Introduction

Most prostate cancers were diagnosed by transrectal ultrasound (TRUS)-guided prostate biopsy. Although it was an efficient diagnostic method, about 65% to 90% of men felt pain or discomfort during TRUS-guided prostate biopsy1. In this condition, some doctors proposed that anesthetic might be a good choice to reduce pains. However, there was a dispute about anesthetic use. Previous study demonstrated that few urologists use any form of local anesthesia for TRUS biopsy2. Though some trials showed that use of local anesthetics made no differences3,4, many clinical studies proved apparent analgesic effect of local anesthesia compared with controls5,6,7. However, there has not been an exact answer about whether to use anesthetic or not up to now.

On the other hand, there were four major kinds of local anesthesia: IRLA, PNB, PPB and IPLA for prostate biopsy at the moment. Various studies have been conducted to investigate and compare the efficacy of different anesthesia methods but did not get a conclusion.

We performed this meta-analysis of RCTs about the use of anesthetic during TRUS-guided prostate biopsy to explore the analgesic efficacy of local anesthetic compared with no anesthesia or placebo, and to figure out which kind of local anesthesia was optimal.

Results

Search results and characteristics of included studies

Our search strategy identified 347 studies in the initial database search (Fig. 1). After screening 46 RCTs1,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49 met our study criteria and were included in our meta-analysis.

Figure 1
figure 1

Flow diagram of trial selection process.

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The characteristics of the included studies were listed in Table 1. In these studies, 42 used PNB, 19 used IRLA, 4 used IPLA, and 2 used PPB. In some studies, a local anesthesia method might be used alone or in combination with another one. PNB was used in most of the studies, but different studies chose different injection sites. We defined the different sites as base, apex and both of them. Base meant the area of neurovascular bundle at the base of the prostate, while apex was the area around the prostatic apex. Most studies used visual analogue scale (VAS) or numerical analogue scale (NAS) as the pain scale to evaluate the pain degree of patients.

Table 1 Characteristics of included studies.
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Quality of the included studies

The risk of bias of included studies was presented with a risk of bias graph (Fig. 2), which showed that the quality of them was moderate. Quality of each study was shown in Supplementary Material (S1).

Figure 2
figure 2

Risk of bias of included studies.

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Meta-analyses

14 eligible studies showed that use of PNB significantly reduced pain compared with placebo injection (−1.27 [95% CI −1.72, −0.82], P < 0.00001; Fig. 3a), while 21 studies indicated that PNB could reduced pain compared with no injection (−1.01 [95% CI −1.2, −0.82], P < 0.00001; Fig. 3b). However, both comparisons had significant heterogeneity. We performed a sensitivity analysis by eliminating the included studies one by one. After deleting the study of Pareek et al.33 in the former comparison, I2 reduced from 92% to 59% and there were no apparent changes to the effect estimates. So this study might be the main source of heterogeneity and the reason might be that it used different pain scale. However, the sensitivity analysis could not find a study that was responsible for the heterogeneity in the later comparison. Thereby we performed a meta-regression analysis to investigate the effect of some variables (year of the study, mean age of patients, prostate biopsy numbers and dose of the anesthetics) on the heterogeneity. The result showed that the mean age of patients was apparently related to the outcomes (Table 2), so it might be a main source of heterogeneity.

Figure 3
figure 3

Forest plot comparing PNB with placebo and no anesthetics.

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Table 2 Meta-regression of moderators in the comparison between PNB and no anesthesia group.
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10 studies showed that use of local anesthesia with lidocaine gel made no noteworthy differences in reducing pain compared with control (−0.1 [95% CI −0.24, 0.04], P = 0.15; Fig. 4a). But 3 eligible studies indicated that use of local prilocaine-lidocaine cream significantly reduced pain compared with control (−0.45 [95% CI −0.76, −0.15], P = 0.003; Fig. 4b).

Figure 4
figure 4

Forest plot comparing IRLA with control.

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The subgroup analysis of three different types of PNB showed that there were some differences between different injection sites. Compared with the PNB at prostatic apex, the PNB using the neurovascular bundles at the base of the prostate showed more effective anesthesia results (P = 0.02; Fig. 5a). However, no apparent difference was found between PNB with both sites and PNB at the neurovascular bundles of prostatic base (P = 0.58; Fig. 5b).

Figure 5
figure 5

Forest plot of subgroup analysis comparing different PNBs.

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There were also some differences among different anesthetic techniques. The use of PNB was more efficient in reducing pain score than intrarectal anesthetic gel (−0.9 [95% CI −1.42, −0.38], P = 0.0007; Fig. 6).The I2 was 93% in this analysis. However, after the sensitivity analysis and meta-regression analysis we did not find any study or any parameter that might be the main source of heterogeneity.

Figure 6
figure 6

Forest plot comparing PNB with IRLA.

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In addition, combined use of PNB and IPLA had better analgesia effect than PNB alone (−0.84 [95% CI −1.11, −0.57], P < 0.00001; Fig.7a). Compared with combination use of PNB and IRLA, combination use of PNB and IRLA could significantly reduce pain score (−1.32 [95% CI −1.59, −1.06], P < 0.00001; Fig. 7b).

Figure 7
figure 7

Forest plot comparing PNB with PNB + IPLA and PPB + IRLA with PNB + IRLA.

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Discussion

In this meta-analysis, local anesthesia significantly alleviated pain during (TRUS)-guided prostate biopsy, except IRLA with lidocaine gel.

Although a similar meta-analysis containing 25 studies had been performed before by Tiong HY et al.50, some new studies were conducted after that and it was necessary to update it. Moreover, this meta-analysis only compared PNB with control or IRLA, while we performed more comparisons with more local anesthesia techniques and added a subgroup analysis.

PNB was the most used local anesthesia method. The first randomized, prospective study was published by Nash et al.31, showing the benefit of periprostatic local anesthesia. Our meta-analysis results suggested that PNB significantly reduced pain compared with placebo and no anesthesia, which was consistent with results from previous meta-analysis50.

Generally speaking, there were three different techniques of PNB: PNB lateral to the neurovascular bundle at the base of the prostate, PNB at the apex of the prostate and PNB with both regions. Our meta-analysis showed that all of the three different techniques significantly reduced pain during TRUS-guided prostate biopsy. We then performed a subgroup analysis to compare the effect of these three techniques. The results showed that anesthetic injection lateral to the neurovascular bundle was more effective than the injection at prostatic apex. But the combined injection in two sites was not superior to the single use of injection lateral to the neurovascular bundle.

The pain caused by prostate biopsy came mainly from the prostate capsule or stroma, because these areas had a rich innervation1. During the PNB, anesthetic infiltrated into the nerves around the prostate and blocked the nerve conduction. Hence it could decrease pain of patients. Fibers derived from the pelvic plexus traveled with vessels, forming the neurovascular bundle, and entered into the prostate at the base of the prostate just lateral to the junction between the prostate and seminal vesicle. Thereby the infiltration of local anesthesia in this region had better analgesic effect.

IRLA was a convenient local anesthesia technique and brought only a little discomfort to patients. But our results showed that IRLA with lidocaine gel could not reduce the pain during the prostate biopsy significantly. Even so, we could not deny the efficacy of IRLA. Our analysis indicated that IRLA with prilocaine-lidocaine cream could alleviate patients’ discomfort during the biopsy. This suggested that combined local anesthesia cream might have better analgesic effect than a single one. We compared the efficacy between PNB and IRLA with lidocaine gel and found that the former was more efficient in decreasing pain. It was a pity that there was not enough studies to compare PNB and IRLA with prilocaine-lidocaine cream.

Our meta-analysis also assessed two other block ways: IPLA and PPB. Mutaguchi et al. showed intraprostatic anesthesia was a new local anesthesia technique to anesthetize the prostate which blocked all sensory nerves from the posterior and anterior sides51. Due to the limited number of relevant studies, we were not able to compare the effect of PNB and IPLA alone. However, our meta-analysis suggested that the combination of IPLA and PNB had better analgesic effect than PNB alone. However, a drawback of the IPLA was that it could cause pain when penetrating the prostate capsule.

The pelvic plexus was an autonomic plexus including sympathetic and parasympathetic nerves. The midpoint of pelvic plexus located just lateral to the tip of the seminal vesicle and it was punched through by abundant branches of inferior vesicle vessels. Because the fibers innervating the prostate were derived mainly from pelvic plexus, local anesthesia in this location might be useful. In PPB, anesthesia was injected bilaterally into the pelvic plexus, therefore blocking all the nerve fibers and thus having a theoretical advantage over PNB21. Our meta-analysis showed that combination use of PPB and IRLA significantly reduced pain when compared with combination use of PNB and IRLA. Restricted by the number of studies, we were not able to compare the effect of PNB and PPB directly.

There were some limitations in our meta-analysis. First of all, significant heterogeneity among studies existed in some comparisons, which might reduce the reliability of our results. Even though we performed both sensitivity analysis and meta-regression analysis to investigate the source of heterogeneity, not all the heterogeneity source could be found. Hence we used the random effect model in our analysis. In addition, there was not enough number of studies in some comparisons. More studies were expected to reinforce our results.

In summary, it was the first meta-analysis about the role of PPB and intraprostatic anesthesia in reducing pain during TRUS-guided prostate biopsy to our knowledge. Our meta-analysis suggested that local anesthesia such as PNB, PPB, IPLA and local prilocaine-lidocaine cream was effective in alleviating pain for TRUS-guided prostate biopsy. Besides, PNB lateral to the neurovascular bundle at the base of prostate had better analgesic efficacy than PNB at the prostatic apex. It was also revealed that PPB might be more effective than PNB. Hence, PPB was potential to be a standard of care for patients undergoing TRUS-guided prostate biopsy.

Methods

Study search

We searched Pubmed and Embase for all papers, including conference abstracts, in any language published before May 1, 2016. Our search strategy was: (prostate biopsy) and ((local anesthesia) or analgesic) and (pain or discomfort) and (randomized or randomization). Reviews and nonhuman studies were not included. In addition, if two studies were conducted by the same authors and parts of their patients were also the same, only the latest one with more patients was included. The search was conducted by two authors separately.

Inclusion criterion

The studies that met the following criteria were included: (1) RCTs; (2) patients underwent TRUS-guided prostate biopsy with local anesthetic; (3) local anesthetic was compared with placebo or no anesthetic group, or different kinds of local anesthesia methods were compared; (4) pain during the biopsy should be recorded by a pain scale.

Data Extraction

All available RCTs that had data about pain during TRUS-guided prostate biopsy were selected for analysis. The major characteristics of included articles were extracted: the first author, the year of publication, study design, the number of patients and groups, the utilized local anesthesia methods and their location and the pain scale.

The mean and standard deviations of pain scores were extracted to perform the analysis. These data were recorded by different pain scales, such as VAS, NAS and others. We extracted the pain scores which were taken immediately at the end of the biopsy for evaluation. If a research used both placebo injection and no analgesic, both groups were used as controls and the patients’ number in the anesthesia group was divided equally into two parts. Similarly, if more than one local anesthesia groups was used in one study, the number of patients of the control group was divided equally by the number of anesthesia groups. All the data were extracted independently by different study authors and any discrepancy was resolved by consensus.

Quality assessment

Quality assessment of the included studies was performed by The Cochrane Collaboration’s tool for assessing risk of bias, including assessments of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias.

Statistical analysis

All meta-analyses were performed using RevMan 5.2 (The Nordic Cochrane Centre, the Cochrane Collaboration, 2012, Copenhagen, Denmark). Continuous outcomes were presented as standardized mean difference (SMD) with 95% confidence interval (CI). Statistical heterogeneity was assessed with the I2 statistic, in whichI2 > 50% was considered to be of high heterogeneity. When significant heterogeneity was present, data were analyzed using the random effect model and a sensitivity analysis or meta-regression analysis was performed to find the source of heterogeneity. The meta-regression analysis was performed by using Stata 12.0. Differences were considered statistically significant when P < 0.05.

Firstly, we compared the outcomes of PNB groups with placebo groups and no anesthesia groups separately. Secondly, we analyzed the anesthesia efficacy of different IRLA methods, including the simple IRLA with lidocaine gel and IRLA with lidocaine-prilocaine cream. And then, we performed subgroup analysis to compare the efficacy of PNB methods with different injection positions. At last we compared the outcomes of different kinds of local anesthesia methods.

Additional Information

How to cite this article: Li, M. et al. Local anesthesia for transrectal ultrasound-guided biopsy of the prostate: A meta-analysis. Sci. Rep. 7, 40421; doi: 10.1038/srep40421 (2017).

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