Combination of intrarectal heated lidocaine gel and periprostatic nerve block for pain control during transrectal ultrasound-guided prostate biopsy: A prospective randomized trial
Prostate biopsy under transrectal ultrasound (TRUS) guidance is the accepted standard technique for prostate cancer diagnosis. Although well tolerated, TRUS-guided prostate biopsy may cause significant discomfort and pain . Therefore, this biopsy requires the use of appropriate anesthesia. Many local anesthesia techniques have been used for pain relief including periprostatic nerve block (PNB) and intrarectal local anesthesia (IRLA) . Nash et al.  initially introduced PNB, which became the standard analgesia method for prostate biopsy. However, PNB can cause discomfort and does not provide adequate pain control throughout the entire biopsy procedure . Also, PNB alone does not provide optimal analgesia during insertion and manipulation of the ultrasound probe . Several studies suggested that combined analgesia provided better pain control than PNB alone, and no increase in complication rate was noted with combined analgesia . In previous studies, heat improved the transport of drug and penetration of analgesic drug . Recently, a research group noted that IRLA with heated (40℃) lidocaine gel showed better pain reduction in TRUS-guided prostate biopsy compared to no local anesthesia or conventional IRLA . Also, a previous trial revealed that IRLA using heated lidocaine gel provided a non-inferior analgesia effect during prostate biopsy compared with PNB . Despite these promising results, its role in combined local anesthesia for alleviating pain during prostate biopsy has not been thoroughly studied. Therefore, the aim of this study was to assess the efficacy and safety of combined anesthesia with IRLA with heated lidocaine gel (ILAHL) and PNB compared to the PNB alone during TRUS-guided prostate biopsy. 

1. Patients and study design After obtaining Institutional Review Board approval of The Catholic University of Korea (approval number: UC-20MESIO050), a prospective, randomized, controlled trial was conducted from July 2021 to June 2022. This trial was registered at the Clinical Research Information Service ( http://cris.nih.go.kr ), number KCT0005266. Inclusion criteria were suspicious digital rectal examination and/or elevated serum prostate-specific antigen (PSA) (≥4.0 ng/mL). Exclusion criteria were previous prostate biopsy; concomitant analgesic or narcotic medication; recent antiplatelet or anticoagulation therapy; presence of bleeding diathesis; and comorbidities including anal stricture, hemorrhoids, inflammatory bowel disease, colorectal cancer, urinary tract infection, urinary stone, or chronic prostatitis, which can interfere with pain assessment. Allergy to lidocaine was another exclusion criterion. The patients who were scheduled for prostate biopsy were randomly allocated into two groups using a computergenerated model: group 1: PNB and group 2: PNB+ILAHL. Informed consent was obtained from all participants. 2. Biopsy protocol Prophylactic oral quinolone administration was started one day before the biopsy and continued until four days post-biopsy. In the left decubitus position, the PNB group received the injection of 2.5 mL 2% lidocaine into the bilateral neurovascular bundle between the prostate base and the seminal vesicle (5 mL in total) under ultrasound guidance using a 200 mm, 22 gauge spinal needle . Five minutes later, the ultrasound probe was reinserted. In the left decubitus position, the ILAHL group received 20 mL 2% lidocaine gel (Instillagel; Farco-Pharma) intrarectally. The gel was kept at 40℃ in a cabinet with controlled temperature (KRS 200D; KARIS) . Upon removal from the cabinet, the gel was promptly administered intrarectally. After 10 minutes, the PNB was carried out. Another five minutes later, the TRUS probe was reinserted. Ultrasound imaging was carried out using a 7.5 MHz biplane probe (Flex Focus 300; BK Medical) and the biopsy was performed using an automatic biopsy gun with an 18 gauge, 200 mm biopsy needle. Every biopsy procedure was conducted by the same urologist. Each patient received a biopsy consisting of 12 systematic cores. 3. Assessment of outcomes The primary outcome was the patient-reported pain score using a visual analogue scale (VAS) from 0 (no pain) to 10 (intolerable pain). The VAS score was collected from each participant at 4 time points: during local anesthesia induction (VAS A), during transrectal probe insertion (VAS B), during biopsy punctures (VAS C), and at 30 minutes after biopsy (VAS D). The secondary outcome was adverse event profile. All patients were followed for 1 week post-biopsy. During follow-up, biopsy results and any side effects were discussed. Two standardized questionnaires were employed to assess patient characteristics and biopsy-related adverse effects. The first questionnaire included variables such as age, diabetes mellitus (DM), American Society of Anesthesiologists (ASA) score, hypertension, PSA value, body mass index (BMI), prostatic volume, and immediate complications. The urologist who performed the biopsy administered this questionnaire. The second questionnaire included biopsy-related bleeding of hematuria, rectal bleeding, or hematospermia and other adverse effects. Patients received telephone interviews at 2 weeks and 4 weeks post-biopsy by another urologist to evaluate the complications using the second questionnaire. Hematuria referred to urine that appeared grossly red or pinkish in color, rectal bleeding was characterized by spontaneous bleeding from the rectum or blood loss during defecation, and hematospermia involved macroscopically evident blood in the semen . 4. Statistical analysis A minimum difference of 0.8 in VAS score was considered statistically significant . A sample size of 70 patients in each of the two groups was calculated to provide 80% statistical power for detecting a difference at a 5% significance level with 1.6 standard deviation (SD), as calculated in our pilot trial. A 10% dropout rate was assumed in the calculation of the necessary sample size. Continuous data are expressed as mean±SD and an independent t-test or Mann–Whitney U test was applied for comparison between the 2 groups. Categorical data are expressed as frequency , and the chi-square test or Fisher's exact test was applied for comparison between the 2 groups. All data were analyzed using SPSS version 13.0 (SPSS Inc.), where p<0.05 was accepted as significant and all statistical analyses were 2-sided. 

After obtaining Institutional Review Board approval of The Catholic University of Korea (approval number: UC-20MESIO050), a prospective, randomized, controlled trial was conducted from July 2021 to June 2022. This trial was registered at the Clinical Research Information Service ( http://cris.nih.go.kr ), number KCT0005266. Inclusion criteria were suspicious digital rectal examination and/or elevated serum prostate-specific antigen (PSA) (≥4.0 ng/mL). Exclusion criteria were previous prostate biopsy; concomitant analgesic or narcotic medication; recent antiplatelet or anticoagulation therapy; presence of bleeding diathesis; and comorbidities including anal stricture, hemorrhoids, inflammatory bowel disease, colorectal cancer, urinary tract infection, urinary stone, or chronic prostatitis, which can interfere with pain assessment. Allergy to lidocaine was another exclusion criterion. The patients who were scheduled for prostate biopsy were randomly allocated into two groups using a computergenerated model: group 1: PNB and group 2: PNB+ILAHL. Informed consent was obtained from all participants. 

Prophylactic oral quinolone administration was started one day before the biopsy and continued until four days post-biopsy. In the left decubitus position, the PNB group received the injection of 2.5 mL 2% lidocaine into the bilateral neurovascular bundle between the prostate base and the seminal vesicle (5 mL in total) under ultrasound guidance using a 200 mm, 22 gauge spinal needle . Five minutes later, the ultrasound probe was reinserted. In the left decubitus position, the ILAHL group received 20 mL 2% lidocaine gel (Instillagel; Farco-Pharma) intrarectally. The gel was kept at 40℃ in a cabinet with controlled temperature (KRS 200D; KARIS) . Upon removal from the cabinet, the gel was promptly administered intrarectally. After 10 minutes, the PNB was carried out. Another five minutes later, the TRUS probe was reinserted. Ultrasound imaging was carried out using a 7.5 MHz biplane probe (Flex Focus 300; BK Medical) and the biopsy was performed using an automatic biopsy gun with an 18 gauge, 200 mm biopsy needle. Every biopsy procedure was conducted by the same urologist. Each patient received a biopsy consisting of 12 systematic cores. 

The primary outcome was the patient-reported pain score using a visual analogue scale (VAS) from 0 (no pain) to 10 (intolerable pain). The VAS score was collected from each participant at 4 time points: during local anesthesia induction (VAS A), during transrectal probe insertion (VAS B), during biopsy punctures (VAS C), and at 30 minutes after biopsy (VAS D). The secondary outcome was adverse event profile. All patients were followed for 1 week post-biopsy. During follow-up, biopsy results and any side effects were discussed. Two standardized questionnaires were employed to assess patient characteristics and biopsy-related adverse effects. The first questionnaire included variables such as age, diabetes mellitus (DM), American Society of Anesthesiologists (ASA) score, hypertension, PSA value, body mass index (BMI), prostatic volume, and immediate complications. The urologist who performed the biopsy administered this questionnaire. The second questionnaire included biopsy-related bleeding of hematuria, rectal bleeding, or hematospermia and other adverse effects. Patients received telephone interviews at 2 weeks and 4 weeks post-biopsy by another urologist to evaluate the complications using the second questionnaire. Hematuria referred to urine that appeared grossly red or pinkish in color, rectal bleeding was characterized by spontaneous bleeding from the rectum or blood loss during defecation, and hematospermia involved macroscopically evident blood in the semen . 

A minimum difference of 0.8 in VAS score was considered statistically significant . A sample size of 70 patients in each of the two groups was calculated to provide 80% statistical power for detecting a difference at a 5% significance level with 1.6 standard deviation (SD), as calculated in our pilot trial. A 10% dropout rate was assumed in the calculation of the necessary sample size. Continuous data are expressed as mean±SD and an independent t-test or Mann–Whitney U test was applied for comparison between the 2 groups. Categorical data are expressed as frequency , and the chi-square test or Fisher's exact test was applied for comparison between the 2 groups. All data were analyzed using SPSS version 13.0 (SPSS Inc.), where p<0.05 was accepted as significant and all statistical analyses were 2-sided. 

In all, during the study period, 200 prostate biopsies were performed. Of these, 60 patients met the exclusion criteria in the trial. Therefore, 140 participants were randomized into 2 groups . shows the demographic characteristics of the patients. There were no significant differences between the 2 groups regarding age, BMI, ASA score, DM, hypertension, PSA value, prostate volume, and prostate cancer detection rate. The outcomes of the VAS pain score evaluation are summarized in . Mean pain scores were significantly lower in group 2 than in group 1 at local anesthesia induction (VAS A) (group 1 vs. group 2; 2.53 vs. 1.60, p=0.001) and transrectal probe insertion (VAS B) (2.47 vs. 1.49, p<0.001). The mean VAS C score during biopsy puncture in group 2 was significantly lower than in group 1 (3.07 vs. 2.20, p=0.001). There was no significant difference in mean VAS D score at 30 minutes after biopsy between groups 1 and 2 (1.06 vs. 0.89, p=0.318). In terms of post-biopsy complications, hematuria was most frequent and occurred in 39.3% (55/140) of all patients with no significant difference in the frequency of hematuria between the 2 groups (group 1 vs. group 2; 35.7% vs. 42.9%, p=0.387). Rectal bleeding (24.3% vs. 22.9%, p=0.842) and hematospermia (12.9% vs. 11.4%, p=0.796) also showed no significant difference between groups 1 and 2. In comparison to bleeding complications after biopsy, other adverse effects like urinary tract infection or lower urinary tract symptoms were relatively infrequent, and no adverse events associated with local anesthesia were noted . 

In this study of 140 enrolled patients, the combination of ILAHL and PNB provided improved analgesic effects during local anesthesia induction, transrectal probe insertion, and biopsy punctures during the TRUS-guided prostate biopsy procedure compared with the use of PNB alone. Numerous techniques and agents that control pain associated with prostate biopsy have been studied, including PNB, IRLA, intraprostatic local anesthesia, low dose spinal anesthesia, caudal block, intravenous sedation, and pelvic plexus block . However, there is no consensus for an application technique recommendation. Although PNB is the most commonly used method in pain control, it cannot eliminate the pain caused by introduction and movement of TRUS probe or by additional punctures during anesthesia application . IRLA has the advantage of being easier to perform and noninvasive in comparison with PNB. However, the ability of IRLA to reduce pain during prostate biopsy is controversial . While both PNB and IRLA have shortcomings in relieving pain during prostate biopsy, several studies noted that the combination of PNB and IRLA may overcome individual shortcomings . However, a metaanalysis by Wang et al.  showed that the results of IRLA combined with PNB for more comprehensive pain control remained complicated. Recently, Jung et al.  reported that in comparison to local anesthesia or conventional IRLA, ILAHL effectively reduced pain for patients undergoing prostate biopsy. Also, Jang et al.  found that ILAHL provided a non-inferior analgesic effect at transrectal probe insertion, biopsy punctures, and 30 minutes after biopsy compared with PNB during prostate biopsy. Also, ILAHL showed superiority over PNB at local anesthesia induction. To our knowledge, this current trial is the first prospective randomized study assessing the analgesic efficacy and safety of the combination of PNB with ILAHL during prostate biopsy. In the present study, we demonstrated that ILAHL combined with PNB effectively decreased pain intensity in patients undergoing prostate biopsy. The inferolateral nerves of the prostate are located close to the wall of the rectum, and the rectal mucosa has an excellent capacity for drug absorption . Sethna et al.  reported that the transportation of lidocaine was improved with heat application. Wood et al.  noted that, with a slight increase of drug partitioning, the fluidization of lipid in the upper layers of epidermis facilitated lidocaine diffusion to 179%–519% at 37℃–45℃ compared to 45% lidocaine diffusion at 27℃. The fluidity of skin lipid is known to increase in relation to lipid phase transitions . In response to heat, skin lipids undergo 2 distinct transitions. At 37℃, “solid to fluid” lipid transition is associated with the lower part, while “orthorhombic to hexagonal” lipid transition is linked to the higher part at 40℃ . These structural changes of the skin increased the transport of lidocaine. Therefore, the significant pain relief by heated (40℃) lidocaine gel could be attributed to the direct anesthetic effect on the rectal wall and the nearby prostate capsule . In this trial, we found that ILAHL did not increase biopsy- or anesthesia-related complications compared with PNB alone. Hematuria, rectal bleeding and hematospermia incidence after prostate biopsy were not significantly different in both groups (hematuria: 35.7%–42.9%, rectal bleeding: 22.9%–24.3%, hematospermia: 11.4%–12.9%, p>0.05). The complication rates were consistent with the literature (hematuria: 10%–84%, rectal bleeding: 11.5%–45%, hematospermia: 1.1%–93%) . The 2.9%–4.3% urinary tract infection and 7.1%–11.4% lower urinary tract symptoms rates showed similar trends to those published previously . The use of heated lidocaine gel increases lidocaine diffusion and transportation, which could lead to adverse effects such as allergic reaction to lidocaine. However, in this study, no additional complications such as allergic reaction to lidocaine were encountered in group 2. This study has some limitations. First, although this trial was a prospective randomized study, the patients' number was relatively small. The small sample size could not have led to sufficient statistical power for some of the tests used. Second, all patients were recruited from a single center. Third, assessments for subanalysis based on prostate volume, age, or comorbidities were not performed. For the future, we suggest a prospective, randomized multicenter trial with a larger cohort of patients to verify the results of this study. Despite these limitations, this study may provide clinical guidance for choosing the optimal anesthetic method. 

Our results demonstrated that a combination of ILAHL and PNB was more effective for pain control during TRUS-guided prostate biopsy than PNB alone, without an increase in complication rates. Additional well-designed trials using heated lidocaine gel to validate our findings are warranted. 

