipients and 40 lidocaine recipients. The mean VAS score for maximum pain within 10 minutes of IUD insertion was significantly lower in the lidocaine group than in the placebo group (28.3 vs. 44.2; P< .0001). The mean between-group difference was 15.9, representing a 36% reduction in VAS score in the lidocaine group. These results are reflected by the distributions of 10-minute VAS scores
Distributions of VAS pain scores in the phase II-study: maximum pain experienced within 10 minutes of insertion of the IUD. Tornblom-Paulander. Topical lidocaine for IUD insertion. Fertil Steril 2015.
in the 2 groups (Fig. 2). Lidocaine recipients tended to have low VAS scores, whereas placebo recipients were spread more evenly across the whole range. A significantly higher percentage of women in the lidocaine group were considered to be essentially pain-free (VAS score %10 mm), and a significantly lower percentage had moderate to severe pain (VAS score >40 mm) (Fig. 3) (12). The stratified ANOVA showed that neither discomfort during administration of the study treatment nor IUD type influenced the effect of the lidocaine. Fifteen midwives were recruited to take part in the study to perform the IUD procedure; for 4 of them, the mean 10-minute VAS score was higher with lidocaine than with the placebo (range: 29.0 to 42.5 mm). Despite this variability, the differences among midwives did not reach statistical significance (P¼ .056). The mean 10-minute VAS score was lower with lidocaine
FIGURE 3
TABLE 1 Participant characteristics in the phase-II study. Characteristic Age (y) Height (cm) Weight (kg) Gynecologic examination Normal Abnormal Menstruation No Yes Hormone contraceptive No Yes Type of IUD Mirena (Bayer HealthCare AG) Nova T 380 (Bayer Schering Pharma AG)
Lidocaine group (n [ 110)
Placebo group (n [ 108)
23.9 4.9 167.0 6.0 64.5 10.6
23.4 4.1 167.9 5.7 64.2 12.1
110 (100) 0 (0)
108 (100) 0 (0)
43 (39) 67 (61)
32 (30) 76 (70)
77 (70) 33 (30)
82 (76) 26 (24)
70 (64)
70 (65)
40 (36)
38 (35)
Note: Data presented as mean SD or n (%).
Percentages of women in the phase-II study considered to be essentially pain-free or to have moderate to severe pain, as assessed by VAS score for maximum pain experienced within 10 minutes of IUD insertion (P99%) and cost-effective birth control without the need for daily medication or cooperation of sexual partners, although IUD insertion can be costly and does require a healthcare professional (15). Pain upon IUD insertion may be a significant barrier to women's preparedness to choose this method of contraception (16). Relief from the pain could increase the number of women who would consider having an IUD inserted, with the possible consequence of reducing unwanted pregnancies. Young women and those who have not given birth are likely to experience more pain during IUD insertion, as a result of having a relatively narrow cervix (16). These women may be considered to have a greater need for pain relief during IUD insertion than women who have previously given birth, and they are likely to benefit more from the effects of lidocaine. Future studies to investigate the efficacy of this lidocaine formulation in various populations would be helpful. The novel thermogel formulation of lidocaine seems to be successful in providing pain relief. The viscosity of the product is designed to ensure continuing delivery of lidocaine to the appropriate tissues after its application; this may not occur with other formulations. The duration of action of lidocaine in humans is dependent on the application site, with various influencing factors, including blood supply. We observed a duration of action of 30–60 minutes, which we consider to be consistent with previously reported values of 70 minutes, for subcutaneous injection (13), and 20 minutes for periodontal scaling/root treatment (17). After 60 minutes in our study, pain intensity was similar for placebo and lidocaine. Lidocaine has a rapid onset of action, reportedly around 2 minutes or less (13, 17). As with duration of action, onset of action is liable to vary among application sites. We allowed 5 minutes to elapse between administration of lidocaine and IUD insertion, and based on the results, this time period is sufficient for the drug to take effect. The range of peak plasma level of lidocaine observed in this study was 64.7–725 ng/mL. Thus, all values were far below the range of 6–10 mg/mL, which represents the VOL. 103 NO. 2 / FEBRUARY 2015
Fertility and Sterility® threshold at which lidocaine toxicities begin to occur (18). This range may therefore explain the lack of lidocaine safety concerns apparent in our study. The adverse events were consistent with those expected to occur after IUD insertion. The overall incidence of adverse events with lidocaine was the same as with placebo, and no adverse events were specifically attributable to pharmacologic effects. These data are consistent with the established safety profile of lidocaine when it is used either locally or intravenously (19, 20). Strengths of the phase-II study include the double-blind design, sufficient statistical power to demonstrate the efficacy of lidocaine vs. placebo, and the inclusion of as many as 15 midwives across 3 centers. This number of midwives should increase the likelihood of the results being representative of those for large-scale clinical practice. Owing to very high levels of interest from potential participants, recruitment could not be stopped at exactly the targeted sample size of 200 participants. This over-recruitment seems unlikely to have influenced the study results. The lack of assessment of efficacy in women who have previously given birth represents a limitation of the phase-II study. In addition, the optimal time interval between lidocaine administration and IUD insertion was not investigated. The fact that lidocaine was shown here to be effective for IUD insertion suggests that it could also be used for other gynecologic procedures, such as biopsies, hysteroscopy, and spontaneous abortion. The duration of anesthesia—at least 30 minutes—should be adequate in a variety of situations. In conclusion, we report 2 early studies suggesting that a short-acting 4% viscous lidocaine solution may be a viable anesthetic for women undergoing IUD insertion, providing highly significant pain relief without any apparent safety concerns. Additional data are needed, but the results are promising, especially given the lack of evidence supporting the use of previously available anesthetics in this setting. In addition, this lidocaine formulation may have potential for other clinical uses. Acknowledgments: The authors thank the following midwives for participating in the study: Eneli Salomonsson, Monica Johansson, Pia Jacobsson, Tuula Ekl€ of, Carina Carlsson, Mari Denckert, Eva Almgren-Lidman, Martina Franck, Tuula Forsberg, Carlotta Bernerstedt, Lina Isaksson, Charlotta Thyden, Karin Zernisson Lagerbrant, Anna-Maria Pettersson, Pia Cederholm. We are similarly grateful to the following doctors for their participation: Esfandiar Nikodell, M.D., Henrik Rabaeus, M.D., Katarina Ernstson, M.D., Niels Fuglede, M.D., Linda J€ager, M.D., Kiriaki Papaikonomou, M.D., Caroline Liliecreutz, M.D., Brynhildsen Jan, M.D., Ph.D. For development of the manuscript, medical writing support was provided by Ken Sutor (Ascendancy Medical Writing Ltd, Cheshire, United Kingdom). Bernhard Huitfeldt, Ph.D. (BH Statistical Consulting, Nykvarn, Sweden) was responsible
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for all statistical aspects of the study, including design, analysis, and reporting of the study results.
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