Pain control according to the periprostatic nerve block site in magnetic resonance imaging/transrectal targeted prostate biopsy

We analyzed the intensity of pain at each site of systemic prostate biopsy (SBx) and compared the intensity of pain among magnetic resonance (MRI)-targeted transrectal biopsies according to the periprostatic nerve block (PNB) site. We collected data from 229 consecutive patients who had undergone MRI-targeted biopsy. Patients were stratified into two groups according to the site of PNB (base versus base and apex PNB). Pain was quantified at the following time points: probe insertion, injection at the prostate base, injection at the prostate apex, MRI cognitive biopsy (CBx), MRI/transrectal ultrasound fusion biopsy (FBx), SBx, and 15 min after biopsy. For all biopsy methods, the average pain were significantly higher in the base PNB group than in the base and apex PNB group (CBx, p < 0.001; FBx, p = 0.015; SBx, p < 0.001). In the base and apex PNB group, FBx was significantly more painful than SBx (p = 0.024). Overall, regardless of the PNB site, pain at the anterior sites was more than that at the posterior sites in FBx (p = 0.039). Base and apex PNB provided better overall pain control than base-only PNB in all biopsy methods. In the base and apex PNB group, FBx was more painful than CBx and SBx.

. Baseline characteristics of groups according to the site of the PNB. Data are expressed as number (%), mean ± standard deviation, and median (IQR range). AUR acute urinary retention, ISUP International Society of Urological Pathology, IQR interquartile, PI-RADS prostate imaging-reporting and data system, PNB periprostatic nerve block, PSA prostate-specific antigen.

Adverse events
Vasovagal syncope 1 (0.  www.nature.com/scientificreports/ apex lesions was more than that at the order lesions (p < 0.001, Fig. 1). For all biopsy methods, patients in the base and apex PNB group reported lower VAS scores than those in the base PNB group (Table 2). In the base and apex PNB group, FBx was painful than CBx and SBx. FBx was significantly more painful than SBx (3.21 vs. 2.88, p = 0.024) and marginally more painful than CBx (p = 0.104). Between CBx and SBx, there was no significant difference in VAS scores (p = 0.327). In the base PNB group, there was no difference in VAS scores among the biopsy methods.
We compared the pain intensity between the anterior and posterior sites (Table 3). In FBx, anterior site biopsy was significantly more painful than posterior site biopsy in all patients regardless of the PNB site (p = 0.039). In the base PNB group, no differences in pain were found between the anterior and posterior sites (p = 0.069). Patients in the base and apex PNB group reported lesser pain in the anterior site biopsy than those in the base PNB group, and the difference was greater for FBx than for CBx.

Complications.
One patient (0.9%) showed vasovagal syncope in the base PNB group, but recovered without any medical therapy. No major complications were observed in the base and apex PNB group (Table 1).

Discussion
Here, we confirmed the efficacy of additional PNB performed at the prostate apex during CBx and FBx, based on previous studies on local anaesthesia in SBx, by comparing the differences in pain intensity among various biopsy methods. FBx was significantly more painful than other biopsy methods in the base and apex PNB group. We compared the difference in the pain intensity during anterior and posterior site biopsies and observed significant differences during FBx and marginally significant differences during CBx. Our findings can help in the selection of the optimal local anaesthesia method according to the core biopsy site, biopsy method, and number of core biopsies.
Studies have compared the pain intensity between FBx and SBx and reported that SBx is relatively more painful than FBx, which contradicts our results [12][13][14]   www.nature.com/scientificreports/ for FBx and 2.0 (1.0-4.0) for SBx, but they included patients in whom only MRI was performed without biopsy in the FBx group 14 . Because of these differences, VAS scores during FBx and SBx were underestimated in these previous studies compared to our study. In a previous literature review, VAS scores during SBx in the base PNB group ranged from 3.37 to 4.97 [15][16][17] . In our study, the mean VAS score (4.00) during SBx was similar to that in the aforementioned studies. We found that biopsy in the anterior site was more painful than that in the posterior site. The base PNB blocks the nerve originating from the presacral and hypogastric plexuses, and the apex PNB blocks the somatic nerve originating from the pudendal canal, but not all nerves. There are a few other nerve fibers on the anterior and superolateral of prostate 9 . Moreover, prostate size is associated with pain during SBx, and the pain intensity is greater during SBx of an enlarged prostate due to the longer distance between the local anesthesia and biopsy sites 4,18 . The distance between the PNB and biopsy sites affects adequate pain control. Additional apex PNB leading to a lower intensity of overall pain is associated with the decreased distance between the PNB and biopsy sites. As the site for PNB is located posteriorly, the anterior site was associated with a greater pain intensity.
VAS scores during anterior site biopsy were lower in the base and apex PNB group than in the base PNB group. The additional apex PNB could have reduced the intensity of anterior site pain. Apex PNB anesthetizes the somatic branch of the inferior rectal nerve from the pudendal nerve and hence reduces the pain intensity below the dentate line, which is the site of needle puncture during apex or anterior prostate biopsy 19 . Although the difference in the pain intensity between the two groups was not significant in our study, more meaningful results could be obtained through subsequent studies with larger sample sizes.
Core biopsies in FBx or CBx are mostly performed in sites that are relatively far from the rectum, such as the anterior prostate, or sites that are at a greater angulation with the natural orientation of the rectum, such as the prostate margin, which are not performed routinely in SBx 20 . Therefore, the probe could impinge on the rectum, leading to greater pain during FBx. FBx was marginally more painful than CBx because the manipulation speed of the freehand is greater and the manipulation is smoother in CBx than in the fusion system of FBx. This is in line with the result of a previous study that probe manipulation could induce pain during biopsy 12,21 . Considering that the prostate volume in Caucasian men is larger than that in Asian men, the angle of manipulation of the probe for biopsy of the apex or anterior site is larger, and the distance from the PNB site to the apex or anterior prostate is greater. Therefore, the pain may be more severe in Caucasian men 22 .
Our results showed no significant difference in the pain intensity according to the biopsy methods in the base PNB group, but pain during FBx in the base and apex PNB group was the most severe. The overall pain was more with all methods in the base PNB group, but the base and apex PNB group exhibited relatively good overall pain control. Therefore, patients in this group were more sensitive to pain during probe manipulation. Considering that the pain tended to be more severe as the biopsy proceeded, FBx is considered more painful than SBx 9,23 .
The present study was planned to determine the efficacy of additional apex PNB in the recent era of MRItargeted biopsy. We found meaningful results on the difference in pain intensity according to the biopsy method with PNB, which have not been demonstrated previously. Nonetheless, our study is not without limitations. First, this is a single-center retrospective pilot study with a relatively small sample size. The patients were blinded as to the methods of nerve block given, but physician was not blinded, therefore the results are not free of bias. In addition, consensus on pain intensity and the possibility of complications due to additional apex injections is needed. Moreover, even if the average pain of each puncture is lower, it is difficult to directly compare the pain level of each method with different core counts. We performed three biopsy methods sequentially, and there was a limitation in directly comparing pain between each biopsy method. Finally, as we attempted to analyze the difference in pain intensity by matching the target site corresponding to the SBx site, obtaining meaningful results was difficult owing to the small sample size. We plan to validate our results through a well-controlled, prospective, double-blind, randomized, multi-center study.
Prostate biopsy methods have undergone innovative changes, such as performing CBx or FBx with SBx. To increase the cancer diagnosis rate, FBx or CBx is often performed with SBx. Therefore, the optimal method of local anaesthesia should be determined based on the procedure planned and the site of the procedure. Additional PNB administered in the prostate apex provides better overall pain control in CBx, FBx, and SBx.

Methods
Ethic approval. This study was approved by the institutional ethics committee (Yonsei university health system, Seoul, Korea, 3-2019-0418), and all procedures were conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments. The informed consent requirement was waived by ethics committee of Yonsei university health system because this study was based on retrospective, anonymous patient data and did not involve patient intervention or the use of human tissue samples.

Patient selection.
We prospectively collected data from 229 consecutive patients who underwent MRItargeted transrectal biopsy between January 2019 and September 2020. Patients who were unable to receive transrectal ultrasound probe injection, had severe haemorrhoids (Grade ≥ III, n = 2), had undergone related surgery (n = 2), and were unable to communicate (n = 4) were excluded. According to prebiopsy history taking, there were no patients with neurologic disease such as paraplegia or hemiplegia, and no patients with chronic pain who took analgesics routinely. Finally, 221 (96.5%) patients were selected for analysis (Fig. 2). Data collection. Patient data pertaining to age, PSA level, prostate volume, history of prostate biopsy, prostate imaging-reporting and data system (PI-RADS) scores, pathology results, time required for PNB and biopsies, adverse events (vasovagal syncope, allergic reaction, acute urine retention, urinary retention because of blood clot, and fever), VAS (0 as no pain to 10 as worst pain) pain scores were collected. MRI protocol and analysis. MRI was performed using a 3.0 Tesla system (Intera Achieva 3.0 T, Phillips Medical System, Best, Netherlands) equipped with a phased array coil (six channels). The MRI protocol involved diffusion-weighted imaging and T2 weighted imaging. T2-weighted turbo spin-echo MRI was acquired in three planes (axial, sagittal, and coronal). MRI datasets were obtained for identical slice locations, with a slice thickness of 3 mm and no intersection gap. Two b-values (0-1400) were used, and the diffusion restriction was quantified via apparent diffusion coefficient mapping. Dynamic contrast-enhanced MRI was also performed. All prostate MRIs were evaluated by an experienced urologic-radiologist and graded according to the PI-RADS Version 2.1 24 . Patients with PI-RADS scores of 3-5 were enrolled.
Local anesthesia methods. All patients were instructed to lie in the left lateral decubitus position during the procedure. All biopsies were performed by an experienced urologist. After povidone iodine rectal preparation, 10 cc of 2% lidocaine gel was applied intrarectally (Instillagel®, Farco-Farma GmbH, Köln, Germany). After 5 min, a transrectal probe was inserted, the prostate volume was measured, and PNB was performed with a Chiba needle (A & A M.D. Inc., Seongnam, Korea). The site of local anesthesia (base PNB vs. base and apex PNB) was determined as follows: (1) Odd days: Patients in the base PNB group received PNB on both sides of the prostate base and 2.5 cc normal saline on both sides of the prostate apex; (2) Even days: Patients in the base and apex PNB group received PNB on both sides of the prostate base as well as the prostate apex. The prostate base injections were aimed at the major neurovascular bundle after confirming the triangular echogenic "Mount Everest sign" between the prostate base and the seminal vesicle on the parasagittal longitudinal view of TRUS 25 . The prostate apex injections were aimed at a smaller triangular echogenic area between the puborectalis muscles and the prostate apex. Each PNB was performed using 2.5 cc of 2% lidocaine 9 . Patients in all groups received base injections before apex injections. www.nature.com/scientificreports/ Concurrent prostate biopsy techniques. We routinely check urine analysis and urine culture prior to biopsy decision-making. If there is pyuria or positive urine culture, sufficient antibiotics are used before the biopsy, and biopsy is performed after the follow-up urine analysis and negative confirmation of urine culture. All of the patients in this study received third-generation cephalosporin orally as prophylactic antibiotics for 2 days after the biopsy. All biopsies were performed using the BK 3000 ultrasound system (Analogic Corporation, Peabody, MA, USA) with a 7.5-12 MHz multiplanar probe, in the following order: CBx, FBx, and SBx. First, CBx was performed with two core biopsies per target. After performing CBx, FBx was performed using the MRI/TRUS fusion system (BioJet; GeoScan, Lakewood Ranch, FL, USA) with two core biopsies per target. Therefore, four core biopsies per target were obtained. After performing CBx and FBx, SBx was performed in the order of the right lateral base, right lateral mid, right lateral apex, right medial base, right medial mid, right medial apex, left lateral base, left lateral mid, left lateral apex, left medial base, left medial mid, and left medial apex. The VAS scores were assessed at various time points: probe insertion, injection at the prostate base, injection at the prostate apex, CBx, FBx, SBx, and 15 min after prostate biopsy. We checked the VAS scores for all injections and punctures. All biopsies were performed using guide channels, which were at 19° to the transducer axis of the side-fire probe (Analogic Corporation, Peabody, MA, USA), and an 18G, 20 cm disposable core biopsy instrument (Max-Core®, CR Bard Inc., Covington, GA, USA). Study endpoints. The primary endpoint was VAS score for each biopsy site and PNB method. The secondary endpoints were differences in pain intensity among the biopsy methods and between the anterior and posterior sites according to CBx and FBx.
Statistical analysis. The VAS scores for injection at the base and apex were defined as the average VAS scores for the right and left sides in base as well as apex injections. The VAS scores during CBx, FBx, and SBx were defined as the average VAS scores during individual core biopsies for the three types of biopsies.
Continuous variables are expressed as the mean ± standard deviation or median (interquartile range). Categorical variables are reported as number and frequency. The base PNB and base and apex PNB groups were compared using the independent t-test for continuous variables and the Chi-square test (Fisher's exact test) for two or more variables. The results are presented using a linear mixed model and mean profile graph. The correlation matrix structure of the linear mixed model that showed the relationship between the collected data at various time points was calculated by applying compound symmetry. Statistical analyses were performed using SAS (version 9.4; SAS Institute, Cary, NC, USA). Statistical significance was set at p < 0.05.

Data availability
The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.