Abstract
Background
To investigate whether intrarectal local anesthesia with heated lidocaine gel (IRLAH) is non-inferior to periprostatic nerve block (PNB) for reducing pain in patients undergoing transrectal ultrasound (TRUS)-guided prostate biopsy.
Methods
We performed a randomized controlled non-inferiority trial with 100 participants who underwent systematic TRUS-guided, 12-core prostate biopsy from August 2019 to July 2020. These participants were randomly assigned to a group receiving intrarectal local anesthesia with 20 mL of heated (40°C) 2% lidocaine gel (n = 50) or PNB (n = 50). The primary outcome was a pain score on a 0–10 visual analogue scale (VAS) at four time points with the non-inferiority margin of 1; VAS-1: during local anesthesia application; VAS-2: during probe insertion; VAS-3: during biopsy; VAS-4: 30 minutes after the procedure. The secondary outcome included complications during and after the procedure.
Results
The IRLAH group (0.1) met non-inferiority as well as superiority criteria for mean VAS-1 score vs. the PNB group (2.33) (P < 0.001), as the difference (95% confidence interval [CI]) between the two groups was −2.23 (−2.66 to −1.79) and the upper bound of the 95% CI were both below the prespecified non-inferiority margin and below zero. For mean VAS-3 score, the difference (95% CI) was 0.3 (−0.38 to 0.98) and the upper bound of the 95% CI did not exceed the predefined non-inferiority margin indicating that IRLAH was non-inferior (IRLAH group, 3.44; PNB group, 3.14). Also, non-inferiority was shown for pain scores at VAS-2 and VAS-4. There were no significant differences in complications.
Conclusion
IRLAH is a noninvasive and non-inferior alternative to PNB for pain control in TRUS-guided prostate biopsy without increased risk of complications.
Keywords: Biopsy, Local anesthesia, Pain, Prostate
1. Introduction
Transrectal ultrasonography (TRUS)-guided prostate biopsy is a well-established procedure for prostate cancer diagnosis. It is also one of the most common procedures performed on an outpatient basis. Although it generally has a low complication rate, the procedure is associated with significant discomfort and pain.1 Therefore, determining optimal methods for anesthesia is essential.
To alleviate pain, various modalities such as periprostatic nerve block (PNB) or intrarectal local anesthesia (IRLA) with lidocaine gel have been evaluated.2 However, no standard technique for pain control in prostate biopsy has been established. Currently, although PNB is considered to be the standard of care for reducing pain, it itself can cause considerable discomfort or pain.3,4 In contrast, IRLA is noninvasive and readily available compared with PNB, but there is doubt regarding its analgesic efficacy.5,6
In previous studies, heat was found to enhance analgesic drug penetration and facilitate drug transport.7,8 Recently, a study showed that IRLA using lidocaine gel heated to 40°C provided better pain control in prostate biopsy compared with conventional IRLA or no local anesthesia, without increased risk of adverse events.9 Despite these promising findings, there have been no studies directly comparing IRLA with heated lidocaine gel (IRLAH) and PNB for pain reduction during prostate biopsy.
Therefore, the purpose of this study was to assess whether IRLAH is inferior to PNB with respect to pain relief for prostate biopsy. To test this, we did a randomized, controlled non-inferiority study in patients undergoing prostate biopsy. We hypothesized that compared to PNB, IRLAH would demonstrate non-inferior pain scores during the prostate biopsy, cause less pain during anesthesia application, and have a similar risk of adverse events.
2. Materials and methods
2.1. Study population
This randomized, controlled, non-inferiority trial was performed from August 2019 to July 2020 with the approval of the institutional review board. This study was registered with the Clinical Research Information Service (http://cris.nih.go.kr, KCT0004584). The eligibility criteria were: abnormal digital rectal examination, prostate-specific antigen (PSA) level ≥4.0 ng/mL, or a combination of these. The exclusion criteria were: bleeding diathesis, history of prostate biopsy, recent intake of antiplatelet or anticoagulation drugs, concomitant analgesic or narcotic medication, comorbidities including inflammatory bowel disease, anal stricture, hemorrhoids, colorectal cancer, urinary stone, chronic prostatitis, or active urinary tract infection, which can affect pain during the procedure, and/or known allergy to local anesthetics. Informed consent was obtained from all participants. After inclusion, patients were randomly assigned to the IRLAH group or the PNB group using a computer-generated model.
2.2. Biopsy protocol
For prophylaxis, oral quinolone was started 1 day prior to prostate biopsy and continued for 4 days after the procedure; aminoglycoside was intramuscularly given just before a biopsy. A cleansing enema was administrated on the morning of biopsy. Patients were put in the left decubitus position. The IRLAH group had 20 ml lidocaine gel (Instillagel 2%; Farco-Pharma, Cologne, Germany) intrarectally that was stored at 40°C in a temperature-regulated cabinet (KRS 200D; KARIS, Seoul, South Korea) for 10 minutes prior to introducing the ultrasound probe. After the lidocaine gel was taken out of the cabinet, it was immediately applied intrarectally. The PNB group received PNB with a 22-gauge, 20-cm spinal needle using 5 mL of 2% lidocaine injection, 2.5 mL on each side into the neurovascular bundle at the prostate-bladder-seminal vesicle angle under TRUS guidance.10 After 5 minutes, the ultrasound probe was reinserted. TRUS examination was performed with a 7.5-MHz biplane probe (Prosound SSD-3500; Aloka, Tokyo, Japan) and prostate biopsy was taken with an automatic biopsy gun using an 18-gauge, 20-cm needle. All biopsy procedures were carried out by a single urologist. All patients underwent a systematic 12-core biopsy.
2.3. Outcome measurement
The primary outcome was a pain score during the prostate biopsy, as measured using a Visual Analogue Scale (VAS) ranging from 0 (no pain) to 10 (the worst pain imaginable). Because all participants were in the left decubitus position during prostate biopsy, the VAS was located at the patient's eye level when laying down so it was easy to mark during prostate biopsy. All participants were asked about their pain degree at four time points during the procedure. The VAS scores were assessed during the local anesthesia procedure (VAS-1), during probe insertion into the rectum (VAS-2), during the biopsy procedure (VAS-3), and 30 minutes after all procedures (VAS-4). The secondary outcome included the side effect profiles. All participants were followed one week after the procedure to discuss histopathologic results and any adverse effects. Two standardized questionnaires were used to investigate the characteristics of patients and adverse events related to biopsy. The first questionnaire was explained and recorded by the urologist who conducted the prostate biopsy and included factors such as age, hypertension, body mass index (BMI), diabetes mellitus (DM), prostatic volume, American Society of Anesthesiologists (ASA) score, PSA level, and immediate side effects. The second questionnaire included the frequency of post-biopsy bleeding (e.g., hematuria, rectal bleeding, hematospermia) and other complications. Complications on the second questionnaire were evaluated two and four weeks after prostate biopsy over the telephone by another urologist. Hematuria was defined as grossly red- or pinkish-colored urine, rectal bleeding was defined as blood loss during defecation or spontaneous blood loss through the rectum, and hematospermia was defined as macroscopically obvious blood from semen.11
2.4. Statistical analyses
The non-inferiority margin of difference in VAS score was defined as 1 based on statistical considerations and previous trials.12, 13, 14, 15 With a non-inferiority margin of 1, a significance level of 5%, a statistical power of 80%, a standard deviation (SD) of 1.9 (calculated from our pilot study), and considering a dropout rate of 10%, a sample size of 50 patients was estimated for each group, totaling 100 patients. Continuous variables were presented as mean (±SD) and analyzed using the Mann-Whitney U test or independent t-test, while categorical variables were presented as the number (percentage) and analyzed using the Fisher's exact test or chi-square test. Non-inferiority analysis for the primary outcome was assessed using a two-sided 95% confidence interval (CI) of the mean difference. Additionally, the 95% CI for the mean difference in VAS score (IRLAH–PNB) was estimated; if the upper limit of the 95% CI was less than the prespecified non-inferiority margin, IRLAH was not inferior to PNB. For secondary outcomes, we evaluated two-sided P values for superiority tests. All data analyses were conducted using SPSS Statistics version 13.0 (SPSS Inc; Chicago, IL, USA), and statistical significance was considered at P < 0.05.
3. Results
In total, we identified 151 patients who underwent prostate biopsy during our trial period. Fifty-one of these patients did not fulfill the eligibility criteria. The remaining 100 participants were randomly assigned to the two groups. Fig. 1 presents the flow of patients throughout the trial. Clinical characteristics and baseline demographic of all participants are summarized in Table 1. There were no significant differences in age, hypertension, DM, PSA value, prostatic volume, BMI, detection rate of prostate cancer, or ASA score between the two groups (Table 1).
Figure 1.
Consolidated standard of reporting trials (CONSORT) flow diagram for patient recruitment and analysis. IRLAH, intrarectal local anesthesia with heated lidocaine gel; PNB, periprostatic nerve block.
Table 1.
Demographic characteristics of patients
| IRLAH | PNB | P | |
|---|---|---|---|
| No. of patients | 50 | 50 | |
| Age (years), mean (SD) | 67.5 (9.6) | 68.4 (8.9) | 0.651 |
| BMI (kg/m2), mean (SD) | 24.4 (2.7) | 24.1 (2.6) | 0.572 |
| ASA score, n (%) | 0.617 | ||
| 1 | 9 (18.0) | 11 (22.0) | |
| 2–3 | 41 (82.0) | 39 (78.0) | |
| Diabetes mellitus, n (%) | 14 (28.0) | 15 (30.0) | 0.826 |
| Hypertension, n (%) | 32 (64.0) | 28 (56.0) | 0.414 |
| PSA level (ng/mL), mean (SD) | 16.0 (26.6) | 14.1 (22.2) | 0.694 |
| Prostate volume (mL), mean (SD) | 52.0 (18.3) | 48.5 (19.1) | 0.354 |
| Prostate cancer, n (%) | 20 (40.0) | 17 (34.0) | 0.534 |
IRLAH, intrarectal local anesthesia with heated lidocaine gel; PNB, periprostatic nerve block; SD, standard deviation.
ASA, American Society of Anesthesiologists; BMI, body mass index; PSA, prostate-specific antigen.
Mean pain score during local anesthesia application (VAS-1) was 0.1 in the IRLAH group and 2.33 in the PNB group; the difference was −2.23 with a 95% CI of −2.66 to −1.79 (P < 0.001; Table 2). The upper limit of the CI did not cross the predefined non-inferiority margin of 1 and also zero. Thus, the IRLAH group met the non-inferiority criterion (upper limit of the 95% CI < 1), as well as the superiority criterion (upper limit of the 95% CI < 0) compared with the PNB group (Fig. 2). IRLAH was superior to PNB at VAS-1. In terms of pain score during the biopsy procedure, mean VAS-3 scores were 3.44 in the IRLAH group and 3.14 in the PNB group (Table 2). The treatment difference between the groups was 0.3 (95% CI, −0.38 to 0.98); the upper bound of the 95% CI did not exceed the prespecified non-inferiority margin, which suggests the non-inferiority of IRLAH compared to PNB in terms of VAS-3 (Fig. 2). Mean pain score during probe insertion into the rectum (VAS-2) was 2.3 in the IRLAH group and 2.01 in the PNB group (Table 2), a difference of 0.29 with a 95% CI of −0.34 to 0.92 (Fig. 2). Pain 30 minutes after all procedures were completed (VAS-4) was 1.04 in the IRLAH group and 1.12 in the PNB group (Table 2). The difference was −0.08 with a 95% CI of −0.25 to 0.09 (Fig. 2). The results of VAS-2 and VAS-4 did not exceed the non-inferiority margin.
Table 2.
Comparison of VAS scores between the groups
| Variable | IRLAH | PNB | Treatment difference (95% CI) | P |
|---|---|---|---|---|
| VAS-1: local anesthesia procedure | 0.10 ± 0.58 | 2.33 ± 1.43 | −2.23 (−2.66 to −1.79) | <0.001 |
| VAS-2: during probe insertion | 2.30 ± 1.63 | 2.01 ± 1.56 | 0.29 (−0.34 to 0.92) | 0.154 |
| VAS-3: during biopsy procedure | 3.44 ± 1.45 | 3.14 ± 1.97 | 0.30 (−0.38 to 0.98) | 0.136 |
| VAS-4 : 30 min after biopsy | 1.04 ± 0.47 | 1.12 ± 0.38 | −0.08 (−0.25 to 0.09) | 0.457 |
CI, confidence interval; IRLAH, intrarectal local anesthesia with heated lidocaine gel; PNB, periprostatic nerve block; VAS, visual analogue scale.
Figure 2.
Mean difference and 95% confidence interval in VAS scores between groups. VAS, visual analogue scale; 1, the non-inferiority margin of the difference in the VAS score; IRLAH, intrarectal local anesthesia with heated lidocaine gel; PNB, periprostatic nerve block.
Regarding post-biopsy adverse events, hematuria was the most common, occurring in 50% (50/100) of all participants, with no significant difference in hematuria incidence between the two groups (IRLAH = 48% vs. PNB = 52%, P = 0.689). Rectal bleeding (IRLAH = 38% vs. PNB = 28%, P = 0.288) and hematospermia (IRLAH = 10% vs. PNB = 20%, P = 0.161) was also similar between the IRLAH and PNB groups. Other adverse events such as urinary tract infections and lower urinary tract symptoms had a relatively low incidence compared to post-biopsy bleeding complications, and there were no allergic reaction or other adverse effects related to local anesthesia (Table 3).
Table 3.
Complications following transrectal ultrasound-guided prostate biopsy between the groups
| Variable | IRLAH | PNB | P |
|---|---|---|---|
| Bleeding complications | |||
| Hematuria, n (%) | 24 (48.0) | 26 (52.0) | 0.689 |
| Rectal bleeding, n (%) | 19 (38.0) | 14 (28.0) | 0.288 |
| Hematospermia, n (%) | 5 (10.0) | 10 (20.0) | 0.161 |
| Other complications | |||
| Urinary tract infection, n (%) | 1 (2.0) | 2 (4.0) | 0.558 |
| Lower urinary tract symptoms, n (%) | 5 (10.0) | 7 (14.0) | 0.538 |
| Allergic reaction, n (%) | 0 | 0 | 1.000 |
IRLAH, intrarectal local anesthesia with heated lidocaine gel; PNB, periprostatic nerve block.
4. Discussion
In this randomized non-inferiority trial, we found that IRLAH provides non-inferior analgesic effects compared with the use of PNB during ultrasound-guided prostate biopsy. Moreover, our study showed superiority in VAS-1 pain score.
Although PNB is the current standard anesthetic technique for prostate biopsy, considerable pain by additional punctures during anesthesia application is one of the major drawbacks.3 Previous studies reported a VAS pain score during PNB of from 1.4 to 4.1.16, 17, 18 The pain score of VAS-1 in our study was 2.33, consistent with previously reported results. There are few published papers that reported VAS pain score during IRLA. Mallick et al. reported that the VAS pain score during IRLA was 0.1.16 In their study, patients received 15 ml of 2% lidocaine gel during IRLA. Our VAS-1 pain score (0.1) was consistent with the value reported in previous studies. Our results indicated that the mean pain score of VAS-1 for IRLAH was significantly less than that for PNB.
Yang et al. suggested that IRLA was an effective and safe pain control method in prostate biopsy.19 Gianneri et al. reported that the advantages of IRLA were noninvasiveness and availability.3 On the contrary, there were conflicting results for the analgesic efficacy of IRLA during prostate biopsy. Some investigators have noted that IRLA with 2% lidocaine gel showed no significant difference in reducing pain compared to simple lubricant or control groups.20,21 In addition, a previous meta-analysis reported that IRLA using lidocaine gel did not provide sufficient pain control during prostate biopsy.22 Recently, Jung et al. found that IRLAH provided effective pain relief for participants undergoing prostate biopsy compared with conventional IRLA or no local anesthesia.9 In the current study, we demonstrated that IRLAH offered a non-inferior analgesic effect compared with PNB in prostate biopsy, as the upper bounds of the 95% CI for mean pain score differences at the VAS-2, VAS-3, and VAS-4 time points were less than the non-inferiority margin of 1. The nerve that supplies the posterolateral part of the prostate is located close to the wall of the rectum, and the mucosa of the rectum has remarkable drug absorption capacity.19 Sethna and colleagues reported that lidocaine exhibited improved transport on heat application.23 In 2012, Wood et al. noted that lipid fluidization in the upper layers of the epidermis at 37-45°C increased lidocaine diffusion to 179-519% compared with lidocaine diffusion of 45% at 27°C with a small increase in drug partitioning.24 Lipid fluidity of skin increases in agreement with phase transitions of lipids.25 There are two distinct transitions in the change of skin lipids in response to heat: the lower part at 37°C is attributed to structural changes of the skin induced by “solid to fluid” lipid transition, and at 40°C, the higher part is attributed to “orthorhombic to hexagonal” lipid transition.26 The structural changes in the aforementioned skin the increased lidocaine transport. Based on this background, the substantial pain control offered by IRLA using heated lidocaine gel (40°C) could be due to a direct analgesia effect on the wall of the rectum and the prostatic capsule close to the rectal wall.
In this study, we found that IRLAH did not increase adverse events after prostate biopsy. Gross hematuria is a common complication after prostate biopsy, ranging from 10 to 84%.11,27,28 The frequency of hematuria in this study was 48–52%, which is consistent with the results of previous studies. The frequency of hematospermia in the literature had a wide variance (1.1–93%).11,27,28 The hematospermia rate in our study was 10–20%, which was also in line with rates reported previously. In terms of rectal bleeding, our study noted rates of 28–38%, which was within the range reported in previous studies (11.5–45%).11,27,28 The incidence of lower urinary tract symptoms and urinary tract infection was 10 to 14% and 2 to 4%, respectively, in our study, similar to those published previously.27,29,30 In the present study, there was no allergic reaction to lidocaine. Additionally, we confirmed that no other adverse events were caused or increased by using heated lidocaine gel in prostate biopsy.
The present study has several limitations. First, the generalization of the results from this trial is limited by the relatively small population. Second, this was a single-center trial, including the possibility of socio-economic and ethnic selection bias. Third, optimal dose, concentration, and duration of local anesthetics for IRLA have yet to be established. Fourth, there was a difference in lidocaine dose between the two groups, although the method of lidocaine anesthesia was different. To the best of our knowledge, despite these limitations, this is the first study to assess the analgesic effect of IRLAH for TRUS-guided prostate biopsy using a non-inferiority design. Therefore, we believe that this research provides important insight into effective analgesic methods for prostate biopsy that will inform future studies.
5. Conclusions
The trial results demonstrated that IRLAH provided non-inferior analgesia compared with PNB for patients undergoing TRUS-guided prostate biopsy, with a lower pain score during local anesthesia application. Also, IRLAH did not increase the incidence of adverse events. In summary, IRLAH is an effective, noninvasive, and safe method for alleviating prostate biopsy-related pain. Therefore, IRLAH appears to be a reasonable alternative to PNB for pain control during prostate biopsy.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Conflicts of interest
The authors declare that there are no conflicts of interest.
Acknowledgment
The authors wish to acknowledge the financial support of the Catholic University of Korea, South Korea, Uijeongbu St. Mary's Hospital Clinical Research Laboratory Foundation made in the program year of 2019.
B.H.P. wishes to acknowledge the financial support of the Catholic Medical Center Research Foundation made in the program year of 2021.
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